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PRANLUKAST

October 21, 2014 10:08 am / 2 Comments on PRANLUKAST

Chemical structure for Pranlukast

PRANLUKAST

Antiasthmatic.

Benzamide, N-(4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl)-4-(4-phenylbutoxy)-
N-(4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl)-p-(4-phenylbutoxy)benzamide
4-Oxo-8-(4-(4-phenylbutoxy)benzoylamino)-2-(tetrazol-5-yl)-4H-1-benzopyran
N-(4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl)-p-(4-phenylbutoxy)benzamide

Launched – 1995 japan

hemihydrate, 103177-37-3 anhydrous, 103180-28-5 (monosodium salt)

150821-03-7, C27 H23 N5 O4 . H2O, 499.5179

Ono-1078
Ono-RS-411
RS-411
SB-205312
Ono-1070 (monosodium salt)

Ultair; Ono-1078; HY-B0290;

Azlaire
CCN 00401
ONO 1078
ONO-1078
ONO-RS 411
Pranlukast
RS 411
SB 205312
UNII-TB8Z891092

N-[4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-4-(4-phenylbutoxy)benzamide hemihydrate

Ono (Originator)Schering-Plough (Licensee)

This is described in…………

J Med Chem 1988, 31(1): 84,

WO 2010002075,

Synth Commun 1997, 27(6): 1065,

WO 1994012492

Leukotriene antagonist.

Prepn: M. Toda et al., EP 173516; eidem, US 4780469 (1986, 1988 both to Ono);

H. Nakai et al., J. Med. Chem. 31, 84 (1988).

Pharmacology: T. Obata et al., Adv. Prostaglandin Thromboxane Leukotriene Res. 15, 229 (1985); idem et al., ibid. 17,540 (1987).

Clinical evaluations in asthma: Y. Taniguchi et al., J. Allergy Clin. Immunol. 92, 507 (1993); H. Yamamoto et al. Am. J. Respir. Crit. Care Med. 150, 254 (1994).

AU 8546462; EP 0173516; JP 8650977; US 4780469; US 4939141

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. It antagonizes or reduces bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.

Pranlukast

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.‘s Singulair (montelukast). It is widely used in Japan.

Medications of this class, which go under a variety of names according to whether one looks at the American, British or European system of nomenclature, have as their primary function the antagonism of bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.

Medications of this group are normally used as an adjunct to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists. There are several similar medications in the group; all appear to be equally effective.

Pranlukast hydrate is a leukotriene CysLT1 (LTD4) and CysLT2 (LTC4) antagonist first launched in Japan in 1995 as capsules for the oral treatment of bronchial asthma and allergic rhinitis. A dry syrup formulation of pranlukast for the treatment of asthma was approved in Japan in 1999. In April 2011, Ono filed a regulatory application in Japan seeking approval of the compound for the treatment of allergic rhinitis in pediatric patients. In December 2011, approval was obtained for this indication and launch took place immediately.

In terms of clinical development, Ono had been evaluating the drug in phase III for the treatment of sinusitis; however, in 2008 the compound was discontinued for this indication when the compound failed to demostrate the expected efficacy in the phase III studies. In March 2006, Ono discontinued development of the compound for the oral treatment of chronic obstructive pulmonary disease (COPD) based on results which suggested no evidence of efficacy. In 2000, Ono signed a license agreement with Schering-Plough to develop and market pranlukast hydrate in Latin America.

Chemical structure for Pranlukast hemihydrate

Pranlukast hemihydrate

Also known as: RTR-006167; 150821-03-7…………..http://chem.sis.nlm.nih.gov/chemidplus/rn/150821-03-7

Benzamide, N-(4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl)-4-(4-phenylbutoxy)-, hydrate (2:1)

UNII-FR702N558K

4-Oxo-8-[(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran · 1/2 hydrate (common name: pranlukast, hereinafter referred to as “pranlukast” in the specification including the claims) represented by formula:

is a compound having a potential antagonistic action against leucotriene C₄(LTC₄) and leucotriene D₄ (LTD₄) and is expected as a treating agent for allergic bronchial or pulmonary diseases, allergic shock, and various allergic inflammatory diseases.

Pranlukast
Systematic (IUPAC) name

N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-chromen-7-yl]-4-(4-phenylbutoxy)benzamide
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	?
Routes	Oral
Pharmacokinetic data
Metabolism	Hepatic (mainly CYP3A4)^[1]
Half-life	1.5 hours^[1]
Identifiers
CAS number	103177-37-3
ATC code	R03DC02
PubChem	CID 4887
DrugBank	DB01411
ChemSpider	4718
UNII	TB8Z891092
ChEMBL	CHEMBL21333
Chemical data
Formula	C₂₇H₂₃N₅O₄
Mol. mass	481.503 g/mol

Toda synthetic complete with 3 – nitro-2 – hydroxyphenyl ko one for raw materials, ni ko with oxalic ester Claisen condensation occurs, and then heated to reflux for cyclization to construct benzo pyran ring; dehydrated by an amide synthesized ring cyano group, the cyano compound and then with sodium azide tetrazole synthesis. The nitro group on the compound in 5% Pd / C catalyzed hydrogenation of amino acid reacted with the compound Pranlukast held. This method directly using 4 – (4 – phenyl-butoxy)-benzoic acid reaction. Synthetic route is as follows:

[0006]

[0007]

[0008] ② Robert Graham and routes are routes to I-bromo-butane as a raw material, were used as a palladium catalyst, ligand compound formylation carbonylation reactions and condensation of potassium tert-butoxide, closed dehydration under acidic conditions benzopyran ring method. Synthetic route is as follows:

[0009] Robert routes:

[0010]

[0011] Graham route:

[0012]

[0013] The two synthetic routes are not disclosed in the I-Bromo butane feedstock pathway.

[0014] ③ Masayohi 2_ cyano synthetic route to a benzopyran derivative and hydrogen sulfide gas in the base-catalyzed addition reaction of 2 – thiocarbamoylbenzothiazol and pyran derivatives, and then were reacted with anhydrous hydrazine group hydrazone, with sodium nitrite under acidic conditions nitrosation reaction occurs tetrazole ring. Synthetic route is as follows:

[0015]

[0016] The materials used are not mentioned route synthesis method, it is only reflected in the improvement of the synthesis of the tetrazole ring.

[0017] ④ Giles, Hideki and Hayler are tetrazole substituent on the increase, making it easier condensation reaction, but the synthesis of substituted on the nitrogen with tetrazole difficult, and ultimately elimination reaction of lithium used tetrahydro aluminum and other hazardous reagents, is not easy to Eri industrialization. Reaction scheme is as follows:

[0018]

[0019] ⑤ Lee NK with 4_ (4_ Phenylbutoxy) benzonitrile and 2_ hydroxy _3_ iodobenzene ko 1H_4_ thiazolyl ketone and ester ko _5_ acid, concentrated sulfuric acid catalyzed cyclization iodide copper and potassium phosphate removal under the action of hydrogen iodide get Pranlukast held. Reaction scheme is as follows:

[0021] does not mention the route starting 4 – (4 – phenyl-butoxy)-benzonitrile synthesis method, while two – hydroxy – 3 – Synthesis of iodobenzene ko difficult one.

The synthesis method comprises the following steps: a. 4 – Synthesis of chlorobutanol THF was added concentrated hydrochloric acid, feeding the mass ratio of I: I. 389 ~ 5. 556,45-80 ° C was stirred for 5-18h, cooled, extracted with methylene chloride, removal of the solvent, distillation under reduced pressure to give 4 – chlorobutanol; b. 4 – phenyl butanol take benzene, aluminum chloride mixture ,0-25 ° C solution of 4 – chlorobutanol, reaction 5 -10h then poured into ice-water, a liquid, in addition to homogeneous solution U, distillation under reduced pressure, and the resulting colorless transparent liquid that is, 4 – phenyl butanol; c. I-bromo-4 – phenyl butane synthesis of 4 – phenyl butanol 40% hydrobromic acid mixture, feeding the mass ratio of I: 2. 857 ~ 11. 428, heat refluxing, cooling, liquid separation, the organic solvent divided by distillation under reduced pressure to give I-bromo-4 – phenyl butane; d. Synthesis of methyl p-hydroxybenzoate take-hydroxybenzoic acid and methanol, concentrated sulfuric acid and refluxed for 5-20h spin methanol, poured into cold water to precipitate a white solid which was filtered and dried to give the hydroxy benzoate; e. 4 – (4 – phenyl-butoxy)-benzoic acid methyl ester _ take I-bromo-4 – phenyl butane,

DMF, toluene, methyl p-hydroxybenzoate and potassium carbonate, a reflux 5 ~ 20h, cooling water, extracted with toluene, light yellow liquid rotary evaporation, recrystallization, and the resulting white solid, that is, 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester; f. 4 – (4 – phenyl-butoxy yl) – benzoic acid taken 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester, 15% NaOH solution was refluxed for I ~ 5h, cooled, acidified, filtered and dried to give 4 – (4 – phenylbutyrate oxy) – benzoic acid; g. sprinkle bromophenyl acetic acid ester molar ratio Preparation of I: I ~ I. 5: O. I ~ I of bromophenol, acetic anhydride, pyridine feeding, reflux 3 ~ 10h, distilled pyridine, acetic acid and excess acetic anhydride distilled under reduced pressure to give the acetic acid esters bromophenol; h. 5 – bromo-2 – Preparation of light taken acetophenone molar ratio of I: I ~ 5: I of acetic acid bromophenol esters, aluminum chloride, tetrachlorethylene for feeding, reflux O. 5 ~ 5. 5h, cooled, the reaction solution was poured into 5% hydrochloric acid and extracted with methylene chloride, the solvent evaporated under reduced pressure, to obtain a gray crystalline 5 – bromo-2 – Light acetophenone; i. 5 – bromo-3 – nitro-2 – Preparation of light acetophenone take 5 – bromo-2 – Light acetophenone, carbon tetrachloride, 50 ~ 90 ° C is added dropwise nitric acid, reflux I ~ 4h, cooled, filtered, and the resulting yellow solid which is 5 – bromo-3 – nitro-2 – hydroxyacetophenone; j. 3 – amino-2 – Light benzene ethanone Preparation of 5 – bromo-3 – nitro-2 – hydroxyacetophenone, 5% Pd / C, methylene chloride, methanol, concentrated hydrochloric acid, water, hydrogenation; the end of the reaction mixture was filtered, the filtrate was The solvent was removed, neutralized with sodium bicarbonate, and the resulting yellow solid ginger i.e., 3 – amino-2 – hydroxyacetophenone; k. 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 _ light base Preparation of acetophenone 4 – (4 – phenyl-butoxy)-benzoic acid, toluene, DMF, 45 ~ 105 ° C was added dropwise SOCl2, 30min the reaction liquid droplets to the 3 – amino-2 – hydroxyphenyl toluene solution of ethyl ketone, the reaction 3 ~ 10h, cooled, neutralized with dilute hydrochloric acid, extracted with toluene, rotary evaporation, and the resulting pale yellow crystals is 3 – [4 – (4_ phenylbutoxy) benzamido] 2_-hydroxyacetophenone; I. 2 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol synthetic sodium, THF, 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – hydroxyacetophenone, diethyl oxalate 4 ~ IOh After stirring the reaction was poured into dilute hydrochloric acid to precipitate the yellow solid which was filtered, and the resulting product, i.e. 2 – [4 – (4_ phenylbutoxy) benzamido] _6_ [1,3 – dioxo-3 – ethoxy propyl intended yl] phenyl discretion ·; m. 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran take 2 – [4 – (4 – phenyl-butoxy yl) benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol, THF, force mouth heat, the addition of concentrated hydrochloric acid, refluxed for 8 ~ 15h, cooled, filtered, and the resulting white solid,

that is, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran; η. 4 – oxo-8 – [ 4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran synthesis take four – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – ethoxycarbonyl-4Η-benzopyran was dissolved in DMF,

and leads to dry ammonia gas, the reaction solution changed from yellow to red, the reaction solution was poured into cold water, adjusted to acidic, and filtered to give the product 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran; P. 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4Η-benzopyran take DMF, S0C12, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoic amido] _2_ aminocarbonyl-4H-benzopyran, O ~ 15 ° C under stirring for 2 ~ IOh poured into cold water, filtered, and the resulting white solid that is, 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4H-benzopyran; q. Synthesis of pranlukast take four – oxo-8 – [4 – (4 – phenyl-butoxy) benzoyl amino]-2_ cyano-4H-benzopyran, ammonium chloride, sodium azide, DMF, heating I ~ 8h then poured into ice-water, dilute hydrochloric acid, filtered, and the resulting white solid that the final product Pranlukast.

The reaction of ethyl 8-nitro-4-oxo-1-benzopyran-2-carboxylate (I) with ammonia in methanol gives the corresponding amide (II), which is dehydrated with POCl3 yielding 2-cyano-8-nitro-1-benzopyran-4-one (III). The cyclization of (III) with sodium azide by means of pyridinium chloride in hot DMF affords 8-nitro-2-(tetrazol-5-yl)-1-benzopyran-4-one (IV), which is hydrogenated with H2 over Pd/C in methanol – HCl giving 8-amino-2-(tetrazol-5-yl)-1-benzopyran-4-one (V). Finally, this compound is condensed with 4-(4-phenylbutoxy)benzoic acid (VI) by means of oxalyl chloride in dichloromethane-pyridine\

………………………..

Synthetic routes

The reaction of ethyl 8-nitro-4-oxo-1-benzopyran-2-carboxylate (I) with ammonia in methanol gives the corresponding amide (II), which is dehydrated with POCl3 yielding 2-cyano-8-nitro-1- benzopyran-4-one (III). The cyclization of (III) with sodium azide by means of pyridinium chloride in hot DMF affords 8-nitro-2- (tetrazol-5-yl) -1-benzopyran-4-one (IV ), which is hydrogenated with H2 over Pd / C in methanol -. HCl giving 8-amino-2- (tetrazol-5-yl) -1-benzopyran-4-one (V) Finally, this compound is condensed with 4- (4-phenylbutoxy) benzoic acid (VI) by means of oxalyl chloride in dichloromethane-pyridine.

……………………………………

PATENT

http://www.google.im/patents/WO2010067913A1?cl=en

Example 1: Synthesis of pranlukast

To 10 g of N-(4-oxo-2-(l-trityl-lH-tetrazol-5-yl)-4H-chromen-8-yl)-4-(4- phenylbutoxy) benzamide (Pharmacostech) was added 100 ml of methanol, and 10 g of a resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-B gel type,

Mitsubishi Chemical Co.) was added to the reaction mixture, followed by refluxing for

5 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was subject to vacuum distillation to obtain a solid substance and the solid was dissolved in 50 ml of dimethyl acetamide (DMAC). Afterwards, 200 ml of aqueous solution was added to the DMAC solution and stirred for 1 hour at room temperature. Then, the solid formed was filtered out, dried, and left for 5 hours at room temperature to give 6.32 g (yield:

95%) of the standard compound represented by the following Formula 5: melting point, 231-233⁰C (decomposed); ¹H-NMR (DMSOd₆, 300 MHz), δ 1.9 (m, 4H), 2,7 (m,2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0

(m, 2H), 8.3 (t, IH), 10.0 (bs, IH).

Example 2: Synthesis of pranlukastOne hundred ml of methanol was added to 10 g of N-(4-oxo-2-(l-trityl-lH- tetrazol-5-yl)-4H-chromen-8-yl)-4-(4-phenylbutoxy) benzamide (Pharmacostech), then 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type, Mitsubishi Chemical Co.) was added to the reaction mixture, followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was subject to vacuum distillation to obtain a solid substance and the solid was dissolved in 50 ml of dimethyl acetamide (DMAC). Afterwards, 200 ml of aqueous solution was added to the DMAC solution and stirred for 1 hour at room temperature. Then the solid formed was filtered out, dried, and left for 5 hours at room temperature to obtain 6.18 g (yield rate: 93%) of the standard compound represent by Formula 5: melting point, 231- 233^°C (decomposed); ¹H-NMR (DMSOd₆, 300 MHz), δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0 (m, 2H), 8.3 (t, IH), 10.0 (bs, IH).

Example 3: Synthesis of pranlukast

One hundred ml of methanol and 100 ml of methylene chloride (MC) were added to 10 g of N-(4-oxo-2-(l-trityl-lH-tetrazol-5-yl)-4H-chromen-8-yl)-4-(4- phenylbutoxy) benzamide (Pharmacostech), then 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type) was added to the reaction mixture, followed by refluxing for 12 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was subject to vacuum distillation to obtain a solid substance and the solid was dissolved in 50 ml of dimethyl acetamide (DMAC). Afterwards, 200 ml of aqueous solution was added to the DMAC solution, and stirred for 1 hour at room temperature. Then the solid formed was filtered out, dried, and left for 5 hours at room temperature to obtain 6.18 g (yield rate: 93%) of the standard compound represent by Formula 5: melting point, 231-233^°C (decomposed); ¹H-NMR (DMSO-d₆, 300 MHz), δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0 (m, 2H), 8.3 (t, IH), 10.0 (bs, IH).

……………………………………………………….

http://www.google.com/patents/WO2010002075A1?cl=en

Pranlukast and its hydrates come into the market as a capsule of Onon® Cap. (112.5 mg pranlukast hydrates/capsule, Dong-A Pharmaceutical).

The conventional method for preparing pranlukast was disclosed in US Pat. No. 5,587,483 and pranlukart is prepared by the following reaction formula I.

Reaction Formula I

As described in the reaction formula I, the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride. The resulting compound is reacted with the compound represented by formula 4. The compound (n = 4) represented by formula 5 is reacted with the tetrazol derivative represented by formula 6 to introduce tetrazol group and then benzopyran ring is formed, preparing pranlukast. However, the preparation method according to the reaction formula I has quite a few problems: (a) difficult manipulation due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature when the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride;

(b) hard elimination of thionyl chlorides toxic in a body after terminating the reactions; (c) requirement of base in an equivalent ratio of above 4 to collect the compound represented by formula 7; (d) unsuitability of massive production in a economical area because the compound is modified into a form of natrium salt and then purified for removal of contaminants after preparing pranlukart.

On the other hand, as described in the following reaction formula II in US Pat. No. 5,874,593, nitril compounds of formula 8 are reacted with hydrazine to prepare amidrazone compounds of formula 9a and 9b, and then pranlukart is fabricated by performing a tetrazol ring reaction using nitrous acids.

Reaction Formula II

However, the preparation method according to the reaction formula II has also the following difficulties: (a) it is difficult to perform the method due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature to obtain the acid chloride derivative in the preparation of the compounds represented by formula 8; (b) it is very difficult and toxic in body to eliminate thionyl chlorides after terminating the reactions; (c) it is not easy to massively produce the compounds of interest in an industrial-scale because much hydrazine toxic in body and nitrogen oxides harmful in environment are generated and unstable nitrous acids are used during the reactions.

Likewise, US Pat. No. 5,874,593, as described in the following reaction formula III, discloses that benzoic derivatives of formula 10′ are reacted with oxalyl chlorides to isolate acid chlorides represented by formula 11′, and the resulting acid chlorides are reacted with benzopyran amine derivatives containing tetrazol of formula 12, producing various derivatives containing pranlukart.

Reaction Formula III

( I D’ ] (H ‘ )

Oxalyl chlorides are massively used because the preparation method according to the reaction formula III is very expensive cost and has highly hygroscopic characteristics. In addition, the method has to be carried out under violent conditions that the temperature is increased up to around reflux temperature using 1,2- dichloroethanol as a solvent and further reacted for 1 hr. It is also difficult to remove harmful carbon monoxide and chlorine gases massively generated in elimination of oxalyl chloride after terminating the reactions, and it is not feasible to be applied into an industrial mass-production because the reaction is carried out under conditions of anhydrous and inactive gases

EXAMPLE 1: Preparation of Pranlukart Hemihydrates 4-(4-phenylbutoxy)benzoic acid (29.1 g; 1.1 equivalent ratio; prepared according to the method disclosed in US Pat. No. 4,780,469) was dissolved in 80 ml dimethylacetamide (DMAC, Aldrich) at 0⁰C and then thionyl chloride (14.2 g, 1.2 equivalent ratio, Aldrich) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0⁰C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H- 1-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio; prepared according to the method disclosed in US Pat. No. 4,780,469) and triethylamine (TEA, 10.1 g, 1 equivalent ratio, Aldrich) dissolved in 80 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C.

The reaction mixture was mixed with 300 ml H₂O and stirred for 1 hr at 25⁰C. The solid material obtained by filtering the solid material produced was washed with 100 ml H₂O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 47.0 g pranlukart hemihydrates (yield rate: 98%): melting point 231-233°C (decomposition); ¹H-NMR (DMSO-d₆, 300 MHz) δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0 (m, 2H), 8.3 (t, IH), 10.0 (bs, IH).

EXAMPLE 2: Preparation of Pranlukart Hemihydrates – Substitution of the Chlorinating Agent

4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 0⁰C and then oxalyl chloride (15.2 g, 1.2 equivalent ratio, Aldrich) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0⁰C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H- 1-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEA, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C.

The reaction mixture was mixed with 300 ml H₂O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 100 ml H₂O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 43.3 g pranlukart hemihydrates (yield rate: 92%).

EXAMPLE 3: Preparation of Pranlukart Hemihydrates – Change of Base Condition

EXAMPLE 4: Preparation of Pranlukart Hemihydrates – Change of Reaction Temperature Condition

4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 0⁰C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at O⁰C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 50⁰C. The reaction mixture was mixed with 300 ml H₂O and stirred for 1 hr at 50⁰C. The solid material obtained by filtering the solid material produced was washed with 100 ml H₂O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 45.6 g pranlukart hemihydrates (yield rate: 95%).

EXAMPLE 5: Preparation of Pranlukart Hemihydrates – Substitution of Reaction Solvent 4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml N-methylpyrrolidine (NMP, Aldrich) at O⁰C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0⁰C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml N-methylpyrrolidine (NMP) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 25⁰C. The reaction mixture was mixed with 300 ml H₂O and stirred for 1 hr at 25°C.

The solid material obtained by filtering the solid material produced was washed with 100 ml H₂O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 43.3 g pranlukart hemihydrates (yield rate: 90%).

EXAMPLE 6: Preparation of Pranlukart Hemihydrates – Equivalent Ratio Change of the Chlorinating Agent

4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 0⁰C and then thionyl chloride (14.2 g, 1 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0⁰C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g, 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 25°C.

……………………..

J. Med. Chem., 1988, 31 (1), pp 84–91

DOI: 10.1021/jm00396a013

http://pubs.acs.org/doi/abs/10.1021/jm00396a013

…………………………………………………..

Geen, G.R.; Giles, R.G.; Grinter, T.J.; Hayler, J.D.; et al.
A direct and high yielding route to 2-(5-tetrazolyl) substituted benzopyran-4-ones: Synthesis of pranlukast
Synth Commun 1997, 27(6): 1065

A direct and high yielding route to 2-(5-tetrazolyl)benzopyran-4-ones 1, including pranlukast 1a is described. This involves the Claisen condensation reaction between the relevant hydroxyacetophenone 2 and the ethyl ester of tetrazole-2-carboxylic acid 5 to give the 1,3-diketone 6, which is then cyclised to give the desired benzopyran-4-ones 1.\

http://www.tandfonline.com/doi/abs/10.1080/00397919708003052?journalCode=lsyc20#.VEctUVfgXXM

………………………………………………..

WO 1994012492

http://www.google.com/patents/WO1994012492A1?cl=en

References

Nakade S, Ueda S, Ohno T, Nakayama K, Miyata Y, Yukawa E, Higuchi S (2006). “Population pharmacokinetics of pranlukast hydrate dry syrup in children with allergic rhinitis and bronchial asthma.”. Drug Metab Pharmacokinet 21 (2): 133–9. doi:10.2133/dmpk.21.133. PMID 16702733.

PRANLUKAST

Advanced Intermediate Flow Studies: Nevirapine

October 20, 2014 1:01 am / Leave a comment

SynthFlow

After looking through a number of flow articles that describe and illustrate processes toward the production of drug final products and advanced intermediates, I thought an article from Florida State — Tyler McQuade (open source Beilstein JOC 2013) was informative and storytelling. He was able to show some of the challenges that go into designing a flow methodology around process that have already been worked out in batch mode, and had been looked at in a number of labs already.

Before talking about the chemistry, Professor McQuade talks about a number of concerns in transferring technology from batch to flow: DOE, solvent exchange (precipitation and moving from one reaction to another), Cost of Goods Analysis – reaction concentrations, solvent costs, process time, by-product formation and purification. There certainly is a lot that goes into the strategy. To give you the framework: this group was looking to make a continuous process…

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System Suitability for USP Chromatographic Methods

October 16, 2014 4:59 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

System Suitability for USP Chromatographic Methods
How should system suitability tests (SSTs) be structured for USP monographs? More about USP experts group’s recommendations on the parameters and acceptance criteria for SSTs and the essential aspects of this new approach can be found in this News.

read

http://www.gmp-compliance.org/enews_4539_System-Suitability-for-USP-Chromatographic-Methods_9150,8369,8488,Z-QCM_n.html

An interesting article from the USP experts group “Small Molecules” has been published in the Pharmacopoeial Forum 39(5). It deals with USP’s future requirements regarding system suitability tests (SST).

SSTs are performed each time an analytical method is used. Together with instruments qualification and methods validation, the SST ensures the quality of analytical test results. The SST shows that a procedure and an instrumental system are performing as they did when the procedure was validated and that the method is thus “fit for purpose” for the intended use.

General requirements can be found in the USP Chapter <621> Chromatography which also contains provisions and acceptance…

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EPILEPSY AND SEIZURES ; 100% CURABLE BY AYURVEDA AND AYUSH TREATMENT

October 16, 2014 1:08 am / 2 Comments on EPILEPSY AND SEIZURES ; 1002 CURABLE BY AYURVEDA AND AYUSH TREATMENT

**आधुनिक युग आयुर्वेद ** ई०टी०जी० आयुर्वेदास्कैन ** DIGITAL AYURVEDA TRIDOSHO SCANNER**AYURVED H. T. L. WHOLE-BODY SCANNER**आयुषव्यूज रक्त केमिकल केमेस्ट्री परीक्षण अनालाइजर ** डिजिटल हैनीमेनियन होम्योपैथी स्कैनर **

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NEWDRUGAPPROVALS Touches 4 lakh views in 198 countries

October 15, 2014 3:30 am / Leave a comment

Inline image 1
NEW DRUG APPROVALS BLOG ON A HIGH

NEW DRUG APPROVALS

ALL ABOUT DRUGS, LIVE, BY DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER, HELPING MILLIONS, 7 MILLION HITS ON GOOGLE, PUSHING BOUNDARIES, ONE LAKH PLUS CONNECTIONS WORLDWIDE, 4 LAKHS PLUS VIEWS ON THIS BLOG IN 198 COUNTRIES

DR ANTHONY, WORLDDRUGTRACKER, HELPING MILLIONS

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MOBILE-+91 9323115463

GLENMARK SCIENTIST , INDIA

Final Concept Paper ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle

October 14, 2014 3:04 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Final Concept Paper ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Currently, there are no harmonised approaches to technical and regulatory considerations for the lifecycle management of pharmaceutical products. Therefore, ICH has just published a Final Concept Paper for a new ICH Q12 Guideline: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle. The proposed ICH Guideline is intended to fill this gap. read

http://www.gmp-compliance.org/enews_4533_Final-Concept-Paper-ICH-Q12-Technical-and-Regulatory-Considerations-for-Pharmaceutical-Product-Lifecycle_8348,8360,Z-PDM_n.html

ICH has just published a Final Concept Paper for a new ICH Q12 guideline: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle.

Currently, there is a lack of a harmonised approach to technical and regulatory considerations for the lifecycle management of pharmaceutical products. Although there are concepts in ICH Q8, Q9, Q10 and Q11 for a more science and risk-based approach for assessing changes across the lifecycle, several gaps exist which hinder a full realization of the benefits intended. The original aim of ‘operational flexibility’…

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Thyme Oil Beats Ibuprofen for Pain Management.

October 14, 2014 1:04 am / Leave a comment

MALOTILATE, Malotilat

October 12, 2014 5:56 am / Leave a comment

Malotilate, Malotilat

(Kantec; Hepation; NKK 105)

Diisopropyl 1,3-dithiol-2-ylidenemalonate

Nihon Nohyaku Co., Ltd. innovator

Malotilate (INN) is a drug used in the treatment of liver disease. It has been shown to facilitate liver regeneration in rats.^[1]

DA-3857
NKK-105

CAS 59937-28-9

Name: 1,3-Dithiol-2-ylidenepropanedioic acid bis(1-methylethyl) ester

Additional Names: diisopropyl 1,3-dithiol-2-ylidenemalonate

Manufacturers’ Codes: NKK-105

Trademarks: Hepation (Nippon Chemiphar); Kantec (Daiichi)

Molecular Formula: C12H16O4S2

Molecular Weight: 288.38

Percent Composition: C 49.98%, H 5.59%, O 22.19%, S 22.24%

Properties: Pale yellow crystals, mp 60.5°. Sol in benzene, cyclohexane, n-hexane, ether.

Melting point: mp 60.5°

Therap-Cat: Hepatoprotectant.

Systematic (IUPAC) name
diisopropyl 1,3-dithiol-2-ylidenemalonate
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	℞ Prescription only
Routes	Oral
Identifiers
CAS number	59937-28-9
ATC code	None
PubChem	CID 4006

UNII	RV59PND975

Chemical data
Formula	C₁₂H₁₆O₄S₂
Mol. mass	288.38 g/mol

Brief background information

Salt	ATC	Formula	MM	CAS
–	A02AD02	C ₁₂ H ₁₆ O ₄ S ₂	288.39 g / mol	59937-28-9

Application

hepatoprotector
in the treatment of liver diseases

Classes of substances

1,2-dithiolane and 1,2-dithiols
- Esters
  - Anilides and other derivatives of malonic acid

It is known that there are a large number of patients who suffer from liver damages caused by various factors such as alcohol, malnutrition, viruses, chemicals, toxicants, etc. The liver diseases may generally be classified by their types into acute hepatitis, chronic hepatitis, liver cirrhosis, and fulminant hepatitis. It is said to be very difficult to treat these liver diseases. Namely, currently available methods for the treatment such as treatments with pharmaceuticals e.g. liver protective agents such as various vitamins, saccharides, amino acids, glutathione, glycyrrhizin, liver hydrolyzates or adrenocortical hormones; cholagogues; immunomodulaters; or antiviral substances against viral hepatitis, are all nothing more than symptomatic treatments, and they are not adequately effective for the treatment of the existing liver damages.
It has recently been reported that 1,3-dithiol derivatives represented by Malotilate as identified below, are effective for the treatment of liver damages (see Japanese Examined Patent Publications No. 18,576/1981, No. 18,577/1981 and No. 18,578/1981).
Other 1,3-dithiol derivatives similar to Malotilate with respect to structure and pharmaceutical properties are described in US-A-4,118,506, EP-A-99 329 and US-A-4,022,907.
As a result of extensive researches, the present inventors have found that certain novel 1,3-dithiol derivatives represented by the after-mentioned formula I, exhibit excellent activities for the treatment of a wide spectrum of liver damages, which are comparable or superior to the above-mentioned conventional 1,3-dithiol derivatives. The present invention has been accomplished on the basis of this discovery.
Namely, the present invention provides a 1,3-dithiol-2-ylidene derivative of the formula:

Synthesis pathway

Synthesis a)

………………

US 4327223

http://www.google.co.in/patents/US4327223

EXAMPLE 1

Diisopropoxycarbonylketene disodium mercaptide crystals (8 g, 0.02 mol) was dissolved in 50 ml of dimethylsulfoxide, and 1,1,1-trichloroethane (2.7 g, 0.02 mol) and subsequently a 30% sodium hydroxide aqueous solution (2.7 g, 0.02 mol NaOH) were added thereto. Thus, reaction was carried out at 60° C. for 1 hour. The resulting mixture was poured into ice-water, and then extracted with benzene. Drying of the extract over anhydrous magnesium sulfate, distillation to remove benzene, and recrystallization from n-hexane gave 2.6 g of the object matter diisopropyl 1,3-dithiol-2-ylidene malonate; m.p. 60.5° C., yield 45%.

EXAMPLE 2

Diisopropyl malonate (18.8 g, 0.1 mol) and carbon disulfide (7.6 g, 0.1 mol) were dissolved in 200 ml of dimethylsulfoxide. Dropping thereto a 45% potassium hydroxide aqueous solution (31 g, 0.25 mol KOH) at 13°-17° C., gave a yellowish red solution containing diisopropoxycarbonylketene dipotassium mercaptide. At 20° C., 1,1,1-trichloroethane (26.6 g, 0.2 mol) was added, and 5 minutes after a 45% potassium hydroxide aqueous solution (18.6 g, 0.15 mol KOH) was dropped thereinto. The temperature was raised to 70° C. to carry out reaction for 30 minutes. The resulting mixture was poured into ice-water and then extracted with benzene. Drying of the extract over anhydrous magnesium sulfate, distillation to remove benzene, and recrystallization from n-hexane gave 23.6 g of the object matter diisopropyl 1,3-dithiol-2-ylidene malonate; m.p. 60.5° C., yield 82.1%.

EXAMPLE 3

Diisopropyl malonate (18.8 g, 0.1 mol) and carbon disulfide (7.6 g, 0.1 mol) were dissolved in 200 ml of dimethylsulfoxide. A 45% potassium hydroxide aqueous solution (49.6 g, 0.4 mol KOH) was dropped thereto at 15° C., then 1,1,1-trichloroethane (13.3 g, 0.1 mol) was added at 20° C., and reaction was carried out at 70° C. for 30 minutes. The resulting mixture was poured into ice-water and then extracted with benzene. Drying of the extract over anhydrous magnesium sulfate, distillation to remove benzene, and recrystallization from n-hexane gave 18.1 g of the object matter diisopropyl 1,3-diethiol-2-ylidene malonate; m.p. 60.5° C., yield 62.8%.

………………………………….

US 4035387

http://www.google.co.in/patents/US4035387

Example 1Synthesis of diisopropyl 1,3-dithiol-2-ylidene malonate (the compound 3)

1.1 Grams (0.03 mole) of 69% purity sodium hydride was suspended in 30 ml. of dry tetrahydrofuran. Into the resulting suspension, 5.6g (0.03 mole) of diisopropyl malonate was gradually dropped with ice-cooling. After completion of the generation of hydrogen gas, 8.2g (0.03 mole) of 2-methylthio-1,3-dithiolium iodide was added. The resulting mixture was heated under reflux for 1 hour, and then the reaction product was poured into a large amount of ice water to deposit crystals. The crystals were recovered by filtration, dried and then recrystallized from n-hexane to obtain 6.7g of white crystals, m.p. 59°-60° C., yield 77.5% .

The 2-methylthio-1,3-dithiolium iodide used as starting material was synthesized in the following manner;

44.4 Grams (0.2 mole) of 1,3-dithiol-2-thion-4,5-dicarboxylic acid was dissolved in 240 ml of nitromethane, and the resulting solution was heated to 80° C. Into this solution, 100 ml of iodomethyl was gradually dropped, and the resulting mixture was refluxed for 6 hours. After completion of the reaction, the formed crystals were recovered by filtration, washed with 100 ml of ether and then air-dried to obtain 48.4g of the desired compound, m.p. 114°-116° C. (decomp.), yield 87.0%.

………………………………………..

Fujinami, T.; et al. The preparation of cyclic dithia and thiaza compounds by the reaction of potassium carbonate with heterocumulenes and alkylene dibromides or carbonate catalyzed by organostannyl compounds
Bull Chem Soc Jpn 1982, 55(4): 1174

https://www.jstage.jst.go.jp/article/bcsj1926/55/4/55_4_1174/_pdf

…………………………………….

Trade Names

Country	Trade name	Manufacturer
Japan	Kantek	Daiichi
Ukraine	No	No

Formulations

200 mg tablets

Links

DOS 2,545,569 (Nihon Nohyaku; appl. 10.10.1975; J-prior. 18.10.1974, 22.10.1974).
US 4,035,387 (Nihon Nohyaku; 12.7.1977; J-prior. 18.10.1974, 22.10.1974).

1H NMR PREDICTIONS

WATCH OUT

13C NMR PREDICTIONS

Literature References: Prepn from diisopropyl malonate: K. Taninaka et al., DE 2545569; eidem, US 4035387 (1976, 1977 both to Nihon Nohyaku); from the corresponding ketene mercaptide: H. Matsui et al., US 4327223 (1982 to Nihon Nohyaku). Effect on CCl4-induced liver injury in rats: Y. Imaizumi et al., Jpn. J. Pharmacol. 31, 15 (1981). Enhancement of rat liver protein synthesis:eidem, ibid. 32, 369 (1982). Pharmacokinetics and pharmacodynamics: M. Buhrer et al., Eur. J. Clin. Pharmacol. 30, 407 (1986). Clinical evaluation in liver cirrhosis: S. Takase et al., Gastroenterol. Jpn. 23, 639 (1988).

References

Niwano et al, Acceleration of Liver Regeneration by Malotilate in Partially Hepatectomized Rats

Bührer M, Le Cotonnec JY, Wermeille M, Bircher J (1986). “Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis”. Eur. J. Clin. Pharmacol. 30 (4): 407–16. doi:10.1007/BF00607952.PMID 3743616.
Siegers CP, Pauli V, Korb G, Younes M (August 1986). “Hepatoprotection by malotilate against carbon tetrachloride-alcohol-induced liver fibrosis”. Agents Actions 18 (5–6): 600–3. doi:10.1007/BF01964970. PMID 3766314.
Younes M, Siegers CP (May 1985). “Effect of malotilate on paracetamol-induced hepatotoxicity”. Toxicol. Lett. 25 (2): 143–6.doi:10.1016/0378-4274(85)90074-8. PMID 4002245.
Mayer, R.; et al.Synthesis of 1,3-dithiol-2-thiones (‘ Isotrithione’)
Angew Chem Int Ed 1964, 76(3): 143
O’Connor, B.R.; Jones, F.N.Reactions of ethylene di- and trithiocarbonates with acetylenes. Anomalous reaction with bromocyanoacetylene to give a thioacyl bromide
J Org Chem 1970, 35(6): 2002
Fujinami, T.; et al. The preparation of cyclic dithia and thiaza compounds by the reaction of potassium carbonate with heterocumulenes and alkylene dibromides or carbonate catalyzed by organostannyl compounds
Bull Chem Soc Jpn 1982, 55(4): 1174

Biological Activity of Malotilate

Malotilate is a Liver Protein Metabolism Improved Compound, Which Selectively INHIBIT the 5-lipoxygenase. IC50 Value : Target : 5-lipoxygenase in vitro : In an in vitro assay using RAT Invasion lung endothelial (RLE) cells, Invasion of tumor cells Which HAD BEEN treated with MT (10 ng / ml, 24 h) was not affected; however, when RLE cells had been treated with MT, invasion was significantly inhibited in three cell lines (SAS, Ca9-22 and HSC-4) and a tendency to inhibition WAS Also Observed in other Cell lines [1]. in Vivo : The Improvement Rates for choline esterase Were Significantly Greater Activity in the malotilate group than in the Control group Levels Significantly Increased Serum albumin in the malotilate group BUT not in the Control group. [2]. In the rats treated with MT for 19 days after iv inoculation of c-SST-2 cells, lung metastasis was also significantly suppressed [3]. Malotilate prevented increases in serum markers of type III and IV collagen synthesis as well as accumulation of the collagens, laminin and fibronectin in the Liver [4]. Toxicity : Malotilate cytotoxicity to PBMCs, Assessed by trypan blue dye Exclusion and lactate dehydrogenase (LDH) Release into the Culture Media, WAS found to be markedly Increased by the Addition of the NADPH generating system, indicating that metabolites play a significant role in toxicity [5].

References on Malotilate

[1] Shibata T, et al Inhibitory Effects of malotilate on in vitro Cell Invasion of lung endothelial monolayer by human oral squamous carcinoma cells Tumour Cell Biol 2000 Sep-Oct; 21 (5):….. 299-308 [2 …] Takase S, et al Effects of treatment on malotilate Alcoholic Liver disease Alcohol 1989 May-Jun; 6 (3):. 219-22. [3] Nagayasu H, et al Inhibitory Effects of malotilate on Invasion and.. Metastasis of RAT mammary carcinoma cells by modifying the Functions of Vascular endothelial cells Br J Cancer 1998 May; 77 (9):.. 1371-7. [4] Ryhanen L, et al The Effect of malotilate on type III and type.. . IV collagen, laminin and fibronectin Liver Metabolism in dimethylnitrosamine-induced fibrosis in the RAT J Hepatol 1996 Feb; 24 (2):. 238-45. [5] Nomura F, et al Detection of malotilate Toxicity in vitro with Peripheral.. . blood mononuclear cells as targets A preliminary report J Hepatol 1990 Jul; 11 (1):.. 65-9.

MITOGLITAZONE

October 11, 2014 12:43 pm / Leave a comment

Chemical structure for 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 KKA^y 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(+)) R_f = 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

……………………………

WILL BE UPDATED…….keep watching this post

Pioglitazone

October 11, 2014 12:18 pm / Leave a comment

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

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.

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Synthesis

PATENT

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.

PATENT

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

PATENT

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

.CLIP

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 S_NAr 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 S_NAr 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.

PATENT

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%

PATENT

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 N₂atmosphere 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:

PATENT

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% Na₂CO₃and 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% K₂CO₃solution 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.