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DIOSMIN, диосмин , ديوسمين , 地奥司明 ,


ChemSpider 2D Image | Diosmin | C28H32O15



  • Molecular FormulaC28H32O15
  • Average mass608.545 Da


4H-1-Benzopyran-4-one, 7-((6-O-(6-deoxy-α-L-mannopyranosyl)-β- D-glucopyranosyl)oxy)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-
4H-1-Benzopyran-4-one, 7-((6-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl)oxy)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-
4H-1-Benzopyran-4-one, 7-[[6-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]oxy]-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-
520-27-4 [RN]
5-Hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxo-4H-chromen-7-yl 6-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranoside
диосмин [Russian] [INN]
ديوسمين [Arabic] [INN]
地奥司明 [Chinese] [INN]
Barosmin / Dalfon (Servier) / Detralex / Diosven / Dioven / Diovenor / Flebosmil / Flebosten / Hemerven / Insuven / Litosmil / Varinon / Ven-detrex / Venosmine, Barosmin,  Diosmine, Venosmine, Diosmil,
Diosmin is a bioflavonoid that strengthens vascular walls.
Diosmin is a semisynthetic drug indicated for the treatment of venous disease. Diosmin is a flavone that can be found in the plant Teucrium gnaphalodes. Diosmin is available as a prescription medicine in several European countries, and is available as a nutritional supplement in the United States and the rest of Europe. It should be noted that clinical studies have been inconclusive and no articles have been published pertaining to its use in the treatment of vascular disease. When used in rats, diosmin has been effective at mitigating hyperglycaemia, and may also have antineurodegenerative properties.

Diosmin is a flavone, a member of the flavonoid family. Diosmin aglycone is diosmetin. It can be found in Teucrium gnaphalodes, a plant endemic to the Iberian Peninsula.[1]




Diosmin is a semisynthetic flavonoid molecule derived from citrus d (modified hesperidin). It is an oral phlebotropic drug used in the treatment of venous disease, i.e., chronic venous insufficiency (CVI) including spider and varicose veins, leg swelling (edema), stasis dermatitis and venous ulcers. It is also used as a stand-alone or surgical adjunctive therapy in hemorrhoidal disease (HD).

There are extensive clinical trials that show diosmin improves all stages of venous disease including venous ulcers and improves quality of life.[2] There are no prospective studies in arterial disease.

Diosmin is currently a prescription medication in some European countries (under the Dio-PP, Venotec, Daflon etc. tradenames), and is sold as a nutritional supplement in the United States.

Diosmin has been found to be effective in mitigating hyperglycemia in diabetic rats.[3] It is also speculated that diosmin might have potential in the treatment of neurodegenerative diseases,[4] such as Alzheimer’s disease.


Diosmin improves lymphatic drainage by increasing the frequency and intensity of lymphatic contractions, and by increasing the total number of functional lymphatic capillaries. Furthermore, diosmin with hesperidine decreases the diameter of lymphatic capillaries and the intralymphatic pressure.Diosmin prolongs the vasoconstrictor effect of norepinephrine on the vein wall, increasing venous tone, and therefore reducing venous capacitance, distensibility, and stasis. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI.

At the microcirculation level, diosmin reduces capillary hyperpermeability and increases capillary resistance by protecting the microcirculation from damaging processes.

Diosmin reduces the expression of endothelial adhesion molecules (ICAM1VCAM1), and inhibits the adhesion, migration, and activation of leukocytes at the capillary level. This leads to a reduction in the release of inflammatory mediators, principally oxygen free radicals and prostaglandins (PGE2, PGF2a).

Society and culture

Diosmin is distributed in the U.S. as a dietary supplement.[5][6]

Diosmin was first reported by O. A. Osterle and G. Wander in HeIv. Chim. Acta. 8, 519 – 536, 1925 and is a naturally occurring flavonoid glycoside that can be isolated from various plant sources, i.e from the peel of the citrus fruit or hesperidin. Diosmin is a protecting agent and is used for the treatment of chronic venous insufficiency, lymphedema, hemorrhoids and varicose veins. It has been also used for other therapeutic purposes such as cancer, premenstrual syndrome, colitis, and diabetes.

The several references are reported in the prior art for conversion of hesperidin to diosmin.

Zemplen and Bogner, in Ber. 76, 452, 1943 reported monobromination of acetylated flavanones by liquid bromine in chloroform solution in presence of ultraviolet radiation to obtain flavone derivative by following loss of hydrogen bromide and deacetylation with alcoholic alkali. The conversion of hesperidin to diosmin reported is 37%.

In the journal reference, J. Org. Chem., 16, 930 – 933, 1951, by N. B. Lorette et. al. N-bromosuccinimide was used for the bromination of acetylated hesperidin in chloroform and benzoyl peroxide was used as a catalyst. Diosmin yield was 44%.

Studies in Organic Chemistry (Amsterdam) (1982), Volume Date 1981, 11, 115-119 describes conversion of Hesperidin, neohesperidin and naringin to diosmin, neodiosmin, and rhoifolin respectively by dehydrogenation with iodine in pyridine. Tianran Chanwu Yabjiu Yu Kaif (2006), 18(6), 896-899 describes separation and purification of diosmin by macroporous resins, and reported 95% pure diosmin.

ES459076 describes the preparation of diosmin by bromination and debromination of hesperidin acetate in tetrahydrofuran with 2-carboxy ethyl triphenyl phosphonium bromide followed by saponification with potassium tertiary butoxide.

ES465156 describes diosmin preparation by reaction of hesperidin with aqueous sodium hydroxide, iodine and pyridine with 66% yield.

DE2740950 describes iodination-dehydroiodination of hesperidin in the presence of pyridine and iodine resulting 89% of diosmin.

EP52086 claims a process for the preparation of diosmin comprising of total acetylation of hesperidin or related flavone by heating it in acetic anhydride and pyridine followed by selective dehydrogenation or oxidation by means of SeO2 in isoamyl alcohol and then deprotection by means of alkaline hydrolysis with inorganic bases under hot condition. The isolated diosmin is purified by base acid treatment with overall reported yield is of 60%.

US4078137 describes a process for diosmin comprising of acetylation of hesperidin, thereby brominating it and the brominated product is hydrolysed to isolate diosmin with bromine content less then 0.1% with over all 65% yield.

In BE 904614, diosmin was prepared by iodination of hesperidin followed by elimination of HI. In the process, iodine in dimethylformamide and pyridine were successively added to hesperidin and the resulting mixture was heated at 100°C to give 96% pure diosmin.

EP 860443 describes the process that involves reaction of hesperidin with iodine in presence of pyridine at reflux temperature for 5 hours. The reaction mixture is cooled to 5°C and the isolated diosmin is purified using base acid treatment to get the quality of diosmin above 90% with 75 % yield.

FR2760015 provides industrial dehydrogenation of hesperidin with potassium iodide in DMSO in presence of cone. H2SO4 resulted in diosmin with 73% yield and pharmacopoeial quality.

WO2000011009 describes reaction of hesperidin with iodine in presence of pyridine and anhydrous alkaline earth metal base. The process involves purifying the reaction mass using morpholine followed by base acid treatment which resulted in diosmin with 80% yield and purity of diosmin meets with pharmacopoeial norms.

EP 1086953 discloses the process for purification of diosmin by reacting with pulverized zinc in aqueous solution followed by filtration and acidification.

Diosmin which is produced by many of the prior art processes is often found to contain impurities and is contaminated with various byproducts, for instance hesperidin, Isorhoifin, acetyl lisovanilone, 6-Iododiosmin, linarin, diosmetin and other organic volatile impurities. Some of the major impurities are resulted from hesperidin during extraction. The impurities of hesperidin have a major effect on the final assay of diosmin. The impurities vary depending upon the source of hesperidin. It is worthy to note that direct crystallization of crude diosmin with aqueous base acid solution does not necessarily improve the assay / purity of diosmin.

The process described in Studies in Organic Chemistry (Amsterdam) (1982), Volume Date 1981, 11, 115-119 is different from the present inventors process.

Although ES459076 teaches the preparation of diosmin by bromination and debromination of hesperidin acetate in tetrahydrofuran with 2-carboxy ethyl triphenyl phosphonium bromide, it does not teach about the final purity of diosmin with pharmaceutical quality as required.

ES465156 and DE2740950 although disclose method of preparation, does not teach a process that gives yields as are taught by present invention.

EP52086 and US4078137 uses acetic anhydride for acetylation of hesperidine with yields around 60%, which are phenomenally less as compared with yields of process described by present invention.

Sequence of addition of reactants in the process as taught by BE 904614 is different than the teachings of the present invention.

FR2760015 teaches use of different reactants under conditions that are different from the teachings of the present invention.

Invention disclosed in present application does not use morpholine as disclosed in WO2000011009.

Though there are reported several processes for preparation of diosmin in the prior art, present invention describes a novel systematic process for the preparation of diosmin by converting hesperidin to diosmin at optimum level i.e. % conversion, and keeping the impurities at minimum level which results in consistently pure diosmin with good yield and the desired quality. The process allows recovery and recycle of major contributing chemicals and solvents such as methanol, pyridine and iodine, without impact on quality, purity or yield of the process making the process more economical and ecofriendly. It is surprisingly found that quality diosmin output obtained is independent of hesperidin quality used


Title: Diosmin
CAS Registry Number: 520-27-4
CAS Name: 7-[[6-O-(6-Deoxy-a-L-mannopyranosyl)-b-D-glucopyranosyl]oxy]-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one
Additional Names: 3¢,5,7-trihydroxy-4¢-methoxyflavone-7-rutinoside; 5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-(O6-a-L-rhamnopyranosyl-b-D-glucopyranosyloxy)chromen-4-one; 5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-b-rutinosyloxy-4H-chromen-4-one; diosmetin 7-b-rutinoside; barosmin; buchu resin
Trademarks: Diosmil (Bellon); Diosven (CT); Diovenor (Innothža); Flebosmil (Bouchara); Flebosten (Bonomelli); Hemerven (Interdelta); Insuven (Berenguer); Litosmil (Evans); Tovene (Kali-Chemie); Varinon (Exa); Ven-Detrex (Zyma); Venosmine (Geymonat)
Molecular Formula: C28H32O15
Molecular Weight: 608.54
Percent Composition: C 55.26%, H 5.30%, O 39.44%
Literature References: Naturally occurring flavonic glycoside; rhamnoglycoside of diosmetin, q.v. Isolation from various plant sources: O. A. Oesterle, G. Wander, Helv. Chim. Acta 8, 519 (1925). Elucidation of structure: G. Zemplén, R. Bognár, Ber. 76, 452 (1943). Prepn from hesperidin, q.v.: eidem, ibid.; N. B. Lorette et al., J. Org. Chem. 16, 930 (1951). Isoln from lemon peel (Citrus limon Linn. Rutaceae): R. M. Horowitz, J. Org. Chem. 21, 1184 (1956); from Zanthoxylum avicennae, Rutaceae: H. R. Arthur et al.,J. Chem. Soc. 1956, 632; H. R. Arthur et al., ibid. 1959, 4007; from flowers of Sophora microphylla Ait. Leguminosae: L. H. Briggs et al., ibid. 1960, 1955. Toxicology studies: H. Heusser, W. Osswald, Arch. Farmacol. Toxicol. 3, 33 (1977). NMR spectrum: J. L. Nieto, A. M. Gutierrez, Spectrosc. Lett. 19, 427 (1986). Mechanism of action: C. Boudet, L. Peyrin, Arch. Int. Pharmacodyn. 283,312 (1986). Pharmacology: J. R. Caseley-Smith, J. R. Caseley-Smith, Agents Actions 17, 1 (1985); M. Damon et al., Arzneim.-Forsch. 37, 1149 (1987). HPLC determn in biological fluids: D. Baylocq et al., Ann. Pharm. Fr. 41, 115 (1983). Clinical study in post-phlebitic ulcers: M. C. Nguyen, K. Morere, Gaz. Med. 92, 71 (1985); in acute hemorrhoids: A. Tajana et al., Minerva Med. 79,387 (1988). Clinical trial in chronic venous insufficiency: R. Laurent et al., Int. Angiol. 7, Suppl. 2, 39 (1988).
Derivative Type: Monohydrate
Molecular Formula: C28H32O15.H2O
Molecular Weight: 626.56
Percent Composition: C 53.67%, H 5.47%, O 40.86%
Properties: mp 275-277° (dec) (Zemplén). Also reported as fine needles from aq pyridine or aq DMF, mp 283° (dec) (Briggs). uv max (ethanol): 255, 268, 345 nm (log e 4.28, 4.25, 4.30). Practically insol in water, alcohol.
Melting point: mp 275-277° (dec) (Zemplén); mp 283° (dec) (Briggs)
Absorption maximum: uv max (ethanol): 255, 268, 345 nm (log e 4.28, 4.25, 4.30)
Derivative Type: Flavonoid extract
Trademarks: Daflon (Servier); Flebopex (Profarma); Flebotropin (Bago)
Therap-Cat: Capillary protectant.
Keywords: Vasoprotectant.


Lee, Sanghyun; Natural Product Sciences 2002, VOL 8(4), P127-128

Siciliano, Tiziana; Journal of Agricultural and Food Chemistry 2004, VOL 52(21), P6510-6515 

 Yin, Feng; Zhongguo Tianran Yaowu 2004, VOL 2(3), P149-151 

Markovic, D.; Farm. Glasnik 1949, VOL 5(No. 7;No. 8), P135-48;153-62 

Nakaoki, Tahitiro; Yakugaku Zasshi 1938, VOL 58, P639-47(in German 197-201)

Wander, G.; Pharmaceutical Journal 1925, VOL 115, P520 

Morita, Naokata; Yakugaku Zasshi 1967, VOL 87(3), P319-20 

“PhysProp” data were obtained from Syracuse Research Corporation of Syracuse, New York (US)

Narasimhachari, N.; Proceedings – Indian Academy of Sciences, Section A 1949, VOL 30A, P151-62 

Horowitz, Robert M.; Journal of Organic Chemistry 1956, VOL 21, P1184-5 


Spectroscopy Letters , An International Journal for Rapid Communication , Volume 19, 1986 – Issue 51H NMR Spectra at 360 MHz of Diosmin and Hesperidin in DMSO Solution

Pages 427-434 | Received 03 Jan 1986, Accepted 03 Jan 1986, Published online: 06 Dec 2006


Journal of Natural Products, 2013, vol. 76, 1, pg. 8 – 12

1 H NMR, 13C NMR, HMQC and HMBC spectra of diosmin (5) ……………….S2



 Journal of Molecular Liquids, 2014, vol. 199, pg. 35 – 41



[0012] BRIEF I: iodine purification process Figure 2: Synthesis of diosmin roadmap

detailed description

[0013] Main reaction: The 80Kg Hesperidin, 40Kg soda ash, 400kg90% ethanol, 80L pyridine, 24kg iodine successively into reactor closed good pot opening, with stirring and heated to 110 ° c with a microwave, heat stirring, until the orange leather glycosides completely dissolved, about ten minutes. Hesperidin is completely dissolved, the solvent was slowly added to 80L of pyridine, combined with sodium iodide 8Kg, heated to 110 ° C, the reaction was stirred for 3-4 hr incubation, the sample is then detected by HPLC detection method, when a peak area less than hesperidin the reaction was terminated when 5% diosmin peak area, heat recovery of the solvent pyridine.

[0014] The filter press: End recovered 25Kg pyridine was added a paste of methanol, was press iodine recycling of waste, the recovery is completed, washed with purified water of 62 ° C, colorless and transparent until the washing water to the water 3 t, remove the filter cake to afford crude diosmin, 125. 4Kg.

[0015] Purification: 16Kg sodium hydroxide into dissolving tank, add purified water 500Kg, dissolved under stirring, and after dissolution the crude into the tank, and the water plus t I stir crystals were filtered into a stainless steel frame filter kettle, adding 42Kg hydrochloric acid, adjusted to PH 6.7, 25Kg of methanol was added, after stirring for 30min, the precipitate was allowed to stand, the I h.

[0016] Washing: The crystalline material tank into the filter press, ere washed with purified water, the washing water to colorless far, four tons of water, remove the filter cake to afford fine diosmin, 118. 5Kg. [0017] The dried, pulverized, mixed: semi-finished products into the oven dried 11.2 hours, 82 ° C temperature conditions, the dried material was crushed with a grinder, then put double cone blender and mixed overall speed 15r / min, each of the positive and negative inversion 20min, diosmin have finished 72Kg, a yield of 90.0%.

[0018] Packaging: for medical packaging with double polyethylene bags, into the drum after passing inspection, into finished products.

[0019] The recovery of iodine: iodine-containing filtrate generated pressure filtration step was slowly added sulfuric acid to adjust the PH 4, left for 5 hours, vacuum distillation, collecting high-boiling fraction, 20Kg hydrogen peroxide was slowly added, stand for 2 hours, filtered, the recovered iodine cloth, can be re-purified to obtain purified iodine! .

[0020] Processing pyridine in water: pyridine pyridine recovered after 400Kg containing moisture added to the kettle, 35Kg of potassium hydroxide was added, heated to 105 ± 5 ° C, collecting it pyridine (105 ° C before the liquid front , is defective, back again into the reaction vessel, then 105 ° C out is a good product), Hugh moisture meter by Karl Fischer detected, less than 2%.


diosmin chemical name is 3 ‘, 5,7-trihydroxy-4’ – methoxy flavone, i.e. (7 – {[6-0- (6-deoxy-mannose -a -L- sugar) _β -D- glucopyranosyl] oxy} -5_ hydroxy-2- (3-hydroxy-_4_ methoxyphenoxy) -4H-L–benzopyran-4-one), the following structure Figure:


Figure CN102875621AD00031

[0004] Diosmin has a comprehensive effect on vascular transfusion system to the venous system, micro-circulatory system and the lymphatic system has a powerful effect. Diosmin can be significantly reduced in addition to the adhesion of leukocytes to vascular endothelial cells, migration, inhibition of leukocyte disintegration and release of inflammatory mediators such as histamine, bradykinin, complement, leukotrienes, prostaglandins, free radical scavenging and the like, It may also reduce blood viscosity, to enhance flow of red blood cells, thus reducing the microcirculation stasis, mainly used in clinical treatment of chronic venous insufficiency.

[0005] diosmin content in natural plant is very low, direct extraction of high cost, so it is through the oxygen

Hesperidin is prepared by chemical synthesis; hesperidin formula below:


Figure CN102875621AD00032

[0007] diosmin synthesis process generally as follows:

[0008] hesperidin and an oxidant, and a solvent after mixing an alkaline reagent can be synthesized by heating the reaction Diosmin; wherein said oxidizing agent is iodine, mainly basic agent mainly inorganic bases, typically hydrogen sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, an alkaline substance, etc., the solvent is pyridine or dimethylformamide.

[0009] Preparation of diosmin conventional synthesis method will inevitably pyridine or dimethylformamide as the reaction solvent, in particular in the main pyridine; as pyridine, dimethylformamide as a reaction solvent after the treatment process is not easy divisible, thus resulting in higher residual solvent in the product; the same time, since the two types of the organic solvent is pyridine, a large irritating odor on the human body have a greater toxic effects, and therefore in the production process and on the environment endanger personnel more apparent.

Example 8

[0081] In addition hesperidin 1000L reaction vessel 100 g, 47 g of sodium hydroxide and 12 g of iodine, and finally adding morpholine: water (60: 40) mixed solvent O. 8 liters, stir until completely dissolved. after heating to 85-90 ° C. was stirred incubated for 9 hours. the reaction liquid becomes viscous liquid was added 3 g of sodium thiosulfate, recovered at 85-90 ° C under vacuum conditions to a 70-80% morpholinyl, after complete recovery morpholine, O. 8 liters of water was added, stirred uniformly filtered to collect the waste. washed with water to give diosmin crude product. the crude product diosmin O. 8-liter and water was added 30 g of sodium hydroxide. stirred to dissolve completely after high-speed centrifuge filtration. into the crystallizer, water was added to the filtrate I. 5 liters of sulfuric acid was added slowly acidified to PH 2-3. standing, filtered and washed with water. diosmin give crude crystals. The crude crystals add water O. 8-liter and 30 g of sodium hydroxide and stirred to dissolve completely, placed in a crystallizer tank, to force saliva I. 5 liters of sulfuric acid was added slowly acidified to PH 2-3. Standing, was filtered, washed with water the drying, grinding to give the finished Diosmin 80. I g. Product purity by HPLC 95.26%, the yield was 80.1%, iodine residual, residual solvent, associated impurities, the content of all standards


Example – 1

100 gm of hesperidin , 700 ml of pyridine, 9.8 gm of sodium hydroxide and 45.6 gm of iodine were charged in 2 liter clean glass assembly, The resulting solution was heated to 95-1050C for 9 – 10 hours. Reaction was monitored by HPLC to get hesperidin less than 1 %. The pyridine was recovered completely by distillation. Charged methanol to the resulting solid, the reaction mass was heated to reflux and filtered at room temperature. Iodine was recovered from mother liquor, solid obtained was treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. pH 2-4 was adjusted with cone, sulfuric acid. Reaction mass was filtered to obtain crude diosmin. Yield : 80 – 86 gm. Recovery of iodine from above methanol mother liquor: Distilled methanol and pyridine mixture. The obtained residue was acidified with sulfuric acid. The resulting pH was less than 1. The brown precipitate formed was filtered. The resulting filtrate was oxidized with hydrogen peroxide at 0-10°C and filtered to obtain crude iodine having assay 50 – 60 %, which was steam distilled to obtain pure iodine with assay 95 %.

Example – 2

100 gm of crude diosmin as prepared in example 1 and 1800 ml of dimethylformamide was charged in 3 liter clean glass assembly. The resulting mass was heated to 90-950C to obtain clear solution. 200 ml of water was added at 90- 950C and maintained for 30 min. The reaction mass was cooled and filtered. The wet solid was collected.

Charged wet solid obtained in 3 liter clean glass assembly and charged 900 ml of water, 900 ml of 5% aqueous NaOH solution. Distilled out approximately 900 ml of water under vacuum below 5O0C. Charged 1000 ml of water and the resulting reaction mass was treated with charcoal and filtered through hyflow. pH 1.8-2.2 was adjusted using sulfuric acid. Stirred the mass for 30 min, filtered and washed it with water, hot water. Solid was dried. Yield : 80 – 85 gm. Assay : 99.9 %.

Example – 3

100 gm of crude diosmin as prepared in example 1, 1800 ml of dimethylformamide and 1800 ml of water was charged in 5 liter clean glass assembly. The resulting solution was heated to 90-950C to obtain slurry and maintained for 30 min. Cooled the reaction mass and filtered, washed with water and hot water. The obtained solid was dried. Yield: 90 – 95 gm. Assay : 97 %. Example – 4

100 gm of crude diosmin as prepared in example 1 and 1800 ml of dimethylformamide was charged in 3 liter clean glass assembly. The resulting solution was heated to 90-950C to obtain clear solution.charged 360 ml of water at 90-950C and maintained for 30 min. The reaction mass was filtered, washed with water and with hot water. Solid obtained was dried. Yield: 90 – 95 gm. Assay : 99.5 %.

Example – 5

100 gm of crude diosmin as prepared in example 1 and 1800 ml of dimethylformamide was charged in 3 liter clean glass assembly. The resulting solution was heated to 90-950C to obtain clear solution, charged 900 ml of water at 90-950C and maintained for 30 min. The reaction mass was filtered, washed with water and with hot water. Solid obtained was dried. Solid obtained was 90 — 95 gm. Assay obtained was 98.8 %.

Example – 6

100 gm of hesperidin , 700 ml of recovered pyridine, 9.8 gm of sodium hydroxide and 45.6 gm of iodine were charged in 2 liter clean glass assembly . The resulting solution was heated to 95-1050C for 9 – 10 hrs. Reaction was monitored by HPLC. Pyridine was recovered completely by distillation. Charged methanol to the resulting solid, the reaction mass was heated to reflux and filtered at room temperature. The solid obtained was treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. pH 2-4 was adjusted with cone, sulfuric acid. Reaction mass was filtered to obtain crude diosmin. Crude diosmin obtained was 80 – 86 gm. Purity was 98.6 %.

Example – 7

100 gm of hesperidin , 700 ml of recovered Pyridine, 9.8 gm of sodium hydroxide and 48 gm (assay 95 %) of recovered iodine were charged in 2 liter clean glass assembly.. The resulting solution was heated to 95-1050C for 9 – 10 hours. Reaction was monitored by HPLC to get hesperidin less than 1 %. The pyridine was recovered by distillation. Charged methanol to the resulting solid, the reaction mass was heated to reflux and filtered at room temperature. The solid obtained was treated with sodium thiosulfate solution and 900 ml, 5% aqueous NaOH solution. pH 2-4 was adjusted with cone, sulfuric acid. Reaction mass was filtered to obtain crude diosmin. Yield:80 – 86 gm. Purity : 95.3 %.



Method for preparing diosminum comprising the steps of mixing amide solvent, hesperidin, alkaline reagent and iodine, and heating the reaction to obtain diosmin . Diosmin is a naturally occurring flavonoid glycoside that can be obtained from various plant sources. It is used in therapy due to its pharmacological activity as phlebotonic and vascular protecting agent, and useful for treating chronic venous insufficiency.

Example 1
1.1 Oxidation reaction: Open the vacuum pump, vacuum inhale 1500L of dimethylformamide into the reaction tank, and add sodium hydroxide to adjust the pH of the solvent between 6 and 7. Add 250.00kg of hesperidin and stir it while feeding. The material and the solvent are in full contact; 125 kg of iodine is added into the reaction tank at a constant rate for reaction; the temperature of the reaction tank is controlled between 70° C. and 100° C. for 14 hours.
1.2 Solvent recovery: After the reaction is complete, open the valve of the turnover tank and dehydration tank and close the return valve. Control the temperature of the material to start depressurizing the solvent at 90°C to 110°C. During the recovery process, attention should be paid to observe the recovery temperature and recovery conditions. When the material is dilute, stop the solvent recovery and enter the next process.
1.3 Crude product crystallization, filtration, washing: open the reaction tank vacuum valve, pump 1500L of purified water from the upper part of the reaction tank, start the mixer, stir for 10-20min, then add 1500L of purified water and stir for 1h; after the mixing is accepted, when the temperature of the crystallization liquid drops After 35°C, the crystallization liquid is pumped into the plate and frame filter press for filtration, and the filtrate is temporarily stored in the storage tank; after the filtered plate nozzle no liquid flows out, the 18000L purified water pump is pumped into the frame filter press for washing; The water wash is discharged into a waterless collection tank for sewage treatment, and the water is washed until the pH of the effluent is measured with a pH test paper of 6 to 7. The beaker sample is observed to be colorless and transparent; after the washing is completed, the water inlet valve is closed and the air pressure is turned on. The valve is air-pressed, the air pressure is controlled at 0.07~0.09 MPa, and the time is maintained for 3 hours. The filter cake is collected and put into the turnover barrel for marking.

1.4 Secondary Dissolution and Filtration: Open the dissolving tank and stir. In the dissolving tank, add 75 kg of alkali A to 1300 L of purified water. After the solution is completely dissolved, add the filter cake in the circulating drum to the tank; after the filter cake is added and stirring is continued for 1 h, Add 1300L of purified water into the tank, stir for 30 minutes, and stand for 3 hours. Filter the filtrate with a frame filter press. The filtered solution is finely filtered by a fine filter and then pumped into a clean area crystallizer.

1.5 secondary crystallization: open the stirrer, slowly put 160 ~ 230kg 36% hydrochloric acid into the clean area crystallization tank, the measured pH of the solution is between 5.0 ~ 6.0, after stirring 20min measured the pH of the solution should be stable and qualified , Stir 1h, make the original record of the process.
1.6 Fine filtration and washing: The crystallization liquid is vacuum-inhaled into the box type filter press for filtration; after the filtration is completed, the washed water is washed with 18,000 to 20,000 L of purified water. After the washing is completed, it is checked that the washing liquid should be colorless and transparent, and the filtrate should be filtrated. Discharge into the sewage treatment system.
1.7 Fine Drying: Open the hot air circulation oven, control the temperature at 100 °C ~ 130 °C, drying time is maintained at 10 ~ 16h; when dried 10h, timely sampling, with a quick moisture meter to determine the moisture, when the sample moisture is less than 5%, Stop drying; after passing the drying, close the oven and transport the material to the next process.
1.8 Fine-grinding: The dried product is crushed with a crusher. The crushing sieve is 80 mesh to obtain Diosmin.
The quality standards of all raw materials in Example 1 are shown in Table 1.
Table 1 Raw material quality standards

[Table 0001]

Original accessories name specification Quality Standard
Hesperidin EC In line with “Hesperidin Quality Standard”
New solvent Industrial grade Meet the “new solvent quality standards”
Alkali A Industrial grade In accordance with the “Alkaline A Quality Standard”
iodine Pharmaceutical grade In line with “Iodine Quality Standards”
hydrochloric acid Analytical purity In line with the “Hydrochloric Acid Quality Standard”
Diosmin Yield Calculation Method:
Diosmin product yield = (Diosmin Fine Quality) / (Hesperidin weight) × 100%


  1. Jump up^ Flavonoid Aglycones and Glycosides from Teucrium gnaphalodes. F. A. T. Barberán, M. I. Gil, F. Tomás, F. Ferreres and A. Arques, J. Nat. Prod., 1985, 48 (5), pages 859–860, doi:10.1021/np50041a040
  2. Jump up^ Jantet, G. (2002-06-01). “Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids”. Angiology53(3): 245–256. ISSN 0003-3197PMID 12025911.
  3. Jump up^ Leelavinothan Pari, Subramani Srinivasan, Antihyperglycemic effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats, Biomedicine & Pharmacotherapy, Volume 64, Issue 7, September 2010, Pages 477-481.
  4. Jump up^ Sirlak, Mustafa; Akar, A. Ruchan; Eryilmaz, Sadik; Cetinkanat, Elif Kuzgun; Ozcinar, Evren; Kaya, Bulent; Elhan, Atilla Halil; Ozyurda, Umit (2010-01-01). “Micronized purified flavonoid fraction in pretreating CABG patients”Texas Heart Institute Journal37 (2): 172–177. ISSN 1526-6702PMC 2851420Freely accessiblePMID 20401289.
  5. Jump up^ “Nutratech dietary supplement notification” (PDF). FDA. November 3, 2000. Archived from the original (PDF) on December 9, 2006.
  6. Jump up^ “Stragen Pharma dietary supplement notification” (PDF). FDA. September 6, 2005.


Publication numberPriority datePublication dateAssigneeTitle
DE2740950A1 *1977-09-101979-03-22Merck Patent GmbhA process for the production of flavones
EP0860443A1 *1997-02-211998-08-26Innokem, SARLIndustrial process for the production of diosmine starting from hesperidine
WO2000011009A2 *1998-08-192000-03-02Innokem, S.A.R.L.Method for industrial production of diosmin from hesperidin by reaction with iodine and pyridine

Publication numberPriority datePublication dateAssigneeTitle

CN102070689A *2011-01-252011-05-25湖南圆通药业有限公司Method for producing diosmin
CN102653549A *2011-12-282012-09-05长沙富能生物技术有限公司Synthesis method of diosmin raw medicine meeting EP7 version quality standards
CN102875621A *2012-10-262013-01-16成都澜绮制药有限公司Synthesis method of diosmin
RU2481353C1 *2011-12-222013-05-10Закрытое акционерное общество “Активный Компонент”Commercial method for preparing officinal diosmin and crystalline form thereof (versions)
CN103772336A *2014-02-232014-05-07闻永举Semi-synthesis method of phenolic hydroxyl flavonoid compounds and iodine recycling method
CN103435666A *2013-07-302013-12-11李玉山Novel production technology of diosmin
CN105732744A *2016-04-292016-07-06南京正大天晴制药有限公司Method for preparing green and economic diosmin
Publication numberPriority datePublication dateAssigneeTitle
DE2740950A1 *1977-09-101979-03-22Merck Patent GmbhA process for the production of flavones
EP1086953A1 *1999-09-242001-03-28IsochemProcess for the purification of diosmine
WO2010092592A2 *2009-02-112010-08-19Elder Pharmaceuticals Ltd.Process for the preparation of diosmin
CN102653549A *2011-12-282012-09-05长沙富能生物技术有限公司Synthesis method of diosmin raw medicine meeting EP7 version quality standards
Clinical data
AHFS/ International Drug Names
Routes of
ATC code
CAS Number
PubChem CID
ECHA InfoCard 100.007.537
Chemical and physical data
Formula C28H32O15
Molar mass 608.545 g/mol
3D model (JSmol)

//////////DIOSMIN, диосмин ديوسمين 地奥司明 , Barosmin,  Diosmine, Venosmine, Diosmil,  



Entecavir, энтекавир , إينتيكافير , 恩替卡韦 , エンテカビル

Entecavir structure.svg

ChemSpider 2D Image | entecavir | C12H15N5O3Entecavir.png


  • Molecular FormulaC12H15N5O3
  • Average mass277.279 Da
SQ 34,676
Entecavir; 142217-69-4; Baraclude; BMS 200475; Anhydrous entecavir; UNII-NNU2O4609D
энтекавир [Russian] [INN]
إينتيكافير [Arabic] [INN]
恩替卡韦 [Chinese] [INN]
エンテカビル  JAPANESE
6H-Purin-6-one, 2-amino-1,9-dihydro-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl)-
6H-Purin-6-one, 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-
9H-purin-6-ol, 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-
Baraclude[Trade name]
CAS 142217-69-4

Baraclude (Entecavir) Film Coated Tablets & Oral Solution
Company:  Bristol-Myers Squibb Pharmaceutical Co.
Application No.:  021797 & 021798
Approval Date: 03/29/2005


BARACLUDE® is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C12H15N5O3•H2O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:

BARACLUDE® (entecavir) Structural Formula Illustration

Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° C ± 0.5° C.

BARACLUDE film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. BARACLUDE 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5 mg tablet only), and iron oxide red (1 mg tablet only). BARACLUDE Oral Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir per milliliter. BARACLUDE Oral Solution contains the following inactive ingredients: maltitol, sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.

Title: Entecavir
CAS Registry Number: 142217-69-4
CAS Name: 2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one
Molecular Formula: C12H15N5O3
Molecular Weight: 277.28
Percent Composition: C 51.98%, H 5.45%, N 25.26%, O 17.31%
Literature References: Deoxyguanine nucleoside analog; inhibits hepatitis B virus (HBV) DNA polymerase. Prepn: R. Zahler, W. A. Slusarchyk, EP481754eidem,US5206244 (1992, 1993 both to Squibb); G. S. Bisacchi et al.,Bioorg. Med. Chem. Lett.7, 127 (1997). In vitro antiviral activity: S. F. Innaimo et al,Antimicrob. Agents Chemother.41, 1444 (1997). Review of pharmacology and clinical experience: P. Honkoop, R. A. de Man, Expert Opin. Invest. Drugs12, 683-688 (2003); T. Shaw, S. Locarnini, Expert Rev. Anti Infect. Ther.2, 853-871 (2004). Clinical comparisons with lamivudine in chronic hepatitis B: T.-T. Chang et al., N. Engl. J. Med.354, 1001 (2006); C.-L. Lai et al., ibid. 1011.
Derivative Type: Monohydrate
CAS Registry Number: 209216-23-9
Manufacturers’ Codes: BMS-200475; SQ-200475
Trademarks: Baraclude (BMS)
Molecular Formula: C12H15N5O3.H2O
Molecular Weight: 295.29
Percent Composition: C 48.81%, H 5.80%, N 23.72%, O 21.67%
Properties: White to off-white powder, mp >220°. [a]D +35.0° (c = 0.38 in water). Soly in water: 2.4 mg/ml. pH of saturated soln in water is 7.9 at 25°±0.5°.
Melting point: mp >220°
Optical Rotation: [a]D +35.0° (c = 0.38 in water)
Therap-Cat: Antiviral.
Keywords: Antiviral; Purines/Pyrimidinones.
Antiviral agents used against HBV

Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection. It is marketed under the trade name Baraclude (BMS).

Entecavir is a guanine analogue that inhibits all three steps in the viral replication process, and the manufacturer claims that it is more efficacious than previous agents used to treat hepatitis B (lamivudine and adefovir). It was approved by the U.S. Food and Drug Administration (FDA) in March 2005.

For the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection.[1] In those with both HIV/AIDS and HBV antiretroviral medication should also be used.[1] Entecavir is taken by mouth as a tablet or solution.[1]

Common side effects include headache, nausea, high blood sugar, and decreased kidney function.[1] Severe side effects include enlargement of the liverhigh blood lactate levels, and liver inflammation if the medication is stopped.[1] While there appears to be no harm from use during pregnancy, this use has not been well studied.[4] Entecavir is in the nucleoside reverse transcriptase inhibitors(NRTIs) family of medications.[1] It prevents the hepatitis B virus from multiplying by blocking reverse transcriptase.[1]

Entecavir was approved for medical use in 2005.[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] In the United States as of 2015 it is not available as a generic medication.[6]The wholesale price is about 392 USD for a typical month supply as of 2016 in the United States.[7]

Medical uses

Entecavir is mainly used to treat chronic hepatitis B infection in adults and children 2 years and older with active viral replication and evidence of active disease with elevations in liver enzymes.[2] It is also used to prevent HBV reinfection after liver transplant[8] and to treat HIV patients infected with HBV. Entecavir is weakly active against HIV, but is not recommended for use in HIV-HBV co-infected patients without a fully suppressive anti-HIV regimen[9] as it may select for resistance to lamivudine and emtricitabine in HIV.[10]

The efficacy of entecavir has been studied in several randomized, double-blind, multicentre trials. Entecavir by mouth is effective and generally well tolerated treatment.[11]

Pregnancy and breastfeeding

It is considered pregnancy category C in the United States, and currently no adequate and well-controlled studies exist in pregnant women.[12]

Side effects

The majority of people who use entecavir have little to no side effects.[13] The most common side effects include headache, fatigue, dizziness, and nausea.[2] Less common effects include trouble sleeping and gastrointestinal symptoms such as sour stomach, diarrhea, and vomiting.[14]

Serious side effects from entecavir include lactic acidosis, liver problemsliver enlargement, and fat in the liver.[15]

Laboratory tests may show an increase in alanine transaminase (ALT), hematuriaglycosuria, and an increase in lipase.[16] Periodic monitoring of hepatic function and hematology are recommended.[2]

Mechanism of action

Entecavir is a nucleoside analog,[17] or more specifically, a deoxyguanosine analogue that belongs to a class of carbocyclic nucleosidesand inhibits reverse transcriptionDNA replication and transcription in the viral replication process. Other nucleoside and nucleotide analogues include lamivudinetelbivudineadefovir dipivoxil, and tenofovir.

Entecavir reduces the amount of HBV in the blood by reducing its ability to multiply and infect new cells.[18]


Entecavir is take by mouth as a tablet or solution. Doses are based on a person’s weight.[15] The solution is recommended for children more than 2 years old who weigh up to 30 kg. Entecavir is recommended on an empty stomach at least 2 hours before or after a meal, generally at the same time every day. It is not used in children less than 2 years old. Dose adjustments are also recommended for people with decreased kidney function.[15]


  • 1992: SQ-34676 at Squibb as part of anti-herpes virus program[19]
  • 1997: BMS 200475 developed at BMS pharmaceutical research institute as antiviral nucleoside analogue à Activity demonstrated against HBV, HSV-1, HCMV, VZV in cell lines & no or little activity against HIV or influenza[20]
  • Superior activity observed against HBV pushed research towards BMS 200475, its base analogues and its enantiomer against HBV in HepG2.2.15 cell line[20]
  • Comparison to other NAs, proven more selective potent inhibitor of HBV by virtue of being Guanine NA[21]
  • 1998: Inhibition of hepadnaviral polymerases was demonstrated in vitro in comparison to a number of NAs-TP[22]
  • Metabolic studies showed more efficient phosphorylation to triphosphate active form[23]
  • 3-year treatment of woodchuck model of CHB à sustained antiviral efficacy and prolonged life spans without detectable emergence of resistance[24]
  • Efficacy # LVD resistant HBV replication in vitro[25]
  • Superior activity compared to LVD in vivo for both HBeAg+ & HBeAg− patients[26][27]
  • Efficacy in LVD refractory CHB patients[28]
  • Entecavir was approved by the U.S. FDA in March 2005.

Patent information

Bristol-Myers Squibb was the original patent holder for Baraclude, the brand name of entecavir in the US and Canada. The drug patent expiration for Baraclude was in 2015.[29][30]On August 26, 2014, Teva Pharmaceuticals USA gained FDA approval for generic equivalents of Baraclude 0.5 mg and 1 mg tablets;[31] Hetero Labs received such approval on August 21, 2015;[32] and Aurobindo Pharma on August 26, 2015.[33]

Chronic hepatitis B virus infection is one of the most severe liver diseases in morbidity and death rate in the worldwide range. At present, pharmaceuticals for treating chronic hepatitis B (CHB) virus infection are classified to interferon α and nucleoside/nucleotide analogue, i.e. Lamivudine and Adefovir. However, these pharmaceuticals can not meet needs for doctors and patients in treating chronic hepatitis B virus infection because of their respective limitation. Entecavir (ETV) is referred to as 2′-cyclopentyl deoxyguanosine (BMS2000475) which belongs to analogues of Guanine nucleotide and is phosphorylated to form an active triple phosphate in vivo. The triple phosphate of entecavir inhibits HBV polymerase by competition with 2′-deoxyguanosine-5′-triphosphate as a nature substrate of HBV polymerase, so as to achieve the purpose of effectively treating chronic hepatitis B virus infection and have strong anti-HBV effects. Entecavir, [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-hydroxymethyl]-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate, and has the molecular formula of C12H15N5O3.H2O and the molecular weight of 295.3. Its structural formula is as follows:

Figure US20140220120A1-20140807-C00001

Entecavir was successfully developed by Bristol-Myers Squibb Co. of USA first and the trademark of the product formulation is Baraclude™, including two types of formulations of tablet and oral solution having 0.5 mg and 1 mg of dosage. Chinese publication No. CN1310999 made by COLONNO, Richard, J. et al discloses a low amount of entecavir and uses of the composition containing entecavir in combination with other pharmaceutically active substances for treating hepatitis B virus infection, however, the entecavir is non-crystal. In addition, its oral formulations such as tablet and capsule are made by a boiling granulating process. The process is too complicated to control quality of products during humidity heat treatment even though ensuring uniform distribution of the active ingredients.

Entecavir, [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, is currently used for treating hepatitis B virus infection, whose structure is composed of a cyclopentane ring having purine, exomethylene, hydroxymethyl, and hydroxy substituents at the 1S-, 2-, 3R-, and 4S-positions, respectively. There have been conducted a number of studies to develop methods for preparing entecavir.

For example, U.S. Pat. No. 5,206,244 and WO 98/09964 disclose a method for preparing entecavir shown in Reaction Scheme 1:Figure imgb0001

The above method, however, has difficulties in that: i) the cyclopentadiene monomer must be maintained at a temperature lower than -30 °C in order to prevent its conversion to dicyclopentadiene; ii) residual sodium after the reaction as well as the sensitivity of the reaction toward moisture cause problems; iii) the process to obtain the intermediate of formula a) must be carried out at an extremely low temperature of below -70 °C in order to prevent the generation of isomers; iv) a decantation method is required when (-)-Ipc2BH (diisopinocampheylborane) is used for hydroboration; v) the process of the intermediate of formula a) does not proceed smoothly; and, vi) separation by column chromatography using CHP-20P resin is required to purify entecavir.

WO 2004/52310 and U.S. Pat. Publication No. 2005/0272932 disclose a method for preparing entecavir using the intermediate of formula (66), which is prepared as shown in Reaction Scheme 2:

Figure imgb0002

The above preparation method of the intermediate of formula (66) must be carried out at an extremely low temperature of -70 °C or less, and the yield of the desired product in the optical resolution step is less than 50%.


Image result for Entecavir

(3-4) Preparation of [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purine-6-one (a compound of formula (1))

34 mg (0.115 mmol) of 4-(2-amino-6-chloro-purine-9-yl)-2-hydroxymethyl-3-methylene-cyclopentanol (a compound of formula (5)) obtained in (3-3) was added to 0.7 ml of 2N aqueous sodium hydroxide, and the resulting mixture was stirred. The solution thus obtained was heated to 72 °C and stirred for 3.5 hrs. After completion of the reaction, the resulting mixture was cooled to 0 °C, controlled to pH 6.3 by adding 2N aqueous hydrochloric acid and 1N aqueous hydrochloric acid, and condensed to obtain 24 mg of the title compound (yield: 70 %, purity: 99 %).

NMR(300MHz, DMSO-d6): δ 10.58 (s, 1H), 7.67 (s, 1H), 6.42 (s, 2H), 5.36 (t, 1H), 5.11 (s, 1H), 4.86 (d, 1H), 4.83 (t, 1H), 4.57 (s, 1H), 4.24 (s, 1H), 3.54 (t, 2H), 2.53(s, 1H), 2.27-2.18 (m, 1H), 2.08-2.01(m, 1H).


Image result for Entecavir

Image result for Entecavir NMR

Image result for Entecavir NMR


Image result for Entecavir NMR

Image result for Entecavir NMR


Total Synthesis of Entecavir: A Robust Route for Pilot Production

Launch-Pharma Technologies, Ltd., 188 Kaiyuan Boulevard, Building D, Fifth Floor, The Science Park of Guangzhou, Guangzhou 510530, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00007
Publication Date (Web): February 12, 2018
Copyright © 2018 American Chemical Society
Abstract Image

A practical synthetic route for pilot production of entecavir is described. It is safe, robust, and scalable to kilogram scale. Starting from (S)-(+)-carvone, this synthetic route consists of a series of highly efficient reactions including a Favorskii rearrangement-elimination-epimerization sequence to establish the cyclopentene skeleton, the Baeyer–Villiger oxidation/rearrangement to afford the correct configuration of the secondary alcohol, and a directed homoallylic epoxidation followed by epoxide ring-opening to introduce the hydroxyl group suitable for the Mitsunobu reaction. In addition, the synthesis contains only four brief chromatographic purifications.

 1: white crystalline solid; HRMS (m/z) calcd for C12H16N5O3 [M + H]+ 278.1253, found 278.1255; [α]D +27.2° [c 1.07, DMF/H2O (1:1)];

1H NMR (500 MHz, DMSO) δ 10.55 (s, 1H), 7.65 (s, 1H), 6.40 (s, 2H), 5.36 (dd, J = 10.3, 8.0 Hz, 1H), 5.10 (s, 1H), 4.85 (d, J = 3.1 Hz, 1H), 4.81 (t, J = 5.3 Hz, 1H), 4.56 (s, 1H), 4.23 (s, 1H), 3.54 (t, J = 6.1 Hz, 2H), 2.55–2.50 (m, 1H), 2.26–2.17 (m, 1H), 2.04 (dd, J = 12.5, 7.8 Hz, 1H);

13C NMR (126 MHz, DMSO) δ 156.8, 153.4, 151.4, 151.3, 135.9, 116.2, 109.2, 70.4, 63.0, 55.1, 54.1, 39.2.



EP 0481754; JP 1992282373; US 5206244, WO 9809964

The regioselective reaction of cyclopentadiene (I) and sodium or commercial sodium cyclopentadienide (II) with benzyl chloromethyl ether (III) by means of the chiral catalyst (-)-diisopinocampheylborane in THF, followed by hydroxylation with H2O2/NaOH, gives (1S-trans)-2-(benzyloxymethyl)-3-cyclopenten-1-ol (IV), which is regioselectively epoxidized with tert-butyl hydroperoxide and vanadyl acetylacetonate in 2,2,4-trimethylpentane, yielding [1S-(1alpha,2alpha,3beta,5alpha)-2-(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexan-3-ol (V). The protection of (V) with benzyl bromide and NaH affords the corresponding ether (VI), which is condensed with 6-O-benzylguanine (VII) by means of LiH in DMF to give the guanine derivative (VIII). The protection of the amino group of (VIII) with 4-methoxyphenyl(diphenyl)chloromethane (IX), TEA and DMAP in dichloromethane gives intermediate (X), which is oxidized at the free hydroxyl group with methylphosphonic acid, DCC and oxalic acid in DMSO or Dess Martin periodinane in dichloromethane, yielding the cyclopentanone derivative (XI). The reaction of (XI) with (i) Zn/TiCl4/CH2Br2 complex in THF/CH2Cl2, (ii) activated Zn/PbCl2/CH2I2/TiCl4 in THF/CH2Cl2 (2), (iii) Nysted reagent/TiCl4 in THF/CH2Cl2 or (iv) Tebbe reagent in toluene affords the corresponding methylene derivative (XII), which is partially deprotected with 3N HCl in hot THF, providing the dibenzylated compound (XI). Finally, this compound is treated with BCl3 in dichloromethane


Bioorg Med Chem Lett 1997,7(2),127

BMS-200475, a novel carbocyclic 2′-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro

BMS-200475, a novel carbocyclic analog of 2′-deoxyguanosine, is a potent inhibitor of hepatitis B virus in vitro (ED50 = 3 nM) with relatively low cytotoxicity (CC50 = 21–120 μM). A practical 10-step asymmetric synthesis was developed affording BMS-200475 in 18% overall chemical yield and >99% optical purity. The enantiomer of BMS-200475 as well as the adenine, thymine, and iodouracil analogs are much less active.

BMS-200475, a novel carbocyclic analog of 2′-deoxyguanosine, is a potent inhibitor of hepatitis B virus in vitro (ED50 = 3nM) with relatively low cytotoxicity (CC50 = 21–120 μM).


Fourier transform infrared (FTIR) spectrogram: The range of wave numbers is measured by using the Nicolet NEXUS 670 FT-IR spectrometer with KBr pellet method, and the range of wave numbers is about 400 to 4000 cm−1. FIG. 3 is a Fourier transform infrared spectrogram of the sample. The infrared spectrogram shows that there are groups in the molecular structure of the sample, such as NH, NH2, HN—C═O, C═C, OH.


Total Synthesis of Entecavir

 Departament de Química Orgànica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Facultat de Química, Universitat de Barcelona, Martí i Franquès 1, 08028-Barcelona, Spain
 R&D Department, Esteve Química S.A., Caracas 17-19, 08030-Barcelona, Spain
§ CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
J. Org. Chem.201378 (11), pp 5482–5491
DOI: 10.1021/jo400607v
*Tel.: +34 934021248. Fax: +34 933397878. E-mail:
Abstract Image

Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron–aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl-catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.


2-Amino-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl)-1H-purin-6(9H)-one Monohydrate (1)

1 (2.102 g, 64% overall yield, 99.47% HPLC purity) with a 6.7% water content (as determined by Karl Fischer titration). Mp 248 °C. [α]D25 +35.0 (c 0.4, H2O). IR (ATR): 3445, 3361, 3296, 3175, 3113, 2951, 2858, 2626, 1709 cm–1.

1H NMR (DMSO-d6, 400 MHz) δ: 10.59 (s, 1H), 7.66 (s, 1H), 6.42 (bs, 2H), 5.36 (ddt, J = 10.6, 7.8, 2.7 Hz, 1H), 5.10 (dd, J = 2.7, 2.2 Hz, 1H), 4.87 (d, J = 3.1 Hz, 1H), 4.84 (t, J = 5.3 Hz, 1H), 4.56 (t, J = 2.4 Hz, 1H), 4.23 (m, 1H), 3.53 (m, 2H), 2.52 (m, 1H), 2.22 (ddd, J = 12.6, 10.8, 4.6 Hz, 1H), 2.04 (ddt, J = 12.6, 7.7, 1.9 Hz, 1H).

13C NMR (DMSO-d6, 101 MHz) δ: 156.9, 153.5, 151.5, 151.3, 136.0, 116.2, 109.3, 70.4, 63.1, 55.2, 54.1, 39.2. HRMS (ESI): m/z calcd for C12H16N5O3+ [M + H]+ 278.1253; found 278.1262.


JP5788398B2 *2009-10-122015-09-30ハンミ・サイエンス・カンパニー・リミテッドNovel production methods and intermediates used to entecavir
US8481728B22010-02-162013-07-09Scinopharm Taiwan, Ltd.Process for preparing entecavir and its intermediates
CA2705953A1 *2010-05-312011-11-30Alphora Research Inc.Carbanucleoside synthesis and intermediate compounds useful therein
CN106928227A2010-07-152017-07-07浙江奥翔药业股份有限公司Synthetic method of entecavir and intermediate compound thereof
EP2474548A12010-12-232012-07-11Esteve Química, S.A.Preparation process of an antiviral drug and intermediates thereof
EP2597096A12011-11-242013-05-29Esteve Química, S.A.Process for preparing entecavir and intermediates thereof
WO2014175974A32013-03-132015-04-09Elitech Holding B.V.Artificial nucleic acids derived from 2-((nucleobase)methyl)butane-1,3-diol
WO2015051900A12013-10-082015-04-16Pharmathen S.A.Process for the preparation of entecavir through novel intermediates
WO2015051903A1 *2013-10-082015-04-16Pharmathen S.A.A novel process for the preparation of chiral cyclopentanone intermediates
CN103675185B *2013-12-102015-10-07上海景峰制药股份有限公司The method of one kind TU entecavir tablet all-trans isomer by high performance liquid chromatography
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CN105037363B *2015-07-132016-08-24山东罗欣药业集团股份有限公司En one kind of new synthetic method of compound entecavir
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KR20080134756A2008-12-262008-12-26Process for preparing entecavir and intermediates used therein
PCT/KR2009/0077862008-12-262009-12-24Novel intermediate and process for preparing entecavir using same


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External links

Entecavir structure.svg
Entecavir ball-and-stick model.png
Clinical data
Pronunciation /ɛnˈtɛkəvɪər/ en-TEK-a-vir or en-TE-ka-veer
Trade names Baraclude[1]
AHFS/ Monograph
MedlinePlus a605028
License data
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability n/a (≥70)[2]
Protein binding 13% (in vitro)
Metabolism negligible/nil
Biological half-life 128–149 hours
Excretion Renal 62–73%
CAS Number
PubChem CID
ECHA InfoCard 100.111.234
Chemical and physical data
Formula C12H15N5O3
Molar mass 277.279 g/mol
3D model (JSmol)
Melting point 220 °C (428 °F) value applies to entecavir monohydrate and is a minimum value[3]

///////////////Entecavir, энтекавир إينتيكافير 恩替卡韦 , BMS-200475,  SQ-200475, エンテカビル, 





STR2 str3



ChemSpider 2D Image | Glimepiride | C24H34N4O5S




  • Molecular FormulaC24H34N4O5S
  • Average mass490.616 Da
  • HOE 490
3-Ethyl-N-{2-[4-({(E)-hydroxy[(trans-4-methylcyclohexyl)imino]methyl}sulfamoyl)phenyl]ethyl}-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboximidic acid
93479-97-1 [RN]
1H-Pyrrole-1-carboxamide, 3-ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-
Amarel [Trade name]
Amaryl [Trade name]
Endial [Trade name]

Glimepiride (original trade name Amaryl) is an orally available medium-to-long-acting sulfonylurea antidiabetic drug. It is sometimes classified as either the first third-generation sulfonylurea,[1] or as second-generation.[2]

Glimepiride is a Sulfonylurea. The chemical classification of glimepiride is Sulfonylurea Compounds.

Glimepiride is a long-acting, third-generation sulfonylurea with hypoglycemic activity. Compared to other generations of sulfonylurea compounds, glimepiride is very potent and has a longer duration of action. This agent is metabolized by CYP2C9 and shows peroxisome proliferator-activated receptor gamma (PPARgamma) agonistic activity.

Glimepiride is only found in individuals that have used or taken this drug. It is the first III generation sulphonyl urea it is a very potent sulphonyl urea with long duration of action. The mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Glimepiride likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin.


Glimepiride is indicated to treat type 2 diabetes mellitus; its mode of action is to increase insulin production by the pancreas. It is not used for type 1 diabetes because in type 1 diabetes the pancreas is not able to produce insulin.[3]


Its use is contraindicated in patients with hypersensitivity to glimepiride or other sulfonylureas.

Adverse effects

Side effects from taking glimepiride include gastrointestinal tract (GI) disturbances, occasional allergic reactions, and rarely blood production disorders including thrombocytopenialeukopenia, and hemolytic anemia. In the initial weeks of treatment, the risk of hypoglycemia may be increased. Alcohol consumption and exposure to sunlight should be restricted because they can worsen side effects.[3]


Two generic oral tablets of glimepiride, 2 mg each

Gastrointestinal absorption is complete, with no interference from meals. Significant absorption can occur within one hour, and distribution is throughout the body, 99.5% bound to plasma protein. Metabolism is by oxidative biotransformation, it is hepatic and complete. First, the medication is metabolized to M1 metabolite by CYP2C9. M1possesses about ​13 of pharmacological activity of glimepiride, yet it is unknown if this results in clinically meaningful effect on blood glucose. M1 is further metabolized to M2metabolite by cytosolic enzymes. M2 is pharmacologically inactive. Excretion in the urine is about 65%, and the remainder is excreted in the feces.

Mechanism of action

Like all sulfonylureas, glimepiride acts as an insulin secretagogue.[4] It lowers blood sugar by stimulating the release of insulin by pancreatic beta cells and by inducing increased activity of intracellular insulin receptors.

Not all secondary sufonylureas have the same risks of hypoglycemia. Glibenclamide (glyburide) is associated with an incidence of hypoglycemia of up to 20–30%, compared to as low as 2% to 4% with glimepiride. Glibenclamide also interferes with the normal homeostatic suppression of insulin secretion in reaction to hypoglycemia, whereas glimepiride does not. Also, glibenclamide diminishes glucagon secretion in reaction to hypoglycemia, whereas glimepiride does not.[5]

Image result for SYNTHESIS Glimepiride

Image result for SYNTHESIS Glimepiride


Nonsteroidal anti-inflammatory drugs (such as salicylates), sulfonamideschloramphenicolcoumadin and probenecid may potentiate the hypoglycemic action of glimepiride. Thiazides, other diuretics, phothiazides, thyroid products, oral contraceptives, and phenytoin tend to produce hyperglycemia.



EP 0031058; US 4379785, Arzneim-Forsch Drug Res 1988,38(8),1079

The condensation of 3-ethyl-4-methyl-3-pyrrolin-2-one (I) with 2-phenylethyl isocyanate (II) at 150 C gives 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-3-pyrrolin-1-carboxamide (III), which is sulfonated with chlorosulfonic acid at 40 C to yield the corresponding benzenesulfonyl chloride (IV). The reaction of (IV) with concentrated NH4OH affords the sulfonamide (V), which is finally condensed with 4-methylcyclohexyl isocyanate (VI) in acetone.


Image result for SYNTHESIS Glimepiride


Image result for SYNTHESIS Glimepiride

Following is one of the synthesis routes: 3-Ethyl-4-methyl-3-pyrrolin-2-one could be condensed (I) with 2-phenylethyl isocyanate (II) at 150 C to produce 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-3-pyrrolin-1-carboxamide (III), which is sulfonated with chlorosulfonic acid at 40 C to yield the corresponding benzenesulfonyl chloride (IV). The reaction of (IV) with concentrated NH4OH affords the sulfonamide (V), which is finally condensed with 4-methylcyclohexyl isocyanate (VI) in acetone.


Image result for SYNTHESIS Glimepiride


Image result for SYNTHESIS Glimepiride


  • Glimepiride, according to U.S. Pat. No. 4,379,785 (EP 031058) issued to Hoechst is prepared via reaction of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (IV) with trans-4-methylcyclohexyl isocyanate (VIII). U.S. Pat. No. 4,379,785 (EP 031058) (hereafter referred to as the ‘785 patent) discloses heterocyclic substituted sulfonyl ureas, particularly 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methyl cyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide i.e. Glimepiride (I). The ‘785 patent teaches the preparation of Glimepiride starting from 3-Ethyl-4-methyl-3-pyrolidine-2-one (II) and 2-phenyl ethyl isocyanate to give [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene (III). The [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene is converted to the 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (IV), by reacting with chlorosulphonic acid, followed by treatment with ammonia solution. This intermediate compound (IV) is then finally reacted with trans-4-methylcyclohexyl isocyanate (VIII) prepared from trans-4-methyl cyclohexylamine HCl (VII) to form Glimepiride.
  • [0004]
    Glimepiride can also be synthesized by reaction of N-[[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]phenyl]sulphonyl]methylurethane (IX) with trans-4-methyl cyclohexyl amine (VII) as reported by R. Weyer, V. Hitzel in Arzneimittel Forsch 38, 1079 (1988).
  • [0005]
    trans-4Methylcyclohexyl isocyanate (VIII) is prepared from trans-4-methyl cyclohexyl amine HCl (VII), by phosgenation.
  • [0006]
    H. Ueda et. al., S.T.P Pharma Sciences, 13(4) 281-286, 2003 discloses a novel polymorph of Glimepiride, Form II obtained by recrystallisation from a solvent mixture of ethanol and water. It also discloses that earlier known form is Form I. Reported solvents for obtaining Form I are methanol, acetonitrile, chloroform, butyl acetate, benzene and toluene.
  • [0007]
    An alternative route is disclosed in WO03057131(Sun Pharmaceutical), where 3-ethyl-4-methyl-2,5-dihydro-N-(4-nitrophenyloxycarbonyl)-pyrrole-2-one is treated with 4-(2-aminoethyl)-benzene sulphonamide to obtain 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (IV) which was then converted to Glimepiride (I). However, nonavailability of raw material and the yield being poor, the process as described in U.S. Pat. No. 4,379,785 is preferred.
  • [0008]
    To obtain Glimepiride of highest purity, following intermediates should be of highest quality:
  • [0009]
    a) 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (IV) with lowest possible content of ortho and meta isomers.
  • [0010]
    b) Trans-4-methyl cyclohexyl amine (VII) and its respective isocyanate (VIII) should have lowest content of the cis isomer.
  • [0011]
    The preparation of the 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide is well disclosed in the patent U.S. Pat. No. 4,379,785. It is prepared by condensation of 3-ethyl-4-methyl-3-pyrrolidine-2-one of Formula (II) with 2-phenyl ethyl isocyanate. The condensed product is then chlorosulphonated with chlorosulphonic acid followed by ammonolysis with liq. ammonia to give compound of Formula (IV). The purity is not well documented in the patents, and by following the patented process, ˜85 to 88% of desired para isomer is obtained. This is evident as the chlorosulphonation is ortho-para directing.
  • [0012]
    Hence, there is a need to develop purification process to maintain undesired ortho and meta isomers below 0.1%.
  • [0013]
    The other key intermediate trans-4-methylcyclohexyl amine HCl (VII) should preferably have lowest possible content of the cis isomer. The commonly used procedure is reduction of 4-methyl cyclohexanone oxime (V) with sodium in alcohol, preferably ethanol.
  • [0014]
    T. P. Johnston, et. al., J. Med. Chem., 14, 600-614 (1971); H. Booth, et. al., J. Chem. Soc (B) 1971, 1047-1050 and K. Ramalingam et. al., Indian Journal of Chem Vol. 40, 366-369 (April 1972) all report the abovementioned reduction. The amine obtained via this process typically contains between 8 to 10% of the cis isomer. However, use of high excess sodium metal (25 eqv.) for reduction makes process commercially and environmentally unviable. Also, the purification of trans amine from the mixture via the distillation is very difficult as the boiling points differ only by about 2° C. Also there is an inherent drawback of said free amine as, it immediately forms carbonate salt. Further purification of the amine to reduce the cis content via crystallization of its salt is not sufficiently documented. Prior art describes purification of crude trans-4-methylcyclohexylamine HCl by crystallization of its hydrochloride but the yield and purity are not sufficiently discussed. A description of such purification is provided in J. Med. Chem, 14, 600-614 (1971), wherein trans-4-methylcyclohexylamine HCl is obtained by triple crystallization in acetonitrile of the crude hydrochloride (m.p. 260° C.) in 27% yield.
  • [0015]
    WO 2004073585 (Zentiva) describes a process for preparation of trans-4-methylcyclohexylamine HCl wherein the highlights of the invention are the use of sodium metal and purification via the pivalic acid salt. However drawbacks of the process are use of sodium metal, which is hazardous and pivalic acid which is expensive. The overall yield is ˜40%.
  • [0016]
    Thus considering the current stringent pharmacopieal requirements for cis content, there is a need for obtaining Glimepiride having cis impurity content well below 0.15% by a cost effective process.
  • [0017]
    Key factors in the production of Glimepiride are:
  • [0018]
    a) Substantial purity of trans-4-methyl cyclohexyl amine HCl (VII) with the lowest possible content of the cis isomer.
  • [0019]
    b) Substantial purity of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (IV) with the lowest possible content of the ortho and meta isomer.
  • [0020]
    The purity of intermediate compound of Formula (IV) when prepared by the process disclosed in ‘785 patent, was found to be 82 to 85% by HPLC.
    • schemes I to III.

      Figure US20070082943A1-20070412-C00001
      Figure US20070082943A1-20070412-C00002
      Figure US20070082943A1-20070412-C00003
    • [0037]
      The purification of trans-4-methyl cyclohexylamine HCl (VII) is accomplished by using an appropriate solvent combination. The mixture of cis/ trans stereoisomers (i.e. 50:50) were dissolved in diluted methanol and the desired trans isomer is coprecipitated by adding acetone to it. The process is repeated with different proportions of the solvent mixture to get the trans-4-Methyl cyclohexylamine HCl (VII) >99.5% with cis isomer less than 0.15%. The overall yield from 4-methyl cyclohexanone is ˜30%. The purification has been achieved using a solvent mixture of alcohol and ketone. A preferred alcohol for dissolution is an aliphatic one wherein carbon chain may be preferably C1-C4. Preferably methanol is used to dissolve the crude trans-4-Methyl cyclohexylamine HCl. The ratio of substrate:methanol:acetone is fixed at 1:1.5:6 for achieving the desired purity. The cosolvent used for precipitation is an aliphatic ketone. The preferred ketone is acetone. The precipitation is carried out at a temperature between 20 to 50° C., preferably between 30 to 50° C. and most preferably at about 40° C. The addition of acetone is carried out over a period of 2 to 6 hrs, more preferably for about 2 to 4 hrs and most preferably in about 3 hrs. The compound thus obtained has a purity >95% by gas chromatography.
    • [0038]
      The enriched trans-4-Methyl cyclohexylamine HCl (VII) (>95%) is further purified using different proportions of the same solvent mixture. The enriched trans isomer is dissolved in alcohol and reprecipitated using an aliphatic ketone. The ratio of substrate:methanol:acetone ratio is fixed at 1:1.5:13.6 for obtaining purity greater than 99.8%.

Image result for SYNTHESIS Glimepiride

    • EXAMPLE 1trans-4-Methyl cyclohexylamine HCl (VII)

    • [0053]
      1.5 Kg of crude 4-Methyl cyclohexyloxime (V) was dissolved in 8.33 L Methanol. To this 0.15 Kg Raney nickel was added. Then the mixture was hydrogenated at 4-5 Kg/cmpressure at 50 to 55° C. After the absorption of Hceases, the reaction mass is cooled down and filtered. From resulting reaction mixture, methanol was distilled completely. Crude concentrated oil obtained is cooled to 15 to 20° C. to which methanolic hydrochloric acid (12 to 13%) is added slowly, when the product i.e. 4-Methylcyclohexylamine HCl precipitates out. The yield obtained 1.5 Kg of crude 4-methyl cyclohexylamine HCl (85%) with ˜50% content of trans isomer. The crude 4-Methyl cyclohexylamine HCl 1.5 Kg (wet) was further purified in methanol/acetone mixture. The crude 4-methyl cyclohexylamine HCl (1.5 Kg) was dissolved in 2.25 L of methanol at 25 to 30° C. Slowly started addition of 13.5 L of acetone over a period of 3 hrs. The trans-4-methyl cyclohexylamine HCl precipitated out. Yield 0.6 Kg. The purity achieved of trans isomer is >95%. The cis isomer at this stage is ˜2 to 3%.
    • [0054]
      The trans-4-methyl cyclohexylamine HCl (0.6 Kg) thus obtained is again taken in 0.9 L of methanol and is dissolved completely at 25 to 30° C. 8.1 L acetone is added slowly over a period of 3 hrs when pure trans isomer precipitates out completely. The purity achieved at this stage is >99.8% and cis isomer well below 0.15%. The yield thus obtained after the second purification is 0.48 Kg of trans-4-Methyl cyclohexylamine HCl (27.2% yield calculated on the starting oxime). Purity of the desired trans isomer is greater than 99.8% by G.C.
    • [0055]
      Melting point of the trans-4-methyl cyclohexylamine HCl thus obtained is 262° C. to 263° C.

EXAMPLE 2Preparation of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (IV)

    • [0056]
      3-Ethyl-4-methyl-2,5-dihydro-1H-pyrrole-2-one (II) (1.0 Kg) and β-phenylethyl isocyanate (1.488 Kg) were mixed in anhydrous toluene (4.0 L) and refluxed for 4 hrs. The toluene was distilled off and hexane (8.0 L) was added to the reaction mixture at 50° C. The product precipitated is cooled to 0 to 5° C. to obtain the solid compound viz. 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene (2.17 Kg). It was filtered & washed with 2.0 L of hexane.
    • [0057]
      To a cooled (15 to 25° C.) solution of chlorosulfonic acid (2.8 L), 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene (2.0 Kg) was added in small portions over a period of 2 to 3 hrs. Further it was stirred for 30 min at this temperature and then temperature was gradually raised to 30 to 35° C. The reaction mass is stirred further for 2 hrs. The reaction mixture was then quenched into ice-water and stirred for 1 hr and filtered to obtain the product 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene sulfonyl chloride (2.0 kg). To a cooled (15 to 20° C.) solution of diluted ammonia (1.4 L) 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonyl chloride was added in small portion over 1 to 2 hrs. The reaction mixture was then heated to 70° C. for 2 hrs when ammonolysis is complete. The product converted is then stirred for 1 hr at R.T. and filtered and dried at 90 to 100° C. to obtain crude 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (2.2 Kg) having HPLC purity in the range of 82 to 88%. The crude compound 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (2.2 Kg) is then purified from mixture of organic solvents chosen from Methanol, Acetone & toluene.

EXAMPLE 3APurification of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene sulfonamide (IV)

    • [0058]
      1st Purification
    • [0059]
      In a reaction vessel containing Toluene (12.0 L), 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (2.0 Kg) was charged at 25 to 30° C. Slowly the temperature was raised to 60 to 65° C. and methanol (5.0 L) was added via the dosing tank slowly when the product dissolved completely. Refluxed it for 0.5 hr. Charcoalised and filtered the product in another reaction vessel. Distill off toluene/methanol mixture till total recovery about 65% under vacuum. White crystalline product precipitated out. After the recovery, cool the reaction mass to 15 to 20° C. The resulting crystallized solid product was filtered and washed two times with chilled acetone (about 2 L) each. The resulting product was dried at 90 to 100° C. in air oven till constant weight to obtain about 1.4 Kg of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene sulfonamide with greater than 95% HPLC purity.

EXAMPLE 3BPurification of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene sulfonamide (IV)

    • [0060]
      2nd Purification
    • [0061]
      In a reaction vessel containing Acetone (8.4 L), (1.4 Kg) of 1st purified 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene sulfonamide was charged at 25 to 30° C. slowly and the temperature was raised to 55 to 60° C. Methanol was added (5.6 L) via the dose tank at this reflux temperature to dissolve it completely. Refluxed it for further 30 min. Distilled off acetone/ methanol mixture till total recovery about 65 to 70%. White crystalline product precipitated out. After the recovery slowly cooled the product to 15 to 20° C. The resultant solid product was filtered, washed two times with chilled acetone (1.4 L) each. The 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide was dried at 90 to 100° C. in air oven till constant weight to obtain about 1.12 Kg of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene sulfonamide (IV) with greater than 99.5% purity with other isomers i.e. ortho and meta well below 0.2% respectively.

EXAMPLE 4Preparation of 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methyl cyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1 H-pyrrole-1-carboxamide (I).

    • [0062]
      In a reaction vessel containing (24.2 L) Acetone, 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl] benzene sulfonamide (1.0 Kg) and potassium carbonate (0.46 Kg) was added and refluxed at about 55 to 60° C. for 1 hr. trans-4-Methyl-cyclohexyl isocyanate was obtained by method known in art from trans-4-methyl-cyclohexylamine. A solution of trans-4-methyl-cyclohexyl isocyanate (0.515 Kg) in toluene (5 L) was prepared and added to the above reaction mixture. This reaction mixture is refluxed for 12 hrs, then cooled. To this cooled reaction mass charge 27 L of water. The reaction mass was filtered and the pH was adjusted to 5.5 to 6.0 by adding acetic acid at about 20 to 25° C. The solid obtained was filtered and washed with water. The 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methyl cyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide (I) obtained is then dried at 90 to 100° C. till constant weight. Yield of the product is 86.3%.

EXAMPLE 5Purification of 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methyl cyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide (I)

  • [0063]
    In a reaction vessel containing 6.0 L methanol and 1.0 Kg crude Glimepiride, dry ammonia gas was purged at 20 to 25° C. till all Glimepiride dissolves and a clear solution is obtained. This homogeneous mass was then charcoalised, filtered and finally neutralized with Glacial acetic acid to pH 5.5 to 6.0, till the entire product precipitates out. The pure Glimepiride was then filtered and dried at 65° C. to 70° C. till constant weight. Yield obtained was ˜90%.


  • Journal of Pharmaceutical Sciences 100(11):4700-9
  • DOI
  • 10.1002/jps.22662

Image result for GLIMEPIRIDE NMR

Magnified 1H NMR spectra of (a) glimepiride and its solid dispersions with hyperbranched polymers containing the (b) hydroxyl and (c) the tertiary amino functional groups.

Magnified 13C NMR spectra of (a) glimepiride and its solid dispersions with hyperbranched polymers containing (b) the hydroxyl and (c) the tertiary amino functional groups.

The difference spectra of the solid dispersions of glimepiride and the hyperbranched polymer containing (a) the hydroxyl groups and (b) the tertiary amino groups. The difference spectra were obtained by subtraction of the spectra of the pure hyperbranched polymers from the spectra of the solid dispersions. The ATR spectra of the pure hyperbranched polymers were recorded on samples that were prepared under the same conditions as solid dispersions, only without the presence of the glimepiride drug.


  1. US6150383
  2. US6211205
  3. US6303640
  4. US6329404
  5. US8071130
  6. US7538125
  7. US7700128
  8. US7358366

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID)
Patent 7358366
Expiration Apr 19, 2020. 7358366*PED expiration date: Oct 19, 2020
Applicant SB PHARMCO
Drug Application
  1. N021700 (Prescription Drug: AVANDARYL. Ingredients: GLIMEPIRIDE
FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID)
Patent 8071130
Expiration Jun 8, 2028
Drug Application
  1. N021925 (Prescription Drug: DUETACT. Ingredients: GLIMEPIRIDE
  3. N021925 (Prescription Drug: DUETACT. Ingredients: GLIMEPIRIDE
FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID)
Patent 7700128
Expiration Jan 30, 2027
Drug Application
  1. N021925 (Prescription Drug: DUETACT. Ingredients: GLIMEPIRIDE
  3. N021925 (Prescription Drug: DUETACT. Ingredients: GLIMEPIRIDE



Journal of  China Pharmaceutical University       1999 , 30(3):163 ~ 165

Ethyl acetoacetate (2) Preparation of literature more, such as with ethyl iodide or ethyl bromide as ethyl reagents will produce a double ethylation or oxyethylation, it is difficult to separate. We use dimethylamine and ethyl acetoacetate reaction enamine, then diethyl sulfate as ethylating agent, you can reduce the side reactions, product purity, the yield up to 80%. Preparation of cyanohydrin (3) Hydrochloric acid anhydrous literature, toxicity, difficult to operate, we use solid sodium cyanide and sodium bisulfite in the aqueous phase reaction, get 3, easy to operate. In the literature 1-acetyl-3- Ethyl-4-methyl-3-pyrrolin-2-one (4) was purified by high vacuum distillation and then hydrolyzed to give 3-ethyl- In the distillation of the product easy to loss, after the change to the crude hydrolysis, two-step yield of 33%. Reported in the literature 5 and phenethyl isocyanate (6) without solvent direct reaction of 3-ethyl-4-methyl-2-oxo-3-pyrroline-1 – N- (2 – phenethyl) A Amide (7), the experiment found that the reaction heat when the heating easy to red material, we add toluene as a solvent, the reaction is smooth, easy to post-treatment. 6 preparation, the general method is to use phosgene, but phosgene often Temperature of gas, highly toxic, difficult to operate, we use triphosgene instead of triphosgene as a yellow solid, easy to transport, weighing, laboratory convenience. We refer to the process of domestic glyburide, 7 chlorosulfonated, ammoniated sulfonamide (9), two-step yield of 77%. The last 9 reacts with trans-4-methylcyclohexylisocyanate to form glimepiride (1). Ethyl acetoacetate as the starting material, eight-step total yield of 11.5%.

Journal of  China Pharmaceutical University       1999 , 30(3):163 ~ 165

Glimepi ride (1) trade name Amary l, chemical name 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido ) Ethyl] phenylsulfonyl] -3- (trans-4-methylcyclohexyl) urea, a new sulfonylurea hypoglycemic agent developed by Hoechst AG in Germany and listed in the Netherlands and Switzerland in 1995, In 1996 the United States FDA approval

  • 1 Campbell RK.Glimepiride :Role  of  a  new   sulfonylurea  in  the t reatment of type 2  diabetes mellitus .An n Pharmacother ,  1998 , 32 :1044
  • 2 Hans P ,   Joachim  K .Synt hesis  of  oxyopsopy rrolecarboxyli c acid

and  further  investigations  in  the  pyrrolone  series.Ann  Chem ,

1964 , 680 :60

  • 3 Glimepiride.Dr ugs F ut , 1992 , 17(9):774
  • 4 Corson BB,   Dodge  RA ,   Harris  SA ,   et  al .M andeli c acid.Org Syn ,  1941 ,   Coll Vol 1 :329
  • 5 M aurice WG ,  Roy  VD,   Brian  I ,   et  a l .A new  synt hesis  of iso- cyanates .J  Chem Soc ,  Perkin  Ⅰ ,  1976 :141
  • 6 天津医药工业研究所.糖尿病药物-优降糖的新合成法.医药工业, 1974 , 4 :11
  • 7 Weyer R, Gei sen K , Hitzel V ,   et  al .Heterocyclic subst ituted sul- f onyl ureas and their  use .Ger O f fen ,  1979 :2951135 A 1
Cited Patent Filing date Publication date Applicant Title
US4379785 * Dec 17, 1980 Apr 12, 1983 Hoechst Aktiengesellschaft Heterocyclic substituted sulfonyl ureas, and their use


  1. Jump up^ Hamaguchi T, Hirose T, Asakawa H, et al. (December 2004). “Efficacy of glimepiride in type 2 diabetic patients treated with glibenclamide”. Diabetes Res. Clin. Pract. 66 Suppl 1: S129–32. doi:10.1016/j.diabres.2003.12.012PMID 15563963.
  2. Jump up^ Davis SN (2004). “The role of glimepiride in the effective management of Type 2 diabetes”. J. Diabetes Complicat18 (6): 367–76. doi:10.1016/j.jdiacomp.2004.07.001PMID 15531188.
  3. Jump up to:a b “Glimepiride: MedlinePlus Drug Information”
  4. Jump up^ Nissen SE, Nicholls SJ, Wolski K, et al. (April 2008). “Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial”. JAMA299 (13): 1561–73. doi:10.1001/jama.299.13.1561PMID 18378631.
  5. Jump up^ Davis, Stephen N. (2005). “60. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas”. In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. p. 1636. ISBN 0-07-142280-3.

External links

Title: Glimepiride
CAS Registry Number: 93479-97-1
CAS Name: 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide
Additional Names: N-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]-benzenesulfonyl]-N¢-4-methylcyclohexylurea; 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenylsulfonyl]-3-(4-methylcyclohexyl)urea
Manufacturers’ Codes: HOE-490
Trademarks: Amaryl (Aventis)
Molecular Formula: C24H34N4O5S
Molecular Weight: 490.62
Percent Composition: C 58.75%, H 6.99%, N 11.42%, O 16.31%, S 6.54%
Literature References: Sulfonylurea. Prepn: R. Weyer et al., DE 2951135eidem, US 4379785 (1981, 1983 both to Hoechst). Synthesis: R. Weyer, V. Hitzel, Arzneim.-Forsch. 38, 1079 (1988). Pharmacology: K. Geisen, ibid., 1120. Effects on insulin and glucagon secretion: V. Leclercq-Meyer et al., Biochem. Pharmacol. 42, 1634 (1991). HPLC determn in biological fluids: K. H. Lehr, P. Damm, J. Chromatogr. 526, 497 (1990). Clinical pharmacokinetics: K. Ratheiser et al., Arzneim.-Forsch. 43, 856 (1993). Toxicity study: U. Schollmeier et al., ibid. 1038. Series of articles on pharmacology and clinical efficacy: Diabetes Res. Clin. Pract. 28Suppl., S115-S149 (1995).
Properties: mp 207°.
Melting point: mp 207°
Therap-Cat: Antidiabetic.
Keywords: Antidiabetic; Sulfonylurea Derivatives.
Clinical data
Trade names Amaryl
AHFS/ Monograph
MedlinePlus a696016
License data
  • US: C (Risk not ruled out)
Routes of
Oral (tablets)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100%
Protein binding >99.5%
Metabolism Complete hepatic (1st stage through CYP2C9)
Biological half-life 5–8 hours
Excretion Urine (~60%), feces (~40%)
CAS Number
PubChem CID
ECHA InfoCard 100.170.771
Chemical and physical data
Formula C24H34N4O5S
Molar mass 490.617 g/mol
3D model (JSmol)

///////////Amaryl, glimepiride, glymepiride, HOE 490



Skeletal formula of triethylenetetramine


  • Molecular Formula C6H18N4
  • Average mass 146.234 Da

112-24-3 CAS

曲恩汀, KD-034, MK-0681, MK-681, TECZA, TETA, TJA-250

1,2-Ethanediamine, N1,N2-bis(2-aminoethyl)-
Image result for TRIENTINE


  • Molecular Formula C6H19ClN4
  • Average mass 182.695 Da

38260-01-4 CAS


Image result for MSD

Image result for VALEANT

Trientine Hydrochloride

C6H18N4▪2HCl : 219.16

Aton Pharma, a subsidiary of Valeant Pharmaceuticals, has developed and launched Syprine, a capsule formulation of trientine hydrochloride, for treating Wilson disease.

Image result for TRIENTINE

Triethylenetetramine, abbreviated TETA and trien and also called trientine (INN), is an organic compound with the formula [CH2NHCH2CH2NH2]2. This oily liquid is colorless but, like many amines, assumes a yellowish color due to impurities resulting from air-oxidation. It is soluble in polar solvents. The branched isomer tris(2-aminoethyl)amine and piperazine derivatives may also be present in commercial samples of TETA.[1]

Trientine hydrochloride is a metal antagonist that was first launched by Merck, Sharp & Dohme in the U.S. in 1986 under the brand name Syprine for the oral treatment of Wilson’s disease.

Orphan drug designation has also been assigned in the U.S. for the treatment of patients with Wilson’s disease who are intolerant or inadequately responsive to penicillamine and in the E.U. by Univar for the treatment of Wilson’s disease

 Trientine hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=90373

By condensation of ethylenediamine (I) with 1,2-dichloroethane (II)

Trientine hydrochloride is N,N’-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether.

The empirical formula is C6H18N4·2HCI with a molecular weight of 219.2. The structural formula is:


Trientine hydrochloride is a chelating compound for removal of excess copper from the body. SYPRINE (Trientine Hydrochloride) is available as 250 mg capsules for oral administration. Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.

Image result for TRIENTINE


TETA is prepared by heating ethylenediamine or ethanolamine/ammonia mixtures over an oxide catalyst. This process gives a variety of amines, which are separated by distillation and sublimation.[2]


The reactivity and uses of TETA are similar to those for the related polyamines ethylenediamine and diethylenetriamine. It was primarily used as a crosslinker (“hardener”) in epoxy curing.[2]

The hydrochloride salt of TETA, referred to as trientine hydrochloride, is a chelating agent that is used to bind and remove copper in the body to treat Wilson’s disease, particularly in those who are intolerant to penicillamine. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.[3]

Coordination chemistry

TETA is a tetradentate ligand in coordination chemistry, where it is referred to as trien.[4] Octahedral complexes of the type M(trien)Cl3 can adopt several diastereomeric structures, most of which are chiral.[5]

Trientine, chemically known as triethylenetetramine or N,N’-bis(2-aminoethyl)-l,2-ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson’s disease.

Image result for TRIENTINE

Trientine dihydrochloride (1)

Trientine dihydrochloride formulation, developed by Aton with the proprietary name SYPRINE, was approved by USFDA on November 8, 1985 for the treatment of patients with Wilson’s disease, who are intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer’s disease and cancer.

Various synthetic methods for preparation of triethylenetetramine (TETA) and the corresponding dihydrochloride salt have been disclosed in the prior art.

U.S. 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using Titania supported phosphorous catalyst while U.S. 4,550,209 and U.S. 5,225,599 disclose catalytic condensation of ethylenediamine and ethylene glycol for the synthesis of linear triethylenetetramine using catalysts like zirconium trimethylene diphosphonate, or metatungstate composites of titanium dioxide and zirconium dioxide.

U.S. 4,503,253 discloses the preparation of triethylenetetramine by reaction of an alkanolamine compound with ammonia and an alkyleneamine having two primary amino groups in the presence of a catalyst, such as supported phosphoric acid wherein the support is comprised of silica, alumina or carbon.

The methods described above for preparation of triethylenetetramine require high temperatures and pressure. Further, due to the various possible side reactions and consequent associated impurities, it is difficult to control the purity of the desired amine.

CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of Ν,Ν’-dibenzyl-,N,N’-bis[2-(l,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N’-dibenzyl-,N,N’-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N’-dibenzyl-,N,N’-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.

CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetrahydrochlonde salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetrahydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetrahydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.

The process is quite circuitous and cumbersome, requiring use of strong bases, filtration of sodium chloride and results in yields as low as 60%.

US 8,394,992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetrahydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetrahydrochloride salt with a strong base like sodium alkoxide to produce the amine free base (TETA) and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether (TBME), followed by removal of sodium chloride salt and finally the amine free base TETA is treated with hydrochloric acid in solvent ethanol to give trientine hydrochloride salt.





Example 1: Preparation of 2-([2-[cyanomethyl]-t-butyloxycarbonylamino]ethyl- 1-butyloxy carbonylamino)acetonitrile (5)

Potassium carbonate (481.9 g) was added to a stirred mixture of ethylenediamine (100.0 g) in acetonitrile (800 ml) and cooled to around 10°C. Chloroacetonitrile (263.8 g) was gradually added at same temperature and stirred at 25-30°C, till completion of the reaction, as monitored by HPLC. The mixture was cooled to 5-15°C and Boc-anhydride (762. lg) was added to it, followed by stirring at the same temperature. The temperature was raised to 25-30°C and the mass was stirred till completion of the reaction, as monitored by HPLC.

The reaction mass was filtered and the filtrate was concentrated. Toluene was added to the residue, and the mixture was heated to around 70°C followed by cooling and filtration to give 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino) acetonitrile (5).

Yield: 506.8 g

% Yield: 89.9 %

Example 2: Preparation of t-butyl( N-2-aminoethyl)N-([2-[(2-aminoethyl)t-butyloxy)carbonylamino] ethyl) carbamate (6)

Raney nickel (120.0 g) in isopropanol (100 ml) was charged into an autoclave, followed by a mixture of Compound 5 (200 g) in isopropanol (400 ml). Cooled ammonia solution prepared by purging ammonia gas in 1400 ml isopropanol, equivalent to 125 g ammonia was gradually charged to the autoclave and the reaction was carried out around 15-25°C under hydrogen pressure of 2-5 Kg/cm2.

After completion of the reaction, as monitored by HPLC, the mass was filtered, concentrated, and methyl tertiary butyl ether was added to the residue. The mixture was heated to around 50°C, followed by cooling of the mass, stirring, optional seeding with compound 6 and filtration to give tertiary butyl-(N-2-aminoethyl)N-([2-[(2-aminoethyl)-(tert-butyloxy) carbonylamino] ethyl) carbamate.

Yield: 174 g

%Yield: 85 %

Example 3: Preparation of triethylenetetramine dihydrochloride (1)

Concentrated hydrochloric acid (121.5 g) was gradually added to a stirred mixture of tertiary-butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy) carbonyl] amino] ethyl} carbamate (Compound 6, 200.0 g) and water (1400 ml) at 20-30°C. The reaction mixture was heated in the temperature range of 100-105°C till completion of the reaction, as monitored by HPLC, with optionally distilling out water, if so required.

The reaction mass was concentrated and ethanol (600 ml) was added to the residue, followed by heating till a clear solution was obtained. The reaction mixture was gradually cooled with stirring, filtered and dried to provide triethylenetetramine dihydrochloride (1).

Yield: 88.9 g, (70 %)

Purity : > 99%


Trientine was said to be used in the synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine in French Patent No. FR2810035 to Guilard et al. Cetinkaya, E., et al., “Synthesis and characterization of unusual tetraminoalkenes,” J. Chem. Soc. 5:561-7 (1992), is said to be directed to synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine from trientine, as is Araki T., et al., “Site-selective derivatization of oligoethyleneimines using five-membered-ring protection method,” Macromol., 21:1995-2001 (1988). Triethylenetetramine may reportedly also be used in the synthesis of N-methylated triethylenetetramine, as reported in U.S. Pat. No. 2,390,766, to Zellhoefer et al.

Synthesis of polyethylenepolyamines, including triethylenetetramines, from ethylenediamine and monoethanolamine using pelleted group IVb metal oxide-phosphate type catalysts was reported by Vanderpool et al. in U.S. Pat. No. 4,806,517. Synthesis of triethylenetetramine from ethylenediamine and ethanolamine was also proposed in U.S. Pat. No. 4,550,209, to Unvert et al. U.S. Pat. No. 5,225,599, to King et al. is said to be directed to the synthesis of linear triethylene tetramine by condensation of ethylenediamine and ethylene glycol in the presence of a catalyst. Joint production of triethylenetetramine and 1-(2-aminoethyl)-aminoethyl-piperazine was proposed by Borisenko et al. in U.S.S.R. Patent No. SU1541204. U.S. Pat. No. 4,766,247 and European Patent No. EP262562, both to Ford et al., reported the preparation of triethylenetetramine by reaction of an alkanolamine compound, an alkaline amine and optionally either a primary or secondary amine in the presence of a phosphorous containing catalyst, for example phosphoric acid on silica-alumina or Group IIIB metal acid phosphate, at a temperature from about 175° C. to 400° C. under pressure. These patents indicate that the synthetic method used therein was as set forth in U.S. Pat. No. 4,463,193, to Johnson. The Ford et al. ‘247 patent is also said to be directed to color reduction of polyamines by reaction at elevated temperature and pressure in the presence of a hydrogenation catalyst and a hydrogen atmosphere. European Patent No. EP450709 to King et al. is said to be directed to a process for the preparation of triethylenetetramine and N-(2-aminoethyl)ethanolamine by condensation of an alkylenamine and an alkylene glycol in the presence of a condensation catalyst and a catalyst promoter at a temperature in excess of 260° C.

Russian Patent No. RU2186761, to Zagidullin, proposed synthesis of diethylenetriamine by reaction of dichloroethane with ethylenediamine. Ethylenediamine has previously been said to have been used in the synthesis of N-carboxylic acid esters as reported in U.S. Pat. No. 1,527,868, to Hartmann et al.

Japanese Patent No. 06065161 to Hara et al. is said to be directed to the synthesis of polyethylenepolyamines by reacting ethylenediamine with ethanolamine in the presence of silica-treated Nb205 supported on a carrier. Japanese Patent No. JP03047154 to Watanabe et al., is said to be directed to production of noncyclic polyethylenepolyamines by reaction of ammonia with monoethanolamine and ethylenediamine. Production of non-cyclic polyethylenepolyamines by reaction of ethylenediamine and monoethanolamine in the presence of hydrogen or a phosphorous-containing substance was said to be reported in Japanese Patent No. JP03048644. Regenerative preparation of linear polyethylenepolyamines using a phosphorous-bonded catalyst was proposed in European Patent No. EP115,138, to Larkin et al.

A process for preparation of alkyleneamines in the presence of a niobium catalyst was said to be provided in European Patent No. 256,516, to Tsutsumi et al. U.S. Pat. No. 4,584,405, to Vanderpool, reported the continuous synthesis of essentially noncyclic polyethylenepolyamines by reaction of monoethanolamine with ethylenediamine in the presence of an activated carbon catalyst under a pressure between about 500 to about 3000 psig., and at a temperature of between about 200° C. to about 400° C. Templeton, et al., reported on the preparation of linear polyethylenepolyamides asserted to result from reactions employing silica-alumina catalysts in European Patent No. EP150,558.

Production of triethylenetetramine dihydrochloride was said to have been reported in Kuhr et al., Czech Patent No. 197,093, via conversion of triethylenetetramine to crystalline tetrahydrochloride and subsequently to triethylenetetramine dihydrochloride. “A study of efficient preparation of triethylenetetramine dihydrochloride for the treatment of Wilson’s disease and hygroscopicity of its capsule,” Fujito, et al., Yakuzaigaku, 50:402-8 (1990), is also said to be directed to production of triethylenetetramine.

Preparation of triethylenetetramine salts used for the treatment of Wilson’s disease was said to be reported in “Treatment of Wilson’s Disease with Triethylene Tetramine Hydrochloride (Trientine),” Dubois, et al., J. Pediatric Gastro. & Nutrition, 10:77-81 (1990); “Preparation of Triethylenetetramine Dihydrochloride for the Treatment of Wilson’s Disease,” Dixon, et al., Lancet, 1(1775):853 (1972); “Determination of Triethylenetetramine in Plasma of Patients by High-Performance Liquid Chromatography,” Miyazaki, et al., Chem. Pharm. Bull., 38(4):1035-1038 (1990); “Preparation of and Clinical Experiences with Trien for the Treatment of Wilson’s Disease in Absolute Intolerance of D-penicillamine,” Harders, et al., Proc. Roy. Soc. Med., 70:10-12 (1977); “Tetramine cupruretic agents: A comparison in dogs,” Allen, et al., Am. J. Vet. Res., 48(1):28-30 (1987); and “Potentiometric and Spectroscopic Study of the Equilibria in the Aqueous Copper(II)-3,6-Diazaoctane-1,8-diamine System,” Laurie, et al., J.C.S. Dalton, 1882 (1976).

Preparation of Triethylenetetramine Salts by Reaction of Alcohol Solutions of Amines and acids was said to be reported in Polish Patent No. 105793, to Witek. Preparation of triethylenetetramine salts was also asserted in “Polycondensation of polyethylene polyamines with aliphatic dicarboxylic acids,” Witek, et al., Polimery, 20(3):118-119 (1975).

Baganz, H., and Peissker, H., Chem. Ber., 1957; 90:2944-2949; Haydock, D. B., and Mulholland, T. P. C., J. Chem. Soc., 1971; 2389-2395; and Rehse, K., et al., Arch. Pharm., 1994; 393-398, report on Strecker syntheses. Use of Boc and other protecting groups has been described. See, for example, Spicer, J. A. et al., Bioorganic & Medicinal Chemistry, 2002; 10: 19-29; Klenke, B. and Gilbert, I. H., J. Org. Chem., 2001; 66: 2480-2483.

FIG. 6 shows an 1H-NMR spectrum of a triethylenetetramine hydrochloride salt in D2O, as synthesized in Example 3. NMR values include a frequency of 400.13 Mhz, a 1H nucleus, number of transients is 16, points count of 32768, pulse sequence of zg30, and sweep width of 8278.15 H

Image result for TRIENTINE


Method of purification: Dissolve Trientine Hydrochloride in water while warming, and recrystallize by addition of ethanol (99.5). Or dissolve Trientine Hydrochloride in water while warming, allow to stand after addition of activated charcoal in a cool and dark place for one night, and filter. To the filtrate add ethanol (99.5), allow to stand in a cool and dark place, and recrystallize. Dry the crystals under reduced pressure not exceeding 0.67 kPa at 409C until ethanol odor disappears.


  1.  “Ethyleneamines” (PDF). Huntsman. 2007.
  2. ^ Jump up to:a b Eller, K.; Henkes, E.; Rossbacher, R.; Höke, H. (2005). “Amines, Aliphatic”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001.
  3. Jump up^ Roberts, E. A.; Schilsky, M. L. (2003). “A practice guideline on Wilson disease” (pdf). Hepatology. 37 (6): 1475–1492. doi:10.1053/jhep.2003.50252. PMID 12774027.
  4. Jump up^ von Zelewsky, A. (1995). Stereochemistry of Coordination Compounds. Chichester: John Wiley. ISBN 047195599X.
  5.  Utsuno, S.; Sakai, Y.; Yoshikawa, Y.; Yamatera, H. (1985). “Three Isomers of the Trans-Diammine-[N,N′-bis(2-Aminoethyl)-1,2-Ethanediamine]-Cobalt(III) Complex Cation”. Inorganic Syntheses. 23: 79–82. doi:10.1002/9780470132548.ch16.
Skeletal formula of triethylenetetramine
Ball and stick model of triethylenetetramine
Spacefill model of triethylenetetramine
Other names

N,N’-Bis(2-aminoethyl)ethane-1,2-diamine; TETA; Trien; Trientine (INN); Syprine (brand name)
3D model (Jmol)
ECHA InfoCard 100.003.591
EC Number 203-950-6
MeSH Trientine
RTECS number YE6650000
UN number 2259
Molar mass 146.24 g·mol−1
Appearance Colorless liquid
Odor Fishy, ammoniacal
Density 982 mg mL−1
Melting point −34.6 °C; −30.4 °F; 238.5 K
Boiling point 266.6 °C; 511.8 °F; 539.7 K
log P 1.985
Vapor pressure <1 Pa (at 20 °C)
376 J K−1 mol−1 (at 60 °C)
A16AX12 (WHO)
GHS pictograms The corrosion pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) The exclamation-mark pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
GHS signal word DANGER
H312, H314, H317, H412
P273, P280, P305+351+338, P310
Corrosive C
R-phrases R21, R34, R43, R52/53
S-phrases (S1/2), S26, S36/37/39, S45
Flash point 129 °C (264 °F; 402 K)
Lethal dose or concentration (LD, LC):
  • 550 mg kg−1 (dermal, rabbit)
  • 2.5 g kg−1 (oral, rat)
Related compounds
Related amines
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////////TRIENTINE, 112-24-3, 曲恩汀 , KD-034 , MK-0681, MK-681, TECZA, TETA, TJA-250, Orphan drug


Calcifediol, カルシフェジオール

Skeletal formula of calcifediol



Ro 8-8892
U 32070E
(3S,5Z,7E,20R)-9,10-Secocholesta-5,7,10-trien-3,25-diol [German] [ACD/IUPAC Name]
(3S,5Z,7E,20R)-9,10-Secocholesta-5,7,10-triene-3,25-diol [ACD/IUPAC Name]
(3S,5Z,7E,20R)-9,10-Sécocholesta-5,7,10-triène-3,25-diol [French] [ACD/IUPAC Name]
19356-17-3 [RN]
1H-indene-1-pentanol, octahydro-4-[(2Z)-2-[(5S)-5-hydroxy-2-methylenecyclohexylidene]ethylidene]-a,a,e,7a-tetramethyl-, (eR,1R,3aS,4E,7aR)-
25-(OH)Vitamin D3
25-hydroxy Vitamin D3
25-hydroxyvitamin D
Molecular form.: C₂₇H₄₄O₂
Appearance: White to Off-White Solid
Melting Point: 75-93ºC
Mol. Weight: 400.64

Calcifediol (INN), also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D),[1] is a prehormone that is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme cholecalciferol 25-hydroxylase which was isolated by Michael F. Holick. Physicians worldwide measure this metabolite to determine a patient’s vitamin D status.[2] At a typical daily intake of vitamin D3, its full conversion to calcifediol takes approximately 7 days.[3]

Calcifediol is then converted in the kidneys (by the enzyme 25(OH)D-1α-hydroxylase) into calcitriol (1,25-(OH)2D3), a secosteroid hormone that is the active form of vitamin D. It can also be converted into 24-hydroxycalcidiol in the kidneys via 24-hydroxylation.[4][5]


Blood test

In medicine, a 25-hydroxy vitamin D (calcifediol) blood test is used to determine how much vitamin D is in the body.[6] The blood concentration of calcifediol is considered the best indicator of vitamin D status.[7]

This test can be used to diagnose vitamin D deficiency, and it is indicated in patients with high risk for vitamin D deficiency and when the results of the test would be used as supporting evidence for beginning aggressive therapies.[8] Patients with osteoporosis, chronic kidney disease, malabsorption, obesity, and some other infections may be high risk and thus have greater indication for this test.[8] Although vitamin D deficiency is common in some populations including those living at higher latitudes or with limited sun exposure, the 25(OH)D test is not indicated for entire populations.[8] Physicians may advise low risk patients to take over-the-counter vitamin D in place of having screening.[8]

It is the most sensitive measure,[9] though experts have called for improved standardization and reproducibility across different laboratories.[7] According to MedlinePlus, the normal range of calcifediol is 30.0 to 74.0 ng/mL.[6] The normal range varies widely depending on several factors, including age and geographic location. A broad reference range of 20–150 nmol/L (8-60 ng/ml) has also been suggested,[10] while other studies have defined levels below 80 nmol/L (32 ng/ml) as indicative of vitamin D deficiency.[11]

US labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L.

Clinical significance

Increasing calcifediol levels are associated with increasing fractional absorption of calcium from the gut up to levels of 80 nmol/L (32 ng/mL).[citation needed]Urinary calcium excretion balances intestinal calcium absorption and does not increase with calcifediol levels up to ~400 nmol/L (160 ng/mL).[12]

A study by Cedric F. Garland and Frank C. Garland of the University of California, San Diego analyzed the blood from 25,000 volunteers from Washington County, Maryland, finding that those with the highest levels of calcifediol had a risk of colon cancer that was one-fifth of typical rates.[13] However, randomized controlled trials failed to find a significant correlation between vitamin D supplementation and the risk of colon cancer.[14]

A 2012 registry study of the population of Copenhagen, Denmark, found a correlation between both low and high serum levels and increased mortality, with a level of 50–60 nmol/L being associated with the lowest mortality. The study did not show causation.[15][16]


Regioselective Hydroxylation in the Production of 25-Hydroxyvitamin D by Coprinopsis cinerea Peroxygenase
ChemCatChem (2015), 7, (2), 283-290

1H NMR 500 MHz, CDCl3: δ= 0.55 (3 H, s, 18-H), 0.94 (1H, d, J= 6.5 Hz, 21-H), 1.06 (1H, m, 22-H), 1.22 (3 H, s, 26-H), 1.22 (3 H, s, 27-H), 1.23 (1H, m, 23-H), 1.27 (1H, m, 16-H), 1.28 (1H, m, 14-H), 1.29 (1H, m, 12-H), 1.37 (1H, m, 22-H), 1.38 (1H, m, 20-H), 1.39 (1H, m, 24-H), 1.42 (1H, m, 23-H), 1.44 (1H, m, 24-H), 1.47 (2 H, m, 11-H), 1.53 (1H, m, 15-H), 1.66 (1H, m, 15-H), 1.67 (1H, m, 2-H), 1.67 (1H, m, 9-H), 1.87 (1H, m, 16-H), 1.92 (1H, m, 2-H), 1.98 (1H, m, 17-H), 2.06 (1H, m, 12-H), 2.17 (1H, m, 1-H), 2.40 (1H, m, 1-H), 2.57 (1H, dd, J= 3.7, 13.1Hz, 4-H), 2.82 (1H, m, 9-H), 3.95 (1H, bm, 3-H), 4.82 (1H, m, 19-H), 5.05 (1H, m, 19-H), 6.03 (1H, d, J=11.2 Hz, 7-H), 6.23 ppm (1H, d, J= 11.2 Hz, 6-H).

13 C NMR 500 MHz, CDCl3: δ = 12.2 (C-18), 19.0 (C-21), 21.0 (C-23), 22.4 (C-11), 23.7 (C-15), 27.8 (C-16), 29.2 (C-9), 29.4 (C-27), 29.5 (C-26), 32.1 (C-1), 35.3 (C-2), 36.3 (C-20), 36.6 (C-22), 40.7 (C-12), 44.6 (C-24), 46.0 (C-13), 46.1 (C-4), 56.5 (C-17), 56.7 (C-14), 69.4 (C-3), 71.3 (C-25), 112.6 (C-19), 117.7 (C-7), 122.2 (C-6), 135.2 (C-5), 142.4 (C-8), 145.3 ppm (C-10).


From Organic & Biomolecular Chemistry, 10(27), 5205-5211; 2012!divAbstract

An efficient, two-stage, continuous-flow synthesis of 1α,25-(OH)2-vitamin D3 (activated vitamin D3) and its analogues was achieved. The developed method afforded the desired products in satisfactory yields using a high-intensity and economical light source, i.e., a high-pressure mercury lamp. In addition, our method required neither intermediate purification nor high-dilution conditions.

Graphical abstract: Continuous-flow synthesis of activated vitamin D3 and its analogues

1H NMR(400 MHz, CDCl3): δ 8.13 (m, 2H), 7.68 (m, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 5.19 (m, 2H), 3.93 (dd, J = 12.7, 8.2, 1H), 3.88 (dd, J = 14.6, 4.9 Hz, 1H), 3.58 (m, 1H), 1.02 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.86 (s, 9H), 0.80-0.84 (m, 9H), 0.09 (s, 3H), 0.00 (s, 3H)

13C NMR  (100 MHz, CDCl3): δ 161.8, 159.6, 138.5, 135.3, 132.6, 132.5, 132.1, 130.6, 130.2, 128.7, 127.0, 126.5, 77.2, 68.5, 67.4, 67.1, 56.5, 50.6, 49.0, 44.2, 42.7, 40.4, 39.9, 39.3, 35.6, 34.7, 33.0, 30.5, 28.2, 25.9, 24.5, 21.9, 20.8, 19.9, 19.7, 18.5, 18.0, 17.4, 13.3, -4.4, -4.9

IR (neat): 2957, 2872, 1653, 1603, 1462, 1311, 1093, 837, 762 cm-1


Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]



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|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway]

Vitamin D Synthesis Pathway edit

  1. Jump up^ The interactive pathway map can be edited at WikiPathways: “VitaminDSynthesis_WP1531”.


  1. Jump up^ “Nomenclature of Vitamin D. Recommendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)” reproduced at the Queen Mary, University of London website. Retrieved 21 March 2010.
  2. Jump up^ Holick, MF; Deluca, HF; Avioli, LV (1972). “Isolation and identification of 25-hydroxycholecalciferol from human plasma”. Archives of Internal Medicine. 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID 4332591.
  3. Jump up^ Am J Clin Nutr 2008;87:1738–42 PMID 18541563
  4. Jump up^ Bender, David A.; Mayes, Peter A (2006). “Micronutrients: Vitamins & Minerals”. In Victor W. Rodwell; Murray, Robert F.; Harper, Harold W.; Granner, Darryl K.; Mayes, Peter A. Harper’s Illustrated Biochemistry. New York: Lange/McGraw-Hill. pp. 492–3. ISBN 0-07-146197-3. Retrieved December 10, 2008 through Google Book Search.
  5. Jump up^ Institute of Medicine (1997). “Vitamin D”. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, D.C: National Academy Press. p. 254. ISBN 0-309-06403-1.
  6. ^ Jump up to:a b “25-hydroxy vitamin D test: Medline Plus”. Retrieved 21 March 2010.
  7. ^ Jump up to:a b Heaney, Robert P (Dec 2004). “Functional indices of vitamin D status and ramifications of vitamin D deficiency”. American Journal of Clinical Nutrition. 80 (6): 1706S–9S. PMID 15585791.
  8. ^ Jump up to:a b c d American Society for Clinical Pathology, “Five Things Physicians and Patients Should Question”, Choosing Wisely: an initiative of the ABIM Foundation, American Society for Clinical Pathology, retrieved August 1, 2013, which cites
      • Sattar, N.; Welsh, P.; Panarelli, M.; Forouhi, N. G. (2012). “Increasing requests for vitamin D measurement: Costly, confusing, and without credibility”. The Lancet. 379 (9811): 95–96. doi:10.1016/S0140-6736(11)61816-3. PMID 22243814.
      • Bilinski, K. L.; Boyages, S. C. (2012). “The rising cost of vitamin D testing in Australia: Time to establish guidelines for testing”. The Medical Journal of Australia. 197 (2): 90. doi:10.5694/mja12.10561. PMID 22794049.
      • Lu, Chuanyi M. (May 2012). “Pathology consultation on vitamin D testing: Clinical indications for 25(OH) vitamin D measurement [Letter to the editor]”. American Journal Clinical Pathology. American Society for Clinical Pathology (137): 831–832., which cites
        • Arya, S. C.; Agarwal, N. (2012). “Pathology Consultation on Vitamin D Testing: Clinical Indications for 25(OH) Vitamin D Measurement”. American Journal of Clinical Pathology. 137 (5): 832. doi:10.1309/AJCP2GP0GHKQRCOE. PMID 22523224.
      • Holick, M. F.; Binkley, N. C.; Bischoff-Ferrari, H. A.; Gordon, C. M.; Hanley, D. A.; Heaney, R. P.; Murad, M. H.; Weaver, C. M. (2011). “Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline”. Journal of Clinical Endocrinology & Metabolism. 96 (7): 1911–1930. doi:10.1210/jc.2011-0385. PMID 21646368.
  9. Jump up^ Institute of Medicine (1997), p. 259
  10. Jump up^ Bender, David A. (2003). “Vitamin D”. Nutritional biochemistry of the vitamins. Cambridge: Cambridge University Press. ISBN 0-521-80388-8. Retrieved December 10, 2008 through Google Book Search.
  11. Jump up^ Hollis BW (February 2005). “Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D”. J Nutr. 135 (2): 317–22. PMID 15671234.
  12. Jump up^ Kimball; et al. (2004). “Safety of vitamin D3 in adults with multiple sclerosis”. J Clin Endocrinol Metab. 86 (3): 645–51. PMID 17823429.
  13. Jump up^ Maugh II, Thomas H. “Frank C. Garland dies at 60; epidemiologist helped show importance of vitamin D: Garland and his brother Cedric were the first to demonstrate that vitamin D deficiencies play a role in cancer and other diseases.”, Los Angeles Times, August 31, 2010. Accessed September 4, 2010.
  14. Jump up^ Wactawski-Wende, J; Kotchen, JM, Women’s Health Initiative Investigators (Mar 9, 2006). “Calcium plus vitamin D supplementation and the risk of colorectal cancer.”. N Engl J Med. 354 (7): 684–96. doi:10.1056/NEJMoa055222. PMID 16481636. Retrieved December 28, 2013.
  15. Jump up^ “Too much vitamin D can be as unhealthy as too little” (Press release). University of Copenhagen. May 29, 2012. Retrieved 2015-05-27.
  16. Jump up^ Durup, D.; Jørgensen, H. L.; Christensen, J.; Schwarz, P.; Heegaard, A. M.; Lind, B. (May 9, 2012). “A Reverse J-Shaped Association of All-Cause Mortality with Serum 25-Hydroxyvitamin D in General Practice: The CopD Study”. The Journal of Clinical Endocrinology & Metabolism. Endocrine Society. 97 (8): 2644–2652. doi:10.1210/jc.2012-1176. Retrieved 2015-05-27.
Skeletal formula of calcifediol
Ball-and-stick model of the calcifediol molecule
IUPAC names

Other names

25-Hydroxyvitamin D3
19356-17-3 Yes
3D model (Jmol) Interactive image
ChEBI CHEBI:17933 
ChemSpider 4446820 
DrugBank DB00146 Yes
ECHA InfoCard 100.039.067
MeSH Calcifediol
PubChem 5283731
Molar mass 400.64 g/mol
A11CC06 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).


Title: Calcifediol
CAS Registry Number: 19356-17-3
CAS Name: (3b,5Z,7E)-9,10-Secocholesta-5,7,10(19)-triene-3,25-diol
Additional Names: 25-hydroxyvitamin D3; 25-hydroxycholecalciferol; 25-HCC
Manufacturers’ Codes: U-32070E
Trademarks: Dedrogyl (DESMA); Didrogyl (Bruno); Hidroferol (FAES)
Molecular Formula: C27H44O2
Molecular Weight: 400.64
Percent Composition: C 80.94%, H 11.07%, O 7.99%
Literature References: The principal circulating form of vitamin D3, formed in the liver by hydroxylation at C-25: Ponchon, DeLuca, J. Clin. Invest. 48, 1273 (1969). It is the intermediate in the formation of 1a,25-dihydroxycholecalciferol, q.v., the biologically active form of vitamin D3 in the intestine. Identification in rat as an active metabolite of vitamin D3: Lund, DeLuca, J. Lipid Res. 7, 739 (1966); Morii et al., Arch. Biochem. Biophys. 120, 513 (1967). Evaluation of biological activity in comparison with vitamin D3: Blunt et al., Proc. Natl. Acad. Sci. USA 61, 717 (1968); ibid. 1503. Isoln from porcine plasma and establishment of structure: Blunt et al., Biochemistry 7, 3317 (1968). Synthesis: Blunt, DeLuca, ibid. 8, 671 (1969). Review of isoln, identification and synthesis: DeLuca, Am. J. Clin. Nutr. 22, 412 (1969). Review of bioassays: J. G. Haddad Jr., Basic Clin. Nutr. 2, 579-597 (1980).
Properties: uv max (ethanol): 265 nm (e 18000) (Blunt, DeLuca).
Absorption maximum: uv max (ethanol): 265 nm (e 18000) (Blunt, DeLuca)
Therap-Cat: Calcium regulator.
Keywords: Calcium Regulator.

/////////Calcifediol, カルシフェジオール



Balsalazide structure.svg


80573-04-2; Colazal; Balsalazide Disodium; AC1NSFNR; P80AL8J7ZP;
Molecular Formula: C17H15N3O6
Molecular Weight: 357.322 g/mol

(3E)-3-[[4-(2-carboxyethylcarbamoyl)phenyl]hydrazinylidene]-6-oxocyclohexa-1,4-diene-1-carboxylic acid


CAS Number 150399-21-6
Weight Average: 437.316
Monoisotopic: 437.08110308
Chemical Formula C17H17N3Na2O8

Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. It is sold under the brand names Giazo, Colazal in the US and Colazide in the UK. It is also sold in generic form in the US by several generic manufacturers.

It is usually administered as the disodium salt. Balsalazide releases mesalazine, also known as 5-aminosalicylic acid, or 5-ASA,[1] in the large intestine. Its advantage over that drug in the treatment of ulcerative colitis is believed to be the delivery of the active agent past the small intestine to the large intestine, the active site of ulcerative colitis.

Balsalazide is an anti-inflammatory drug used in the treatment of Inflammatory Bowel Disease. It is sold under the name “Colazal” in the US and “Colazide” in the UK. The chemical name is (E)-5-[[-4-(2-carboxyethyl) aminocarbonyl] phenyl]azo] –2-hydroxybenzoic acid. It is usually administered as the disodium salt. Balsalazide releases mesalazine, also known as 5-aminosalicylic acid, or 5-ASA, in the large intestine. Its advantage over that drug in the treatment of Ulcerative colitis is believed to be the delivery of the active agent past the small intestine to the large intestine, the active site of ulcerative colitis.

Balsalazide disodium and its complete synthesis was first disclosed by Chan[18] in 1983, assigned to Biorex Laboratories Limited, England, claiming product ‘Balsalazide’ and process of its preparation. The synthesis involves converting 4-nitrobenzoyl chloride (6) to 4- nitrobenzoyl-β-alanine (7), hydrogenating with Pd/C (5%) in ethanol and isolating by adding diethyl ether to produce 4-aminobenzoyl-β-alanine (8). Thereafter, 4-aminobenzoyl-β-alanine (8) was treated with hydrochloric acid and sodium nitrite to generate N-(4-diazoniumbenzoyl)- β-alanine hydrochloride salt (9) which was reacted at low temperature with disodium salicylate to furnish Balsalazide disodium insitu which was added to dilute hydrochloric acid at low temperature to produce Balsalazide (1) (Scheme-1.1). Thus obtained Balsalazide was recrystallized with hot ethanol and converted to pharmaceutically acceptable salt (disodium salt).

Optimization of this diazonium salt based process was performed by Huijun et al[19] and reported the preparation of the title compound in 64.6% overall yield. Zhenhau et al[20] have synthesized 1 from 4-nitrobenzoic acid (12) via chlorination, condensation, hydrogenation, diazotization, coupling and salt formation with overall yield 73%. Li et al[21] have given product in 73.9% total yield starting from 4-nitrobenzoyl chloride (6), where as Yuzhu et al[22] confirmed chemical structure of Balsalazide disodium by elemental analysis, UV, IR, 1H-NMR and ESI-MS etc. Shaojie et al[23] have also followed same process for its preparation. Yujie et al[24] synthesized 1 in this way; preparation of 4-nitrobenzoyl-β-alanine (7) under microwave irradiation of 420 W at 52oC for 10sec., reduction in ethyl acetate in the presence of Pd/C catalyst then diazotization, coupling and salt formation. Eckardt et al[25] have developed a process for the preparation of Balsalazide which comprises, conversion of 4-aminobenzoyl-β-alanine (8) to 4-ammoniumbenzoyl-β-alanine sulfonate salt using a sulfonic acid in water. This was treated with aq. sodium nitrite solution at low temperature to generate 4-diazoniumbenzoyl-β-alanine sulfonate salt (11) which was quenched with aq. disodium salicylate to furnish Balsalazide disodium solution. This was further acidified to allow isolation of 1 and then conversion to disodium salt (Scheme-1.2) in 76% yield.

IR (KBr, cm-1 ): 3371 and 3039 (OH and NH), 1705 and 1699 (C=O), 1634 (C=O amide), 1590 and 1538 (C=C aromatic), 1464 and 1404 (aliphatic C-H), 1229 (C-N), 1073 (C-O), 773 and 738 (Ar-H out of plane bend). 1H NMR (DMSO-d6, 300 MHz, δ ppm): 2.54 (t, 2H), 3.50 (m, 2H), 6.95 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.95 (dd, J = 8.8 Hz and 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.68 (t, J = 5.5 Hz, 1H), 12.12 (brs, 1H). MS m/z (ESI): 356 [(M-H)- ], Calculated; m/z 357.


Balsalazide synthesis: Biorex Laboratories, GB 2080796 (1986).

  1. Starting material is 4-aminohippuric acid, obtained by coupling para-aminobenzoic acid and glycine.
  2. That product is then treated with nitrous acid to give the diazonium salt.
  3. Reaction of this species with salicylic acid proceeds at the position para to the phenol to give balsalazide.

Sodium balsalazide (Balsalazide sodium)

Brief background information

Salt ATC Formula MM CAS
A07EC04 C 17 H 13 N 3 Na 2 O 6 401.29 g / mol 82101-18-6
(E) is the free acid A07EC04 C 17 H 15 N 3 O 6 357.32 g / mol 80573-04-2A


  • resolvent

Classes substance

  • β-alanine (3-aminopropionic acid)
    • m-aminobenzoic acid and esters and amides thereof
      • p-aminobenzoic acid and esters and amides thereof
        • azobenzene
          • salicylic acid

Synthesis Way

Synthesis of a)

Trade names

A country Tradename Manufacturer
United Kingdom Kolazid Shire
Italy Balzid Menarini
USA Kolazal Salix
Ukraine no no


  • capsules in 750 mg (as disodium salt)


Balsalazide disodium (1) represents an effective gastrointestinal anti-inflammatory compound useful as a medicament for the treatment of diseases such as ulcerative colitis. It is delivered intact to the colon where it is cleaved by bacterial azoreduction thereby generating 5-aminosalicylic acid as the medicinally active component.

Figure US07271253-20070918-C00001

To date, relatively few patents or literature articles have dealt with the preparation of Balsalazide or the disodium salt. For instance, U.S. Pat. No. 4,412,992 (Biorex, 1983) is the first patent that we uncovered that claims the compound Balsalazide and a strategy of how to prepare it which strategy is depicted in Scheme 1.

Figure US07271253-20070918-C00002

Optimization of this diazonium-based process is detailed in Shan et al., Zhongguo Yaowu Huaxue Zazhi, 11, 110 (2001) and Shi et al., Zhongguo Yiyao Gongye Zazhi, 34, 537 (2003).

Problems arise with the above strategy and the optimization process.

It is well-documented in the literature, for instance in Thermochimica Acta, 225, 201-211 (1993), that diazonium salts can be involved in serious accidents in their use. A possible cause of some of the diazonium salt related accidents is that, for one reason or another, an intermediate material appeared in crystalline form in the vessel of the reaction. As a result, a potentially severe drawback of the above processes occurs. Since the intermediate hydrochloride salt of 4-aminobenzoyl-β-alanine has poor solubility in water, it may pose a safety-risk in the subsequent diazotation reaction.

Also, it is well-known that certain diazonium salts possess high mechanical and heat sensitivity and that their decomposition goes through the liberation of non-condensable nitrogen gas which results in the possibility of runaway reactions and explosions. Obviously this safety consideration becomes more pertinent upon further scale-up.

Therefore, for commercial production of Balsalazide disodium, there was a need to develop a scalable and intrinsically better process

Example 1 Batch Process

N-(4-Aminobenzoyl)-β-alanine (100 g) was suspended in water (1300 mL) and methanesulfonic acid (115.4 g) was added to this mixture. The mixture was cooled to 10° C. and a solution of sodium nitrite (34.46 g) in water (200 mL) was added at a rate such that the temperature stayed below 12° C. The mixture was stirred for 30 min and added to an ice-cold solution of salicylic acid (69.65 g), sodium hydroxide (40.35 g) and sodium carbonate (106.9 g) in 1 L water at 7-12° C. After 3 hours at 10° C., the mixture was heated to 60-65° C. and acidified to pH 4.0-4.5 by the addition of hydrochloric acid. After a further 3 hours at 60-65° C., the mixture was cooled to ambient temperature, filtered, washed with water and dried in vacuo to yield Balsalazide. Yield ca. 90%. Balsalazide was transformed into its disodium salt in ca. 85% yield by treatment with aqueous NaOH solution followed by crystallization from n-propanol/methanol.

1H-NMR (400 MHz; D2O): δ=8.04 ppm (s); 7.67 ppm (d; J=8.2 Hz); 7.62 ppm (d, J=9.2 Hz); 7.53 ppm (d; J=8.2 Hz); 6.84 ppm (d; J=8.9 Hz); 3.57 ppm (t, J=7.1 Hz); 2.53 ppm (t; J=7.2 Hz).

Example 2 Continuous Process

For the continuous operation, a conventional dual-head metering pump (Ratiomatic by FMI) was used to deliver the mesylate solution and the aqueous sodium nitrite solution. The schematic diagram shown in FIG. 4 represents a set-up used for the continuous process. The first pump-head was set at 13.9 g/min whereas the second was set at 2.1 g/min. These flow rates offered a residence time of 9.4 min. The yield of the coupled intermediate from this residence time was 93%. The working solutions were prepared as follow:

The mesylate solution was prepared by the addition into a 2 L 3-necked round bottom flask, of N-(4-aminobenzoyl) β-alanine (120 g) followed by of DI water (1560 g) and methanesulfonic acid (177.5 g) (Batch appearance: clear solution). The first pump-head was primed with this solution and the flow rate was adjusted to 13.9 g/min.

The sodium nitrite solution was prepared by dissolving of sodium nitrite (41.8 g) in of DI water (240 g) (Batch appearance: clear solution). The second pump-head was primed with this solution and the flow rate adjusted to 2.1 g/min.

The quenching solution (sodium salicylate) was made by adding salicylic acid (139.3 g) to DI water (900 g) followed by of sodium carbonate (106.9 g) and 50% aqueous sodium hydroxide (80 g).

The diazotation reaction was performed in a 500 ml jacketed flow reactor with a bottom drain valve. The drain valve was set at 16 g/min. For reactor start-up, the flow reactor was charged with 150 mL of DI water as a working volume and cooled to the reactions initial temperature of 0-5° C. Concomitantly, the additions of the mesylate and sodium nitrite solutions were started and the bottom valve of the flow reactor was opened. During the diazotization, the flow rate of both solutions remained fixed and the temperature was kept below 12° C. and at the end of additions the pumps were stopped while the remaining contents in the flow reactor were drained into the quenching salicylic acid solution. Analysis of the contents in the quenching reactor indicated no signs of uncoupled starting material (diazonium compound). The reactor contents were heated to 60-65° C. for 2-3 hrs before adjusting the pH to precipitate the coupling product. This provided 191.5 g of product.

Cited Patent Filing date Publication date Applicant Title
US4412992 Jul 8, 1981 Nov 1, 1983 Biorex Laboratories Limited 2-Hydroxy-5-phenylazobenzoic acid derivatives and method of treating ulcerative colitis therewith
US6458776 * Aug 29, 2001 Oct 1, 2002 Nobex Corporation 5-ASA derivatives having anti-inflammatory and antibiotic activity and methods of treating diseases therewith
1 Chai, et al., Huaxi Yaoxue Zazhi, Jiangsu Institute of Materia Medica, Nanjing, China, 2004, 19(6), 431-433.
2 Shan, et al., Zhongguo Yaowu Huaxue Zazhi, Institute of Materia Medica, Peking Union Medical College, Beijing China, 2001, 11(2), 110-111.
3 Shi, et al., Zhongguo Yiyao Gongya Zazhi, Shanghai Institute of Pharmaceutical Industry, Shanghai, China, 2003, 34(11), 537-538.
4 Su, et al., Huaxue Gongye Yu Gongcheng (Tianjin, China), College of Chemistry and Chemical Eng., Donghua Univ., Shanghai, China, 2005, 22(4), 313-315.
5 Ullrich, et al., Decomposition of aromataic diazonium compounds, Thermochimica Acta, 1993, 225, 201-211.


  • Prakash, A; Spencer, CM: Drugs (DRUGAY) 1998 56 83- 89.
  • DE 3128819 (Biorex the Lab .; appl 07/21/1981;. GB -prior 07/21/1980, 07.07.1981.).


  1. Jump up^ Kruis, W.; Schreiber, I.; Theuer, D.; Brandes, J. W.; Schütz, E.; Howaldt, S.; Krakamp, B.; Hämling, J.; Mönnikes, H.; Koop, I.; Stolte, M.; Pallant, D.; Ewald, U. (2001). “Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses”. Gut. 49 (6): 783–789. doi:10.1136/gut.49.6.783. PMC 1728533Freely accessible. PMID 11709512.
1 to 5 of 5
Patent ID Patent Title Submitted Date Granted Date
US8232265 Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients 2007-04-26 2012-07-31
US2007213304 Use of Aminosalicylates in Diarrhoea-Predominent Irritable Bowel Syndrome 2007-09-13
US7119079 Bioadhesive pharmaceutical compositions 2004-07-22 2006-10-10
US6699848 Bioadhesive anti-inflammatory pharmaceutical compositions 2004-03-02
Balsalazide structure.svg
Clinical data
Trade names Colazal, Giazo
AHFS/ Monograph
MedlinePlus a699052
  • US: B (No risk in non-human studies)
ATC code A07EC04 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability <1%
Protein binding ≥99%
Biological half-life 12hr
CAS Number 80573-04-2 Yes
PubChem (CID) 5362070
DrugBank DB01014 Yes
ChemSpider 10662422 Yes
ChEBI CHEBI:267413 Yes
ECHA InfoCard 100.117.186
Chemical and physical data
Formula C17H15N3O6
Molar mass 357.318 g/mol
3D model (Jmol) Interactive image


Title: Balsalazide
CAS Registry Number: 80573-04-2
CAS Name: 5-[(1E)-[4-[[(2-Carboxyethyl)amino]carbonyl]phenyl]azo]-2-hydroxybenzoic acid
Additional Names: (E)-5-[[p-[(2-carboxyethyl)carbamoyl]phenyl]azo]-2-salicylic acid
Molecular Formula: C17H15N3O6
Molecular Weight: 357.32
Percent Composition: C 57.14%, H 4.23%, N 11.76%, O 26.87%
Literature References: Analog of sulfasalazine, q.v. Prodrug of 5-aminosalicylic acid where carrier molecule is 4-aminobenzoyl-b-alanine. Prepn: R. P. K. Chan, GB 2080796; idem, US 4412992 (1982, 1983 both to Biorex). Toxicology study and clinical metabolism: idem et al., Dig. Dis. Sci. 28, 609 (1983). Review of pharmacology and clinical efficacy in ulcerative colitis: A. Prakash, C. M. Spencer, Drugs 56, 83 (1998).
Properties: Crystals from hot ethanol, mp 254-255°.
Melting point: mp 254-255°
Derivative Type: Disodium salt dihydrate
CAS Registry Number: 150399-21-6; 82101-18-6 (anhydrous)
Manufacturers’ Codes: BX-661A
Trademarks: Colazal (Salix); Colazide (Shire)
Molecular Formula: C17H13N3Na2O6.2H2O
Molecular Weight: 437.31
Percent Composition: C 46.69%, H 3.92%, N 9.61%, Na 10.51%, O 29.27%
Properties: Orange to yellow microcrystalline powder, mp >350°. Nonhygroscopic. Freely sol in water, isotonic saline; sparingly sol in methanol, ethanol. Practically insol in organic solvents.
Melting point: mp >350°
Therap-Cat: Anti-inflammatory (gastrointestinal).
Keywords: Anti-inflammatory (Gastrointestinal); Anti-inflammatory (Nonsteroidal); Salicylic Acid Derivatives.




P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Happy New Year's Eve from Google!

Glenmark Launches First and Only Generic Version of Zetia® (Ezetimibe) in the United States

Glenmark launches generic version of Zetia in US

Illustration Image Courtesy…

“We have launched ezetimibe, the first and only generic version of Zetia (Merck) in the United States for the treatment of high cholesterol,”……….



Glenmark Launches First and Only Generic Version of Zetia® in the United States 

Mumbai, India; December 12, 2016: Glenmark Pharmaceuticals Inc., USA today announced the availability of ezetimibe, the first and only generic version of ZETIA® (Merck) in the United States for the treatment of high cholesterol. The availability of ezetimibe is the result of a licensing partnership with Par Pharmaceutical, an Endo International plc operating company, with whom Glenmark will share profits. Glenmark and its partner, Endo will be entitled to 180 days of generic drug exclusivity for ezetimibe as provided for under section 505(j)(5)(B)(iv) of the FD&C Act.

Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-
C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) in patients with primary
(heterozygous familial and non-familial) hyperlipidemia.
According to IMS Health data for the 12-month period ending October 2016, annual U.S. sales of Zetia®
10 mg were approximately $2.3 billion.
“Glenmark has a deep heritage of bringing safe, effective and affordable medicines to patients around
the world,” said Robert Matsuk, President of North America and Global API at Glenmark
Pharmaceuticals Ltd. “Our partnership with Par to bring the first generic version of ZETIA® to market
only underscores our joint commitment to bridging the gap between patients and the medicines they
need most.”
“We, along with our partners at Glenmark, are proud to be able to offer patients managing their
cholesterol levels the first generic version of ZETIA®,” said Tony Pera, President of Par Pharmaceutical.
“Par remains committed to providing patients access to high quality and affordable medicines.”
Glenmark’s current portfolio consists of 111 products authorized for distribution in the U.S. marketplace
and 64 ANDA’s pending approval with the U.S. Food and Drug Administration. In addition to these
internal filings, Glenmark continues to identify and explore external development partnerships to
supplement and accelerate the growth of its existing pipeline and portfolio.

About Glenmark Pharmaceuticals Ltd.:
Glenmark Pharmaceuticals Ltd. (GPL) is a research-driven, global, integrated pharmaceutical organization headquartered at Mumbai, India. It is ranked among the top 80 Pharma & Biotech companies of the world in terms of revenue (SCRIP 100 Rankings published in the year 2016). Glenmark is a leading player in the discovery of new molecules both NCEs (new chemical entity) and NBEs (new biological entity). Glenmark has several molecules in various stages of clinical development and is primarily focused in the areas of Inflammation [asthma/COPD, rheumatoid arthritis etc.] and Pain [neuropathic pain and inflammatory pain]. The company has a significant presence in the branded generics markets across emerging economies including India. GPL along with its subsidiaries operate 17 manufacturing facilities across four countries and has five R&D centers. The Generics business of Glenmark services the requirements of the US and Western European markets. The API business sells its products in over 80 countries including the US, EU, South America and India………

About Endo International plc:
Endo International plc (NASDAQ / TSX: ENDP) is a global specialty pharmaceutical company focused on improving patients’ lives while creating shareholder value. Endo develops, manufactures, markets and distributes quality branded and generic pharmaceutical products as well as over-the-counter medications though its operating companies. Endo has global headquarters in Dublin, Ireland, and U.S. headquarters in Malvern, PA. Learn more at


Dec 08, 2016, 08.16 PM | Source: CNBC-TV18 Glenmark to launch cholesterol drug Zetia in US on Dec 12 Glenmark was the first to file for the generic version of Zetia and it means that after the launch on December 12, only Glenmark and Merck will sell generic Zetia in the US market for the next 6 months. Glenmark   is launching cholesterol drug Zetia with 6 months exclusivity in the US on December 12. The company has partnered with Par Pharma on the drug and has a 50:50 profit sharing agreement with Par on Zetia. Glenmark was the first to file for the generic version of Zetia and it means that after the launch on December 12, only Glenmark and Merck will sell generic Zetia in the US market for the next 6 months. Total revenue estimated to be generated is around USD 400-500 million and post profit sharing with Par, Glenmark should make around USD 200-250 million.

Read more at:

////////////Glenmark,  Launches,  First,  Only,  Generic Version,  Zetia®,  United States, ezetimibe, par pharmaceutical, cholesterol, Endo International plc

ацетазоламид , أسيتازولاميد [, 乙酰唑胺 , ACETAZOLAMIDE

ChemSpider 2D Image | acetazolamide | C4H6N4O3S2

ацетазоламид ,  أسيتازولاميد [,  乙酰唑胺 ,
CAS 59-66-5
Acetamide, N-(5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl)-
MW 222.245,MF  C4H6N4O3S2
Title: Acetazolamide
CAS Registry Number: 59-66-5
CAS Name: N-[5-(Aminosulfonyl)-1,3,4-thiadiazol-2-yl]acetamide
Additional Names: 5-acetamido-1,3,4-thiadiazole-2-sulfonamide; 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide
Manufacturers’ Codes: 6063
Trademarks: Acetamox (Tobishi-Santen); Atenezol (Tsuruhara); Défiltran (Gallier); Diamox (Barr); Didoc (Sawai); Diuriwas (IFI); Donmox (Horita); Edemox (Wassermann); Fonurit (Chinoin); Glaupax (Erco)
Molecular Formula: C4H6N4O3S2
Molecular Weight: 222.25
Percent Composition: C 21.62%, H 2.72%, N 25.21%, O 21.60%, S 28.85%
Literature References: Carbonic anhydrase inhibitor. Prepn: R. O. Roblin, J. W. Clapp, J. Am. Chem. Soc. 72, 4890 (1950); J. W. Clapp, R. O. Roblin, US 2554816 (1951 to Am. Cyanamid). HPLC determn in pharmaceuticals: Z. S. Gomaa, Biomed. Chromatogr. 7, 134 (1993). Effect on retinal circulation: S. M. B. Rassam et al., Eye 7, 697 (1993). Clinical trial in postoperative elevation of intraocular pressure: I. D. Ladas et al., Br. J. Ophthalmol. 77, 136 (1993). Comprehensive description: J. Parasrampuria, Anal. Profiles Drug Subs. Excip. 22, 1-32 (1993). Review of efficacy in acute mountain sickness: L. D. Ried et al.,J. Wilderness Med. 5, 34-48 (1994).
Properties: Crystals from water, mp 258-259° (effervescence). Weak acid. pKa 7.2. Sparingly sol in cold water. Slightly sol in alcohol, acetone. Practically insol in carbon tetrachloride, chloroform, ether. Soly (mg/ml): polyethylene glycol-400 87.81; propylene glycol 7.44; ethanol 3.93; glycerin 3.65; water 0.72.
Melting point: mp 258-259° (effervescence)
pKa: pKa 7.2
Derivative Type: Sodium salt
CAS Registry Number: 1424-27-7
Trademarks: Vetamox (Am. Cyanamid)
Therap-Cat: Antiglaucoma; diuretic; in treatment of acute mountain sickness.
Therap-Cat-Vet: Diuretic.
Keywords: Antiglaucoma; Carbonic Anhydrase Inhibitor; Diuretic; Sulfonamide Derivatives.
Starting reaction occurs in-between hydrazine hydrate and ammonium thiocyanate that produces 1, 2-bis (thiocarbamoyl) hydrazine which on further treatment with phosgene undergoesrearrangements, particularly  molecular rearrangement through loss of ammonia to form 5-amino-2-mercapto-1, 3, 4-thiadiazole. Upon acylation of 5-amino-2-mercapto-1, 3, 4-thiadiazole gives a corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride. The final step essentially consists of amidation by treatment with ammonia.





14N NQR, 1H NMR and DFT/QTAIM study of hydrogen bonding and polymorphism in selected solid 1,3,4-thiadiazole derivatives

Corresponding authors
a»Jozef Stefan« Institute, Jamova 39, 1000 Ljubljana, Slovenia
Fax: +386 1 2517281
Tel: +386 1 4766576
bFaculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia
cFaculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland
Phys. Chem. Chem. Phys., 2010,12, 13007-13019

DOI: 10.1039/C0CP00195C,!divAbstract

Graphical abstract: 14N NQR, 1H NMR and DFT/QTAIM study of hydrogen bonding and polymorphism in selected solid 1,3,4-thiadiazole derivatives

The 1,3,4-thiadiazole derivatives (2-amino-1,3,4-thiadiazole, acetazolamide, sulfamethizole) have been studied experimentally in the solid state by 1H–14N NQDR spectroscopy and theoretically by Density Functional Theory (DFT). The specific pattern of the intra and intermolecular interactions in 1,3,4-thiadiazole derivatives is described within the QTAIM (Quantum Theory of Atoms in Molecules)/DFT formalism. The results obtained in this work suggest that considerable differences in the NQR parameters permit differentiation even between specific pure association polymorphic forms and indicate that the stronger hydrogen bonds are accompanied by the larger η and smaller ν and e2Qq/h values. The degree of π-electron delocalization within the 1,3,4-thiadiazole ring and hydrogen bonds is a result of the interplay between the substituents and can be easily observed as a change in NQR parameters at N atoms. In the absence of X-ray data NQR parameters can clarify the details of crystallographic structure revealing information on intermolecular interactions.

////////////ацетазоламид ,  أسيتازولاميد [,  乙酰唑胺 , ACETAZOLAMIDE





Febuxostat; 144060-53-7; Uloric; Adenuric; Tei 6720; 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid;
Molecular Formula: C16H16N2O3S
Molecular Weight: 316.37484 g/mol

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid

Febuxostat is a thiazole derivative and inhibitor of XANTHINE OXIDASE that is used for the treatment of HYPERURICEMIA in patients with chronic GOUT.

CAS 144060-53-7

  • 2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid
  • 2-(3-Cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
  • FBX
  • Febugood
  • Feburic
  • Febutaz
  • TMX 67
  • Zurig


Febuxostat (INN; trade names Adenuric in Europe and New Zealand, Uloric in the US, Goturic in Latin America, Feburic in Japan) is a drug that inhibits xanthine oxidase, thus reducing production of uric acid in the body. It is used in the treatment of chronicgout and hyperuricemia.

Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998. Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe. Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008, Takeda obtained FDA approval in February 2009, and Teijin obtained approval from the Japanese “Pharmaceuticals and Medical Devices Agency” in 2011.

Medical uses

Febuxostat is used to treat chronic gout and hyperuricemia.[2] National Institute for Health and Clinical Excellence concluded that febuxostat is more effective than standard doses of allopurinol, but not more effective than higher doses of allopurinol.[2]

Uloric 40 mg tablet

Febuxostat is in the US pregnancy category C; there are no adequate and well-controlled studies in pregnant women.[3]

Side effects

The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.[3][4]

Drug interactions

Febuxostat is contraindicated with concomitant use of theophylline and chemotherapeutic agents, namely azathioprine and 6-mercaptopurine, because it could increase blood plasma concentrations of these drugs, and therefore their toxicity.[3][5]

Mechanism of action

Febuxostat is a non-purine-selective inhibitor of xanthine oxidase.[3] It works by non-competitively blocking the molybdenum pterincenter which is the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine andxanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. Febuxostat inhibits both oxidized as well as reduced form of xanthine oxidase because of which febuxostat cannot be easily displaced from the molybdenum pterin site.[4]


Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998.[6] Teijin partnered the drug withTAP Pharmaceuticals in the US and Ipsen in Europe.[7][8][9]

Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008,[10] Takeda obtained FDA approval in February 2009,[11][12] and Teijin obtained approval from the Japanese authorities in 2011.[13] Ipsen exclusively licensed its European rights to Menarini in 2009.[14] Teijin partnered with Astellas for distribution in China and southeast Asia.[15][16]

Society and culture


In the UK, NICE has found that febuxostat has a higher cost/benefit ratio than allopurinol and on that basis recommended febuxostat as a second-line drug for people who cannot use allopurinol.[2]

Trade names

Febuxostat is marketed as Adenuric in Europe and New Zealand, Uloric in the US, Goturic and Goutex in Latin America, Feburic in Japan, and is generic in several countries and is available by many names in those countries.[1]

Febuxostat (Formula I) is an inhibitor of xanthine oxidase, which was discovered by the Japanese company Teijin Pharma Ltd and it is indicated for use in the treatment of hyperuricemia and chronic gout. Its chemical name is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- l,3-thiazole-5-carboxylic acid. It is marketed under the brand names Adenuric in Europe, Feburic in Japan and Uloric in USA and Canada.

In EP0513379B1 Febuxostat is prepared from 4-hydroxy-3-nitrobenzaldehyde, according to the following scheme.

This particular process suffers from major drawbacks. Not only it is very long, including seven steps from the starting material to the final product, but, most importantly, it employs the use of cyanides, which are extremely toxic reagents. Cyanide salts are likely to generate hydrocyanide, which sets a high amount of risk in an industrial scale process.

In Japanese patent JP06345724A(JP2706037B) the intermediate ethyl ester of Febuxostat is prepared from p-cyano-nitrobenzene, in three steps. Febuxostat may, then, be prepared by alkaline hydrolysis, according to prior art.


The use of extremely toxic potassium cyanide makes this process unsuitable for manufacturing purposes.

Route A

In Japanese patent JP3202607B Febuxostat ethyl ester is prepared, according to the above scheme, through two similar routes. Route A uses flash column chromatography for the purification of the hydroxylamine reaction product, while Route B suffers from low yield and the use of chlorinated solvents for recrystallization. In addition, the reaction solvent is, in both cases, formic acid which causes severe skin burns and eye damage to humans. Formic acid is also corrosive towards metal-based materials of construction (MOC), like stainless steel and nickel alloys, limiting the options, essentially, to glass reactors or vessels. The drawbacks of using this solvent are also related to the high volumes of formic acid required per batch, which hinder the waste treatment.

In CN101723915B focus is made to the improvement of the hydroxylamine reaction. Formic acid is replaced with dimethylformamide (DMF) and other solvents. However, according to widely used organic chemistry textbooks, such as March’s Advanced Organic Chemistry, pi 287, 6th edition, M. B. Smith and J. March, ISBN 0-471-72091-7, the mechanism of the reaction involves the formation of an oxime, upon the action of hydroxylamine, which further dehydrates to form a nitrile, with the aid of a suitable reagent, for example formic acid, or acetic anhydride. In the absence of such a reagent, it is expected that the reaction will, at least, not lead to completion, thereby leading to low yields and undesired impurity levels, namely the intermediate oxime. Such impurities, arising from the reactions of the process and which exhibit similar structure of the desired product, are often difficult to remove with common industrial techniques, e.g. crystallization.

In WO2010142653A1 the intermediate Febuxostat ethyl ester is prepared from 4-cyanophenol, through a five-step process. Febuxostat can be prepared from its respective ethyl ester via alkaline hydrolysis, as in the previous case.


1: patents US5614520 febuxostat synthetic process:

Figure CN104418823AD00031

2: Patent JP1994329647 febuxostat synthesis

Figure CN104418823AD00032
Figure CN104418823AD00041


Gout occurs because the body produces too much uric acid and renal clearance capacity decreased, uric acid accumulation in the body, leading to urate crystals deposited in the joints and organs. Therefore, it means the treatment of gout usually taken to be: to promote uric acid excretion and suppression of uric acid, and the use of appropriate measures to improve symptoms. Uric acid formation and purine metabolism, the final step in the purine metabolism, hypoxanthine generation xanthine xanthine oxidoreductase (XOR) effect, further generate uric acid, inhibit the activity of the enzyme can effectively reduce uric acid production. Febuxostat is currently the world’s newly developed XOR inhibitors, which act by highly selective to the oxidase, reduce uric acid synthesis, reduce uric acid levels, so as to effectively treat the disease ventilation.

Compared with the traditional treatment of gout drug allopurinol, febuxostat has obvious advantages: (1) allopurinol reduced the XOR only inhibit rather than febuxostat of oxidized and reduced form are XOR significant inhibition, thus reducing the role of uric acid, which is more powerful and lasting; (2) Since allopurinol is a purine analogue, the inevitable result of the purine and other activity related to the impact of pyridine metabolism. So allopurinol treatment should be repeated large doses of the drug to maintain a high level. Which also brought serious or even fatal adverse reactions due to drug accumulation due.Instead of febuxostat non-purine XOR inhibitors, so it has better security.

Document TMX-67. Drugs Fut2001, 26, I, 32, and EP0513379, US5614520, W09209279, public

The detailed preparation febuxostat. Using 3-nitro-4-hydroxybenzaldehyde as the starting material is first reacted with hydroxylamine hydrochloride, to give 3-nitro-4-hydroxybenzonitrile. In effect then HCl, reaction with thioacetamide to give 3-nitro-4-hydroxy-thiobenzamide. Closed loop then reacted with 2-chloro ethyl acetoacetate to give 2- (3_ nitro-4-hydroxyphenyl) methyl-5-thiazolyl -4_ carboxylic acid ethyl ester. Followed by potassium carbonate effect, isobutane is reacted with bromo, to give 2- (3_ nitro-4-isobutyloxyphenyl) -4-methyl-5-carboxylic acid ethyl ester. Under the catalytic action of palladium on carbon, hydrogen reduction to give 2- (3-amino-4-isobutyloxyphenyl) -4-methyl-5-thiazole carboxylic acid ethyl ester. Followed by diazotization with sodium nitrite occur, was added cuprous cyanide and potassium cyanide, to give 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid ethyl ester. Finally, under the effect of the hydrolysis of sodium hydroxide, to give the product 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl – thiazole-5-carboxylic acid, to obtain febuxostat.The process route is as follows:

Figure CN102936230AD00041

This route in the preparation of febuxostat, there are many disadvantages: raw 3-nitro-4-hydroxybenzaldehyde in the country is difficult to buy; requires the use of palladium-carbon catalytic hydrogenation reaction under the factory equipment higher requirements, there is a certain danger; the cyano preparation, the need to use sodium nitrite diazotization, could easily lead to corrosion of equipment; the cyano preparation, the need to use toxic cyanide copper, potassium cyanide, pollution, higher risk.

Document JP1994329647, JP1998045733, US3518279 reported another synthesis of febuxostat

Methods. From 4-hydroxy-thiobenzamide as a starting material, and the cyclization reaction to give ethyl 2-bromo-acetyl occurred

2- (4_ hydroxyphenyl) -4_ methyl-5-carboxylic acid ethyl ester in polyphosphoric acid effect, HMTA (hexamethylene tetramine) reacts with 2- (3_ aldehyde – 4-hydroxyphenyl) methyl-5-thiazolyl -4_ carboxylic acid ethyl ester. Then two cases: the first case, the effect of potassium carbonate, is reacted with isobutane to give bromo-2- (4-isobutyloxyphenyl 3_ aldehyde) -4_-methyl-5- thiazole carboxylic acid ethyl ester, and then reacted with hydroxylamine hydrochloride to give 2- (3_-cyano-4-isobutyloxyphenyl) -4_-methyl-5-thiazole carboxylic acid ethyl ester; second case is the first with hydroxylamine hydrochloride to give 2- (3_ cyano-4-hydroxyphenyl) methyl-5-thiazolecarboxylic -4_ carboxylic acid ethyl ester, and then under the effect of potassium carbonate, and reacted with isobutane to give bromo-2- (3 _-cyano-4-isobutyloxyphenyl) -4-methyl-5-carboxylic acid ethyl ester.

Finally, under the effect of the hydrolysis of sodium hydroxide, to give the product 2- (3_-cyano-4-isobutyloxyphenyl) -4_ methyl – thiazole-5-carboxylic acid, i.e., to obtain febuxostat . The process route is as follows:

Figure CN102936230AD00051

This synthesis route febuxostat process, since the introduction of aldehyde HMTA in PPA (polyphosphoric acid) effect. So there are a lot of phosphorus wastewater, serious environmental pollution, but also because PPA has great viscosity, and therefore difficult to stir the production, operation is extremely inconvenient.

Document Heterocyclesl998, 47,2,857 JP1994345724 also reported the synthesis method of febuxostat, using p-nitrophenyl-carbonitrile as a starting material in the reaction with potassium cyanide in DMSO solvent, and then the carbonate lower potassium catalyzed reaction of isobutane and brominated 1,3-cyano-4-diisobutoxybenzene ether. By reaction with thioacetamide to afford

3-cyano-4-isobutyloxyphenyl thiobenzamide. Under heating, and 2-chloro ethyl acetoacetate, ring closure reaction occurs to give 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-carboxylic acid ethyl ester, and finally hydrolysis under the effect of sodium hydroxide, to give the product 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl – thiazole-5-carboxylic acid, to obtain febuxostat.

The present invention febuxostat new technology system, comprising the steps of:

(1) 2-hydroxy-5-cyano – NaSH reacted with benzaldehyde to give 4-hydroxy-3- aldehyde thiobenzamide;

Figure CN102936230AD00061

(2) the step (I) to give 4-hydroxy-3-aldehyde thiobenzamide reaction with ethyl 2-halo-acetyl, closed

Ring to give 2- (3-aldehyde-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole;

Figure CN102936230AD00062

X is a halogen, preferably Cl or Br;

(3) the step (2) to give 2- (3-aldehyde-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole with hydroxylamine in formic acid in the reaction solution to give 2- (3- cyano-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole;

Figure CN102936230AD00063

(4) The step (3) to give 2- (3-cyano-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole isobutane with halo effect in potassium carbonate, to give 2- (3-aldehyde-4-isobutyloxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole;

(5) in step (4) to give 2- (3-aldehyde-4-isobutyloxyphenyl) -4-methyl-5-ethoxycarbonyl-thiazol-off hydrolyzable ester group, to obtain a non-Tendon Disposition Tanzania.

[0011] Scheme of the method is as follows:

Figure CN102936230AD00071

X is halogen, may be Cl, Br;

Preparation 5 febuxostat Example

To a 500ml reaction flask was added 200ml of absolute ethanol, the product of Step 4 was added with stirring (60g, O. 174mol),

5% sodium hydroxide was added 100ml. Stirring heated to 40 degrees, until it is completely dissolved. 40 degrees heat, reaction 4h. The reaction by TLC tracking. After completion of the reaction, the reaction solution was added 10% hydrochloric acid to adjust the pH to 3, the precipitated solid was filtered. And dried to give a pale yellow solid. Dried over anhydrous recrystallized from methanol to give 31. 2g of white crystals, yield 56.7%.

 TLC monitoring of the reaction. Eluent: petroleum ether / ethyl acetate = 3: 1 Melting point:. 201 · 7 ~202 30C (literature value 201 ~202 ° C)

1H-NMR δ:. 1 01 (m, 6H), 2.06 (m, lH), 2.57 (m, 3 H), 3.96 (d, 2H), 7.30 (d, lH), 8.13 (m, 1H), 8. 19 (d, 1H);

MS (m / z):. 316 O (M +)

Infrared detection: 3550-3400cm_1; 2961, 2933,2874; 2227cm_1; 1680U604U511cm_1; 1425cm_1; 1296U283CHT1;

Elemental analysis for C, Η, N, S purified product actual measurement of the content of C, H, N, S content: C:. 60 57%, H:. 5 32%, N:. 8 86%, S: 10. 16%; theoretical value: In C16H16N203S calculated C: 60 74%, H: 510%, N: 885%, S: 1014%..


Facile OnePot Transformation of Arenes into Aromatic Nitriles …

Facile OnePot Transformation of Arenes into Aromatic Nitriles under MetalCyanideFree Conditions



synthesis  describes synthesis of febuxostat (I) from 4-hydroxybenzonitrile (II) in six stages. The synthesis shown is a short, concise route and does not require use of poisonous reagents such as KCN (14). Compound II was converted to 4-hydroxybenzothioamide (III) with 85% yield using NaHS in the presence of hydrated magnesium chloride as Lewis acid. Intermediate III, on cyclization with ethyl-2-chloroacetoacetate, gave thiazole ester (IV) with quantitative yield. In these two stages, the source of potential impurities was identified as an ortho isomer (i.e., 2-hydroxybenzonitrile), which can lead to Impurity VIII and subsequently to Impurity IX . Impurities VIII and IX can be controlled in starting material II with appropriate specification.

Figure 2
Figure 2: Impurities identified during the various stages of synthesis of febuxostat.

The ortho formylation of hydroxyl compound IV by using Duff condition (hexamine/TFA) gave aldehyde V (15). The major impurity identified in this reaction was dialdehyde X. Although we have used only 1.0 equivalence of hexamine with respect to Compound IV, the dialdehyde X impurity was formed to a 5-10% ratio in only 2.5 h. It is, therefore, impossible to get rid of this impurity during the reaction, and only effective recrystallization will eliminate it. Impurity X was minimized (≤ 2%) by recrystallization using IPA/H2O (3:5) to get aldehyde V with 50% yield and & #8805; 97% HPLC purity.

Aldehyde V, on alkylation with isobutyl bromide in the presence of potassium carbonate base, gave compound VI with 90% yield. In this stage, Impurities XI and XII were alkylations of carryover Compound IV and dialdehyde, respectively. Two more isomeric impurities n-butyl-aldehyde XIII and 1-methyl propyl-aldehyde XIV were also identified in this stage. Both isomeric impurities can be controlled with appropriate specification for isobutyl bromide. The reaction of Compound VI with hydroxylamine hydrochloride and sodium formate in formic acid at reflux temperature gave Compound VII with 85% yield. Impurities XIII and XIV will also carry forward to impurities n-butyl-nitrile XV and 1-methyl propyl-nitrile XVI, respectively.

In the final step, Compound VII was hydrolyzed using sodium hydroxide in a MeOH:THF:H2O (1:1:1) solvent combination to yield febuxostat (85%). During saponification, methyl ester Impurity XVII was identified via trans-esterification. Its hydrolysis was comparatively slower than its ethyl isomer VII. One way to avoid Impurity XVII is to replace methanol with ethanol. Carryover impurities XI, XV, and XVI were also hydrolyzed to their respective acid derivatives impurities XVIII, XIX, and XX. However, the acid derivatives of impurities X and XII were unexpectedly absent as impurities. It is believed that, because they were present in low concentrations during workup, they were eliminated in the mother liquor. Two additional impurities, amide XXI and diacid XXII, formed by the side reaction of the febuxostat nitrile group with sodium hydroxide, were identified during saponification. The amide XXI and diacid XXII impurities can be controlled by using appropriate equivalence of sodium hydroxide and controlled reaction time. Febuxostat, on acetone recrystallization and seed Crystal A at 45°C, gave pure febuxostat with 75% yield.


  1. international names for febuxostat Page accessed June 25, 2015
  2.  Febuxostat for the management of hyperuricaemia in people with gout (TA164) Chapter 4. Consideration of the evidence
  3.  Uloric label Updated February, 2009.
  4.  Love BL, Barrons R, Veverka A, Snider KM (2010). “Urate-lowering therapy for gout: focus on febuxostat”. Pharmacotherapy 30 (6): 594–608. doi:10.1592/phco.30.6.594.PMID 20500048.
  5.  Ashraf Mozayani; Lionel Raymon (2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science+Business Media.
  6. Teijin Febuxostat Story Page accessed June 25, 2015
  7.  Tomlinson B. Febuxostat (Teijin/Ipsen/TAP). Curr Opin Investig Drugs. 2005 Nov;6(11):1168-78. PMID 16312139
  8.  Bruce Japsen for the Chicago Tribune. August 17, 2006. FDA puts gout treatment on hold
  9.  Note: TAP Pharmaceuticals was a joint venture between Abbott Laboratories and Takedathat was dissolved in 2008 per this press release: Takeda, Abbott Announce Plans to Conclude TAP Joint Venture
  10.  “Adenuric (febuxostat) receives marketing authorisation in the European Union” (PDF). Retrieved 2008-05-28.
  11.  “Uloric Approved for Gout”. U.S. News and World Report. Retrieved 2009-02-16.
  12.  Teijin and Takeda. February 14, 2009 Press release: ULORIC® (TMX-67, febuxostat) Receives FDA Approval for the Chronic Management of Hyperuricemia in Patients with Gout
  13.  Teijin. January 21, 2011 Press release: TMX-67 (febuxostat) Approved in Japan
  14.  Genetic Engineering News. October 2009. Menarini to Market Takeda/Ipsen Gout Therapy in 41 European Countries
  15.  First Word Pharma. April 1st, 2010 Teijin Pharma and Astellas Pharma enter into agreement for marketing rights of TMX-67 in China and Hong Kong
  16.  Research Views. Aug 11 2011 Teijin Pharma Enters Into Distribution Agreement With Astellas Pharma For Febuxostat

Febuxostat is an inhibitor of xanthine oxidase, and was developed by Teijin pharma. This compound is known as a new drug that is effective against gout and hyperuricemia, and it has been 40 years since the last time a drug of this kind of drug was developed.

Febuxostat has therefore gained a lot of popularity and it has already been accepted as a drug in Europe, USA, Korea and Japan. The synthesis of this molecule have been reported in patents by Teijin pharma as shown below.[1,2]


Recently, Itami group was reported the rapoid synthesis of febxostat by using Ni-catalyzed direct coupling of azoles and arylhalides[3]


Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32

[1] Hasegawa, M.; A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile. Heterocycles 1998, 47, 2, 857. [2] Hasegawa, M.;  Hasegawa, M.; Komoriya, K. (Teijin Ltd.); Cyano cpds. and their preparation method. JP 1994345724 . [3] “Nickel-Catalyzed Biaryl Coupling of Heteroarenes and Aryl Halides/Triflates”

Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733-1736. DOI: 10.1021/ol9001587


Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)2/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAc)2/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.


A final example of a thiazole containing drug is given in the novel xanthine oxidase inhibitor febuxostat (359, Uloric) which was approved by the FDA in 2009. This inhibitor works by blocking xanthine oxidase in a non-competitive fashion. Consequently, the amount of the oxidation product uric acid is reduced. Thus it is an efficient treatment for hyperuricemia in gout. In order to prepare febuxostat first a synthesis of the noncommercial 4-isobutoxy-1,3-dicyanobenzene building block (363), has to be conducted. An elegant way of achieving this was shown through the reaction of 4-nitrocyanobenzene (360) with potassium cyanide in dry DMSO followed by quenching with isobutyl bromide under basic conditions (Scheme 70). It is suggested that a Meisenheimer-complex intermediate 361 is initially formed, which after rearomatisation, undergoes nucleophilic aromatic substitution of the nitro group by the DMSO solvent [107]. Upon hydrolysis and O-alkylation the desired 4-isobutoxy-1,3-dicyanobenzene (363) is obtained in good overall yield. Subsequently, the less hindered nitrile is converted to the corresponding thioamide 365 in an intriguing reaction using thioacetamide (364). The thiazole ring is then formed by condensation with chloroacetoacetate 366 followed by ester hydrolysis (Scheme 70).


107 Hasegawa, M. Heterocycles 1998, 47, 857–864. doi:10.3987/COM-97-S(N)89

Paper | Special issue | Vol 47, No. 2, 1998, pp.857-864

DOI: 10.3987/COM-97-S(N)89
A Facile One-Pot Synthesis of 4-Alkoxy-1,3-benzenedicarbonitrile

Masaichi Hasegawa

*Teijin Institute, Bio-Medical Research, Asahigaoka 4-3-2, Hino, Tokyo 191, Japan


2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxlic acid (TEI-6720) was prepared. The introduction of cyano group to 4-nitrobenzonitrile with KCN in dry DMSO followed by quenching with alkyl halide afforded the key intermediates, 4-alkoky-1,3-benzenedicarbonitriles, in good yield. The reaction was completed in dry DMSO, while no reaction occurred in dry DMF. This observation can be suggested by the participation of DMSO in the reaction.

PDF (208KB)


Synthesis and characterization of process-related impurities of an anti-hyperuricemia drug-Febuxostat

Venkateswara Rao Vallu,$ Krunal Girishbhai Desai, Sandip Dhaya Patil, Rajendra Agarwal, Pratap Reddy Padi and Mahesh Reddy Ghanta

*Process Research Laboratory-I, Research & Development Centre, Macleods Pharmaceuticals Ltd, G-2, Mahakali Caves Road, Shantinagar, Andheri (East), Mumbai, Maharastra, India

$Department of Chemistry, Pacific University, Pacific Hills, Airport Road, Pratap Nagar Extension, Debari, Udaipur, Rajasthan, India _____________________________________________________________________

Der Pharma Chemica, 2014, 6(3):300-311 (

Synthesis of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (1) [10] A solution of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (1 tech grade, 5.0 g, 0.015 mol.) in methanol (50.0 mL) was heated the reaction mass at 60-65°C till clear solution was obtained. Water (50.0 mL) was added drop wise into reaction mass with in 30.0 min. at 60-65°C. Resultant white crystalline solid was filtrated, Mahesh Reddy Ghanta et al Der Pharma Chemica, 2014, 6 (3):300-311 _____________________________________________________________________________ 302 washed with water (10.0 mL) and dried in vacuum tray drier at 50-55°C under vacuum to give

2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (1). Yield: 95.0 % (4.75 g)

mp 239°C. Purity by HPLC: 99.74 % (10.2 min. retention time),

Anal. Calcd for C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85. Found: C, 60.70; H, 5.11; N, 8.87 %;

IR (KBr) υmax (in cm−1): 3834.61, 3742.03, 3680.30, 3556.85, 3456.55, 2962.76, 2877.89, 2661.85, 2546.12, 2353.23, 2229.79, 2168.06, 2029.18, 1921.16, 1790.00, 1674.27, 1604.83, 1512.24, 1427.37, 1381.08, 1280.78, 1172.76, 1118.75, 1010.73, 918.15, 833.28, 771.55, 725.26, 648.10, 524.66, 462.93; 1H NMR (300 MHz, CDCl3 or DMSO-d6) δH (in ppm): 1.00-1.02 (d, 6H, (CH3)2-CH-), 2.49-2.50 (m, 1H, (CH3)2-CH-), 3.97-3.99 (d, 2H, -CH-CH2−), 7.33–8.25 (d, dd, 3H, Ar-H), 2.64 (s, 3H, -CH3), 13.39 (s, 1H, -COOH);

13C NMR (300 MHz, DMSO–d6) δC (in ppm) (Positiona ): 166.3 (l), 162.9 (p), 162.2 (n), 159.6 (e), 133.1 (g), 131.6 (i), 125.5 (m), 123.0 (h), 115.5 (k), 114.0 (f), 101.7 (j), 75.2 (d), 27.7 (b), 18.8 (a, c), 17.1 (o);

MS m/z (%) (70 eV): m/z =317.0 (100.0 %) [M+1], 318.0 (16.0 %) [M+2], 403.0 (63.0 %), 512.0 (47.0 %), 482.0 (46.0 %), 405.0 (27.0 %), 468.0 (25.0 %), 570.0 (24.0 %).



WO 2012066561

As per the present invention, hydroxylamine hydrochloride is added to compound of Formula-Ill in presence of a polar aprotic solvent like DMSO, DMA, ACN or DMF. To this reaction mixture acetyl halides or sulfonyl chlorides are added and temperature raised to 70 -80 °C. Acetyl halides are selected from acetyl bromide or acetyl chloride. Sulfonyl chlorides are selected from methane sulfonyl chloride or para toluene sulfonyl chloride. To this reaction mixture a base selected from alkali metal carbonates like potassium carbonate or sodium carbonate, preferably potassium carbonate and alkyl halide selected from isobutyl bromide is successively added. The reaction mass is washed with water and compound of Formula-II is isolated. In one embodiment the present invention provides, process for the preparation of Febuxostat comprising the steps of:

a) reacting the compound of Formula-III(a) with hydroxylamine hydrochloride in presence of organic solvent;

Figure imgf000008_0001


b) adding acyl halides or sulfonyl chlorides to the reaction mixture;

c) optionally isolating compound of Formula- IV (a)

Figure imgf000008_0002


d) reacting with isobutyl bromide in presence of base;

e) isolating the compound of Formula-II(a); and

Figure imgf000008_0003


f) hydrolyzing the compound of Formula-II(a) to get Febuxostat.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art. Experimental procedure:

Example – 1: Preparation of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyI thiozole -5-carboxylate

A mixture of 10. Og of Ethyl -2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 40 g of Dimethyl sulfoxide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 70 -80°C for 2-3 hours. Reaction mass was cooled to room temperature and to this 19 g of potassium carbonate and 19 g of isobutyl bromide was added successively. The reaction mass was stirred for 5 hours at 70-80°C. Reaction mass was diluted with 200 ml of purified water. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxyltae (yield 84.0%)

Example – 2: Preparation of Ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl thiozole – 5-carboxylate

A mixture of 10. Og of Ethyl-2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 30 g of Dimethylformamide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 90°C for 2-3 hours. Reaction mass was cooled to room temperature and diluted with 100 ml of water and stir for 2 hours. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-hydroxy phenyl)-4- methyl thiozole -5-carboxyltae (yield 99.0%).

Example – 3: Preparation of Ethyl 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylate

A mixture of 10. Og of Ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate, 30 g of NMP, 9.6 g of potassium carbonate and 7.2 g of isobutyl bromide were stirred for 3 hours at 90°C. Reaction mass was diluted with 100 ml of purified water. The reaction mass was filtered and washed with purified water and ethanol to give 10.5 g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxyltae (yield 88.0%). Example – 4: Preparation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5- carboxylic acid

A mixture of 10. Og of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5- carboxyltae, 2.0g of sodium hydroxide was heated at 45-60°C in 75 ml of aqueous methanol for 1 hour. Reaction mass was cooled to ambient temperature and pH adjusted to 2.0 to 2.5 with dilute hydrochloric acid and precipitated crystal was collected by filtration to give 8.8g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid (yield 95.8%).

Example – 5-13: Preparation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole – 5-carboxylic acid

The above compound was prepared by following the procedure as disclosed in Example- 4, using the below listed solvents instead of aqueous methanol.

Figure imgf000010_0001

Example – 14: Preparation of pure 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid

10.0 g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid was dissolved in 100 ml of ethanol at reflux temperature. After dissolution reaction mass was cooled and precipitated crystal was collected by filtration to give 9.6 g of pure 2-(3- cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid (yield 96%).


KR 201603732


WO 2015018507


of compound of formula lib

Dissolve 14.14g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula III) in 55 ml dimethylformamide, at ambient temperature. Add 40g of potassium carbonate, along with 15.9 ml isobutyl bromide. Heat the reaction to 75-80 °C and stir for 4 hours. Cool to 25-30 °C, while 165 ml process water is added. Further cool to 0-5 °C and stir for 30 minutes at this temperature. Filter off the precipitated solid and wash the filter cake with 55 ml process water. The wet cake is dried under vacuum at 40 °C for 7 hours, to furnish 16.43 g of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula lib).

of compound of formula Illb

In a 25 mL round-bottomed flask charge under stirring at 25-30 °C, 1.0 g (2.88 mmol) of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate in 3.0 mL dimethylformamide. Add 34 mg (0.19 mmol) copper acetate under stirring at 25-30 °C. Flush with oxygen (02) and add 0.66 ml (34.92 mmol) 25% aqueous ammonia. Flush again with 02. Heat the reaction mixture to 80-82 °C overnight. Check the progress of the reaction by TLC (cyclohexanerethyl acetate 3:1). Cool reaction mass to 25-30 °C. Add 25mL ethyl acetate and 25mL brine at the reaction mass, separate organic layer and extract aqueous layer twice with 25mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate till dry. The residue is purified with column chromatography (cyclohexane:ethyl acetate 9:1). afforded 0.754g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb) Yield: 75.4%.

EXAMPLE 3: Preparation of compound of formula Illb

In a 25 mL round-bottomed flask charge under stirring at 25-30 °C, 0.17 g (0.49 mmol) of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate in 2.5 mL tetrahydrofuran. Add 2.9 mL (153.43 mmol) 25% aqueous ammonia, under stirring at 25-30 °C. Add 137 mg (0.54 mmol) iodine (I2) to the reaction mass, stir the reaction mixture at 25-30 °C for 15-30 min. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 3:1). Starting material is consumed. Add 2.5 mL 5% w/v aqueous sodium thiosulfate Na2S203 and 15mL ethyl acetate at the reaction mass, separate organic layer and extract twice aqueous layer with 15mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate till dry. 0.158g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb) are collected.

EXAMPLE 4: Preparation of Febuxostat

In a 100 ml 2-neck round-bottomed flask charge 2.407g of ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylhiazole-carboxylate in 20ml tetrahydrofuran under stirring, at 25-35 °C, 0.748g of sodium hydroxide and heat reaction mass to 60-65 °C for approximately 8 hrs. Check the progress of the reaction by TLC (cyclohexane:ethyl acetate 3:1). Cool reaction mass to 0-5 °C and add 50 ml process water keeping temperature within 0-5 °C. Adjust pH to 1-2 with 4.5 ml 6 N hydrochloric acid, keeping temperature within 0-5 °C. Warm up reaction mass to 25-30 °C and stir reaction mass at the above temperature for 15 min. Filter off the precipitated solid through Buchner funnel under reduced pressure, spray wash with 2 ml process water and suck dry for 20-30 min. Transfer the crude solid in a 50 ml round-bottomed flask, charge 12 ml process water and 12 ml acetone at 25-30°C. Heat the reaction mass to 50-60 °C for 60 min. Cool down reaction mass to 0-5 °C and stir for 60 min at the above temperature. Filter off the precipitated solid though Buchner funnel under reduced pressure, spray wash with 2 ml of a 1 : 1 mixture of acetone and process water and suck dry for 30-45 min. Dry under vacuum at 60 °C. 1.821g of (compound I) Febuxostat are collected, Purity: 82.6%, Yield: 0.62w/w.

on of compound of formula Ilia

In a 50 mL round-bottomed flask charge under stirring 0.5g (1.72 mmol) of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate in 8.6 mL THF, at 25-30 °C. Add 10.3 mL (544.94 mmol) 25% aqueous ammonia, under stirring at 25-30 °C. Add 480 mg (1.89 mmol) iodine (I2) to the reaction mass, stir the reaction mixture at 25-30 °C for 15-30 min. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 1 :1). Starting material is consumed. Add 8.6 mL 5% w/v aqueous thiosulfate and 40 mL ethyl acetate at the reaction mass, separate organic layer and extract aqueous layer twice with 40 mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate to dryness. Purification of the residue with column chromatography (cyclohexane: ethyl acetate 3: 1) afforded 0.213 g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula Ilia). Yield : 42.6%.

EXAMPLE 6: Preparation of compound Illb

Dissolve 2.2 g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula VI) in 7 ml dimethylformamide and to this mixture add 6.6 g of potassium carbonate and 3.14 g of isobutyl bromide. Stir the reaction at 75 °C for 15 hours and then cool to 40 °C. Add 15 ml process water and cool to 0-5 °C. Filter the precipitated solid off and wash with 15 ml process water, which, after drying, affords 2.28 g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb).

EXAMPLE 7: Preparation of compound I (Febuxostat)

In a 100 ml 2-neck round-bottomed flask charge 2.131 g of ethyl-2(3-cyano-4-isobutoxyphenyl)-4-methylhiazole-carboxylate, 64 ml methanol and 2.5 ml process water are added under stirring at 25-35 °C. Add 1.718 g potassium carbonate and heat reaction mass to reflux for approximately 2-3 hrs. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 3:1). Cool reaction mass to 20-25 °C. Concentrate solvent at below 40 °C. To the residue add 43 ml process water, 21 ml ethyl acetate and stir for 30 min at 25-35 °C. Separate layers and transfer aqueous layer in a 100 ml round-bottomed flask. Adjust pH to 2.3-2.7 with 25 ml 1 N hydrochloric acid, at 25-35 °C. Warm up reaction mass to 40 °C and stir reaction mass at this temperature for 60-90 min. Cool down reaction mass to 25-35 °C. Filter off the precipitated solid through Buchner funnel under reduced pressure, spray wash with 5 ml process water and suck dry for 30-45 min. Dry under vacuum at 60 °C. 1.708g of (compound I) Febuxostat are collected, Purity: 86.7%, Yield: 0.69w/w.

EXAMPLE 8: Preparation of Febuxostat crystalline form III

In a 250 mL round-bottomedflask charge under stirring at 25-30 °C 10 g of crude 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (Febuxostat) in 200 mL ethyl acetate. Heat reaction mass to reflux and stir for 30 min. Cool reaction mass to 25-30°C. Warm again reaction mass and partially distill off solvent from the reaction mass at temperature below 40 °C under reduced pressure. Cool reaction mass to 25-30°C. Filter off the precipitated solid through Buchner funnel under reduced pressure and spray wash with 10 mL ethyl acetate. Dry under vacuum at 60°C. 8.5 g of Febuxostat are collected. Yield: 85 % w/w. XRPD of crystalline compound is in accordance with the one reported in Chinese patent CN101412700B.


CN 104418823

Figure CN104418823AD00042


CN 103588723

Chinese patent CN1275126 described by the Japanese company Teijin invention relates febuxostat Form A, B, C, D, G, and six kinds of amorphous and crystalline preparation method, reported in the literature Form A relatively stable . The method used is a solvent of methanol and water, patent phase diagram (Figure 7 Zone I) can be obtained in anhydrous crystalline Form A (hereinafter referred to as “Form A”), the mixing process by a temperature and the formation of methanol and water to determine the composition of the solvent, and the need to add a certain amount of Form a as a seed crystal to induce precipitation of crystals to control crystallization conditions are very harsh, operable range is very small, easy to form methanol solvate, hydrate or stable crystalline type C, to obtain reproducible single crystal type a low, it is difficult to achieve industrial production, and no mention of the preparation of Form a yield and purity in this patent.


[0012] Chinese patent CN102267957A invention discloses a method for preparing febuxostat Form A, the solvent is preferably acetone, dissolved into 25 ~ 40 ° C was allowed to stand, when there began to crystallize when stirred for 20 to 40 minutes, then placed in -15 ~ 0 ° C to continue the crystallization of 8 to 10 hours. The crystallization process need to well below zero, when industrial mass production, resulting in high production costs, is not conducive to industrial production, the process yield up to 95.4%.

[0013] Chinese patent CN101139325 of Example 7 discloses the preparation of Form A with acetone method, although the process is simple, but the yield is low, only 50%.

[0014] Although the Chinese patent CN101684108A isopropyl alcohol as a solvent is disclosed a method for preparing crystalline form, the crystalline form of preparation is used to cool and heat a phased manner was allowed to stand, the crystallization temperature, long crystallization time, about 30 hours, the yield is low, and its products are not crystalline Form A.

[0015] In addition, Chinese patent CN101525319A, CN101805310, CN101926795A, CN101926794, W02012020272A2 are disclosed ethanol as a solvent or aqueous ethanol as a solvent preparation methods, and its products are crystalline ethanol solvate.

[0016] World Patent W02011139886A2 discloses the use of a mixed solvent of alcohol, and its products are not obtained polymorph A0


Letters in Organic Chemistry (2015), 12(3), 217-221

Synthesis of the Major Metabolites of Febuxostat

Author(s): Xiao Long Li, Rui Qiu, Wei Li Wan, Xu Cheng, Li Hai and Yong Wu

Affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Graphical Abstract:


Total synthesis of three Febuxostat metabolites, named 67M-1, 67M-2, and 67M-4,is described in this article. Through condensation of the key intermediate compound A with different side chains, and then oxidation and hydrolysis, we obtained three target compounds with an overall yield of 19.5%-28.0%.

Page: [217 – 221]
Pages: 5
DOI: 10.2174/1570178612666150108000805

ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16H16N2O3S.

The chemical structure is:


ULORIC (febuxostat) Structural Formula Illustration

Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C.

LORIC tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. ULORIC tablets are coated with Opadry II, green.

CN1642546A * Mar 28, 2003 Jul 20, 2005 Teijin Ltd. Containing a single crystalline solid preparation
CN102471295A * Jul 14, 2010 May 23, 2012 Teijin Pharma Ltd. The method of manufacturing the poor solvent additive method of 2- (3-cyano-4-isobutyl-phenyl) -4-methyl-5-carboxylic acid crystalline polymorph of
EP2502920A1 * Mar 25, 2011 Sep 26, 2012 Sandoz Ag Crystallization process of Febuxostat from A
JP2011020950A* Title not available
WO2015018507A3 * Jul 30, 2014 Oct 22, 2015 Pharmathen S.A. A novel process for the preparation of febuxostat
CN103304512A * Jun 4, 2013 Sep 18, 2013 华南理工大学 Preparation method for febuxostat
WO2011031409A1 * Aug 12, 2010 Mar 17, 2011 Teva Pharmaceutical Industries Ltd. Processes for preparing febuxostat
JP2834971B2 Title not available
JP3202607B2 Title not available
JPH1045733A * Title not available
US5614520 Jan 30, 1995 Mar 25, 1997 Teijin Limited 2-arylthiazole derivatives and pharmaceutical composition thereof
CN102229581A * Nov 15, 2010 Nov 2, 2011 邹巧根 Preparation method for febuxostat intermediate
JPH1045733A * Title not available
CN101497589A * Feb 26, 2009 Aug 5, 2009 沈阳药科大学 Method for synthesizing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-carboxylate
CN101863854A * Jun 29, 2010 Oct 20, 2010 沈阳药科大学 Synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid
JP2706037B2 * Title not available
1 * HASEGAWA, M. ET AL.: ‘A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile‘ HETEROCYCLES vol. 47, no. 2, 1998, pages 857 – 864
Citing Patent Filing date Publication date Applicant Title
WO2012131590A1 * Mar 28, 2012 Oct 4, 2012 Sandoz Ag An improved process for preparation of febuxostat and its polymorphic crystalline form c thereof
WO2014009817A1 * Mar 19, 2013 Jan 16, 2014 Alembic Pharmaceuticals Limited Pharmaceutical composition of febuxostat
WO2014057461A1 Oct 10, 2013 Apr 17, 2014 Ranbaxy Laboratories Limited Process for the preparation of crystalline form g of febuxostat
Systematic (IUPAC) name
1,3-thiazole-5-carboxylic acid
Clinical data
Trade names Uloric, Adenuric, Atenurix, Feburic, Goturic, Goutex. Generic in several countries.[1]
AHFS/ Monograph
MedlinePlus a609020
License data
  • US: C (Risk not ruled out)
Routes of
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~49% absorbed
Protein binding ~99% to albumin
Metabolism via CYP1A2, 2C8, 2C9,UGT1A1, 1A3, 1A9, 2B7
Biological half-life ~5-8 hours
Excretion Urine (~49% mostly as metabolites, 3% as unchanged drug); feces (~45% mostly as metabolites, 12% as unchanged drug)
CAS Number 144060-53-7 
ATC code M04AA03 (WHO)
PubChem CID 134018
DrugBank DB04854 Yes
ChemSpider 118173 Yes
UNII 101V0R1N2E Yes
KEGG D01206 Yes
ChEMBL CHEMBL1164729 Yes
Chemical data
Formula C16H16N2O3S
Molar mass 316.374 g/mol

/////////Febuxostat, 144060-53-7, Uloric, Adenuric,  Tei 6720,  thiazole derivative, inhibitor of XANTHINE OXIDASE,  treatment of HYPERURICEMIA, chronic GOUT, FBX, Febugood, Feburic, Febutaz, TMX 67, Zurig


Title: Febuxostat
CAS Registry Number: 144060-53-7
CAS Name: 2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid
Additional Names: 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
Manufacturers’ Codes: TEI-6720; TMX-67
Molecular Formula: C16H16N2O3S
Molecular Weight: 316.37
Percent Composition: C 60.74%, H 5.10%, N 8.85%, O 15.17%, S 10.14%
Literature References: Xanthine oxidase/xanthine dehydrogenase inhibitor. Prepn: S. Kondo et al., EP 513379eidemUS5614520 (1992, 1997 both to Teijin). Synthesis: M. Hasegawa, Heterocycles 47, 857 (1998). Mechanism of action and crystal structure study: K. Okamoto et al., J. Biol. Chem. 278, 1848 (2003). Pharmacology: Y. Osada et al., Eur. J. Pharmacol. 241, 183 (1993). Clinical pharmacokinetics: M. D. Mayer et al., Am. J. Therap. 12, 22 (2005). Clinical evaluation in hyperuricemia and gout: M. A. Becker et al., N. Engl. J. Med. 353, 2450 (2005). Review of clinical development: B. Tomlinson, Curr. Opin. Invest. Drugs 6,1168-1178 (2005).
Properties: Crystals from ethanol, mp 238-239° (dec). Also reported as crystals from acetone, mp 201-202° (Hasegawa).
Melting point: mp 238-239° (dec); mp 201-202° (Hasegawa)
Therap-Cat: Treatment of hyperuricemia and chronic gout.
Keywords: Antigout; Xanthine Oxidase Inhibitor.




Rifaxidin; Rifacol; Xifaxan; Normix; Rifamycin L 105;L 105 (ansamacrolide antibiotic), L 105SV


 CAS 80621-81-4,  4-Deoxy-4-methylpyrido[1,2-1,2]imidazo[5,4-c]rifamycin SV,

4-Deoxy-4′-methylpyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV, Rifacol

Molecular Weight: 785.87854 g/mol

XIFAXAN tablets for oral administration are film-coated and contain 200 mg or 550 mg of rifaximin.

Rifaximin is an orally administered, semi-synthetic, nonsystemic antibiotic derived from rifamycin SV with antibacterial activity. Rifaximin binds to the beta-subunit of bacterial DNA-dependent RNA polymerase, inhibiting bacterial RNA synthesis and bacterial cell growth. As rifaximin is not well absorbed, its antibacterial activity is largely localized to the gastrointestinal tract.

Rifaximin (trade names:RCIFAX, Rifagut, Xifaxan, Zaxine) is a semisynthetic antibiotic based on rifamycin. It has poor oral bioavailability, meaning that very little of the drug will be absorbed into the blood stream when it is taken orally. Rifaximin is used in the treatment of traveler’s diarrhea, irritable bowel syndrome, and hepatic encephalopathy, for which it receivedorphan drug status from the U.S. Food and Drug Administration in 1998.

 Rifaximin is a rifamycin that was launched in 1988 by Alfa Wasserman for the treatment of bacterial infection, and was commercialized in 2004 by Salix for the treatment of Clostridium difficile-associated diarrhea. In 2008, the product was launched in Germany for the treatment of travelers’ diarrhea caused by non-invasive enteropathogenic bacteria in adults. In 2015, Xifaxan was approved in the U.S. for the treatment of abdominal pain and diarrhea in adult men and women with irritable bowel syndrome with diarrhea. At the same year, Aska filed an application for approval of the product in Japan for the treatment of hepatic encephalopathy.

Rifaximin is licensed by the U.S. Food and Drug Administration to treat traveler’s diarrhea caused by E. coli.[1] Clinical trials have shown that rifaximin is highly effective at preventing and treating traveler’s diarrhea among travelers to Mexico, with fewside effects and low risk of developing antibiotic resistance.[2][3][4] It is not effective against Campylobacter jejuni, and there is no evidence of efficacy against Shigella or Salmonella species.

Launched – 1988 Alfa Wassermann Infection, bacterial
Launched – 2004 Salix Traveler’s diarrhea
Launched – 2010 Salix Encephalopathy, hepatic
Launched – 2015 Salix Irritable bowel syndrome (Diarrhea predominant)
Launched Alfa Wassermann
Merck & Co.

The drug is also at Salix in phase II trials for the treatment of Crohn’s disease. Alfa Wasserman is also conducting phase II trials for Crohn’s disease. The product was approved and launched in the U.S. for the maintenance of remission of hepatic encephalopathy in 2010. Mayo Clinic is conducting phase II clinical trials in the U.S. for the treatment of primary sclerosing cholangitis and the University of Hong Kong is also conducting Phase II trials for the treatment of functional dyspepsia.

It may be efficacious in relieving chronic functional symptoms of bloating and flatulence that are common in irritable bowel syndrome (IBS),[5][6] especially IBS-D.

In February 1998, Salix was granted orphan drug designation by the FDA for the use of rifaximin to treat hepatic encephalopathy. In 2009, a codevelopment agreement was established between Lupin and Salix in the U.S. for the development of a new formulation using Lupin’s bioadhesive drug delivery technology.

There was recentlya pilot-study done on the efficacy of rifaximin as a means of treatment for rosacea, according to the study, induced by the co-presence of small intestinal bacterial overgrowth.[7]

In the United States, rifaximin has orphan drug status for the treatment of hepatic encephalopathy.[8] Although high-quality evidence is still lacking, rifaximin appears to be as effective as or more effective than other available treatments for hepatic encephalopathy (such as lactulose), is better tolerated, and may work faster.[9] Hepatic encephalopathy is a debilitating condition for those with liver disease. Rifaximin is an oral medication taken twice daily that helps patients to avoid reoccurring hepatic encephalopathy. It has minimal side effects, prevents reoccurring encephalopathy and high patient satisfaction. Patients are more compliant and satisfied to take this medication than any other due to minimal side effects, prolong remission, and overall cost.[10] Rifaximin helps patients avoid multiple readmissions from hospitals along with less time missed from work as well. Rifaximin should be considered a standard prescribed medication for those whom have episodes of hepatic encephalopathy.

The drawbacks to rifaximin are increased cost and lack of robust clinical trials for HE without combination lactulose therapy.

Also treats hyperammonemia by eradicating ammoniagenic bacteria.

Mechanism of action

Rifaximin interferes with transcription by binding to the β-subunit of bacterial RNA polymerase.[11] This results in the blockage of the translocation step that normally follows the formation of the first phosphodiester bond, which occurs in the transcription process.[12]


A 2011 study in patients with IBS (sans constipation) indicated 11% showed benefits over a placebo.[13] The study was supported by Salix Pharmaceuticals, the patent holder.[13] A 2010 study in patients treated for Hepatic Cirrhosis with hospitalization involving Hepatic encephalopathy resulted in 22% of the rifaxmin treated group experiencing a breakthrough episode of Hepatic encephalopathy as compared to 46% of the placebo group. The majority patients were also receivingLactulose therapy for prevention of hepatic encephalopathy in addition to Rifaximin.[14] Rifaximin shows promising results, causing remission in up to 59% of people with Crohn’s disease and up to 76% of people with Ulcerative Colitis.[15]


In the United States, Salix Pharmaceuticals holds a US Patent for rifaximin and markets the drug under the name Xifaxan, available in tablets of 200 mg and 550 mg.[16][17] In addition to receiving FDA approval for traveler’s diarrhea and (marketing approved for)[17] hepatic encephalopathy, Xifaxan received FDA approval for IBS in May 2015.[18] No generic formulation is available in the US and none has appeared due to the fact that the FDA approval process was ongoing. If Xifaxan receives full FDA approval for hepatic encephalopathy it is likely that Salix will maintain marketing exclusivity and be protected from generic formulations until March 24, 2017.[17] Price quotes received on February 21, 2013 for Xifaxan 550 mg in the Denver Metro area were between $23.57 and $26.72 per tablet. A price quote received on June 24, 2016 for Xifaxan 550 mg was $31.37 per tablet.

Rifaximin is approved in 33 countries for GI disorders.[19][20] On August 13, 2013, Health Canada issued a Notice of Compliance to Salix Pharmaceuticals Inc. for the drug product Zaxine.[21] In India it is available under the brand names Ciboz and Xifapill.[










Direct infusion mass analysis ESI (+)







Rifaximin is a broad-spectrum antibiotic belonging to the family of Rifamycins and shows its antibacterial activity, in the gastrointestinal tract against localized bacteria that cause infectious diarrhoea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn’s disease, and/or pancreatic insufficiency.

Rifaximin is sold under the brand name Xifaxan® in US for the treatment of Travellers’ diarrhoea and Hepatic Encephalopathy. The chemical name of Rifaximin is (2S , 16Z, 18E,20S ,21 S ,22R,23R,24R,25S ,26S ,27S ,28E)-5,6,21 ,23 ,25-pentahydroxy-27-methoxy-2,4,1 l,16,20,22,24,26-octamethyl-2,7(epoxypentadeca-[l,l l,13]trienimino) benzofuro[4,5-e]pyrido[l,2-a]-benzimidazole-l,15(2H)-dione,25-acetate and the molecular formula is G^HsiNsOn with a molecular weight of 785.9. The structural formula of Rifaximin is:

Formula I

Rifaximin was first described and claimed in Italian patent IT 1154655 and U.S. Pat. No.4,341,785. These patents disclose a process for the preparation of Rifaximin and a method for the crystallisation thereof. The process for the preparation of Rifaximin is as depicted in scheme I given below:

Scheme -I

U.S. Pat. No. 4,179,438 discloses a process for the preparation of 3-bromorifamycin S which comprises reaction of rifamycin S with at least two equivalents of bromine, per one mole of rifamycin S in the presence of at least one mole of pyridine per each equivalent of bromine and in the presence of ethanol, methanol or mixtures thereof with water at a

temperature not above the room temperature. The process is shown in the scheme given below:

Rifamycin S 3-Bromo-Rifamycin-S

U.S. Patent No.4,557, 866 discloses a process for one step synthesis of Rifaximin from Rifamycin O, which is shown in scheme II given below:

Rifamycin O                                                                                                               Rifaximin

Scheme -II

US ‘866 patent also discloses purification of Rifaximin by performing crystallization of crude Rifaximin from a 7:3 mixture of ethyl alcohol/water followed by drying both under atmospheric pressure and under vacuum. The crystalline form which is obtained has not been characterized.

U.S. Patent No. 7,045,620 describes three polymorphic forms α, β and γ of Rifaximin. Form a and β show pure crystalline characteristics while the γ form is poorly crystalline. These polymorphic forms are differentiated on the basis of water content and PXRD. This patent also discloses processes for preparation of these polymorphs which involve use of specific reaction conditions during crystallization like dissolving Rifaximin in ethyl alcohol at 45-65°C, precipitation by adding water to form a suspension, filtering suspension and washing the resulted solid with demineralized water, followed by drying at room temperature under vacuum for a period of time between 2 and 72 hours. Crystalline forms a and β are obtained by immediate filtration of suspension when temperature of reaction mixture is brought to 0°C and poorly crystalline form γ is obtained when the reaction mixture is stirred for 5-6 hours at 0°C and then filtered the suspension. In addition to above these forms are also characterized by specific water content. For a form water content should be lower than 4.5%, for β form it should be higher than 4.5% and to obtain γ form, water content should be below 2%.

U.S. Patent No. 7,709,634 describes an amorphous form of Rifaximin which is prepared by dissolving Rifaximin in solvents such as alkyl esters, alkanols and ketones and precipitating by addition of anti-solvents selected from hydrocarbons, ethers or mixtures thereof.

U.S. Patent No. 8,193,196 describes two polymorphic forms of Rifaximin, designated δ and ε respectively. Form δ has water content within the range from 2.5 to 6% by weight (preferably from 3 to 4.5%).

U.S. Patent No 8,067,429 describes a-dry, β-1, β-2, ε-dry and amorphous forms of Rifaximin.

U.S. Patent No. 8,227,482 describes polymorphs Form μ, Form π, Form Omicron, Form Zeta, Form Eta, Form Iota and Form Xi of Rifaximin.

International application publications WO 2008/035109, WO 2008/155728, WO 2012/035544, WO 2012/060675, and WO 2012/156533 describes various amorphous or poorly crystalline forms of Rifaximin.

These polymorphic forms are obtained under different experimental conditions and are characterized by XRPD pattern.

The polymorphic forms of Rifaximin obtained from the prior art methods have specific water content. Transition between different polymorphic forms of Rifaximin occurs by drying or wetting of the synthesized Rifaximin. Hence, it is evident from above that Rifaximin can exist in number of polymorphic forms, formation of these polymorphic forms depends upon specific reaction conditions applied during crystallization and drying.

Rifaximin is a semi-synthetic, rifamycin-based non-systematic antibiotic. It is chemically termed as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26 S,27S, 28E)-5,6,21,23,255-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]-benzimida-zole-1,15(2H)-dione,25-acetate (I).

Figure imgb0001

Rifaximin is used for treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli.

Rifaximin was first disclosed in US4341785 which also discloses a process for its preparation and a method for crystallization of rifaximin using suitable solvents or mixture of solvents. However, this patent does not mention the polymorphism of rifaximin.

Canadian patent CA1215976 discloses a process for the synthesis of imidazo rifamycins which comprises reacting rifamycin S with 2-amino-4-methyl pyridine.

US4557866 discloses a process for preparation of rifaximin, but does not mention the polymorphs of rifaximin.

US7045620 discloses crystalline polymorphic forms of rifaximin which are termed as rifaximin α, rifaximin β and rifaximin γ. These polymorphic forms are characterized using X-ray powder diffraction. Further this patent mentions that γ form is poorly crystalline with a high content of amorphous component. This patent also discloses processes for preparation of these polymorphs which involve use of processes of crystallization and drying as disclosed in US4557866along with control of temperature at which the product is crystallized, drying process, water content thereof. Further, according to this patent, crystal formation depends upon the presence of water within the crystallization solvent.

The above patent discloses rifaximin α which is characterized by water content lower than 4.5% & powder X-ray diffractogram having significant peaks are at values of diffraction angles 2θ of 6.6°; 7.4°; 7.9°, 8.8°, 10.5°, 11.1 °, 11.8°, 12.9°, 17.6°, 18.5°, 19.7°, 21.0°, 21.4°, 22.1°; rifaximin β which is characterized by water content higher than 4.5% & powder X-ray diffractogram having significant peaks are at values of diffraction angles 2θ of 5.4°; 6.4°; 7.0°, 7.8°, 9.0°, 10.4°, 13.1°, 14.4°, 17.1°, 17.9°, 18.3°, 20.9° and rifaximin γ which is characterized by poorer powder X-ray diffractogram because of poor crystallinity. The significant peaks are at values of diffraction angles 2θ of 5.0°; 7.1°; 8.4°.

US2005/0272754 also discloses polymorphs of rifaximin namely rifaximin α form, rifaximin β form & rifaximin γ form characterized by powder X-ray diffractogram, intrinsic dissolution rates and processes of preparation of polymorphic forms of rifaximin. However, none of the above patents disclose a wholly amorphous form of rifaximin.

It is a well known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties. The amorphous form of a drug may exhibit different dissolution characteristics and in some case different bioavailability patterns compared to crystalline forms.

Further, amorphous and crystalline forms of a drug may have different handling properties, dissolution rates, solubility, and stability.

Furthermore, different physical forms may have different particle size, hardness and glass transition temperatures. Amorphous materials do not exhibit the three-dimensional long-range orders found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random.

Amorphous solids do not give a definitive x-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a specific melting point and tend to liquefy at some point beyond the glass transition temperature. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide enhanced bioavailability characteristics such as a higher rate and extent of absorption of the compound from the gastrointestinal tract. Also, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in the manufacturing process of solid dosage form such as compressibility.


The schematic representation for preparation of amorphous rifaximin is as follows :

Figure imgb0002

Amorphous rifaximin according to the present invention can be characterized by various parameters like solubility, intrinsic dissolution, bulk density, tapped density.

Rifaximin is known to exist in 3 polymorphic Forms namely α Form, β Form & γ Form of which the α Form is thermodynamically the most stable. Hence, the amorphous form of rifaximin was studied in comparison with α Form.

Further, when intrinsic dissolution of amorphous rifaximin is carried out against the α Form, it is observed that the amorphous rifaximin has better dissolution profile than α Form which is shown in table below (this data is also shown graphically in Figure 3):

Dissolution medium : 1000 ml of 0.1M Sodium dihydrogen phosphate monohydrate + 4.5g of sodium lauryl sulphate

Temperature : 37±0.5°C

Rotation speed : 100 rpm

Particle size : Amorphous rifaximin – 11 microns

α Form of rifaximin – 13 microns

  • Time in minutes % Release of Amorphous Rifaximin % Release of α Form of Rifaximin
    15 1.1 0.8
    30 1.9 1.8
    45 2.9 3.0
    60 3.7 4.4
    120 8.1 11.0
    180 12.6 18.0
    240 16.6 24.6
    360 24.7 38.7
    480 32.0 47.5
    600 39.5 52.7
    720 46.4 56.4
    960 60.4 62.9
    1200 72.9 67.8
    1400 83.0 72.7
    Amorphous rifaximin exhibits bulk density in the range of 0.3 – 0.4 g/ml and tapped density is in the range of 0.4 – 0.5 g/ml while the α Form rifaximin exhibits bulk density in the range of 0.2 – 0.3 g/ml & tapped density is in the range of 0.3 – 0.4 g/ml. These higher densities of amorphous rifaximin are advantageous in formulation specifically in tablet formulation, for example, it gives better compressibility.


Rifaximin (CAS NO.: 80621-81-4), with other name of 4-Deoxy-4-methylpyrido[1,2-1,2]imidazo[5,4-c]rifamycin SV, could be produced through many synthetic methods.

Following is one of the reaction routes:

The reaction of rifamycin S (I) with pyridine perbromide (II) in 2-propanol/chloroform (70/30) mixture at 0 C gives 3-bromorifamicin S (III), which is then condensed with 2-amino-4-methyl-pyridine (IV) at 10 C. The o-quinoniminic compound (V) is then obtained. This compound is finally reduced with ascorbic acid.


Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class, exactly it is a pyrido-imidazo rifamycin described and claimed in Italian Patent IT 1154655, while European Patent EP 0161534 describes and claims a process for its production starting from rifamycin O (The Merck Index, XIII Ed., 8301).

Both these patents describe the purification of rifaximin in a generic way stating that crystallization can be carried out in suitable solvents or solvent systems and summarily showing in some examples that the reaction product can be crystallized from the 7:3 mixture of ethyl alcohol/water and can be dried both under atmospheric pressure and under vacuum without specifying in any way either the experimental conditions of crystallization and drying, or any distinctive crystallographic characteristic of the obtained product.

The presence of different polymorphs had just not been noticed and therefore the experimental conditions described in both patents had been developed with the goal to get a homogeneous product having a suitable purity from the chemical point of view, independent from the crystallographic aspects of the product itself.

It has now been found, unexpectedly, that there are several polymorphous forms whose formation, besides the solvent, depends on time and temperature conditions under which both crystallization and drying are carried out.

In the present application, these orderly polymorphous forms will be, later on, conventionally identified as rifaximin α (FIG. 1) and rifaximin β (FIG. 2) on the basis of their respective specific diffractograms, while the poorly crystalline form with a high content of amorphous component will be identified as rifaximin γ (FIG. 3).

Rifaximin polymorphous forms have been characterized through the technique of the powder X-ray diffraction.

The identification and characterization of these polymorphous forms and, simultaneously, the definition of the experimental conditions for obtaining them is very important for a compound endowed with pharmacological activity which, like rifaximin, is marketed as medicinal preparation, both for human and veterinary use. In fact it is known that the polymorphism of a compound that can be used as active ingredient contained in a medicinal preparation can influence the pharmaco-toxicologic properties of the drug. Different polymorphous forms of an active ingredient administered as drug under oral or topical form can modify many properties thereof like bioavailability, solubility, stability, colour, compressibility, flowability and workability with consequent modification of the profiles of toxicological safety, clinical effectiveness and productive efficiency.

What mentioned above is confirmed by the fact that the authorities that regulate the grant of marketing authorization of the drugs market require that the manufacturing methods of the active ingredients are standardized and controlled in such a way that they give homogeneous and sound results in terms of polymorphism of production batches (CPMP/QWP/96, 2003—Note for Guidance on Chemistry of new Active Substance; CPMP/ICH/367/96—Note for guidance specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances; Date for coming into operation: May 2000).

The need for the above-mentioned standardization has further been strengthened in the field of the rifamycin antibiotics by Henwood S. Q., de Villiers M. M., Liebenberg W. and Lotter A. P., Drug Development and Industrial Pharmacy, 26 (4), 403-408, (2000), who have ascertained that different production batches of the rifampicin (INN) made from different manufacturers differ from each other in that they show different polymorphous characteristics, and as a consequence they show different dissolution profiles, along with a consequent alteration of the respective pharmacological properties.

By applying the crystallization and drying processes generically disclosed in the previous patents IT 1154655 and EP 0161534 it has been found that under some experimental conditions a poorly crystalline form of rifaximin is obtained, while under other experimental conditions other polymorphic crystalline forms of Rifaximin are obtained. Moreover it has been found that some parameters, absolutely not disclosed in the above-mentioned patents, like for instance preservation conditions and the relative ambient humidity, have the surprising effect to determine the polymorph form.

The polymorphous forms of rifaximin object of the present patent application were never seen or hypothesized, while thinking that, whichever method was used within the range of the described condition, a sole homogeneous product would always have been obtained, irrespective of crystallizing, drying and preserving conditions. It has now been found that the formation of α, β and γ forms depends both on the presence of water within the crystallization solvent, on the temperature at which the product is crystallized and on the amount of water present in the product at the end of the drying phase. Form α, form β and form γ of rifaximin have then been synthesized and they are the object of the invention.

Moreover it has been found that the presence of water in rifaximin in the solid state is reversible, so that water absorption and/or release can take place in time in presence of suitable ambient conditions; consequently rifaximin is susceptible of transition from one form to another, also remaining in the solid state, without need to be again dissolved and crystallized. For instance polymorph α, getting water by hydration up to a content higher than 4.5%, turns into polymorph β, which in its turn, losing water by drying up to a content lower than 4.5%, turns into polymorph α.

These results have a remarkable importance as they determine the conditions of industrial manufacturing of some steps of working which could not be considered critical for the determination of the polymorphism of a product, like for instance the washing of a crystallized product, or the preservation conditions of the end product, or the characteristics of the container in which the product is preserved.

The above-mentioned α, β and γ forms can be advantageously used as pure and homogeneous products in the manufacture of medicinal preparations containing rifaximin.

As already said, the process for manufacturing rifaximin from rifamycin O disclosed and claimed in EP 0161534 is deficient from the point of view of the purification and identification of the product obtained; it shows some limits also from the synthetic point of view as regards, for instance, the very long reaction times, from 16 to 72 hours, not very suitable to an industrial use and moreover because it does not provide for the in situ reduction of rifaximin oxidized that may be formed within the reaction mixture.

Therefore, a further object of the present invention is an improved process for the industrial manufacturing of the α, β and γ forms of rifaximin, herein claimed as products and usable as defined and homogeneous active ingredients in the manufacture of the medicinal preparations containing such active ingredient.


FIG. 1 is a powder X-ray diffractogram of rifaximin polymorphic form α.

FIG. 2 is a powder X-ray diffractogram of rifaximin polymorphic form β.

FIG. 3 is a powder X-ray diffractogram of rifaximin polymorphic form γ.


Patent US20130004576

Rifaximin (INN; see The Merck Index, XIII Ed., 8304, CAS no. 80621-81-4), IUPAC nomenclature (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25 pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-(1,11,13)trienimino)benzofuro(4,5-e)pyrido(1,2,-a)benzimidazole-1,15(2H)-dione,25-acetate) is a semi-synthetic antibiotic belonging to the rifamycin class of antibiotics. More precisely rifaximin is a pyrido-imidazo rifamycin described in the Italian patent IT 1154655, whereas the European patent EP 0161534 discloses a process for rifaximin production using rifamycin O as starting material (The Merck Index, XIII Ed., 8301).

U.S. Pat. No. 7,045,620, US 2008/0262220, US 7,612,199, US 2009/0130201 and Cryst. Eng. Comm., 2008, 10 1074-1081 (2008) disclose new forms of rifaximin.

WO 2008/035109 A1 discloses a process to prepare amorphous rifaximin, which comprises reaction of rifamycin S with 2-amino-4 picoline in presence of organic solvent like dichloromethane, ethylacetate, dichloroethylene, chloroform, in an inert atmosphere. When water is added to the reaction mixture, a solid precipitate corresponding to amorphous rifaximin is obtained.

The process described in this document can be assimilated to a crash precipitation, wherein the use of an anti-solvent causes the precipitation of rifaximin without giving any information about the chemical physical and biological characteristics of the rifaximin obtained.

WO 2009/108730 A2 describes different polymorphous forms of rifaximin and also amorphous forms of rifaximin. Amorphous forms are prepared by milling and crash precipitation and with these two different methods the amorphous rifaximin obtained from these two different processes has the same properties.

FIG. 4: 13C-NMR spectrum of rifaximin obtained by spray drying process.

FIG. 5: FT-IR spectrum of rifaximin obtained by spray drying process.


WO 2015014984

Rifaximin, lUPAC name:

(2S,16Z,18E,20S,21 S,22H,23H,24H,25S,26S,27S,28£)-5,6,21 ,23,25-pentahydroxy- 27-methoxy-2,4,1 1 ,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1 ,1 1 ,13]-trienimmino)-benzofuro-[4,5-e]-pirido-[1 ,2-oc]-benzimidazol-1 , 15(2 -/)-dione,25-acetate, is the compound of formula (I):

Rifaximin is a broad-spectrum antibiotic belonging to the family of rifamycins, devoid of systemic activity. In view of its physicochemical properties, it is not adsorbed in the gastrointestinal tract and therefore exerts its antimicrobial action inside the gastrointestinal tract. Rifaximin therefore has applications in the treatment of diarrhoea and of microbial infections of the gastrointestinal tract typically caused by E. coli, a microorganism which, being incapable of passing through the mucosa of the gastrointestinal tract, remains in contact with the gastrointestinal fluids. Rifaximin also has applications for the treatment of irritable bowel syndrome, Crohn’s disease, diverticulitis and for antibiotic prophylaxis preceding surgical operations on the intestines.

Rifaximin was obtained and described for the first time in the EP161534 starting from rifamycin O and 2-amino-4-picoline in the presence of ethanol/water and

ascorbic acid/HCI to obtain raw rifaximin which is then treated with Ethanol/water to obtain crystallized rifaximin.

Polymorphic forms of rifaximin, and processes for their synthesis and purification, are described in various documents of the known art.

Rifaximin K was firstly described in WO2012/156951 . Such a crystalline form resulted to be more stable in the presence of humidity than the other known crystalline forms of rifaximin, thus enabling the storage, even for prolonged periods. Such a polymorph was obtained by a process starting from rifaximin comprising the following steps: -suspending or dissolving rifaximin in a 1 ,2-dimethoxyethane based solvent, recovering the product and drying to remove said 1 ,2-dimethoxyethane based solvent. In one of the embodiments of the invention 1 ,2-dimethoxyethane is used as the unique solvent of rifaximin, in other 1 ,2-dimethoxyethane is described as used in combination of n-heptane, methanol, acetonitrile, R-COO-R1 esters wherein R and R1 are independently C3-C6 alkyl radicals, and C3-C7 alkyl ketones, ethanol, isopropanol and water.


The synthesis of 4-deoxypyrido(1′,2′-1,2)imidazo(5,4-c)rifamycin SV derivatives
J Antibiot 1984, 37(12): 1611




Treatment of rifamycin S (I) with Pyr·Br2 in 2-PrOH/CHCl3 gives 3-bromorifamycin S (II) (1), which upon cyclocondensation with 2-amino-4-methyl-pyridine (III) (1,2,3) in CHCl3 (2) or EtOH (3) yields imine derivative (IV). Finally, reduction of (IV) with L-(+)- ascorbic acid (1,2,3) in MeOH (2) or EtOH (3) provides the target rifaximin (1,2,3).



WO 2005044823, WO 2012035544, WO 2015014984


Rifaximin is prepared by the cyclocondensation of rifamycin-O  with 2-amino-4-picoline  in a solvent mixture such as acetone, acetonitrile, EtOH, MIBK, propylene glycol, i-PrOH or t-BuOH and H2O at 50 °C or EtOH/aceone/H2O or optionally in the presence of I2 in CH2Cl2


WO 2015159275

The process is shown in the scheme given below:




Example 1;

5g of Rifamycin S, 3.1 gms of 2-amino-4-methyl pyridine, 0.45 g of iodine, 1.65 ml of acetic acid and 20ml of acetonitrile were charged in a clean and dry round bottom flask followed by stirring the resultant reaction mixture at about 30°C for about 30 hours. The reaction progress was monitored by TLC, after completion of reaction, the reaction mass was quenched by adding a mixture of 4.0g of ascorbic acid dissolved in 20 ml of water. The resultant reaction suspension was stirred at about 25°C for about 15mins. 25 ml of dichloromethane was charged and stirred for about 15mins. followed by separation of organic and aqueous phases. The aqueous phase was extracted with 25 ml of dichloromethane followed by separation of organic and aqueous phases. The organic phases were combined and distilled at below about 50°C to yield Rifaximin as residue. 11.25ml of purified water and 11.25ml of ethanol were charged to the residue and stirred at about 30°C for about 15 mins. The resultant reaction

suspension was heated to about 75°C and stirred for about 30mins. The resultant reaction solution further cooled to about 25 °C and stirred for about 2 hours followed by further cooling to about 5°C for about 3 hours. The solid precipitated was filtered and the solid was washed with a mixture of 2.5ml of ethanol and 2.5 ml of purified water. The solid obtained was dried at about 50°C for about 10 hours to afford 3 g. of Rifaximin as crystalline form. Purity by HPLC: 99.85 area %.


European journal of medicinal chemistry (2015), 103, 551-62



Example 1 : Purification of Rifamycin S

Rifamycin S (500g) and Ethanol (1.5L) were stirred and refluxed for 1 hour. The reaction mixture was then cooled slowly to ambience, stirred at this temperature for 2 hour and filtered. The product dried in vacuum oven at 40 °C to obtain 475g of pure Rifamycin S showing the des acetyl impurity below to 0.6%.

Example 2: Preparation of rifaximin

Rifamycin S (300 g) was stirred in dichloromethane (900 ml) at room temperature for 15 minutes to get a clear solution and then 2-Amino-4-methyl pyridine (139.2g) was added at room temperature under nitrogen atmosphere. Iodine (57. Og) dissolved in dichloromethane (2100ml), was added drop wise in 30-45 minutes at room temperature. The reaction mass was stirred for 22-24 hours at 25-30 °C. After completion of the reaction, a 20% solution of L(-) ascorbic acid in water (300 ml) was added. The reaction mixture was stirred for 45-60 minutes at room temperature and then cooled to 10-15 °C. The pH of the resulting solution was adjusted to 1.5-2.0 with slow addition of dilute hydrochloric acid under stirring. The reaction mass was stirred for 15-20 minutes and layers were separated. The organic layer was washed with demineralized water (1500 ml), 10% sodium thiosulfate solution (1500 ml) and with demineralized water till pH was neutral. The solvent was distilled off under vacuum at 40-45 °C to get a residue which was taken in cyclohexane (1500 ml) and stirred for 1 hour. The resulting solid was filtered, washed with cyclohexane (300 ml) crystallized from a mixture of ethyl alcohol and water (600ml; 420ml ethyl alcohol and 180 ml water) to get 240g of crude rifaximin having purity 99.3% by HPLC.

Example 3: Preparation of rifaximin

Step-1: Preparation of crude rifaximin

Rifamycin S (300 g) was stirred in dichloromethane (900 ml) at room temperature for 15 minutes to get a clear solution and then 2-amino-4-methyl pyridine (139.2g) was added at room temperature under nitrogen atmosphere. Iodine (57. Og) dissolved in dichloromethane (2100ml), was added drop wise in 30-45 minutes at room temperature and was stirred for 22-24 hours. After completion of the reaction, a 20% solution of L (-) ascorbic acid in water (300 ml) was added and stirred for 45-60 minutes. The reaction mass was cooled to 10-15 °C and pH of the resulting solution was adjusted to 1.5-2.0 with slow addition of dilute hydrochloric acid under stirring. The reaction mass was stirred for 15-20 minutes and layers were separated and the organic layer was washed with demineralized water (1500 ml), with 10% sodium thiosulfate solution (1500 ml) and demineralized water till pH was neutral. The solvent was distilled off under vacuum at 40-45 °C to obtain a residue which was crystallized from a mixture of ethyl alcohol and water (378ml ethyl alcohol and 162 ml water) and dried at 35-40 °C to obtain 240g crude rifaximin having purity 98.8% by HPLC. Step-2: Purification of crude rifaximin

Crude rifaximin (240g) was stirred in dichloromethane (2400ml) at room temperature, a neutral alumina (240g) was added, stirred for 1 hour and filtered. The solvent was then distilled off and residue was treated with ethyl acetate (2400ml) and stirred to dissolution. The resulting residue was crystallized from a mixture of ethyl alcohol and water (302ml ethyl alcohol and 130ml water) and dried at 35-40 “C to obtain 192g of rifaximin having purity 99.8% by HPLC.






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CN103269587A * Jun 3, 2011 Aug 28, 2013 萨利克斯药品有限公司 New forms of rifaximin and uses thereof
WO2011153444A1 * Jun 3, 2011 Dec 8, 2011 Salix Pharmaceuticals, Ltd New forms of rifaximin and uses thereof


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External links

Patent Number Pediatric Extension Approved Expires (estimated)
US6861053 No 1999-08-11 2019-08-11 Us
US7045620 No 2004-06-19 2024-06-19 Us
US7452857 No 1999-08-11 2019-08-11 Us
US7605240 No 1999-08-11 2019-08-11 Us
US7612199 No 2004-06-19 2024-06-19 Us
US7718608 No 1999-08-11 2019-08-11 Us
US7902206 No 2004-06-19 2024-06-19 Us
US7906542 No 2005-06-01 2025-06-01 Us
US7915275 No 2005-02-23 2025-02-23 Us
US7928115 No 2009-07-24 2029-07-24 Us
US7935799 No 1999-08-11 2019-08-11 Us
US8158644 No 2004-06-19 2024-06-19 Us
US8158781 No 2004-06-19 2024-06-19 Us
US8193196 No 2007-09-02 2027-09-02 Us
US8309569 No 2009-07-18 2029-07-18 Us
US8518949 No 2006-02-27 2026-02-27 Us
US8642573 No 2009-10-02 2029-10-02 Us
US8741904 No 2006-02-27 2026-02-27 Us
US8829017 No 2009-07-24 2029-07-24 Us
US8835452 No 2004-06-19 2024-06-19 Us
US8853231 No 2004-06-19 2024-06-19 Us
US8946252 No 2009-07-24 2029-07-24 Us
US8969398 No 2009-10-02 2029-10-02 Us
Rifaximin ball-and-stick.png
Systematic (IUPAC) name
Clinical data
Trade names Xifaxan, Xifaxanta, Normix, Rifagut
AHFS/ Monograph
MedlinePlus a604027
  • US: C (Risk not ruled out)
Routes of
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability < 0.4%
Metabolism Hepatic
Biological half-life 6 hours
Excretion Fecal (97%)
CAS Number 80621-81-4 Yes
ATC code A07AA11 (WHO) D06AX11(WHO) QG51AA06 (WHO)QJ51XX01 (WHO)
PubChem CID 6436173
DrugBank DB01220 Yes
ChemSpider 10482302 Yes
UNII L36O5T016N Yes
KEGG D02554 Yes
ChEBI CHEBI:75246 
Chemical data
Formula C43H51N3O11
Molar mass 785.879 g/mol

Giuseppe Viscomi, Manuela Campana, Dario Braga, Donatella Confortini, Vincenzo Cannata, Paolo Righi, Goffredo Rosini, “Polymorphic forms of rifaximin, processes for their production and uses thereof.” U.S. Patent US20050272754, issued December 08, 2005.


///////Rifaximin,  Rifaxidin,  Rifacol,  Xifaxan,  Normix,  Rifamycin L 105, 80621-81-4


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