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Calcifediol (INN), also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D), 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. At a typical daily intake of vitamin D3, its full conversion to calcifediol takes approximately 7 days.
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.
In medicine, a 25-hydroxy vitamin D (calcifediol) blood test is used to determine how much vitamin D is in the body. The blood concentration of calcifediol is considered the best indicator of vitamin D status.
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. Patients with osteoporosis, chronic kidney disease, malabsorption, obesity, and some other infections may be high risk and thus have greater indication for this test. 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. Physicians may advise low risk patients to take over-the-counter vitamin D in place of having screening.
It is the most sensitive measure, though experts have called for improved standardization and reproducibility across different laboratories. According to MedlinePlus, the normal range of calcifediol is 30.0 to 74.0 ng/mL. 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, while other studies have defined levels below 80 nmol/L (32 ng/ml) as indicative of vitamin D deficiency.
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.
Increasing calcifediol levels are associated with increasing fractional absorption of calcium from the gut up to levels of 80 nmol/L (32 ng/mL).Urinary calcium excretion balances intestinal calcium absorption and does not increase with calcifediol levels up to ~400 nmol/L (160 ng/mL).
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. However, randomized controlled trials failed to find a significant correlation between vitamin D supplementation and the risk of colon cancer.
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.
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
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.
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]
- The interactive pathway map can be edited at WikiPathways: “VitaminDSynthesis_WP1531”.
- “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.
- 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.
- Am J Clin Nutr 2008;87:1738–42 PMID 18541563
- 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.
- 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.
- “25-hydroxy vitamin D test: Medline Plus”. Retrieved 21 March 2010.
- 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.
- 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
- 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.
- Institute of Medicine (1997), p. 259
- 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.
- 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.
- Kimball; et al. (2004). “Safety of vitamin D3 in adults with multiple sclerosis”. J Clin Endocrinol Metab. 86 (3): 645–51. PMID 17823429.
- 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.
- 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.
- “Too much vitamin D can be as unhealthy as too little” (Press release). University of Copenhagen. May 29, 2012. Retrieved 2015-05-27.
- 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.
|3D model (Jmol)||Interactive image|
|Molar mass||400.64 g/mol|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|80573-04-2; Colazal; Balsalazide Disodium; AC1NSFNR; P80AL8J7ZP;|
|Molecular Weight:||357.322 g/mol|
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, 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 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 and reported the preparation of the title compound in 64.6% overall yield. Zhenhau et al have synthesized 1 from 4-nitrobenzoic acid (12) via chlorination, condensation, hydrogenation, diazotization, coupling and salt formation with overall yield 73%. Li et al have given product in 73.9% total yield starting from 4-nitrobenzoyl chloride (6), where as Yuzhu et al confirmed chemical structure of Balsalazide disodium by elemental analysis, UV, IR, 1H-NMR and ESI-MS etc. Shaojie et al have also followed same process for its preparation. Yujie et al 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 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.
- Starting material is 4-aminohippuric acid, obtained by coupling para-aminobenzoic acid and glycine.
- That product is then treated with nitrous acid to give the diazonium salt.
- 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
β-alanine (3-aminopropionic acid)
m-aminobenzoic acid and esters and amides thereof
p-aminobenzoic acid and esters and amides thereof
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.
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.
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.).
- 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 . PMID 11709512.
|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|
|US2011319267||AROMATIC CARBOXYLIC ACID DERIVATIVES FOR TREATMENT AND PROPHYLAXIS OF GASTROINTESTINAL DISEASES INCLUDING COLON CANCERS||2011-12-29|
|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|
|Trade names||Colazal, Giazo|
|ATC code||A07EC04 (WHO)|
|Chemical and physical data|
|Molar mass||357.318 g/mol|
|3D model (Jmol)||Interactive image|
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“We have launched ezetimibe, the first and only generic version of Zetia (Merck) in the United States for the treatment of high cholesterol,”……….http://health.economictimes.indiatimes.com/news/pharma/glenmark-launches-generic-version-of-zetia-in-us-market/55951453
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
“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………http://www.glenmarkpharma.com/
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 http://www.endo.com
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.
////////////Glenmark, Launches, First, Only, Generic Version, Zetia®, United States, ezetimibe, par pharmaceutical, cholesterol, Endo International plc
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.
Keywords: Antiglaucoma; Carbonic Anhydrase Inhibitor; Diuretic; Sulfonamide Derivatives.
14N NQR, 1H NMR and DFT/QTAIM study of hydrogen bonding and polymorphism in selected solid 1,3,4-thiadiazole derivatives
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DOI: 10.1039/C0CP00195C, http://pubs.rsc.org/en/content/articlelanding/2010/cp/c0cp00195c#!divAbstract
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 Weight:||316.37484 g/mol|
Febuxostat is a thiazole derivative and inhibitor of XANTHINE OXIDASE that is used for the treatment of HYPERURICEMIA in patients with chronic GOUT.
- 2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid
- 2-(3-Cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
- TMX 67
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.
Febuxostat is used to treat chronic gout and hyperuricemia. 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.
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.
Mechanism of action
Febuxostat is a non-purine-selective inhibitor of xanthine oxidase. 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.
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 authorities in 2011. Ipsen exclusively licensed its European rights to Menarini in 2009. Teijin partnered with Astellas for distribution in China and southeast Asia.
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.
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.
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.
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:
2: Patent JP1994329647 febuxostat synthesis
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:
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:
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;
(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;
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;
(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.
 Scheme of the method is as follows:
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%..
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.
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.
- Drugs.com Drugs.com international names for febuxostat Page accessed June 25, 2015
- Febuxostat for the management of hyperuricaemia in people with gout (TA164) Chapter 4. Consideration of the evidence
- Uloric label Updated February, 2009.
- 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.
- Ashraf Mozayani; Lionel Raymon (2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science+Business Media.
- Teijin Febuxostat Story Page accessed June 25, 2015
- Tomlinson B. Febuxostat (Teijin/Ipsen/TAP). Curr Opin Investig Drugs. 2005 Nov;6(11):1168-78. PMID 16312139
- Bruce Japsen for the Chicago Tribune. August 17, 2006. FDA puts gout treatment on hold
- 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
- “Adenuric (febuxostat) receives marketing authorisation in the European Union” (PDF). Retrieved 2008-05-28.
- “Uloric Approved for Gout”. U.S. News and World Report. Retrieved 2009-02-16.
- 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
- Teijin. January 21, 2011 Press release: TMX-67 (febuxostat) Approved in Japan
- Genetic Engineering News. October 2009. Menarini to Market Takeda/Ipsen Gout Therapy in 41 European Countries
- 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
- 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
Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32
 Hasegawa, M.; A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile. Heterocycles 1998, 47, 2, 857.  Hasegawa, M.; Hasegawa, M.; Komoriya, K. (Teijin Ltd.); Cyano cpds. and their preparation method. JP 1994345724 .  “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 . 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
■ A Facile One-Pot Synthesis of 4-Alkoxy-1,3-benzenedicarbonitrile
*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.
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 (http://derpharmachemica.com/archive.html)
Synthesis of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (1)  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 http://www.scholarsresearchlibrary.com 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 %).
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;
b) adding acyl halides or sulfonyl chlorides to the reaction mixture;
c) optionally isolating compound of Formula- IV (a)
d) reacting with isobutyl bromide in presence of base;
e) isolating the compound of Formula-II(a); and
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.
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%).
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.
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.
 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%.
 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%.
 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.
 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.
 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.
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%.
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:
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|
|Trade names||Uloric, Adenuric, Atenurix, Feburic, Goturic, Goutex. Generic in several countries.|
|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)|
|ATC code||M04AA03 (WHO)|
|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
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 licensed by the U.S. Food and Drug Administration to treat traveler’s diarrhea caused by E. coli. 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. 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)|
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.
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.
In the United States, rifaximin has orphan drug status for the treatment of hepatic encephalopathy. 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. 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. 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. 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.
A 2011 study in patients with IBS (sans constipation) indicated 11% showed benefits over a placebo. The study was supported by Salix Pharmaceuticals, the patent holder. 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. 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.
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. In addition to receiving FDA approval for traveler’s diarrhea and (marketing approved for) hepatic encephalopathy, Xifaxan received FDA approval for IBS in May 2015. 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. 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. On August 13, 2013, Health Canada issued a Notice of Compliance to Salix Pharmaceuticals Inc. for the drug product Zaxine. In India it is available under the brand names Ciboz and Xifapill.[
LINK IS CLICK
APT 13C NMR RIFAXIMIN
1H NMR PARTIAL
Direct infusion mass analysis ESI (+)
- [-]ESI FRAG PATHWAY
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:
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:
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
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).
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 :
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 72.7Amorphous 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.
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.
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.
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