WO2003029251A1

WO2003029251A1 - Novel process for the synthesis of thiazolidinedione derivatives

Info

Publication number: WO2003029251A1
Application number: PCT/IN2001/000163
Authority: WO
Inventors: Sandhya Ujire; Madhavan Sridharan; Sambasivam Ganesh
Original assignee: Biocon Ltd; Biocon India Ltd
Current assignee: Biocon Ltd
Priority date: 2001-09-28
Filing date: 2001-09-28
Publication date: 2003-04-10
Anticipated expiration: 2004-03-28

Abstract

Compounds of formula (I), which are useful in the treatment of non-insulin dependent diabetes, and wherein Ar is optionally substituted heteroaryl, X is CH or N, R is H or alkyl, and n is 1 or 2, are prepared by reacting compounds of formula (II) with compounds of formula (VI) wherein G is OH or F.

Description

TITLE OF THE INVENTION

Novel Process for tile synthesis of thiazolidinedione derivatives

FIELD OF THE INVENTION

$ The present invention relates to process of preparing thiazolidinedione derivatives of formula I known for the treatment of non-insulin dependent diabetes. BACKGROUND OF THE INVENTION

Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic 0 disorder leading to long-term complications and premature atherosclerosis.

Compounds of class like, sulfonylureas, biguanides were used for treatment of patients suffering from such disorders. Substituted 5- arylthiazolidinediones demonstrated potent activity towards non-insulin s dependent diabetes. European patent application numbers 0 008 203, 0 139 421, 0 155 845, 0 177 353, 0 193 256, 0 207 581, 0 208420 and 0 306 228 describes a number of thiazolidinedione derivatives which are disclosed as having hypoglycemic and hypolipidaemic activity.

Traditionally the desired alcohol was first alkylated with the aryl o benzaidehyde followed by condensation with thiazolidinedione to give the benzylidine intermediate, which on hydrogenation afforded the desired product. EP 0 306 228 describes such a procedure for the synthesis of a number of thiazolidinedione derivatives.

US patent 5,726,055 describes a process wherein a yeast reductase, R odotorula giutinis the microbial reductase source for the reduction of the benzylidine group to the desired product. WO 99/23095 describes a process using a noble metal mediated reduction for the benzylidine group while, EP 0306 228 discloses a process for the benzylidine group reduction using dissolving metal methods.

The present invention offers a more general procedure for the synthesis of variety of thiazolidinedione derivatives from a common intermediate, namely 5=(4-hydroxyphenyl)benzyl=2,4=thiazolidϊnedione, which can be alkylated with a suitable alcohol to give the desired pharmaceutical intermediate.

SUMMARY OF THE INVENTION

The present invention details a process for the preparation of compounds of formula I,

Formula I where Ar is a substituted or unsubstituted heteroaryl, X is CH or N, R is hydrogen or alkyl group and n is 1 or 2; is prepared by reacting a compound of formula II with a compound of formula VI, where G is F or OH, and Ar, X, R and n are defined with respect to formula I.

Compounds of formula VI are obtained by reacting a compound of formula IV with thiazolidinedione (formula III) as shown in scheme 1 in the presence of alumina/lithium hydroxide or in the presence of a base chosen from β-alanine, piperidine, pyridine and a solvent chosen from toluene, xylene etc to give a intermediate of formula V.

Formula V

Reacting a compound of formula V with magnesium in the presence of iodine in methanol or a reagent chosen from NaBHcCoCfe or MgBH4 or KBH4 or UBH4 in tetrahydrofuran as solvent to give an intermediate of formula VI as shown in the scheme 2 Formula VI

Reacting a compound of formula VI where G = F or OH with a compound of formula II to give a compound of formula I as shown in the scheme 3. DETAILED DESCRIPTION OF THE INVENTION

This invention particularly relates to a process for the preparation of thiazolidinedione derivatives of the general formula L

The process for the synthesis of compounds of formula I (where Ar is an unsubstituted or substituted heteroaryl, X can be either CH or N, R can be either H or alkyl, n is 1 when X is CH and R is H, n is 2 when X is N and R is CH₃) comprising of reacting a compound of formula II (where Ar is an unsubstituted or substituted heteroaryl, X can be either CH or N, R can be either H or alkyl, n is 1 when X is CH and R is H, n is 2 when X is N and R is CH₃) with a compound of formula VI (where G = F or OH). The process wherein the compound of formula VI (where G = F or

OH) is reacted with a compound of formula Ha to get a compound of formula la.

The process wherein the compound of formula VI (where G = F or OH) is reacted with a compound of formula lib to get a compound of formula lb.

The process wherein the reaction is carried out in the presence the potassium carbonate-dimethyl formamide, sodium hydride-dimethyl formamide or potassium carbonate-dimethyl sulphoxide.

The process wherein the reaction is carried out by using a compound of formula II where the alcoholic hydroxy group is substituted.

The process wherein the compound of formula VI (where G = F or OH) is prepared by: (i) reacting a compound of formula III with a compound of formula IV(where G = F or OH) to give an intermediate of formula V (where G = F or OH) (ii) hydrogenating the intermediate V(where G = F or OH) in to get the compound of formula VI (where G = F or OH).

The process wherein the reaction in step (i) is carried out in the presence of a mixture of alumina/lithium hydroxide.

The process wherein the reaction in step (i) is carried in an organic solvent selected from dimethyl formamide, acetonitrile, toluene or xylene.

The process wherein the hydrogenation agent in step (ii) is selected from sodium in methanol, magnesium in methanol, NaBH₄-

C0CI2, MgBH_4/ KBH₄or LiBH₄. The process wherein the hydrogenation in step (ii) is carried in tetrahydrofuran.

The invention is described with the help of the following examples not to be considered as limiting.

Example 1 Synthesis of 4-Hydroxybenzylidine-2,4-thiazolϊdinedione

(Formula V)

To a mixture of lOg of lithium hydroxide and 40g of basic alumina,

25g of 2,4-thiazolidinedione and 29.2 ml of 4-hydroxy benzaidehyde were added followed by 125ml of DMF. The contents were stirred at room temperature over a period of 24h. The reaction mixture was filtered and the alumina cake was washed with ethyl acetate. The combined filtrate was concentrated to remove ethyl acetate and DMF.

The gummy residue was triturated in isopropanol and the solid obtained was filtered and washed thoroughly with isopropanol and dried to give 29g of the title compound in 64% yield. H NMR (DMSO) - 9.8 (s, 1H), 7.4 (d, 2H), 7.2 (s, 1H), 6.9 (d, 2H) Example 2

5 Synthesis of 5-(4-Fluorobenzγlidine)-2,4-thiazGlidinedione (Formula V )

To a mixture of lOg of lithium hydroxide and 40g of basic alumina, 25g of 2,4-thiazolidinedione and 29.2 ml of 4-fluorobenzaldehyde were added followed by 125ml of DMF. The contents were stirred at room o temperature over a period of 24h. The reaction mixture was filtered and the alumina cake was washed with ethyl acetate. The combined filtrate was concentrated to remove ethyl acetate and DMF. The gummy residue was dissolved in isopropanol and the solid obtained was filtered and washed thoroughly with isopropanol and dried to give 27g of the title s compound in 61% yield. *H NMR (DMSO) - 12.2 (s, 1H), 7.8 (s, 1H), 7.65 (m, 2H), 7.4 (m, 2H) Example 3

Synthesis of 5-(4~Hydroxyphenyl)-2,4-thiazolidinedione (Formula VI) o To a solution of 33g of cobalt chloride in 200 ml of water, 4%

NaOH (330mL) was added. The contents were stirred for 45min at RT and 8.8g of DMG dissolved in 100ml of THF was added over a period of 30min. lOg of the compound from example 1 was added and the contents were cooled to 5°C 8g of sodium borohydride was added in 5 portions and the reaction mixture was allowed to stir at 10°C for 24h. 10% charcoal in 50mL of acetone was added and the contents were stirred for lh and the reaction mixture was filtered through celite. The filtrate was acidified with acetic acid until the product precipitates and the resulting solid was filtered and dried to give 7.5g of the compound melting at 154-156°C.

*H NMR (in DMSO) 2.9-3.0 (m, 1H), 3.2-3.3 (m, 1H), 4.8-4.9 (m, 1H),

6.65 (d, 2H), 7.0 (d, 2H), 9.4 (bs, 1H), 12 (bs, 1H) Example 4

Synthesis of 5-(4-Hydroxγphenγ!)-2,4-thiazolϊdinedione

(Formula VI)

To a solution of 5-(4-hydroxybenzylidine)-2,4-thiazolidinedione (5g in 125ml of methanol), magnesium turnings (5g) was added. The reaction mixture was stirred vigorously for 2h at room temperature.

Vigorous effervescence was observed and the temperature of the reaction mixture rose to 65oc. The stirring was continued for 2h. The reaction mixture was diluted with 100ml of water. The solid was filtered and the filtrate was extracted into 500ml of ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to yield 3g of the desired product.

*H NMR (in DMSO) 2.9-3.0 (m, 1H), 3.2-3.3 (m, 1H), 4.8-4.9 (m, 1H),

6.65 (d, 2H), 7.0 (d, 2H), 9.4 (bs, 1H), 12 (bs, 1H)

Example 5 Synthesis of 5-{4-[(5-Ethyl-2-pyridyl)ethoxγ]benzyl}-2,4- thiazolidinedione (Formula la)

To a stirred solution of 2-(5-ethylpyridiyl)ethanol 5g in DMF (50ml) under an atmosphere of argon, sodium hydride was added in portions.

After the vigorous reaction subsided, the compound from example 4 was added and the reaction mixture was refluxed at 90-110°C for 24h. The reaction mixture was cooled to 0-5°C, excess hydride quenched with water, DMF was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic extracts were washed with water, brine and dried. Upon removal of the solvent the title compound was obtained in 62% yield.

Example 6

Synthesis of 5-{4-[2-(N-methyl-N-(2- pyridyI)amino)ethoxy]benzyl}-2,4-thiazolidinedione (Formula lb)

To a stirred solution of 2-(N-methyl-N-(2-pyriylamino)ethanol 5g in DMF (50ml) under an atmosphere of argon, sodium hydride was added in portions. After the vigorous reaction subsided, the compound from example 4 was added and the reaction mixture was refluxed at 90-110°C for 24h. The reaction mixture was cooled to 0-5°C, excess hydride quenched with water, DMF was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic extracts were washed with water, brine and dried. Upon removal of the solvent the title compound was obtained in 54% yield.

Scheme - 1

G = F or OH Scheme - 2

G = F or OH

Scheme - 3

Where, Ar is an unsubstituted or substituted heteroaryl

X can be either CH or N

R can be either H or alkyl n is 1 when X is CH and R is H n is 2 when X is N and R is CH₃ and G is either F or OH

Claims

CLAIMSWe claim:

1. A process for the synthesis of compounds of formula I

Formula I where Ar is an unsubstituted or substituted heteroaryl X can be either CH or N R can be either H or alkyl n is 1 when X is CH and R is H n is 2 when X is N and R is CH₃

comprising of reacting a compound of formula II with a compound of formula VI

Formula II Formula VI where G = F or OH where, Ar is an unsubstituted or substituted heteroaryl X can be either CH or N

R can be either H or alkyl n is 1 when X is CH and R is H n is 2 when X is N and R is CH₃

2. The process of claim 1, wherein the compound of formula VI, where G = F or OH is reacted with a compound of formula Ha to get a compound of formula la.

Formula Ila Formula la

3. The process of claim 1, wherein the compound of formula VI, where G = F or OH is reacted with a compound of formula lib to get a compound of formula lb.

Formula lib Formula lb

4. The process of claim 1, wherein the reaction is carried out in the presence the potassium carbonate-dimethyl formamide, sodium hydride- dimethyl formamide or potassium carbonate- dimethyl sulphoxide.

5. The process of claim 1, wherein the compound of formula VI is prepared by:

Formula VI where G = F or OH (i) reacting a compound of formula III with a compound of formula IV to give an intermediate of

Formula III Formula IV where G = F or OH

(ii) hydrogenating the intermediate V in to get the compound of formula VI.

Formula V where G = F or OH

6. The process of claim 5, wherein the reaction in step (i) is carried out in the presence of a mixture of alumina/lithium hydroxide.

7. The process of claim 5, wherein the reaction in step (i) is carried in an organic solvent selected from dimethyl formamide, acetonitrile, toluene or xylene.

8. The process of claim 5, wherein the hydrogenation agent in step (ii) is selected from sodium in methanol, magnesium in methanol, NaBH₄- CoCI₂, MgBH₄, KBH₄or LiBH₄.

9. The process of claim 5, wherein the hydrogenation in step (ii) is carried in tetrahydrofuran.