1 RAGAGLITAZAR
2 TROGLITAZONE
3 MITOGLITAZONE
4 PIOGLITAZONE
5 NAVEGLITAZAR
6 SAROGLITAZAR
7 CIGLITAZONE
8
9
10

2 MURA
3 INDE

Indeglitazar

1
Ragaglitazar ........Dr. Reddy's Research Foundation
1

Ragaglitazar

NNC-61-0029, (-) – DRF-2725, NN-622,

(−)DRF 2725

cas 222834-30-2

222834-21-1 (racemate)

Hyperlipidemia; Hypertriglyceridemia; Lipid metabolism disorder; Non-insulin dependent diabetes

PPAR alpha agonist; PPAR gamma agonist

(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID,

(2S)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid, DRF, 1nyx

Molecular Formula: C25H25NO5

Molecular Weight: 419.4697 g/mol

Dr. Reddy’s Research Foundation (Originator), Novo Nordisk (Licensee)

Reddy Research Foundation……….. Braj Bhushan Lohray,

Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists

Phase III

…………………..

EP 1049684; JP 2001519422; WO 9919313

Several related procedures have been described for the synthesis of the title compound. The Horner-Emmons reaction of 4-benzyloxybenzaldehyde (I) with triethyl 2-ethoxyphosphonoacetate (II) afforded the unsaturated ester (IIIa-b) as a mixture of E/Z isomers. Simultaneous double-bond hydrogenation and benzyl group hydrogenolysis in the presence of Pd/C furnished phenol (IV). Alternatively, double-bond reduction by means of magnesium in MeOH was accompanied by transesterification, yielding the saturated methyl ester (V). Further benzyl group hydrogenolysis of (V) over Pd/C gave phenol (VI). The alkylation of phenols (IV) and (VI) with the phenoxazinylethyl mesylate (VII) provided the corresponding ethers (VIII) and (IX), respectively. The racemic carboxylic acid (X) was then obtained by hydrolysis of either ethyl- (VIII) or methyl- (IX) esters under basic conditions.

…………………………………………

see all at http://www.drugfuture.com/synth/syndata.aspx?ID=275437

……………………………………………………..

The synthesis of ragaglitazar (Scheme 1) was commenced by treating substrate 2 under optimized phase-transfer catalyzed conditions, using solid cesium hydroxide monohydrate as the base, a pivalate protected benzyl bromide and the Park and Jew triflurobenzyl-hydrocinchonidinium bromide salt 1. We were delighted to find that this reaction produced 3 in good yield with good selectivity. Subsequent removal of the diphenylmethyl (DPM) group under Lewis acidic conditions followed by a Baeyer-Villager like oxidation yielded the - hydroxy aryl ester 4. At this point, we were again pleased to find that this ester could be recrystalized from warm ether to give essentially enantiomerically pure products (~95% ee). The free hydroxyl was then alkylated using triethyloxonium tetrafluoroborate, and then transesterification under catalytic basic conditions produced 5. A mesylated phenoxazine alcohol reacted with 5 to yield the methyl ester of 6, which was obtained by treatment with sodium hydroxide in methanol. The overall synthesis proceeds with 47% overall yield (41% from commercially available reagents) and is eight linear steps from the alkoxyacetophenone substrate 2, including a recrystalization.

……………………………………………………………..

J Med Chem 2001,44(16),2675

http://pubs.acs.org/doi/abs/10.1021/jm010143b

(−)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPARα and PPARγ. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.

Scheme 1 a

a (a) NaH, DMF, 0−25 °C, 12 h; (b) triethyl 2-ethoxy phosphosphonoacetate, NaH, THF, 0−25 °C, 12 h; (c) Mg/CH3OH, 25 °C, 12 h; (d) 10% aq NaOH, CH3OH, 25 °C, 6 h; (e) (1) pivaloyl chloride, Et3N, DCM, 0 °C, (2) (S)-2-phenyl glycinol/Et3N; (f) 1 M H2SO4, dioxane/water, 90−100 °C, 80 h.

Compound 6 is prepared from phenoxazine using a synthetic route shown in Scheme 1. Phenoxazine 7 upon reaction with p-bromoethoxy benzaldehyde 89 gave benzaldehyde derivative 9. Reacting 9 with triethyl 2-ethoxy phosphonoacetate afforded propenoate 10 as a mixture of geometric isomers. Reduction of 10 using magnesium methanol gave propanoate 11, which on hydrolysis using aqueous sodium hydroxide gave propanoic acid 12 in racemic form. Resolution of 12 using (S)(+)-2-phenyl glycinol followed by hydrolysis using sulfuric acid afforded the propanoic acid 6 in (−) form.

Nate, H.; Matsuki, K.; Tsunashima, A.; Ohtsuka, H.; Sekine, Y. Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. II. 2-(phenylpiperazinoalkoxyphenyl)thiazolidine-3-thiocarboxyamides and corresponding carboxamides. Chem. Pharm. Bull. 1987, 35, 2394−2411

(S)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-eth-oxypropanoic Acid (6). as a white solid, mp: 89−90 °C.

[α]D 25 = − 12.6 (c = 1.0%, CHCl3).

1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J = 7.0 Hz, 3H), 1.42−1.91 (bs, 1H, D2O exchangeable), 2.94−3.15 (m, 2H), 3.40−3.65 (m, 2H), 3.86−4.06 (m, 3H), 4.15 (t, J = 6.6 Hz, 2H), 6.63−6.83 (m, 10H), 7.13 (d, J = 8.5 Hz, 2H). Mass m/z (relative intensity): 419 (M+, 41), 197 (15), 196 (100), 182 (35), 167 (7), 127 (6), 107 (19).

Purity by HPLC: chemical purity: 99.5%; chiral purity: 94.6% (RT 27.5).

…………………………………

http://www.google.com/patents/US6608194?cl=zh

EXAMPLE 23 (−) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid:

The title compound (0.19 g, 54%) was prepared as a white solid from diastereomer [(2S-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenyl)ethylpropanamide (0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example 22. mp: 89-90° C.

[α]D 25=−12.6 (c=1.0% CHCl3)

1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J=7.02 Hz, 3H), 1.42-1.91 (bs, 1H, D2O exchangeable), 2.94-3.15 (complex, 2H), 3.40-3.65 (complex, 2H), 3.86-4.06 (complex, 3H), 4.15 (t, J=6.65 Hz, 2H), 6.63-6.83 (complex, 10H), 7.13 (d, J=8.54 Hz, 2H).

………………………..

http://www.google.com/patents/EP1049684A1?cl=en

Example 23

(S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid :

The title compound (0.19 g, 54 %) was prepared as a white solid from diastereomer [(2S- N(lS)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l- phenyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example 22. mp : 89 – 90 °C. [α]D 25 = – 12.6 (c = 1.0 %, CHC13)

*H NMR (CDC13, 200 MHz) : δ 1.16 (t, J = 7.02 Hz, 3H), 1.42 – 1.91 (bs, IH, D20 exchangeable), 2.94 – 3.15 (complex, 2H), 3.40 – 3.65 (complex, 2H), 3.86 – 4.06 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.63 – 6.83 (complex, 10H), 7.13 (d, J = 8.54 Hz, 2H).

PATENT	SUBMITTED	GRANTED
Benzamides as ppar modulators [US2006160894]	2006-07-20
Novel tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US2002077320]	2002-06-20
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US7119198]	2006-07-06	2006-10-10
Tricyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them [US6440961]		2002-08-27
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6548666]		2003-04-15
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6608194]		2003-08-19
CRYSTALLINE R- GUANIDINES, ARGININE OR (L) -ARGININE (2S) -2- ETHOXY -3-{4- [2-(10H -PHENOXAZIN -10-YL)ETHOXY]PHENYL}PROPANOATE [WO0063189]	2000-10-26
Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds [US6897199]	2002-11-14	2005-05-24
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6939988]		2005-09-06

WO-2014181362

wo/2014/181362 a process for the preparation of 3 … – WIPO

patentscope.wipo.int/search/en/WO2014181362

Nov 13, 2014 - (WO2014181362) A PROCESS FOR THE PREPARATION OF 3-ARYL-2-HYDROXY PROPANOIC ACID COMPOUNDS …

A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds

ragaglitazar; saroglitazar

Council of Scientific and Industrial Research (India)

Process for preparing enantiomerically pure 3-aryl-2-hydroxy propanoic acid derivatives (eg ethyl-(S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate), using S-benzyl glycidyl ether as a starting material. Useful as intermediates in the synthesis of peroxisome proliferator activated receptor agonist such as glitazars (eg ragaglitazar or saroglitazar). Appears to be the first filing on these derivatives by the inventors; however see WO2014181359 (for a concurrently published filing) and US8748660 (for a prior filing), claiming synthesis of enantiomerically pure compounds.

Dolling, U. H.; Davis, P.; Grabowski, E. J. J. Efficient Catalytic Asymmetric Alkylations. 1. Enantioselective Synthesis of (+)-Indacrinone via Chiral Phase-Transfer Catalysis. J. Am. Chem. Soc. 1984, 106, 446–447.
Andrus, M. B.; Hicken, E. J.; Stephens, J. C. Phase-Transfer Catalyzed Asymmetric Glycolate Alkylation. Org. Lett. 2004, 6, 2289–2292.
Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. Asymmetric Phase-Transfer Catalyzed Glycolate Alkylation, Investigation of the Scope, and Application to the Synthesis of (-)-Ragaglitazar. J. Org. Chem. 2005, ASAP.
Henke, B. R. Peroxisome Proliferator-Activated Receptor  Dual Agonists for the Treatment of Type 2 Diabetes. J. Med. Chem. 2004, 47, 4118–4127.
Wilson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 2000, 46, 1306–1317.
Uchida, R.; Shiomi, K.; Inokoshi, J.; Masuma, R.; Kawakubo, T.; Tanaka, H.; Iwai, Y.; Omura, A. Kurasoins A and B, New Protein Farnesyltrasferase Inhibitors Produced by Paecilomyces sp. FO-3684. J. Antibio. 1996, 49, 932–934.

.......................

TROGLITAZONE

Troglitazone, GR-92132X, CI-991, CS-045, Romozin, Prelay, Rezulin, Noscal

CAS 97322-87-7

C24 H27 N O5 S, 441.54

(±)-5-[4-(6-Hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-ylmethoxy)benzyl]thiazolidine-2,4-dione

2,4-Thiazolidinedione, 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-

CI 991
CS 045
Depotox
GR 92132X
Noscal
Rezulin

Romglizone
Troglitazone

Withdrawn – 2000

Crystals, m.p. 184-6 °C

Daiichi Sankyo Co., Ltd. INNOVATOR

Trademarks: Noscal (Sankyo); Prelay (Sankyo); Rezulin

Percent Composition: C 65.28%, H 6.16%, N 3.17%, O 18.12%, S 7.26%

Properties: Crystals from benzene-acetone, mp 184-186°.

Therap-Cat: Antidiabetic.

Insulin Sensitizer.

Troglitazone

Type-II diabetes mellitus (DM) is characterized by insulin resistance, glucose intolerance, increased hepatic glucose production, and decreased pancreatic insulin secretion. In the past, the drug classes used for type-II DM have targeted the last three of these abnormalities. Sulfonylurea agents bind to ATP-dependent potassium efflux channels to stimulate pancreatic insulin secretion at b-islet cells. The biguanides decrease hepatic glucose production, and thea-glucosidase inhibitors delay carbohydrate digestion to improve glucose tolerance. Until the recent advent of the thiazolidinedione drugs (ciglitazone was first synthesized in 1982), there was no therapy specifically targeting insulin resistance. Drugs of this class all share a common thiazolidine-2-4-dione structure. Marketed drugs of this class include pioglitazone, rosiglitazone, and troglitazone [Figure 1] – the first to reach the market.

The “glitazones” act to reduce insulin resistance and also correct hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Thiazolidinediones bind to the gisoform of the peroxisome proliferator-activated receptor (PPARg), a nuclear transcription factor that regulates the expression of several insulin-responsive genes involved in glucose and lipid metabolism, and the differentiation of fibroblasts into adipose tissue. The net effect is to reduce insulin resistance, mostly through increased glucose uptake by muscle tissue; however, the exact biochemical mechanism is unclear. Effects on lipid metabolism include decreased triglycerides and free fatty acids, and a slight increase or no change in high-density lipoprotein, low-density lipoprotein, and total cholesterol. There also appear to be acute increases in insulin-stimulated glucose uptake that are PPAR-independent. This effect is too rapid to occur via gene transcription, and in the case of troglitazone may result from action of its quinone metabolite. Troglitazone also decreases production of various inflammatory mediators and may antagonize TNFa.

Troglitazone�s most common adverse effect is fluid retention, which may increase preload and induce cardiac hypertrophy. Troglitazone is contraindicated in congestive heart failure, and cases of pulmonary edema have been reported. Troglitazone induces colon polyps in murine models and is therefore contraindicated for patients with familial polyposis coli. Troglitazone and pioglitazone (but not rosiglitazone) induce cytochrome P450 (CYP) 3A4. This enzyme induction can result in decreased drug levels or drug effects with estradiol, terfenadine, cyclosporine, simvistatin, tacrolimus, and other drugs metabolized by CYP 3A4. A small fraction of troglitazone is metabolized by CYP (not 3A4) to an active quinone metabolite, but it is mostly conjugated to sulfate and glucuronide. Troglitazone enhances the anticoagulant effect of warfarin, probably through competitive serum protein binding, and has other drug interactions at the PPAR level. Troglitazone interferes with gemfibrozil’s binding to PPARa, and may decrease NSAID effectiveness by competing for PPARg.

Rezulin� (tradename troglitazone by Parke-Davis) was FDA approved January 29, 1997, and was first marketed in March 1997. Over 600,000 American patients received troglitazone, with an additional 200,000 in Japan. Pre-marketing studies showed 1.9% of patients on troglitazone developed serum alanine aminotransferase levels in excess of three times the upper limit of normal, vs. 0.6% with placebo. Such hepatotoxicity was typically asymptomatic and reversible. A few patients developed overt liver injury, and two liver biopsies among these patients showed hepatocellular injury pattern. It was estimated that only 1 patient in 50,000 to 60,000 would die from liver failure or require liver transplantation. On November 3, 1997, the FDA released a warning regarding 150 adverse events with troglitazone, 35 with acute liver injury, and 3 deaths in Japan from liver failure. The warnings and restrictions about troglitazone were extended in December 1997, July 1998, and June 1999. Troglitazone was voluntarily withdrawn from the US market on March 21, 2000, after it had been demonstrated that Rezulin� was more toxic than either Avandia� (rosiglitazone) or Actos�(pioglitazone).

Troglitazone hepatotoxicity appears to be idiosyncratic. The onset is typically delayed, usually 2-5 months after initiating therapy, although one case was reported after only four doses. Although hypersensitivity has been suggested in several cases, the hallmarks of immune mechanisms, fever, rash, and eosinophilia, are usually absent. Histologic specimens usually show hepatocellular injury, bridging fibrosis and necrosis, intracanalicular cholestasis, and lack of regenerative activity. Samples vary in the amount of WBC infiltration (with or without eosinophils) and steatosis.

Idiosyncratic (or host-dependent) drug reactions are either due to hypersensitivity or to metabolic aberrations. It is not clear whether troglitazone hepatotoxicity is caused by hypersensitivity. Proposed metabolic aberrations include oxidation/reduction reactions with thea-tocopherol moiety on troglitazone (although it is usually considered an antioxidant), reactions from the quinone metabolite (similar to acetaminophen’s quinone metabolite), and genetic variations in cytokines and their receptors, the apoptosis cascade, mitochondrial respiration, and regenerative response. It is unlikely that CYP polymorphisms play a major role, as the incidence of troglitazone hepatotoxicity is too low. Two cases of hepatic toxicity associated with rosiglitazone have also been reported. Although the patients had co-morbidities, exposures to other drugs, and one case may have been due to shock, these cases suggest that hepatotoxicity may be an emerging “class-effect” of thiazolidinediones.

Troglitazone (Rezulin, Resulin, Romozin, Noscal) is an antidiabetic and anti-inflammatory drug, and a member of the drug class of thethiazolidinediones. It was prescribed for patients with diabetes mellitus type 2.[1] It was developed by Daiichi Sankyo Co.(Japan). In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with anidiosyncratic reaction leading to drug-induced hepatitis. One F.D.A. medical officer evaluating troglitazone, John Gueriguian, did not recommend its approval due to potential high liver toxicity,[2] but a full panel of experts approved it in January 1997.[3] Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from theUnited States market in 2000, and from the Japanese market soon afterwards. It didn’t get approval in the rest of Europe.

Approval history

Troglitazone was developed as the first anti-diabetic drug having a mechanism of action involving the enhancement of insulin sensitivity. At the time it was widely believed that such drugs, by addressing the primary metabolic defect associated with Type 2 diabetes, would have numerous benefits including avoiding the risk of hypoglycemia associated with insulin and earlier oral antidiabetic drugs. It was further believed that reducing insulin resistance would potentially reduce the very high rate of cardiovascular disease that is associated with diabetes.[4][5]

Parke-Davis/Warner Lambert submitted the diabetes drug Rezulin for U.S. Food and Drug Administration (F.D.A.) review on July 31, 1996. The medical officer assigned to the review, Dr. John L. Gueriguian, cited Rezulin’s potential to harm the liver and the heart and he questioned its viability in lowering blood sugar for patients with adult-onset diabetes, recommending against the drug’s approval. After complaints from the drugmaker, Gueriguian was removed on November 4, 1996 and his review was purged by the F.D.A.[6][7]Gueriguian and the company had a single meeting, at which Gueriguian used “intemperate” language; The company said it’s objections were based on inappropriate remarks made by Gueriguian.[8] Parke-Davis said at the advisory committee that the risk of liver toxicity was comparable to placebo and that additional data of other studies confirmed this.[9] According to Peter Gøtzsche, when the company provided these additional data one week after approval, they showed a substantial greater risk for liver toxicity.[10]

The F.D.A. approved the drug on January 29, 1997, and it appeared in pharmacies in late March. At the time Dr. Solomon Sobel, a director at the F.D.A., overseeing diabetes drugs, said in a New York Times interview that adverse effects of troglitazone appeared to be rare and relatively mild.[11]

Glaxo Wellcome P.L.C. received approval from the British Medicines Control Agency (MCA) to market troglitazone, as Romozin, in July 1997.[12] After reports of sudden liver failure in patients receiving the drug, the Parke-Davis and the FDA added warnings to the drug label requiring monthly monitoring of liver enzyme levels.[13] Glaxo removed troglitazone from the market in Britain on December 1, 1997.[6] Glaxo had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.[14][15]

On May 17, 1998, a 55-year old patient named Audrey LaRue Jones died of acute liver failure after taking troglitazone. Importantly, she had been monitored closely by physicians at the National Institutes of Health as a participant in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) diabetes prevention study.[16][17] This called into question the efficacy of the monitoring strategy. The N.I.H. responded on June 4 by dropping troglitazone from the study.[7][18] Dr. David J. Graham, an F.D.A. epidemiologist charged with evaluating the drug, warned on March 26, 1999 of the dangers of using it and concluded that patient monitoring was not effective in protecting against liver failure. He estimated that the drug could be linked to over 430 liver failures and that patients incurred 1,200 times greater risk of liver failure when taking Rezulin.[7][19] Dr. Janet B. McGill, an endocrinologist who had assisted in the Warner–Lambert’s early clinical testing of Rezulin, wrote in a March 1, 2000 letter to Sen. Edward M. Kennedy (D-Mass.): “I believe that the company . . . deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies.”[20]

On March 21, 2000, the F.D.A. withdrew the drug from the market.[21] Dr. Robert I. Misbin, an F.D.A. medical officer, wrote in a July 3, 2000 letter to the House Energy and Commerce Committee of strong evidence that Rezulin could not be used safely, after having been threatened by the FDA with dismissal in March 2000.[6][22] By that time the drug had been linked to 63 liver-failure deaths and had generated sales of more than $2.1 billion for Warner-Lambert.[19] The drug cost $1,400 a year per patient in 1998.[15] Pfizer, which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.[23]

Lawsuits

In 2009 Pfizer Inc. resolved all but three of 35,000 claims over its withdrawn diabetes drug Rezulin for a total of about $750 million. Pfizer, which acquired rival Wyeth for almost $64 billion, paid about $500 million to settle Rezulin cases consolidated in federal court in New York, according to court filings. The company also paid as much as $250 million to resolve state-court suits. In 2004, it set aside $955 million to end Rezulin cases.[24]

Mode of action

Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating peroxisome proliferator-activated receptors (PPARs).

Troglitazone is a ligand to both PPARα and – more strongly – PPARγ. Troglitazone also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation:[25] troglitazone use was associated with a decrease of nuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response.

rosiglitazone, ciglitazone, darglitazone, englitazone, rosiglitazone, pioglitazone, rosiglitazone, troglitazone

SYSTEMATIC (IUPAC) NAME
(RS)-5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione
CLINICAL DATA
LEGAL STATUS	?
PHARMACOKINETIC DATA
HALF-LIFE	16-34 hours
IDENTIFIERS
CAS NUMBER	97322-87-7
ATC CODE	A10BG01
PUBCHEM	CID 5591
IUPHAR LIGAND	2693
DRUGBANK	DB00197
CHEMSPIDER	5389
UNII	I66ZZ0ZN0E
KEGG	D00395
CHEBI	CHEBI:9753
CHEMBL	CHEMBL408
CHEMICAL DATA
FORMULA	C24H27N O5S
MOL. MASS	441.541 g/mol

………………….

………………..

A new synthesis of [14C]-labeled CS-045 has been reported: The condensation of 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone (I) with phenoxyacetone (II) by means of morpholine and p-toluenesulfonic acid in refluxing benzene gives 6-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-benzo[b]pyran-4-one (III), which is reduced with NaBH4 in methanol to the corresponding carbinol (IV). The dehydration of (IV) by means of p-toluenesulfonic acid in refluxing benzene affords 2-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-benzo[b]pyran (V), which is hydrogenated with H2 over Pd/C in methanol to give the corresponding 3,4-dihydro derivative (VI). The hydrolysis of (VI) with NaOH in methanol yields the corresponding phenol (VII), which is chloromethylated with paraformaldehyde and dry HCl in dioxane to afford 2-[4-(chloromethyl)phenoxymethyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-6-ol (VIII). The protection of (VIII) with chloromethyl methyl ether by means of potassium tert-butoxide in THF gives the corresponding 6-(methoxymethoxy) derivative (IX), which is condensed with [5-14C]-thiazolidine-2,4-dione (X) by means of butyllithium in THF-HMPT to yield 5-[4-[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-2-ylmethoxy]benzyl]-[5-14C]-thiazolidine-2,4-dione (XI). Finally, this compound is deprotected with concentrated HCl in ethylene glycol monomethyl ether at 130 C.

……………….

A new short synthesis of troglitazone has been described: Condensation of the bromoacetal (I) with 4-hydroxybenzaldehyde (II) by means of K2CO3 and NaI in refluxing acetone gives the unsaturated ether (III), which is cyclized with trimethylhydroquinone (IV) by means of bis(trifluoromethylsulfonyl)imide in dichloromethane to yield the 6-hydroxybenzopyran (V). Acylation of (V) with acetic anhydride and DMAP in THF affords the expected acetoxybenzopyran (VI), which is condensed with thiazolidine-2,4-dione (VII) by means of piperidine in toluene to provide the 6-benzylidene-thiazolidine (VIII). The hydrogenation of (VIII) with H2 over Pd/C in methanol gives the corresponding benzyl derivative (IX), which is finally deacetylated with AcOH/HCl/water (3:1:1) in MeOH.

…………..

European Journal of Medicinal Chemistry, 51, 206-215; 2012

http://www.sciencedirect.com/science/article/pii/S0223523412001353

……………………………………….

see Indian Journal of Heterocyclic Chemistry, 15(4), 407-408; 2006

……………………………………………………….

Bioorganic & Medicinal Chemistry Letters, 14(10), 2547-2550; 2004

http://www.sciencedirect.com/science/article/pii/S0960894X04003038

Figure 1.

Scheme 2.

(a) t-Butyldimethylsilyl chloride, imidazole, DMF; (b) LAH, rt, 3 h (75.9%, two steps); (c) 4-fluorobenzaldehyde, KtOBu, DMF, 80 °C, 8 h; (d) 2,4-thiazolidinedione, AcOH, piperidine, toluene, reflux, 4 h (37%, two steps); (e) HCl, MeOH, 15 min; (f) CoCl2, DMG (84%).

………………………

Patent

http://www.google.co.in/patents/US5700820

EXAMPLE-1

A mixture of 70 g of ethyl-3- 4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl!-2-chloropropionate, 13.12 g of thiourea and 80.2 ml of sulpholane was reacted for 80 min., under a nitrogen stream at 115°-120° C. Subsequently, a 656.2 ml Acetic acid, 218.7 ml conc. hydrochloric acid and 109.4 ml water was added to this and the resulting mixture was further heated for 12 hrs at 85°-90° C. The reaction mixture was cooled to room temperature and 196.8 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the crude product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution & water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off. The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 40 g of the required 5-{4-(6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl-methoxy) benzyl) thiazolidine-2,4-dione (Troglitazone) with a HPLC purity of ˜67-70%. The elution of column was continued further to yield 5- 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl!2-iminothiazolidine-4-one with HPLC purity of ˜70%.

Lit References:

Oral hypoglycemic agent which improves insulin sensitivity and decreases hepatic glucose production. Prepn: JP Kokai 85 51189; T. Yoshioka et al., US 4572912 (1985, 1986 both to Sankyo); T. Yoshioka et al.,

J. Med. Chem. 32,421 (1989).

Mechanism of action studies: T. P. Ciaraldi et al., Metabolism 39, 1056 (1990); M. Kellerer et al., Diabetes 43, 447 (1994).

Clinical evaluation: T. Kuzuya et al., Diabetes Res. Clin. Pract. 11, 147 (1991).

Clinical metabolic effects: S. L. Suter et al., Diabetes Care 15, 193 (1992).

References

Fisher, Lawrence (4 November 1997). “Adverse Diabetes Drug News Sends Warner-Lambert Down”. The New York Times. Retrieved 12 December 2012.
Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights, wired.com
Cohen, J. S. (2006). “Risks of troglitazone apparent before approval in USA”.Diabetologia 49 (6): 1454–5. doi:10.1007/s00125-006-0245-0. PMID 16601971.
Henry RR (September 1996). “Effects of troglitazone on insulin sensitivity”. Diabet. Med.13 (9 Suppl 6): S148–50.PMID 8894499.
Keen H (November 1994). “Insulin resistance and the prevention of diabetes mellitus”. N. Engl. J. Med. 331 (18): 1226–7.doi:10.1056/NEJM199411033311812. PMID 7935664.
Willman, David (20 December 2000). “NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal”. The Los Angeles Times. Retrieved 12 December 2012.
Willman, David (4 June 2000). “The Rise and Fall of the Killer Drug Rezulin”. The Los Angeles Times. Retrieved 12 December 2012.
“Report: FDA Removes Medical Officer”.
Avorn, J (2005). Powerful medicines. New York: Vintage books.
Gøtzsche, Peter (2013). Deadly medicines and organised crime : how big pharma has corrupted healthcare. London [u.a.]: Radcliffe Publ. p. 185. ISBN 9781846198847.
Leary, Warren (31 January 1997). “New Class of Diabetes Drug Is Approved”. The New York Times. Retrieved 12 December 2012.
Sinclair, Neil (31 July 1997). “Glaxo Wellcome gets approval for Romozin”. ICIS News. Retrieved 12 December 2012.
“www.accessdata.fda.gov”.
British Broadcasting Corporation (1 December 1997). “Diabetes drug withdrawn from sale”. BBC. Retrieved 12 December 2012.
Fisher, Lawrence (17 January 1998). “Drug Makers at Threshold of a New Therapy; With a Dose of Biotechnology, Big Change Is Ahead in the Treatment of Diabetes”. The New York Times. Retrieved 12 December 2012.
Diabetes Prevention Research Group (April 1999). “Design and methods for a clinical trial in the prevention of type 2 diabetes”.Diabetes Care 22 (4): 623–634.doi:10.2337/diacare.22.4.623. Retrieved 12 December 2012.
Diabetes Prevention Program Research Group (7 February 2002). “Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin”. The New England Journal of Medicine 346 (6): 393–403.doi:10.1056/NEJMoa012512.PMC 1370926. PMID 11832527. Retrieved 12 December 2012.
Gale, Edwin (January 2006). “Troglitazone: the lesson that nobody learned?”.Diabetologia 49 (1): 1–6. doi:10.1007/s00125-005-0074-6.
Willman, David (16 August 2000). “FDA’s Approval and Delay in Withdrawing Rezulin Probed”. The Los Angeles Times. Retrieved 12 December 2012.
Willman, David (10 March 2000). “Fears Grow Over Delay in Removing Rezulin”. The Los Angeles Times. Retrieved 12 December 2012.
U.S. Food and Drug Administration. “2000 Safety Alerts for Human Medical Products”. U.S. Food and Drug Administration. Retrieved 12 December 2012.
Willman, David (March 17, 2000). “Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal”. Los Angeles Times.
Pfizer. “Pfizer Annual Report 2001″. Pfizer. Retrieved 12 December 2012.
Feeley, Jef (March 31, 2009). “Pfizer Ends Rezulin Cases With $205 Million to Spare”.Bloomberg. Retrieved 6 April 2014.
Aljada A, Garg R, Ghanim H, et al. (2001). “Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action?”. J. Clin. Endocrinol. Metab. 86 (7): 3250–6.doi:10.1210/jc.86.7.3250. PMID 11443197.

External links

Diabetes Monitor article on troglit

US4316849 *	11 Jul 1980	23 Feb 1982	Blasinachim S.P.A.	Process for preparing a crystalline polymorphous type of chenodeoxycholic acid
US4572912 *	28 Aug 1984	25 Feb 1986	Sankyo Company Limited	Treatment of hyperlipemia and hyperglycemia
US5248699 *	13 Aug 1992	28 Sep 1993	Pfizer Inc.	Hydrochloride salt, antidepressant, anorectic
US5319097 *	11 Dec 1991	7 Jun 1994	Imperial Chemical Industries Plc	Pharmaceutical agents
AU3255984A*				Title not available
EP0014590A1*	7 Feb 1980	20 Aug 1980	Eli Lilly And Company	Crystalline forms of N-2-(6-methoxy)benzothiazolyl-N’-phenyl urea and process for their preparation
EP0022527A1*	4 Jul 1980	21 Jan 1981	BLASCHIM S.p.A.	Process for preparing a solvent-free crystalline polymorphous form of chenodeoxycholic acid
EP0490648A1*	11 Dec 1991	17 Jun 1992	Zeneca Limited	Pharmaceutical agents

MITOGLITAZONE

MITOGLITAZONE MSDC-0160; CAY 10415; 146062-49-9 5-[4-[2-(5-Ethylpyridin-2-yl)-2-oxoethoxy]benzyl]thiazolidine-2,4-dione 5-[[4-[2-(5-ethylpyridin-2-yl)-2-oxoethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione 5-(4-(2-(5-cthylpyridin-2-yl)- 2-oxoethoxy)benzyl)-1,3 -thiazolidiiie-2,4-dione Pfizer, INNOVATOR phase 2 MSD-9 MSDC-0160 PNU-91325 U-91325 BACKGROUND Thiazolidinedione analogs either prevent or ameliorate an insulin resistance state, which occurs genetically or is induced by dietary means. 5-(4-(2-(5-Ethylpyridin-2-yl)-2- oxoethoxy)benzyl)-l,3-thiazolidine-2,4-dione of Formula (I) (Mitoglitazonc) is an antidiabetic thiazolidinedione being evaluated for the treatment of non-insulin-dependent diabetes mellitus. Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease characterized by a reduction in the response of the peripheral target tissue to insulin and the inability of pancreatic insulin reserves to overcome the reduced response. Improvement of insulin sensitivity of the target tissue not only reduces the consequences of the disease but actually aids in the prevention of NIDDM. The synthesis of Mitoglitazone has been reported (J. Med. Chem. , 1996, 39, 5053- 5063; Org. Pro. Res. & Dev. (OPRD), 2002, 6, 721-728 and U.S. PaL No. 5,441,971). .................................. http://www.google.com/patents/WO1992018501A1?cl=en ..........................................

Org. Proc. Res. Dev., 2002, 6 (5), pp 721–728

DOI: 10.1021/op025549s

http://pubs.acs.org/doi/abs/10.1021/op025549s

An efficient six-step synthesis has been developed for the preparation of the thiazolidinedione analogue PNU-91325 (3) from the commercially available olefin 12. This process involves a novel epoxide ring opening with a deactivated phenol under phase-transfer conditions. Significant improvements were made in the oxidation of a secondary alcohol to the ketone and the 1,4-reduction of an enone from a previous process. Overall, this route allows for the preparation of PNU-91325 in 25% yield.

........................................... US5,441,971 http://www.google.com/patents/US5441971 ...................................

J. Med. Chem., 1996, 39 (26), pp 5053–5063

DOI: 10.1021/jm9605694

http://pubs.acs.org/doi/abs/10.1021/jm9605694 Pioglitazone (5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, 2) is a prototypical antidiabetic thiazolidinedione that had been evaluated for possible clinical development. Metabolites 6−9 have been identified after dosing of rats and dogs. Ketone 10has not yet been identified as a metabolite but has been added to the list as a putative metabolite by analogy to alcohol 6 and ketone 7. We have developed improved syntheses of pioglitazone (2) metabolites 6−9 and the putative metabolite ketone 10. These entities have been compared in the KKAy mouse model of human type-II diabetes to pioglitazone (2). Ketone 10 has proven to be the most potent of these thiazolidinediones in this in vivo assay. When 6−10 were compared in vitro in the 3T3-L1 cell line to 2, for their ability to augment insulin-stimulated lipogenesis, 10 was again the most potent compound with 6, 7, and 9roughly equivalent to 2. These data suggest that metabolites 6, 7, and 9 are likely to contribute to the pharmacological activity of pioglitazone (2), as had been previously reported for ciglitazone (1). 5-((4-(2-(5-Ethyl-2-pyridyl)-1-oxoethoxy)phenyl)methyl)-2,4-thiazolidinedione (10). MITOGLITAZONE free flowing white powdery solid (mp 146−147 °C): TLC (Merck; MeOH−CH2Cl2, 5:95, UV(+)) Rf = 0.21; 1H-NMR (CDCl3) δ 8.95 (brs, 1), 8.52 (d, J = 2.0 Hz, 1), 8.02 (d, J = 8.0 Hz, 1), 7.70 (dd, J = 8.0, 2.0 Hz, 1), 7.16 (d, J = 8.7 Hz, 2), 6.94 (d, J = 8.7 Hz, 2), 5.62 (s, 2), 4.49 (dd, J = 9.7, 3.8 Hz, 1), 3.47 (dd, J = 14.2, 3.8 Hz, 1), 3.08 (dd, J = 14.2, 9.7 Hz, 1), 2.76 (q, J = 7.6 Hz, 2), 1.31 (t, J = 7.6 Hz, 3); 13C-NMR (CDCl3) δ 194.7, 174.1, 170.4, 157.7, 149.7, 148.9, 144.7, 136.3, 130.3, 128.4, 121.9, 115.2, 70.5, 53.7, 37.8, 26.4, 15.0; EI/MS (70 eV) 370 (M+, 19.4), 341 (6.9), 254 (20.6), 148 (base). Anal. (C19H18N2O4S) C, H, N, S. ..................................... 1H NMR PREDICTION

13C NMR PREDICTION

....

4 PIOGLITAZONE

Pioglitazone

5-[[4-[2-(5-ethyl-2-pyridinyl)-ethoxy]phenyl] methyl]- 2,4- thiazolidinedione

5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione

cas 111025-46-8

5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione

Additional Names: (±)-5-[p-[2-(ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione

Manufacturers’ Codes: AD-4833

Molecular Formula: C19H20N2O3S

Molecular Weight: 356.44

Percent Composition: C 64.02%, H 5.66%, N 7.86%, O 13.47%, S 9.00%

Properties: Colorless needles from DMF + water, mp 183-184°.

Melting point: mp 183-184°

Therap-Cat: Antidiabetic.

Pioglitazone (Actos) is a prescription drug of the class thiazolidinedione (TZD) with hypoglycemic (antihyperglycemic, antidiabetic) action to treat diabetes. Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion. While pioglitazone does decrease blood sugar levels, studies on the main cardiovascular outcomes has not yielded statistically significant results. Its cardiovascular safety profile compares favorably with rosiglitazone (Avandia), which was withdrawn after concerns about an increased risk of cardiac events. Pioglitazone has been found to be associated with bladder tumors and has been withdrawn in some countries.

Medical uses

Pioglitazone is used for the treatment of diabetes mellitus type 2 either alone or in combination with a sulfonylurea, metformin, orinsulin. There was, however, no statistically significant difference in the main outcomes studied.

Pioglitazone has also been used to treat non-alcoholic steatohepatitis (fatty liver), but this use is presently considered experimental.

CLINICAL DATA
(RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione
TRADE NAMES	Actos
AHFS/DRUGS.COM	monograph
MEDLINEPLUS	a699016
LICENCE DATA	EMA:Link, US FDA:link
PREGNANCY CAT.	C
LEGAL STATUS	UK: POM US: ℞-only
ROUTES	oral
PHARMACOKINETIC DATA
PROTEIN BINDING	>99%
METABOLISM	liver (CYP2C8)
HALF-LIFE	3–7 hours
EXCRETION	in bile
IDENTIFIERS
CAS NUMBER	111025-46-8
ATC CODE	A10BG03
PUBCHEM	CID 4829
IUPHAR LIGAND	2694
DRUGBANK	DB01132
CHEMSPIDER	4663
UNII	X4OV71U42S
KEGG	D08378
CHEBI	CHEBI:8228
CHEMBL	CHEMBL595
CHEMICAL DATA
FORMULA	C19H20N2O3S
MOL. MASS	356.44 g/mol

Derivative Type: Hydrochloride

CAS Registry Number: 112529-15-4

Manufacturers’ Codes: U-72107A

Trademarks: Actos (Takeda)

Molecular Formula: C19H20N2O3S.HCl

Molecular Weight: 392.90

Percent Composition: C 58.08%, H 5.39%, N 7.13%, O 12.22%, S 8.16%, Cl 9.02%

Properties: Colorless prisms from ethanol, mp 193-194°. Sol in DMF; slightly sol in ethanol; very slightly sol in acetone, acetonitrile. Practically insol in water; insol in ether.

Melting point: mp 193-194°

nda 021073, actos, 15-7-99, tablet, takeda usa,

ACTOSView pdf

US PATENT NO	EXPIRY DATE	PATENT USE CODE
5965584	Jun 19, 2016	U-753
6150383	Jun 19, 2016	U-418
6150384	Jun 19, 2016	U-419
6166042	Jun 19, 2016	U-414
6166043	Jun 19, 2016	U-415
6172090	Jun 19, 2016	U-416
6211205	Jun 19, 2016	U-410
6271243	Jun 19, 2016	U-411
6303640	Aug 9, 2016	U-425
6329404	Jun 19, 2016	U-753

DMF

DMF16635	STATUSA	TYPEII	SUMISSION6/11/2003	BIOCON LTD	PIOGLITAZONE HYDROCHLORIDE AS MANUFACTURED IN BALGALORE, INDIA.
16672	A	II	6/30/2003	CIPLA LTD	PIOGLITAZONE HYDROCHLORIDE USP (ESUB) AS MANUFACTURED IN PUNE, MAHARASHTRA, INDIA
16675	A	II	7/2/2003	DR REDDYS LABORATORIES LTD	PIOGLITAZONE HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH, INDIA.
16682	A	II	7/3/2003	RANBAXY LABORATORIES LTD	PIOGLITAZONE HYDROCHLORIDE AS MANUFACTURED IN PUNJAB, INDIA.
16684	A	II	7/8/2003	USV LIMITED	PIOGLITAZONE HYDROCHLORIDE (ESUB) AS MANUFACTURED IN MUMBAI, INDIA.

more.clickhttp://www.usactives.com/z1/search.php?zoom_query=PIOGLITAZONE

Synthesis

………………………….

http://www.google.com/patents/WO2004101560A1?cl=en

Many thiazolidinedione derivatives or “glitazones” are known to exhibit hypoglycemic activity and/or blood lipid lowering activity and have been proposed for use in treating, inter alia, diabetes. Some of the more well known and/or studied glitazones include pioglitazone, troglitazone, and rosiglitazone. Pioglitazone, chemically 5-[[4-[2-(5-ethyl-2-pyridinyl)-ethoxy]phenyl] methyl]- 2,4- thiazolidinedione of formula

(1)

is a commercially approved antidiabetic agent. Pharmaceutical compositions comprising pioglitazone, as the hydrochloride salt, are marketed under the brand name ACTOS® (Takeda Chemical Ind.) for treatment of type II diabetes.

Pioglitazone and its hydrochloride have been disclosed in EP 193256 and corresponding U.S. Patent No. 4,687,777. In these patents, the glitazone, such as pioglitazone, can be formed by cyclizing an alpha-bromo acid ester (2) with thiourea. The resulting imino-thiazolidinone (3) is then hydrolyzed to make the corresponding glitazone. For pioglitazone, the reaction can be represented as follows:

The starting alpha-bromo acid ester (2) is taught to be prepared by Meerwein arylation. This process comprises preparing the corresponding aniline (4), diazotation thereof in the presence of hydrobromic acid, and coupling of the product of diazotation with an acrylic acid ester (5) under catalysis by cuprous oxide as shown below:

reduction

(4) (5)

However, forming the alpha-bromo acid ester by the Meerwein arylation reaction can be problematic. The sequence of reactions within this transformation must be controlled precisely. Otherwise the diazo-compound generated during the reaction would react with another nucleophile such as the bromide anion leading to a complicated outcome. Therefore, the reaction often gives a complicated result and lower chemical yield. Furthermore, the preparation of the starting aniline derivative (4) comprises a hydrogenation step that requires a special apparatus, which gives some difficulties when scaling-up.

EP 0 008 203, which is related to U.S. Patent Nos. 4,287,200 and 4,481,141, discloses additional glitazones, i.e., not pioglitazone, that can be formed by several possible methods. In addition to the general scheme described in EP 193256, two more synthetic routes are proposed. One technique comprises a cyclization reaction as shown below to form the intended glitazone:

However, the formation of the starting thiocyano compound is not described. The other technique mentioned in EP 0 008 203 involves coupling the thiazolidine-containing moiety and the substituted alkyl moiety via alkylation of a phenolic oxygen to form the glitazone. If applied to pioglitazone, the reaction would be represented as follows:

(9) (10)

Example 11

Pioglitazone (from 2-thiocyanato-3- {4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]- phenyl} -propionic acid). 0.50 g of 2-thiocyanato-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}- propionic acid was dissolved in 10 mL of methanesulfonic acid, and the resulting brown solution was stirred overnight. Then, the reaction mixture was poured onto crushed ice upon stirring and sodium hydrogencarbonate was added in portions to neutralize the mixture. Precipitated light brown crystals were filtered off and dried to give 0.70 g of raw product, which was further purified by mixing with 12 % ethanolic solution of hydrogen chloride. The undissolved portion was filtered off, and the filtrate was precipitated with sodium bicarbonate, which gave crystals of pioglitazone

with a m.ρ. of 180 – 184°C.

………………………………..

EP 0193256; ES 8705886; JP 1986267580; US 4687777

The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluoronitrobenzene (II) by means of NaH in DMF gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (III), which is reduced with H2 over Pd/C in methanol to yield the corresponding aniline (IV). The reaction of (IV) with NaNO2/HBr and methyl acrylate (V) in acetone/methanol affords the 2-bromopropionate derivative (VI), which is cyclized with thiourea (VII) by means of NaOAc in refluxing ethanol to provide the 2-imino-4-thiazolidinone (VIII). Finally, this compound is hydrolyzed with refluxing 2N HCl.

http://www.drugfuture.com/synth/syndata.aspx?ID=164965

……………………………..

EP 0506273

This compound has been obtained by several different methods. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ts-Cl and NaOH in THF gives the corresponding tosylate (II), which is condensed with 4-hydroxybenzaldehyde (IV) by means of BnNBu3Cl and NaOH or K2CO3 to yield the aryl ether (V) (1-3). The condensation of (V) with thiazolidine-2,4-dione (VI) in refluxing ethanol affords the 5-benzylidenethiazolidinedione (VII), which is finally reduced with H2 over Pd/C in DMF or dioxane. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ms-Cl and TEA in dichloromethane THF gives the corresponding mesylate (III), which is condensed with 4-hydroxybenzaldehyde (IV) by means of K2CO3 to yield the already reported aryl ether (V). The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluorobenzonitrile (VIII) by means of NaH gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzonitrile (IX), which is reduced with RaNi and HCOOH to yield the already reported 4-ethoxybenzaldehyde derivative (V).

http://www.drugfuture.com/synth/syndata.aspx?ID=164965

………………………….

11th Symp Med Chem (Dec 4-5, Tokushima) 1990,Abst P-11

Two new related syntheses of pioglitazone hydrochloride have been described: 1) The condensation of 2-(5-ethylpyridin-2-yl)ethanol (I) with 4-hydroxybenzaldehyde (II) by means of benzyltributylammonium chloride, NaOH and tosyl chloride gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (III), which is condensed with thiazolidine-2,4-dione (IV) in basic medium to afford 5-[-4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione (V). Finally, this compound is hydrogenated in the usual way. 2) The condensation of alcohol (I) with 4-fluorobenzonitrile (VI) by means of NaH gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzonitrile (VII), which is reduced with Raney Nickel and formic acid to the aldehyde (III), already obtained.

http://www.drugfuture.com/synth/syndata.aspx?ID=164965

…………………..

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265

Beilstein J. Org. Chem. 2013, 9, 2265–2319.

Pioglitazone is clearly related to rosiglitazone (1.40) with its structure only differing in the substitution pattern of the parent pyridine ring. Its synthesis begins with the hydroxymethylation of 2-methyl-5-ethylpyridine (1.11), a commodity chemical obtained from the condensation of acetaldehyde with ammonium acetate (Scheme 12) [43].

At elevated temperatures and pressures 2-methyl-5-ethylpyridine undergoes a condensation reaction with formaldehyde allowing isolation of the chain extended hydroxyethylpyridine 1.70upon distillation although in poor yield [44].

Following subsequent SNAr reaction aryl ether 1.71 is obtained, which is used as crude material in the subsequent Knoevenagel condensation with thiazolidinedione 1.68. In order to reduce the intermediate benzylidene double bond in this example sodium borohydride is used in the presence of cobalt chloride efficiently delivering pioglitazone in high purity.

Scheme 12: Synthesis of pioglitazone.

Other syntheses of pioglitazone use related pyridine building blocks and aim to generate late stage intermediates that deliver the target compound upon de novo synthesis of the thiazolidinedione ring system. For instance phenyl ether 1.73 can be obtained via Williamson ether synthesis between mesylate 1.74 and phenol 1.75 (Scheme 13).

Removal of the acetyl protecting group under acidic conditions renders aniline 1.76 which is subsequently subjected to a Meerwein arylation reaction which occurs via diazotisation and subsequent treatment with acrylonitrile in the presence of cuprous oxide [45-48].

Scheme 13: Meerwein arylation reaction towards pioglitazone.

Alternatively, an equivalent acid functional material can be prepared starting from tyrosine (1.78) via a dual protection of the amino acid unit as the methyl ester and the amine as the benzaldehyde imine (Scheme 14). This is then followed by analogous ether formation with the previously generated mesylate 1.74.

Intermediate 1.80 is then hydrolysed to reveal once again the amino acid functionality, which upon diazotisation in the presence of hydrobromic acid selectively forms the α-bromo ester 1.82.

Scheme 14: Route towards pioglitazone utilising tyrosine.

A more direct SNAr approach utilising 4-fluorobenzonitrile as the acceptor and the sodium alkoxide of hydroxyethylpyridine 1.84 as the nucleophile has been successfully conducted (Scheme 15) [49].

The nitrile unit is partially reduced and hydrolysed to the benzaldehyde 1.71 using Raney-Ni under transfer hydrogenation conditions in wet formic acid. A Darzens reaction between this aldehyde and ethyl chloroacetate in the presence of sodium ethoxide delivers epoxide 1.87.

The material is next subjected to hydrogenolysis using Pd/C in methanol with a 1 bar hydrogen pressure to reductively ring open the epoxide. Finally, the transformation of the alcohol to the mesylate 1.88 occurs under standard conditions.

Scheme 15: Route towards pioglitazone via Darzens ester formation.

In order to complete the syntheses of pioglitazone as outlined in the previous schemes several procedures for the installation of the thiazolidinedione ring system have been reported [50]. For instance the α-bromoester of intermediate 1.82 will render the desired heterocycle upon treatment with sodium isothiocyanate (Scheme 16, A).

Alternatively, the α-amino acid portion of 1.81 can be diazotised under standard conditions and will subsequently deliver the same product when treated with lithium isothiocyanate (Scheme 16, B).

Finally, α-bromonitrile 1.77 can be condensed with thiourea to give pioglitazone after aqueous work-up (Scheme 16, C).

Scheme 16: Syntheses of the thiazolidinedione moiety.

ref for above

43 Frank, R. L.; Pilgrim, F. J.; Riener, E. F. Org. Synth. 1950, 30. doi:10.1002/0471264180.os030.15

44 McGall, G. H.; Barone, A. D. Nucleic Acid Labeling Compounds. U.S. Patent 2001/0018514 A1, Aug 30, 2001.

45 Finch, H.; Fox, C.; Sajad, A. Respiratory Disease Treatment. W.O. Patent WO2010015818, Feb 11, 2010.

46 Adiyaman, M.; Guner, D.; Ridvanoglu, N.; Yurdakul, A. A. Process for the Production of substituted Phenyl Ethers. W.O. Patent WO2004000810, Dec 31, 2003.

47 Nersesian, D. L.; Black, L. A.; Miller, T. R.; Vortherms, T. A.; Esbenshade, T. A.; Hancock, A. A.; Cowart, M. D.Bioorg. Med. Chem. Lett. 2008, 18, 355–359. doi:10.1016/j.bmcl.2007.10.067
48 Halama, A.; Hejtmankova, L.; Lustig, P.; Richter, J.; Srsnova, L.; Jirman, J. Method for obtaining Pioglitazone as an antidiabetic agent. W.O. Patent WO02088120, Nov 7, 2002.

49 Thijs, L.; Zhu, J. Processes for making Pioglitazone and compounds of the processes. W.O. Patent WO2005080387, Sept 1, 2005.

50 Bhanja, C.; Jena, S. J. Chem. Pharm. Res. 2012, 4, 4323–4333.

………………………………..

http://www.google.com/patents/WO2012153312A1?cl=en

Pioglitazone of Formula I, chemically (±)-5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin- dependent diabetes mellitus or “NIDDM”).

The commercially available form of pioglitazone is its monohydrochloride salt.

Dehydropioglitazone (hereinafter referred to as “DHP” or “DHP of Formula II”) is known as an intermediate in the synthesis of pioglitazone or salts thereof.

In addition, DHP is also present as a process impurity or degradation product in pioglitazone or salts thereof. Several reasons are attributed for the generation of DHP in pioglitazone. Some factors linked to the generation of this impurity include the incomplete reduction of DHP and the oxidation of pioglitazone during isolation or while on stability.

Several processes are known in the literature for making pioglitazone or a salt thereof, for example, U.S. Patent Nos. 4,687,777; 5,585,495; 4,812,570; 5,554,758; 5,952,509; and 6,100,403; U.S. Publications 2002/0106762 and 2002/0050563; WO 03/53367; WO 03/80056; WO 2004/07490; WO 2004/024059; WO 2004/101560; WO 2004/101561 , WO 2005/049610; WO 2008/075380; WO 2006/1 17654; WO

2008/142706; WO 2005/058827; WO 2009/104200; and WO 2009/133576.

U.S. Publication 2006/0252803 provides a process for the preparation of pioglitazone which involves dissolving DHP of Formula II in formic acid and hydrogenating with hydrogen in the presence of 10% Palladium on Carbon under 2 atmospheric pressures and a temperature of 80°C. This process reportedly provides pioglitazone having less than about 0.14 % of the impurity at RRT 0.64 (HPLC).

It also provides a process for the preparation of pioglitazone which involves combining DHP of Formula II with dimethylformamide and hydrogenating with hydrogen in the presence of Palladium on Carbon under 3 atmospheric pressures and a temperature of 50°C. It is reported that -68.5% of DHP was converted to pioglitazone, containing about 3.5 % impurities (HPLC).

U.S. Publication 2009/118514 provides various purification methods for pioglitazone. It provides obtaining a solution of pioglitazone with a mixture of dimethylformamide (DMF) and 4% water, DMF and 5% methanol, DMF and 10% methanol, 1 ,4-dioxane or DMF and isopropyl alcohol at a temperature of about 90°C and precipitating pioglitazone from the solution by cooling to a temperature of about 25°C.

U.S. Publication 2007/0078170 provides a process for the preparation of pioglitazone which involves obtaining a clear solution of pioglitazone in

dimethylformamide at 85°C and adding methanol at a temperature of 60°C and further cooling to 10°C to precipitate pioglitazone.

Impurities in pioglitazone or its hydrochloride salt, or any active pharmaceutical ingredient (“API”), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. The purity of an API is critical for commercialization. The product of a chemical reaction is rarely just the target compound. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product in varying amounts. Extra effort is often required to get pharmaceutically acceptable levels of purity of the target compound.

EXAMPLES

Example 1 : Purification of Pioglitazone

Dimethylformamide (10 mL) was heated to 80°C to 82°C and pioglitazone (2 g) was added to the hot solution and stirred at 80°C to get a clear solution. The solution was cooled to 75 °C and mixture of acetone (10 mL) and methanol (10 mL) was added to the solution in 30 to 45 minutes at 70°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with dimethylformamide/acetone/methanol mixture (6 mL).

DHP impurity content after purification: 0.05%

DHP impurity content before purification: 0.16%

Yield: 90% Example 2: Purification of Pioglitazone

Dimethylformamide (200 mL) was heated to 80°C to 85 °C and pioglitazone (40 g) was added to the hot solution and stirred at 80°C to get a clear solution. The solution was cooled to 75°C and mixture of acetone (200 mL) and methanol (200 mL) was added to this solution in 30 minutes to 45 minutes at 65°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (100 mL).

DHP impurity content after purification: 0.04%

DHP impurity content before purification: 0.15%

Yield: 92%

Example 3: Purification of Pioglitazone (Control)

Dimethylformamide (25 mL) was heated to 80°C to 85 °C and pioglitazone (5 g) was added at 85°C. The solution was cooled to 55°C and a mixture of acetone (25 mL) and methanol (25 mL) was added to the solution in 30 minutes to 45 minutes at 55°C to 60°C. After complete addition, the reaction mass was cooled to 35°C to 37°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (10+lOmL).

DHP impurity content after purification: 0.11%

DHP impurity content before purification: 0.12%

Yield: 92%

………………………………………

http://www.google.com/patents/US20070078170

EXAMPLE 5

Conversion of Pioglitazone to Pioglitazone Hydrochloride

Pioglitazone hydrochloride was prepared in a similar manner as exemplified in Example 4. To de-ionized water (7 L) heated to 80° C. added the product obtained from Example 4 (1 Kg) under stirring at 80° C. It was further stirred for 10 min at 80 – 82° C. and conc. HCI (0.5 L) was added to it under stirring at 80° C. The resultant mass was further stirred for 10 min at 80-82° C. to obtain a clear solution. The solution was filtered through celite bed directly into RB flask and the bed was washed with IN HCI (1 L) at 80-82° C. It was cooled to 5° C. under stirring at 5-0° C. for 1 hr. The solids were filtered under N2 atmosphere and dried on the Büchner funnel for about 15 minutes. The product obtained was then dried under vacuum at 55-60° C. to afford the title compound.

Yield: 930.0 g (93%)

HPLC Purity: 99.61%

Samples of pioglitazone hydrochloride prepared in examples 4 and 5 were studied for their solubility, as set forth below:

………………………

US 2014088127

http://www.google.com/patents/US20140088127

5-[4-[2-(5-ethylpyridyl)ethoxy]benzyl-2,4-thiazolidinedione (Pioglitazone hydrochloride, R in 1 is 5-ethyl).

EXAMPLE 55

5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione (1)

To 5 g (0.0121 mol) of 5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione dissolved in 25 mL acetic acid was added 1.62 (0.0243 mol) g zinc in 5 min. Stirring continued for 15 hours at 25-30° C. Reaction mixture was poured in excess water, made alkaline using 10% Na2CO3 and extracted with ethyl acetate. After distilling off ethyl acetate in vacuo, methanol was added to precipitate out 1.13 g (25%) g of the crystalline solid product. The two impurities identified in this reaction were 5-ethyl-2-vinyl-pyridine 0.128 g (10%) and 5-(4-hydroxy benzyl)-thiazolidin-2,4-dione 0.342 g (12%).

The product obtained was characterized by IR, Mass, 13C NMR, and 1H NMR, which are as given below. pioglitazone base

IR spectrum (cm−1): 3417 (N—H str.), 1693, 1743 (C═O str.), 1037 (C—O—C str.)

Mass spectrum (m/z) 357.1 (M+H)+

13C-NMR (DMSO-d6): δ 176.5, 172.5, 157.8, 152.1, 145.9, 142.0, 141.1, 131.2, 129.9, 127.8, 115.2, 66.2, 53.8, 37.0, 33.2, 25.4, 15.5

1H-NMR (DMSO-d6): δ 12.0 (1H, s), 6.84-8.71 (7H, m), 4.86 (1H, dd), 4.38 (2H, t), 3.48 (2H, t), 3.25 (1H, dd), 3.04 (1H, dd), 2.75 (2H,q), 1.21 (3H, t)

Melting point 172-175° C.

The final product was dissolved into 12 mL methanol and 0.05 mL con. HCl was added into it at 25° C. Reaction mixture was refluxed for 30 min. and cooled to 10° C. Precipitated hydrochloride salt was filtered off and dried to yield 1.1 g (22%) of the salt, which was characterized by IR, Mass, 13C NMR and 1H NMR, which are as given below.

pioglitazone hydrochloride

IR spectrum (cm−1): 3257 (N—H str.), 1689, 1743 (C═O str.), 1155, 1244 (C—O—C str.)

Mass spectrum (m/z): 357.1 (M+H)+

13C-NMR (DMSO-d6): δ 175.7, 171.7, 157.0, 151.0, 141.1, 129.0, 145.4, 139.8, 127.2, 130.4, 114.4, 65.4, 53.0, 39.2, 36.2, 24.6, 14.6

1H-NMR (DMSO-d6): δ 12.09 (1H, s), 6.82-8.7 (7H, m), 4.8 (1H, dd), 4.38 (2H, t), 3.5 (2H, t), 3.0 (2H, m), 2.75 (2H,q), 1.21 (3H, t)

Melting point: 190-193° C.

EXAMPLE 565-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione (1)

The procedure described in example 55 was repeated except that temperature was maintained 5-10° C., and substantially the same results were achieved. In this particular case, the final product 5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione obtained was 0.911 g (20%), is identical in every respect with the product of example 55. m.p. 172° C.

EXAMPLE 575-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione (1)

To a solution of 0.8 g (0.00184 mol) of 5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione dissolved in 10 mL ethyl acetate was added 0.8 mL (0.014 mol) acetic acid and 0.119 g (0.00184 mol) zinc in 5 minutes at 25-30° C. Stirring continued for 9 hr. at 30-35° C. Solid material separated was filtered off and dried to get titled compound. Yield of the product was 0.3 g (41%). m.p. 173° C.

The product obtained was characterized by IR, Mass, 13C NMR, and 1H NMR, which was found to be identical with the product obtained in example 55. The impurity profile was also similar to the product obtained in example 55.

EXAMPLE 585-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione (1)

The procedure described in example 57 was repeated except that acetic acid was replaced by 1.038 g (0.014 mol) propionic acid, and substantially the same results were achieved. In this particular case, the final product 5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione obtained was 0.3 g (41%), is identical in every respect with the product of example 55. m.p. 172° C.

EXAMPLE 595-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione (1)

The procedure described in example 57 was repeated except that tetrahydrofuran was used as solvent, and substantially the same results were achieved. In this particular case, the final product 5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione obtained was 0.13 g (18%), is identical in every respect with the product of example 55. m.p. 173° C.

EXAMPLE 605-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione (1)

To a mixture of 5 mL 35% Con. HCl and 5 mL water, 0.5 g (0.0012 mol) of 5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione was added followed by the addition of 0.039 g (0.0006 mol) zinc (tlc). Reaction mixture was poured into 20 mL water, made alkaline by 10% K2CO3 solution and product was extracted with 25 mL ethyl acetate. Organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. Methanol was added to the residual mass to get 0.1 g (22%) crystalline titled product. m.p. 174° C.