SA98190168B1 - Process for preparing substituted thiazolidinedione derivatives - Google Patents

Abstract

Abstract: This invention relates to a process for preparing a compound of formula (I): This process includes the reduction of a compound of formula (II): or a tautomeric form thereof or a pharmaceutically acceptable salt or a pharmaceutically acceptable solubility thereof, where: J represents a substituted or unsubstituted aryl group substituted and TO1 representing T1 is O or S, or a tautomeric form thereof, or a salt thereof, or a soluble thereof, wherein T and T1 have the same significance as in formula (1), with a complex hydride reducing agent or source of a complex hydride reducing agent, and thereafter, as Application, preparation of a pharmaceutically acceptable salt or a pharmaceutically acceptable solute from a compound of formula (1) or a tautomeric form thereof.

Description

Y _ _ Process for preparing substituted thiazolidinedione derivatives Full Description BACKGROUND The present invention relates to a new process and specifically to the process of vn ail substituted thiazolidinedione derivatives. And it was mentioned in the European BE application, declaration No. Y A 7 that? | cen at thiazolidinedione 0 is given with the formula (hm): A) R® ¥ ¥ 0 (CHy)py—0 {a CH—C for A? / Ny NH 0 or a tautomeric form thereof or a pharmaceutically acceptable salt; or solubles thereof that are pharmaceutically acceptable, where: A? represents a substituted or unsubstituted aromatic heterocyclyl group; “m Jud hydrogen atom ¢ alkyl group ¢ acyl group; an aralkyl group « 0 where the aralkyl moiety can be a substituted or unsubstituted or a substituted or unsubstituted aryl group ¢ and a each is a hydrogen or eR sR” representing a bond; A represents a peptrine ring containing a total of up to five substituents; and a

— 7 b '« represent an integer in the limits of ? to +; It was also mentioned in European Patent No. 01774; Description of a process for the reduction of compounds of formula (a) where lee RS SRY represent the benzylidene thiazolidine-2,4- diones of the corresponding compounds of formula (a) in which “18” and R® each represent hydrogen ( benzylthiazolidine-2,4-diones) ° The special reduction methods mentioned in EP 705774 are catalytic hydrogenation methods and metal-solvent reduction methods. dione by complex hydride reducing agents considered on Lgl provides the basis for a commercial ALE application due to the general expectation that the desired selectivity will not be achieved; 0 with particular reference to aluminum hydrides and/or that the reaction will It gives weak production rates, and we have now had the unexpected discovery that the benzylidene thiazolidine-2,4- dione group is selectively reduced to the corresponding benzyl thiazolidine-2,4-dione by using a complex hydride reducing agent in the process of Commercially viable and with a high yield rate GENERAL DESCRIPTION OF THE INVENTION 1 Accordingly, this invention presents a process for preparing a compound of formula (1): 0 0 Mn 1 NH > J or a tautomeric form thereof or A pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solubility thereof; a a a

— $ — where: J stands for ¢OorS; T 1 stands for aryl ic substituent or unsubstituted and : 1 stands for QorS ; This process includes; Reduction of a compound of formula (I) 01 0 mm H 1 / NH 51 J 0 or a tautomeric form thereof or a salt thereof or a soluble thereof ¢ where T and !2 have The same indication as in the formula (\ ); with a complex reducing hydride agent or a complex reducing hydride Jalal source + 0 followed by that; according to demand; preparing a pharmaceutically acceptable salt or a pharmaceutically acceptable solute from a compound of formula (1) (or a tautomeric form of it. 0 and include the appropriate nodal hydride reducing agents; borohydride reducing agents and aluminum hydride reducing agents. Detailed Cia ol: suitable borohydride reducing agents include ¢ diborane and metal borohydrides. It represents 1 alkali metal borohydride ¢ “usliall metal borohydride such as lithium borohydride d ¢ potassium sl sodium” and in particular lithium or potassium. These include borohydrides; borohydrides Not replaced and replaced

__m_ Suitable substituted borohydrides include “borohydrides with three substituents on boron selected from groups such as alkyl and phenyl groups. The appropriate alkyl groups ' represent alkyl le gana 6 0 ¢ as ethyl Ole gana and in particular 0 butyl Sle sana 0 and the special butyl le sana ¢ represents binary and ternary butyl Ole gana . 056's special reducing agents are those that include the trihydroborane moiety; triethylborane or tributylborane . Preferred borohydride reducing agents include: lithium tri-sec-butyl borohydride, potassium tri-sec-butyl borohydride/lithium chloride, soditun tri-sec-butyl borohydride, potassium triphenylborohydride, lithium 01 triethylborohydride, lithium borohydride and Sodium borohydride. Lithium borohydride Jal sc is one of them. One of the preferred borohydride reducing agents is lithium tri-sec-butyl borohydride and when unsubstituted metal borohydride is used as a reducing agent; No reduction is preferred in the presence of a pyridine base ¢ pyridine Je substituent ¢ quinoline ¢ quinoline substituent ¢ piperidine ¢ secondary or tertiary amine or triethylamine or triphenylphosphine phosphine. It is convenient for said base to be used as the solvent or co-solvent for the reaction; And the preferred base is pyridine.” a

The suitable reducing agent aluminum hydride is “lithium hydride aluminum. The reaction conditions of the reduction conditions are the appropriate Cag yall imposed by the nature of the chosen complex hydride reducing agent. And in one aspect; When the reagent is a reductive borohydride reagent; © Suitable solvents include alkanols; methanol Js and tetrahydrofuran ethanol and piperidine or mixtures thereof. When the reducing reagent is an alkali metal borohydride the preferred solvent is pyridine/tetrahydrofuran. and when the reducing reagent is alkali metal trialkyl ar triphenyl borohydride 0 ; The solvent of choice is tetrahydrofuran and die borohydride is reduced to a temperature that gives an appropriate rate of yield ¢ and usually at ambient or elevated temperature; It is appropriate at an elevated temperature; It is preferable to 0°C, for example 10°C, and it is appropriate at the reflux temperature of the required solvent. The reaction components are usually mixed at room temperature and \o : the reaction mixture is heated at the reflux temperature of the solvent. On the other hand; When the reagent is an aluminum hydride reduction reagent ¢ suitable solvents include tetrahydrofuran Jie aprotic solvents. The aluminum hydride is reduced at a temperature that gives an appropriate rate to form the required product ¢ and usually a lower temperature to the ambient temperature (for example, a temperature of 7 degrees ranging from or Ya m); It is appropriate for it to be between o− and zero m . for you

VY — — It is understood that the reduction of compounds of formula (7); where !1 represents cup; In particular when the reducing agent is a borohydride reducing agent ¢ induced by an intermediate of formula (II): (IID) ON T S S T = N 0 | 0 0 a tautomeric form 4 ¢ or a salt thereof or a soluble Ada ¢ where J and T have the same significance as in formula (I) and the medium of formula (11) is obtained at the rate Better yield Laie The reduction is carried out at a low temperature Thus, in another aspect 6 This invention presents a process for preparing a compound of the aforementioned formula (I), where this process includes: the reduction of a compound of the aforementioned formula (11) 0 The male with a metal hydride reducing agent 0 and a borohydride reducing agent is preferred; it is preferable when the reaction is carried out at a low temperature and it is appropriate that it be lower than the ambient temperature; for example, between zero and m; and this is followed by; according to demand; salt preparation Or the solubility of a compound with formula (I), which is the preferred reducing agent for the preparation of a compound with the formula potassium tri-sec- (IH) butylborohydride Vo (known as L- selectride or K selectride ) « and preferably lithium tri-sec- .butylborohydride a

A — — This invention also consists of a compound of formula (II) aforementioned or a tautomeric form thereof or a salt thereof; or soluble thereof; This compound is considered useful as a mediator. This invention also includes a process for converting the aforementioned compound of formula (I) into the aforementioned compound of formula (]); This process includes heating the compound of formula (I) ¢ 0 and appropriately in a solvent ' followed by the preparation of a pharmaceutically acceptable or soluble salt as required. It is understood from the previous description that the reduction of the compound of formula (IT) to obtain a compound in "formula () \ ; especially when using borohydride reducing agents » is preferably done when Alle temperature sufficient to ensure the conversion of the medium of formula (YF) to the compound of formula (1). Reaction solvent The general reaction conditions suitable for reductions of aluminum hydride 5 borohydrides Vo are also as described in “Reductions by aluminum and borohydrides in organic synthesis” by (J.

Seyden-Penne (VCH Publishers, Inc.)

Lavoisier- Tec & Doc, ‎published 1991); and the references indicated therein. Compounds of formulas (1) and (11) are isolated from the reaction and then purified using known isolation and purification methods such as chromatography and crystallization/recrystallization.

The complex hydride reducing agents in the process can usually be obtained commercially or they can be prepared using common methods; For example, aluminum borohydride reagents 06 can be prepared using methods such as those described in 'Reductions by Alumino - Borohydrides in Organic Synthesis' (ibid) and in particular in the references described therein. borohydride is easily prepared on site, for example, lithium tri-sec-butyl borohydride is easily prepared from tri-sec-butyl borane, and lithium aluminum hydride, and also, lithium borohydride is easily prepared from sodium borohydride and lithium Inorg salt for known methods such as those described in Chem. 1981, 20,4454; J.

Am.

Chem.

Soc. 1953, 75,209; Nature 1954 , 173, 125 and 00 J.Am.

Chem.

Soc. 195 5,77, 6209. It is appropriate that T represents a term chosen from the list 1(a) » V) (2 1(c) (30(V)e (BY) ez) + 1g(1) 1( (—=) j) (oY) ep) (DY) (EY) 1 (s) HS) se) I (1) Al=—N—(CHy7—O0O \o in which AL A? 18, and “ have the same denotation as in formula (V) of European Patent No. 7117 A

- 1. : (Iz)

Al—N—(CH)7—0 and EP No. (V) as in formula ANA and 13 have the same as 12, LR? in which ? 01 0 0 A Y 0 y (Ic)

RS

RY 0 l k (CHp—O -) (

R30 Ww 2 and European Patent No. (1) as in form ANA and “has the same 7,1818328 Led m that (Id) RJ AN Sat TAM

R3 and EP No. 7371778; (1) in which, 7,182 has the same significance as in the form (Ie)a

Lond

R N

and European Patent No. (V) as in the form ANY the same as LIX and 182,8, A in which 0 ne 0 A

_— \ \ — 1 00 "p CH, & R N R! sR, BA has the same meaning as formula ( 1 ) and EP No. 1 (Ig) 0 PORAS HO in which a has the same denotation as in formula (1) and EP No. 484557; (Ih) 1c x 0 for rR ys ano and luc 7 be 2 R} R*R! and m have the same denotation as in the formula ( \ ) and European Patent No. Mh Hm Ara A | Lg XX 5 ZZ 01100 [ N in which a has the same denotation as in the formula (V) and EP No. 07579781; 0 RS Rr!0 8 m Tmo the w 0p R?a

Y — \ — whose led e sum, RRR' RAR, 7 has the same significance as in formula (1) and EP No. 018878; (Ik) 0 bs when RAR, A and L have the same ANA as in Formula (1) and EP No. 71 0 0 ¢ 0 for ( ) (CHY7—0) jQuery (2) N 1 X R ?1c when smZX, RAR! “ has the same LS ANA in formula (1) and EP No. “YVYVYoY ¢ (Im) Cr 2 0 0 according to formula (1) EP No. 141483 (in) x! (Dn JY n B ma Ny ) r" J SF YY A

1_b in which .263.8, a22,16, and 2 have the same significance as in formula (1) and EP No. 771711; (Io) Ny | | (CHW 2' 7 in which ZZ YX WV and “ have the same denotation as in EP No. 27737777; (Ip) /__\ in which © and X have the same denotation as in Formula (1) of the patent application ISBN 01 57/188. It is preferable that 7 represents a part of the aforementioned formula 1 (a) + 1 (c) + (1e) 111) 1 (i); 1 (k) or (1h). In particular, 1 represents a term chosen from the list consisting of (( ' (b) ¢ (z) ' ) 2 ( ' (e) ) and (eB) Oe 000

—_ \ $ —_ 8 0

CH3 215

HO 7 All of the words “about” and (©) ; (d)

CH

QT as 0 eh = y (e), ® 0

AT

(2),

V.Y.A

Vo — - 0 CH; 0 ry the 1 / N 0 0 CH; 0 N ,and \ N 0 )0 d b preferably T It represents a part of the aforementioned formula 1 (a). Separately, 21 represents a cup. Preferably, J stands for i . o Thus ¢ in a preferred aspect ¢ the invention performs 2 processes for the preparation of a compound with 1 (dana) as shown in the European patent No. IA) 1 i

Al—N— (CHp)7—0 {ay CH,— 7 m 8 NY NH 0 of it or a salt thereof is pharmaceutically acceptable '0 soluble of it is pharmaceutically acceptable (tautomeric ET) or: where 0 a

Al stands for aromatic heterocyclyl Ac sana substituted or unsubstituted ; R' is a hydrogen atom; alkyl group; acyl group; The Cua group “aralkyl aryl moiety can be substituted or unsubstituted” or the aryl ic group is substituted or unsubstituted. A represents a benzene ring that has a total of up to five substituents; and « represent an integer in terms of ? 0 to 7 This process includes the treatment of a compound of formula (1IB) (: (1B) 1 mL Al—N— (CH; NH) by 5 0 or a tautomeric form thereof or a salt Ak; or soluble thereof, where Al, Ha, Lem, the same signifier as in Formula 1(aa a) with a complex hydride reducing agent or a reducing agent source 0 68l70020i_complex ¢ (fie reducing agent borohydride or a source of a borohydride reducing agent “and this is followed, according to demand, by preparing a pharmaceutically acceptable salt or a pharmaceutically acceptable solubility from the compound of the formula [RB { or a tautomeric form thereof. In a preferred aspect, the compound of the formula) 7( is a compound of formula (TA) (ITA) H R! > 8 mothr 2 8 3 2 0 and zyne) Al—N— ma 5 tron 0 > ( 5 0 YYYA

in which cA m ; 18 and “has the same meaning as Formula 1(aa) in this description. Unless otherwise stated in this description; be appropriate values; The accepted and preferred for each variable in the above-mentioned flats of the formula (1) ¢ (2) (c) » ( ) 6 ) = ( )> (0) (FV) + (i) and 1(j) 1 (1k)n 1( fe) (IN) n) 1(1 o) or 1(p) as described in the aforementioned European, International or US patent applications Lad relates to each of the aforementioned formulas. In particular; The appropriate accepted and preferred values for the variables Sm sR eA? CAD format oe (TT) (7 bb); and (TTF) as indicated in Formula 1 (European Patent No. 7137748 0. The most preferred value is a in Formula 1 (aa) » (¥ b b); and (117) a group? (IB) 1 (IA) and (ITA) represent a methyl group “methyl v2” and the most preferred value for “«: in formula 0 (UB) « (IA) and (TTA) is equal to ? and more Preference is given that 7 represents a fraction of the aforementioned formula (a).

The most preferred value with the formula (AT) is: 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione ¢ or an isoform tautomeric thereof or a soluble salt thereof. The most preferred value with the formula (8311) represents: ¢5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene }-2,4-thiazolidined ° or an isoform tautomeric 0 salt thereof or soluble thereof. When the reaction includes a compound with the formula (IBB) as a substitute, it is preferable to perform the reaction at an elevated temperature; preferably higher than 00 m; For example, at 19 pm. A preferred example of a compound with formula (IIB) is -{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl }-3-{1-[2,4-dioxothiazol) idin-5-yl]- 0 ,-[4-(2-(N-methyl-N-(2-pyridyl)amino)ethoxy)phenyl methyl }-2,4 thiazolidinedione 1 The suitable salts are the salts that are approved by the pharmacy. The appropriate solutes are the solutes that are approved by the pharmacy. Unless otherwise stated in the description; The suitable preferred and pharmacologically acceptable salts are vo and the tautomeric conjugate form of each of the compounds (0) + (b) « (c) « (3) + (e) « (f) (g (1 x) » ( i) and 1(j); (k)n (ON) (m) (1n) (1o) or (a) as described in the aforementioned European, International or US patent applications with respect to each Of the aforementioned formulas: YYYA

1- - In particular; It should be mentioned that the appropriate salts that are approved by the pharmacy include mineral salts, for example, aluminum and alkali metal salts such as potassium sl sodium ¢ and magnesium calcium Jw alkaline earth metal salts and salts (Jai «Sl ammonium] Such as those with lower alkylamines such as: triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)- ° amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or 1 with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline. In addition, those pharmaceutically acceptable salts that are formed by pharmaceutically acceptable acids, including mineral acids, must be mentioned, for example, in compounds of formula (1) in which 1 represents the moiety of formula (1a); the appropriate salts are those contained in International Patent Application No. 057549/94, including salts formed by mineral acids, such as hydrochloric acids <hydrobromic and sulphuric acids, and organic acids such as maleic acids, tartaric, methanesulphonic' Vo ¢, and in particular -maleic acid tartaric Compounds of formula (1) can be prepared according to known methods; For example, by using the appropriate method contained in European and international patent applications or American patents. The contents of the aforementioned European, international and US patent applications are included in this description for reference. In particular, compounds of formula “BB” may be prepared according to the methods contained in EP 57748. ka

YY. The following examples illustrate the invention, but do not specify its scope in any way. Example 1: 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione (IA) via reduction of 5-{4 -[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}2,4- thiazolidinedi one (IIB) ° (i) using lithium tri-sec-butyl borohydride was added 1 M solution of tri-sec-butyl borohydride in YY.) tetrahydrofuran mL; YY mol) to a suspension of 1 bb (0.0 ¥ g).+ mol) in tetrahydrofuran (10 µL) at 2 km for 0 ? minute . The resulting mixture was heated and kept at the reflux temperature for two and a half hours, then cooled to . an aqueous solution of ZY (sodium hydroxide and You mL ¢ 6.75 mol) was added; followed by -777 Sle hydrogen peroxide (+0 mL); ; mall) . The resulting solution was stirred at 69 °C for three hours. dilute with water (0 milliliters); It was then concentrated by vacuum distillation until a residual sedimentary volume of 00 milliliters was achieved. Hydrochloric acid (2¥,0) was added approximately; You milliliters) to the mixture stirred rapidly at yo 010 to oO am and the resulting precipitate was filtered 0, washed with water and dried at decomposition temperature in vacuum; to give 1( a a ) ) 8 Ye, g). The crude product was recrystallized from 748 (71.71 milliliters) per body of 1(aa) crude to give an average total product of 7979. (b) Using lithium borohydride a lithium solution of lithium borohydride (11, 8 g 1 1,*g) in tetrahydrofuran ~~ ¥. (4 L) via a tube injection device into a stirred suspension from ("door") -

10 liters) at 11 °C (pyridine 5 ml) (40 +) tetrahydrofuran mol) at 0.4 g (0 0 h). The mixture was heated to reflux and stirred for 1.8 minutes. nitrogen at room temperature in a hydrochloric atmosphere for hours, cool to room temperature, and turn off the stirred reaction mixture in acid

Yo) tetrahydrofuran for 0+ hour using oA) ml) and water 4 ; liters) at TV) an hour; and heated to 1,705 mL) to remove residue. The extinguished mixture was stirred at 17°C for oo hours; Nominated within IY hours. The hot mixture was allowed to remain for a period of +, reflux and stirred for a period of time, and the residue was withdrawn until dry and washed with water (000 milliliters). The water wash products were added, ccelite, for an hour. The precipitated product was collected by 16 filtrate and stirred at room temperature for 16 minutes and drawn until dry. The (TA) filtrate was washed in a vacuum; Pulled to dryness, washed with water pf0 mL) and dried at 500 XY. The wet solid was methylated with 0 methylated alcohol. ) 7909 g (YATE) AA) 1 hour to give VY for a period in lithium borohydride (preparation of lithium chloride in sodium borohydride using Na (5 g pyridine), » 1.74 mmol) in 4 07 (sodium borohydride) stir a solution of . h and then heat to 19 °C under reflux +, Yo sad nitrogen mL) at 6 °C in atmosphere (0 mL)©)pyridine In (Use g ¢ 4.44 mL +, £4) lithium chloride was added and a solution of in the form of drops via a tube-syringe method was added to the mixture stirred at 15 m and kept at 10 mL) and heated at 10 (tetrahydrofuran 2 hours; reduce this temperature with sad lle VAY reflux for another 0 hours. The mixture is cooled to 0 C (7 bb) (1.0 g; mol) in portions and the reaction mixture is heated to reflux for hours. A solution of 0 ;- [= (n-methyl-n = (*pyridyl)amino)ethoxy ( =o mL) 1) hydrochloric acid 5-{4-[2] was added -(N-methyl-N-(2-thiazolidinedibutylliter) - 4 eo - ? {du ka

Y Y — b pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione and water (10 milliliters) in droplets to the reaction mixture at 0 8°C and concentrate the mixture in space 4 and add pyridine ( ¢ milliliter) and water (1 milliliter) and the mixture was stirred at *m with the pH adjusted to + using hydrochloric acid. 01 (ele) was added and the mixture was stirred for an hour. the commentator nominated; The remaining ° was washed with water (0 milliliters), drawn to dryness and dried at 86°C for an hour to give (IAA Can AA) (TT) Example 01 Preparation: Preparation of 5-{4-[2 -(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4- thiazolidinedione (IA) via reduction of 5-{4-[2-(N-methyl-N-(2) - pyridyl)amino)ethoxy]benzylidene}2,4-thiazolidinedi one (IIB), Ve using 0 aluminum hydride to a suspension of 1 7 lithium aluminum hydride g 00 mol eq) in (lila Yo ) tetrahydrofuran at Safram; 01 - (oY) g added; 1 mole in parts for V0 min. The temperature was kept below C during the addition. The mixture 0 was stirred at 0 °C Fo sad min; then at 10 °C until the completion of the reaction was judged by HPLC (oy) as (Rela), Vo) (wma). The rate of the resulting solution was 1 (AA) 754 Example Preparation: 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy|benzyl }-5-{1-[2,4-dioxothiazol idin] -5- y1]-1-[4-(2-(N-methyl-N-(2-pyridyl)amino)ethoxy)phenyl] methyl}-2,4-t a

Y 7 _ — hiazolidinedione (IIIA) from 5-{4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzylidene}2,4-thiazolidinedi one (IIB) To a solution of tetrahydrofuran (p > ¥,01) (IIBB) 011 ¢ THF (mL) at o− to 0 °C a 1 M solution of lithium tri-sec-butylborohydride (L-selectride) was added ) in e YY ( THF milliliters) 0 and the resulting mixture was stirred for 500 min; Then cool to 10 °C to stop the reaction. And (0 ¢ 5/57 +) Sodium hydroxide (mL) was carefully added followed by an excess of hydrogen ike (7797 and/or 1 01 mL) to ensure damage to the borohydride reagent. THF was removed in a vacuum; The aqueous mixture was neutralized to a pH of 1 using oY of hydrochloric acid. The resulting solid was filtered and separated; And cool the filter to m. After staying overnight 0 a second product of the solid was obtained and purified twice by flash column chromatography using methanol [dichloromethane . A compound 9GJJ was isolated (in the form of white crystals, pala 08 ¢, an isolated product rate of v%). Example: 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy ]benzyl}-2,4-thiazolidine-2,4-dione (ID) via reduction of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzilidene}-2,4-thiazolidine -2,4-dione (IID) Vo a 0.0 of a solution of lithium borohydride in (YY) tetrahydrofuran milliliters « Y 1.0 mmol) was added as drops to a stirred suspension of: Coax 0 ) 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzilidene}-2,4-thiazolidine-2,4-dione (YA, YY mmol) in tetrahydrofuran ) 4) milliliters) 5 YY) pyridine milliliters) at 10°C in 0 nitrogen atmosphere. And heat the resulting mixture under 2 minutes of boiling; h (reaction controlled by HPLC KB) then cooled to ambient temperature and added as drops to a

this? -

A well stirred solution of concentrated hydrochloric acid (Y¥,0 milliliters) in ele (88.7 milliliters) between 0°C and 70°A and heat the resulting orange suspension to reflux temperature and store Ye sad for a minute, then Cool to ambient temperature. The resulting suspension was stirred for yo min, collected by filtration and washed with yo water) milliliters (FX). The crude product was heated to reflux in acetic acid (0*mL) and vegetable mg (1.0 g) was added to the resulting solution; which was then diluted 00 milliliters; It was filtered through ceelite and the layer was washed with hot ethanol —celite (04 mL). The filtrate and wash products were collected together and allowed to cool to #C. This resulted in crystallization of a white solid, which was isolated by filtration to give a compound of 1(dd) 0.73 g; 787). A second product was obtained from

Substance by partial concentration of the original liquid (AY) g 6 (EAN) ca

Claims (1)

Yo - - Elements of Protection 1 1 - Operation; To prepare a compound of formula (e]1): 1) ee R! H ih (CHp;—0 CH,— - : NH > 5 0 v or a tautomeric form thereof or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solubility thereof (dia) where it has: ° important represents an aromatic heterocyclyl group with or without a substitution; “and !8” represents a hydrogen atom », an alkyl ¢ group, an acyl group, or an “aralkyl group” in which an aryl moiety can be substituted OR unsubstituted or A unsubstituted; or an aryl group with or without a substitution; A?q representing a benzene ring with a total of up to five substitutions; and Ya and © representing an integer ranges from ? to 6; 1 and this process involves treating a compound of formula (IIB) (IIB) RY 0 VY with Al—N—(CHy)y—0 NH > 0 YYYA | a Vy or a tautomeric form thereof or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable soluble thereof; where has Al © wa RD 50 A? ; and “is as defined in respect of the formula (IA) by a hydride complex reducing agent or a source of V1 complex hydride reducing agent . \" - process according to claim 0 in which (IA) is: 5-{4-[2-(N-methyl-N-2-pyridyl)amino)ethoxy]benzyl}-2,4 -thiazolidinedione Y 1” or a tautomeric form of it or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solubility; - Pharmaceuticalally (IB) is: 5-{4-[2-(N-methyl-N) -(2-pyridyl)amino)ethoxy]benzylidene }-2,4-thiazolidined © ione 1 7 or a tautomeric form thereof or an acceptable salt dia Ly or an acceptable solubility A ion Ly : 1 » - a process of claim 0 further comprising the step of preparing a pharmaceutically acceptable or soluble 0 salt of a compound of formula (IA) or a tautomeric ¥ form thereof. A process for preparing a compound, which is: 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione Y 1 or an emotype thereof or a pharmaceutically acceptable salt thereof or acceptable solubility; > pharmaceutically; comprising: ° Reduction: a 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4- 1 thiazolidinedione v 0 A or a tautomeric form thereof; or salt thereof; or dissolved thereof with hydride complex 4 reducing agent selected from borohydride reducing agents and aluminum hydride 01 reducing agents; and : optionally after that form a pharmaceutically acceptable salt; or a pharmaceutically acceptable soluble of Vy 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4- VY thiazolidinedione Wy of it. ¢ 0 1 © - Process under claim of in which the complex reducing agent includes a Y borohydride reducing agent . 1 1 — Process of © claim in which the borohydride reducing agent comprises diborane Y or a metal borohydride . V 1 — Process of claim 1 in which the borohydride reducing agent comprises an alkali metal borohydride Y. A 1 — process of claim "; in which the alkali metal borohydride is .potassium borohydride 0 lithium Y erased 1 4 - Process pursuant to claim 5; in which the borohydride reducing agent comprises metal borohydride Y which is either unsubstituted or substitutable by up to 1 of three selected alkyl and phenyl substituents. 1 0 - operation according to the protection element ©; wherein the borohydride reducing agent ¥ is chosen from the group consisting of potassium tri-sec-butyl borohydride > sodium tri- potassium triphenylborohydride ¢ sec-butyl ~~ borohydride 3 + and lithium triethylborohydride ¢ ¢ and lithium triethylborohydride » and lithium borohydride ¢ .sodium borohydride ° 11 1 - A process according to the claim Oe, in which the reducing agent borohydride Y is selected from the group consisting of: lithium tri-sec-butyl borohydride lithium borohydride ¥ VY 1 - A process according to the claim of, in which a borohydride reducing agent 1 is prepared in situ. VF \ - process according to the claim of, in which the complex reducing agent includes aluminum hydride reducing agent Y. 1 4 - A process according to claim VF in which the aluminum hydride reducing agent Y includes lithium aluminum hydride as Ve - process pursuant to claim 9; where the metal borohydride has no :substitution and the reduction reaction is carried out in the presence of a base. 1 1 - A process according to claim 10, whereby the base is selected from group Y consisting of pyridine – and pyridines have a substitution and quinoline » and quinolines aa ¥ have a substitution and .phosphines ¢ tertiary amine « secondary amines 11 1 - process by claim 1 in which the base is pyridine VA 1 - process by claim Cua of by which is reduced: 5-{4-[ 2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidined y ione ¥ 3 or a tautomeric form thereof. 1 4 - A process according to the claim of, in which a salt is reduced from: L-5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2, 4- thiazolidinedione ¥ ¢ or a tautomeric 43 sia form thereof. 0 1 - Process according to claim V9 in which a mineral acid salt is reduced from * 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2 ,4-Y and a thiazolidinedione” or a tautomeric form thereof. For you Dr. Dr. YY 1 - A process according to the element of protection oF es, in which the mineral acid is hydrobromic acid ¥ or hydrochloric acid or sulfuric acid. : process pursuant to claim 90; Where the salt of an organic acid is reduced from - YY 1 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene} - Y 2,4-thiazolidinedione ¥ from it. tautomeric 4 sua or Fig ¢ YY 1 - Process pursuant to claim 77; Where the organic acid is methanesulphonic acid Y or tartaric acid. 5-{4-[2-(N-methyl-N-(2-) the succinate compound is - YE 1 or a pharmaceutically acceptable salt + pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione Y Produced 'dia tautomeric or antagonistically NENT and/or acceptable solubility' Ala 7 by claim process m ¢: whereby the compound (TE) is a process according to claim - Yo 1 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione v 7 ' as a pharmaceutically acceptable salt. With protection element (Yo), whereby the pharmaceutically acceptable salt is a metal salt selected from aluminum salts and alkaline earth « alkali metal salts .metal salts v ( YO, whereby the pharmaceutically acceptable salt is Y salt of ammonium, i.e. ammonium has a substitution Y4 1 - The compound contained in the protective element (YO, wherein the pharmaceutically acceptable salt is Y salt of a mineral acid mineral acid salt. Contained in claim element (YO) in which the pharmaceutically acceptable salt is organic acid salt Y. tartaric acid ¢ or .maleic acid YY 1 - The compound included in the claim Cus (FY) in which the organic acid is maleic acid Y or .tartaric acid YYYA