WO2000078314A1

WO2000078314A1 - Process for making arylthiazolidinedione derivatives

Info

Publication number: WO2000078314A1
Application number: PCT/US2000/016716
Authority: WO
Inventors: Michael H. Kress; Gordon W. Chiu; M. David Weingarten; James Mcnamara
Original assignee: Merck & Co., Inc.
Priority date: 1999-06-18
Filing date: 2000-06-16
Publication date: 2000-12-28
Also published as: AU5876900A; WO2000078314A8

Abstract

Substituted 5-aryl-2,4-thiazolidinediones (I) are useful in the treatment, control, and prevention of diabetes and diseases and conditions that commonly occur with diabetes, including hyperglycemia, hyperlipidemia, atherosclerosis, obesity, vascular restenosis, and others. The compound 5-[3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione having the x-ray powder diffraction of Table 1 is particularly suitable for this use. The process for making substituted 5-aryl-2,4-thiazolidinediones and 5-[3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione has been improved. (Formula I); n = 0 to 3; X, Y, Ar?1 and Ar2¿ are as in the application.

Description

TITLE OF THE INVENTION

PROCESS FOR MAKING ARYLTfflAZOLIDINEDIONE DERIVATIVES

FIELD OF THE INVENTION The instant invention is concerned with processes for making arylthiazolidinediones and pharmaceutically acceptable salts thereof, which are useful as therapeutic compounds, particularly for the treatment of non-insulin dependent diabetes mellitus (NTDDM) and conditions that are associated with NIDDM.

RELATED APPLICATIONS

Co-pending, commonly assigned U.S. Patent No. 6,008,237 contains related subject matter.

BACKGROUND OF THE INVENTION Arylthiazolidinediones having structures of Formula I below have only recently been described in U.S. Patent No. 6,008,237. These compounds have activity as PPAR gamma and/or alpha agonists and are useful in the treatment, prevention and control of non-insulin dependent diabetes and various diseases and disorders that commonly accompany diabetes, such as obesity, atherosclerosis, and various lipid disorders, such as hyperlipidemia and hypercholesterolemia. Methods of synthesizing the compounds are described in the patent. These are suitable for laboratory scale synthesis. Improvements in these syntheses have now been made which are suitable for commercial scale production of the compounds.

SUMMARY OF THE INVENTION

The instant invention discloses improved methods for making arylthiazolidinediones having structure I and methods for making pharmaceutically acceptable salts, including a synthesis of a particularly preferred compound, crystal forms of that compound, and its sodium salt. The sodium salt is also new. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for making arylthiazolidinediones having the formula I:

wherein Arl is (1) arylene or

(2) heteroarylene, wherein arylene and heteroarylene are optionally substituted with from

1 to 4 groups selected from R^a; Ar2 is (1) ortho-substituted aryl or (2) ortho-substituted heteroaryl, wherein said ortho substituent is selected from R; and aryl and heteroaryl are optionally further substituted with from 1-4 groups independently selected from R^a; X and Y are independently O, S, or N-Rb; n is 0 to 3;

R is (1) C3-10 alkyl optionally substituted with 1-4 groups selected from halo and C3.6 cycloalkyl,

(2) C3-10 alkenyl, or

(3) C3-8 cycloalkyl; R is (1) C1-15 alkanoyl,

(2) Ci-15 alkyl,

(3) C2-15 alkenyl,

(4) C2-15 alkynyl,

(5) halo, (6) OR^b,

(7) aryl, or

(8) heteroaryl, wherein said alkyl, alkenyl, alkynyl, and alkanoyl are optionally substituted with from 1-5 groups selected from Re, and said aryl and heteroaryl optionally substituted with 1 to 5 groups selected from Rd;

Rb is (1) hydrogen,

(2) Ci-ioalkyl,

(3) C2-10alkenyl,

(4) C2-10alkynyl,

(5) aryl,

(6) heteroaryl,

(7) aryl Ci-15 alkyl,

(8) heteroaryl Ci-15 alkyl,

(9) Ci-15 alkanoyl,

(10) C3_8cycloalkyl, wherein alkyl, alkenyl, alkynyl are optionally substituted with one to four substituents independently selected from Re, and cycloalkyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rd;

RC is (1) halo,

(2) aryl,

(3) heteroaryl _;

(4) CN,

(5) NO₂,

(6) OR^f;

(7) S(O)_mRf, m = 0, 1 or 2, provided that Rf is not H when m is 1 or 2;

(8) NR^fR^f,

(9) NR^fCOR^f,

(10) NR^fCO2R^f,

(11) NR^fCON(R^f)2,

(12) NR^fSO2R^f, provided that Rf is not H,

(13) COR^f,

(14) CO2R^f,

(15) CON(R^f)2,

(17) OCON(R^f)2, or

(18) C3_8cycloalkyl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 3 groups of halo or Cχ. alkyl; Rd is (1) a group selected from Re,

(2) CMO alkyl,

(3) C2-10 alkenyl,

(4) C2-10 alkynyl,

(5) aryl Ci-ioalkyl, or (6) heteroaryl Cι_ιo alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R^e; Re is (1) halogen,

(2) amino, (3) carboxy,

(4) Ci.₄alkyl,

(5) Ci-4alkoxy,

(6) hydroxy,

(7) aryl, (8) aryl Ci^alkyl, or

(9) aryloxy; Rf is (1) hydrogen,

(2) Ci-ioalkyl,

(3) C2-10alkenyl, (4) C2-10alkynyl,

(5) aryl,

(6) heteroaryl,

(7) aryl Ci-15 alkyl,

(8) heteroaryl Ci-15 alkyl, (9) Ci-15 alkanoyl, or

(10) C3-8cycloalkyl; wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally substituted with one to four groups selected from R^e- The process comprises the steps summarized in Schemes la and lb and Scheme 2 below. In Schemes la and lb, the symbols ArL Ar2 , X , Y, and n have the same definitions as in the description of the product.

Scheme la

Base

HX-Ar² + L-H₂C- (CH₂)_n -CH₂— L'

(A2) CD

(B2)

Base

RgOOC-CHg-Ar¹— YH + _(B2) ^

(Al) ^""

RgOOC-CH₂- Ar¹— Y-CH₂- (CH₂)_n -CH^X-Ar²

(G)

Scheme 1 b

RgOOC-CH₂-Ar¹— YH ₊ L-H₂C- (CH₂)_n -CH₂— L' ^►

(Al) (I)

RgOOC-CH₂-Ar¹— Y-CH₂- (CH_gJn-CHg-L (Bl)

Base Bl + HX-Ar² - C

(A2) Schemes la and lb show alternate syntheses of intermediate C, which contains an Arl moiety and an Ar2 moiety connected by a >4 atom tether having > 2 methylene groups. Rg represents an alkyl group having 1-15 carbon atoms, where Rg can be linear or branched, and can also be substituted with an aryl group, a cycloalkyl group, a heterocyclic group, or a heteroaryl group. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, benzyl, 2-phenethyl, and the like. Rg may also be a silane group, preferably a trialkylsilane, such as trimethylsilane, triethylsilane, tert-butyldimethylsilane, and so forth. The silane groups specifically listed above are all available in large scale quantities as their chlorides. Intermediate C may be prepared by convergent synthesis by first attaching the tether T having two terminal leaving groups to either Arl ₀r Ar2 (i.e. A_! or A2 to yield B _. or B_2). In T, L and L' represent independently of each other a conventional leaving group such as halide (for example bromide), sulfonyloxy (e.g. mesylate, tosylate, trifluoromethanesulfonate, and the like), and carboxylates that have strong electron withdrawing substituents, such as trifluoroacetate. These are leaving groups that are readily displaced in nucleophilic displacement reactions (i.e. SN2 reactions). Treatment of the tethered intermediate Bl or B_2_with the other aryl moiety A2 or A , respectively in the presence of a base (e.g. CS2CO3) in solution (e.g. DMF) provides the tethered arylacetate ester intermediate C. The two displacement steps are catalyzed by a base, preferably an inorganic base, such as CS2CO3, KOH, NaOH, K2CO3_; potassium tert-butoxide, sodium tert-amylate, and other carbonates, hydroxides, and alkoxides of Li, Na, Cs, and K. The displacement reactions take place in a solvent, preferably a polar aprotic solvent, such as DMF, NMP, HMPA, DMSO, DMAc, and the like. The starting materials T, Al, and A2 are either commercially available or may be prepared using known organic synthesis procedures. Compounds of formula A2 may be prepared according to the methods described in published PCT Applications 97/27857, 97/28115 and 97/28137. In order to improve the selectivity in the displacement reactions of Al or A2 with T, so that the final product has been substituted with one molecule of Al and one molecule of A2, it is preferred that leaving groups L and L' on T are different both in structure and in their ease of displacement, as for example Cl and Br. Then, when T is reacted with one equivalent of Al or A2, the more easily displaced group (Br in the case of Br and Cl) will be displaced preferentially to yield the product Bl or B2 in high yield, with a minimal amount of by-product having either two Al substituents or two A substituents. To accomplish the second displacement, more forcing conditions (such as a higher reaction temperature) may be required. Since there is only one group still to be displaced at this step (Cl in the case of Br and Cl), the selectivity to the desired product is expected to be high with respect to substitution, except that elimination takes place in higher yields as the temperature is increased. To accelerate the displacement of Cl, iodide can be added as a catalyst, since iodide is both a good nucleophile and is also readily displaced. An alternate method of making C_selectively is to use a tether precursor T_ in which L' is halo (e.g. bromo) or one of the other kinds of leaving groups described above, and L is hydroxy, or a protected hydroxy. The better leaving group is displaced first in a base catalyzed substitution with Al or A2, and then the hydroxy group L (after deprotection, if needed) is coupled to the aromatic phenol group of the other of Al or A2 by the well-known Mitsonobu coupling reaction. See Organic Reactions, Vol. 42, pp. 377-656, John Wiley and Sons, New York, 1992. This route could also be carried out with the Mitsonobu coupling first and the substitution reaction second.

Another alternate route uses the reaction of an allyl halide or other compound having an allylic leaving group with Al or A2 in the presence of a base to form an intermediate with an allyl group that will become the tether group. The terminal olefin of the allyl group is functionalized with a terminal leaving group for the second displacement reaction . The second leaving group can be introduced by several routes that are known to practitioners in the art, such as hydroboration followed by oxidation, which yields a terminal alcohol. The terminal alcohol can then be coupled to an aromatic phenol by a Mitsonobu reaction, or it can be subjected to a displacement reaction. Scheme 2

RgOOC-CH₂- Ar¹— Y-CH₂- (CH₂)_n -CH_jrX— Ar²

(C)

a. Alpha-brominate b. Cyclize to TZD

In Scheme 2, alpha-halogenation of the arylacetate ester intermediate C with a halogenating agent (e.g. chlorine, bromine, N-bromosuccinimide, N- chlorosuccinimide, dimethyl-N,N-dichlorohydantoin, dimethyl-N,N- dibromohydantoin, α-bromomalonates, α-chloromalonates, α-bromo or α-chloro- Meldrum's acid, carbon tetrachloride, carbon tetrabromide, hexachloroethane, pyridinium tribromide, N-bromoacetamide, and the like) in the presence of a base produces an alpha-halo intermediate which may be ring-closed with thiourea in the presence of an aqueous acid or a base (e.g. a salt of a carboxylic acid, such as sodium acetate, an inorganic salt, such as sodium hydroxide or cesium carbonate, or an extra 1-2 equivalents of thiourea) in an alcoholic solvent, such as 2-methoxyethanol, isopropyl alcohol, n-butanol, ethanol, and the like, or other organic solvent that will dissolve thiourea, such as THF, DMF, or DMAc, at elevated temperatures to give an imine compound that is hydrolyzed in the presence of acid to a compound having the structure I. In an alternate embodiment, ester intermediate C is first saponified to a salt of the free carboxylic acid, which in many cases is more easily purified. The carboxylic acid salt form of C (e.g. a lithium salt) is water soluble, allowing impurities that are soluble in organic solvents that are not miscible with water to be separated from an aqueous solution of the salt. The salt can then be neutralized with acid and isolated as the carboxylic acid, which may be pure enough or may be suitable for recrystallization. Alternatively, the carboxylic acid can then be reacted with a base (for example ammonia, alkylamine, dialkylamine, or an alkali metal hydroxide or carbonate), to yield a salt (for example an ammonium, alkylammonium, dialkylammonium, or an alkali metal salt), which can be purified in accordance with its crystallinity and solubility characteristics. The salt or free acid is then halogenated in the position alpha to the carboxylic acid group to yield an alpha-halo carboxylic acid as the free acid or a salt, and this is subsequently cyclized in two steps to a thiazolidinedione. The halogenation reaction of the free acid is carried out with two equivalents of base and two equivalents of a silylating agent, such as TMSC1, TESC1, tert-butyldimethylchlorosilane, and the like. This results in an intermediate which is believed to be a silylketene acetal, which is then halogenated by treatment with a halogenating agent, such as chlorine, bromine, N-bromosuccinimide, N- chlorosuccinimide, dimethyl-N,N-dichlorohydantoin, dimethyl-N,N- dibromohydantoin, α-bromomalonates, α-chloromalonates, α-bromo or α-chloro- Meldrum's acid, pyridinium tribromide, N-bromoacetamide, and the like. Cyclization is brought about by treatment of the alpha-halo acid with thiourea. Hydrolysis of the resulting imine can be achieved with the addition of an acid catalyst. Suitable acids include strong aqueous acids, such as HC1 or H2SO4, in an alcohol solvent, such as 2- methoxyethanol, propanol, and isopropanol, as well as other organic solvents, such as THF or DMF. Other alcohol solvents may also be used , such as any of the alkyl or branched alcohols up through the C15 alcohol. The hydroxyl groups can be on primary, secondary, or tertiary positions on the alkyl portion of the alcohol.

Salts

The compounds prepared by the above process are acidic at the 3- position of the thiazolidinedione ring, and may be isolated as salts by reacting the compounds with a base. Pharmaceutically acceptable salts are those that are non- toxic, and they include salts of both organic and inorganic bases. Preferred salts include ammonium, sodium, potassium, calcium, and magnesium salts. These are all made by reacting the acid form of the compound with a solution of an alkali or alkaline earth hydroxide (about one equivalent, preferably concentrated), an alkoxide, ammonia, or an amine that yields a non-toxic salt to make a solution of the salt in water or a non-toxic organic solvent. The salt is then crystallized by cooling the solution and/or adding a miscible non-toxic liquid that is a poor solvent for the salt.

Other products.

The above process is applicable to the preparation of various preferred subsets of compounds of Formula I. In one subset of compounds of formula I , Arl is arylene optionally substituted with 1-4 groups selected from R^a. Preferably, Arl j_s phenylene optionally substituted with 1-2 groups selected from halogen and Ci-4 alkyl. More preferably Arl i_s phenylene.

In another subset of compounds of formula I, X and Y are each O or S. Preferably X and Y are each O.

In another subset of compounds of formula I, Ar2 is

R is C3-4alkyl optionally substituted with one to four groups selected from halo and C3_6cycloalkyl, and R^a' is selected from R^a, or 2 Ra' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from N, O and S(O)m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra. In a preferred subset, R^a' is selected from ORb, aryl optionally substituted with 1 to 5 groups independently selected from Rd, and Ci-15 alkyl optionally substituted with 1 to 5 groups independently selected from R^c. In another preferred subset, 2 R^a' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 1-2 heteroatoms selected from N, O and S(O)m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra. In a more preferred subset, Ra' is selected from O-phenyl in which phenyl is optionally substituted with 1 to 4 groups selected from Rd, phenyl which is optionally substituted with 1 to 2 halogens, and C1-.5 alkyl which is optionally substituted with 1 to 5 groups independently selected from halogen, phenyl, and C3-8cycloalkyl. In another more preferred subset 2 R^a' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring selected from isoxazole, thiophene (S-oxide and S-dioxide), furan each of which is optionally substituted with 1 to 2 groups selected from R^a. In another subset of compounds of formula I n is 1 or 2. The process is also applicable to a preferred embodiment of formula I comprising compounds of formula la:

la

wherein R^a' is selected from Ra, or 2 Ra' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from

N, O and S(O)m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from R^a;

X, Y, n, R, and R^a are as defined under formula I. The process is also applicable to a subset of compounds of formula la comprising compounds of formula Ia(i):

Ia(i) Another subset of compounds of formula la that can be made by this process comprises compounds of formula Ia(ii):

Ia(ϋ)

Another preferred embodiment that can be made by this method comprises compounds of formula la wherein Y is S or O, and X is O.

Another preferred embodiment that can be made by this method comprises compounds of formula la wherein R is C3-4alkyl.

Another preferred embodiment that can be made by this method comprises compounds of formula la wherein n is 1 or 2.

Another preferred embodiment that can be made by this method comprises compounds of formula la wherein R^a' is O-aryl optionally substituted with 1 to 3 groups independently selected from Rd, aryl optionally substituted with 1-3 groups selected from Rd, or Ci-5alkyl optionally substituted with 1-5 groups selected from R^c, or 2 R^a' groups on adjacent carbon atoms taken together complete a 5- or 6- membered aromatic ring containing 0-2 heteroatoms selected from N, O and S(O)_m

(m is 0-2), said ring being optionally substituted with 1-2 groups selected from R^a.

An even more preferred embodiment that can be made by this method comprises compounds of formula la wherein

X is O;

Y is (1) O or

(2) S;

R is C3-4 alkyl;

Ra is (1) halogen or

(2) C1-5 alkyl; R^a' is (1) O-aryl optionally substituted with 1 to 3 groups independently selected from Rd,

(2) aryl optionally substituted with 1-3 groups selected from Rd,

(3) Ci-5alkyl optionally substituted with 1-5 groups selected from Re, or

2 R^a' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from N, O and S(O)m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra.

A highly preferred embodiment is the compound whose synthesis is described in Example 1 (below). The synthesis of the sodium salt is illustrated in Example 3.

Definitions

"Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

"Alkenyl" means carbon chains which contain at least one carbon- carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

"Alkynyl" means carbon chains which contain at least one carbon- carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.

"Cycloalkyl" means mono- or bicyclic saturated carbocyclic rings, each of which has from 3 to 10 carbon atoms. The term also includes a monocyclic ring fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Aryl" (and "arylene") means mono- or bicyclic aromatic rings containing only carbon ring atoms. The term also includes aryl groups fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point(s) of attachment is on the aromatic portion. "Heterocyclyl" means a fully or partially saturated ring containing at least one heteroatom selected from N, S and O, each of said rings having from 3 to 10 atoms. Examples of aryl include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, and the benzene rings of 2,3- dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like. "Heteroaryl" (and heteroarylene) means a mono-, bi- or tricyclic aromatic ring containing at least one ring heteroatom selected from N, O and S (including SO and SO2), with each ring containing 5 to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, dibenzofuran and the like.

"Halogen" includes fluorine, chlorine, bromine and iodine. The term "ortho-substituted" means the substituent is attached to a ring atom that is adjacent to the point of attachment to the backbone of the molecule.

The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Abbreviations

DSC - differential scanning calorimetry DMAc - N,N-dimethylacetamide DMF - N,N-dimethylformamide DMSO - dimethylsulfoxide IPA-isopropyl alcohol IPAc - isopropyl acetate LHMDS - lithium hexamethyldisilazane HMPA - hexamethylphosphoramide NBS - N-bromosuccinimide NCS - N-chlorosuccinimide NMP - N-methylpyrollidinone TESC1 - triethylchlorosilane TGA - thermogravimetric analysis THF - tetrahydrofuran

TMEDA - tetramethylethylenediamme TMSC1 - trimethylchlorosilane TZD - thiazolidinedione

EXAMPLES

The following examples are provided to more clearly illustrate the invention and are not to be construed as limiting the scope of the invention in any way.

EXAMPLE 1 5-[3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione

The synthesis of a particularly preferred embodiment of the invention is illustrated in Scheme 3. Compounds 1 and 3 correspond to A2 and A! respectively in Schemes la and lb. The route described in Scheme la is preferred to that of Scheme lb for this particular compound because the selectivity is better and byproducts are easier to remove. The final acid product (neutral form of thiazolidinedione) is shown as compound 8. The conditions for carrying out the reactions are shown in Scheme 3. The overall yield to Compound 8 starting with compounds 1 and 3 is about 75%, with the isolated yield of intermediate compound 5 from compounds 1 and 3 being about 80%, and the yield of compound 8 from intermediate 5 being greater than 90%. The products that are isolated are outlined in boxes in Scheme 3 and are all crystalline solids: Compound 5, m.p. 56-58°C, and Compound 8, m.p. 111-113°C.

In this scheme, the two alkylation steps are carried out sequentially without purification. The product of these, ester 4, is saponified to yield the lithium salt of the carboxylic acid as part of a biphasic solution at the end of the reaction. The biphasic mixture is diluted with approximately equal volumes of 3% NaCl solution and methyl t-butyl ether. The lithium salt of compound 5 is in the organic layer. After separating the two phases, the organic phase is combined with water, which now results in the lithium salt dissolving in the aqueous phase. The aqueous phase is washed with MTBE, and the combined organic layers are discarded. The pH of the aqueous layer is adjusted to about 3.0, which results in the separation of acid 5 as a concentrated oil. The solvent for the organic phase is switched to heptane by adding heptane and distilling off the residual organic solvent. Carboxylic acid product 5 crystallizes out of solution. Scheme 3

5.cp 7: Alkylation 1 Step 2: Alkylation 2 Step 3: Saponification

The carboxylic acid 5 is then brominated as shown in Scheme 3 by first adding slightly more than two equivalents of TMSCI and slightly more than two equivalents of strong base (LHMDS) in THF, which is believed to yield a silyl ketene acetal, and then adding a slight excess of NBS as a brominating agent. The reaction is quenched with 2M HCl, and the organic phase which contains Compound 6 is then treated with about 1 equivalent of thiourea in THF to yield imine 7 in solution. Imine 7 is diluted with isopropanol, and excess THF is then removed by distillation. Imine 7 is then hydrolyzed with 1M HCl in refluxing isopropanol to yield compound 8, which is 5-[3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione. The isopropanol solution of Compound 8 is diluted with isopropyl acetate (IP Ac) and cooled, resulting in phase separation into two liquid layers. The organic phase, containing IP Ac, some isopropanol, and compound 8, is washed with brine and is then concentrated to remove isopropanol, yielding a solution of Compound 8 in IP Ac. Addition of heptane to the IP Ac solution of Compound 8 yields crystalline Compound 8. This is a crystal form of Compound 8 which exhibits a melting endotherm by DSC, with an onset temperature of 95.9"C and a peak temperature of 96.6°C (98.2 J/g). The x-ray powder diffraction pattern of this crystal form is shown in Figure 1 and Table 1.

Recrystallization of this material from isopropanol affords a higher melting crystal form, as characterized by DSC, with an onset temperature of 113.6°C and a peak temperature of 115.4°C (112.5 J/g). The x-ray powder diffraction pattern of this crystal form is shown in Figure 2 and Table 2.

The crystal form having the higher melting point (about 114°C) is the preferred crystal form of the material for pharmaceutical uses. The lower melting crystal form is a useful synthetic intermediate.

The NMR of Compound 8 isolated by either method follows: iH NMR (400MHz, CDC1₃): 6 8.48 (brs, 1H), 7.32-7.24 (m, 3H), 7.02-6.79 (m, 9H),

5.30 (s, IH), 4.16 (t, 2H, J=6.2Hz), 4.11 (t, 2H, J=6.1Hz), 3.67 (s, 3H), 3.57 (s, 2H), 2.55 (t, 2H, J=6.2Hz), 2.27 (quint, 2H, J=6.3Hz), 1.56 (hex, 2H, J=7.2Hz), 0.96 (t, 3H, J=7.3Hz).

EXAMPLE 2 An alternate method of isolating Compound 8 is to cool the isopropanol solution that results from hydrolysis of the imine 7. Compound 8 crystallizes out upon cooling of the isopropanol solution. It is washed with water when it is filtered. The product has the NMR spectrum characteristic of Compound 8 and the x-ray powder diffraction spectrum characteristic of the crystal form described above that has a melting point of about 114°C. DSC analysis of this product shows an endotherm having an onset at 102.97°C and a peak at 108.47°C (86.65 J/g). The melting point measured in a capillary is about 105°C - 110°C. The product that is isolated by this route is therefore the crystal form that has a melting point of about 114°C in Example 1.

EXAMPLE 3 Sodium salt. The sodium salt of Compound 8 is made by adding sufficient 50 wt% sodium hydroxide solution (about 1 equivalent) to an isopropyl alcohol solution of Compound 8 at about 60°C to neutralize it. After cooling, the sodium salt crystallizes out.

DSC analysis of the product shows two endotherms, one having a peak at 81.53°C (22.15 J/g, onset at 77.04°C) and a second having a peak at 229.26°C (38.74 J/g, onset at 222.20°C), the second endotherm being associated with decomposition.

The product is crystalline and has the powder x-ray diffraction pattern shown in Table 3 and Figure 3. The product is referred to hereinafter as "salt form I."

Second Sodium Salt. A second crystal form of the sodium salt ("salt form LT") has also been obtained using the above procedure. Salt form II is converted to salt form I by heating salt form II to about 75°C as a dry powder. Alternatively, salt form II can be converted to salt form I by heating a slurry of the salt in isopropyl alcohol to the reflux temperature of isopropyl alcohol. The DSC of salt form π has four endotherms with peaks at 80.2°C (5.22 J/g, onset at 74.5°C); 85.4°C (15.3 J/g, onset at 82.5°C); 205.1°C (1.877 J/g, onset at 190.5°C); and 230.6°C (47.54 J/g, onset at 225.6°C). The x-ray powder diffraction pattern of salt form II is shown in Figure 4 and Table 4. Salt form I is the preferred salt form for pharmaceutical uses. Salt form II may be a useful synthetic intermediate for making salt form I. TABLE 1

X-RAY POWDER DIFFRACTION PATTERN OF LOW MELTING CRYSTAL FORM OF COMPOUND 8

Used wavelength: K- Alpha 1

K-Alpha l wavelength (A): 1.54056 K-Alpha2 wavelength (A): 1.54439 K- Alpha2/K- Alpha 1 intensity ratio: 0.50000 K-AIpha wavelength (A): 1.54056 K-Beta wavelength (A): 1.39222

Peak search parameter set: As Measured Intensities Peak positions defined by: Minimum of 2^nd derivative Minimum peak tip width (°2Theta): 0.01 Minimum peak tip width (°2Theta): 1.00 Peak base width (°2Theta): 2.00 Minimum significance: 0.60 d-spacing Relative . Angle Peak Background Tip Significance

Intensity Height Width (A) (%) (°2Theta) (counts) (counts) (°2Theta)

32.52537 0.07 2.71406 0.62 4.46 0.80000 1.16 12-39363 6.74 7.12660 57.38 22.95 0.14000 2.30 9.89231 5.64 8.93189 48.01 25.62 0.08000 1.31 8.34150 21.38 10.59684 181.90 28.03 0.08000 1.38 8.19350 10.90 10.78881 92.74 28.37 0.10000 1.48 6.92795 19.27 12.76720 163.96 32.65 0.12000 1.41 6-74616 25.41 13.11271 216.17 33.54 0.14000 2.85 6.23171 39.33 14.20058 335.04 36.32 0.10000 3.01 5.96464 5.23 14.83992 44.51 37.95 0.16000 1-28 5.40981 27.62 15.37186 234.95 41.87 0.16000 4.95 5-24109 15.03 16.90270 127.88 43.23 0.12000 2.29 4.97953 45.97 17.79757 391.09 45.52 0.10000 3.05 4.66434 35.81 19.01099 304.64 48.63 0.20000 2-32 4.52973 44.92 19.58143 382.14 50.08 0.12000 2.39 4.32021 21.73 20.54113 184.86 52.54 0.10000 0-92 4.16142 100.00 21.33394 850.79 54.57 0.16000 6.01 4.09728 40.23 21.67191 342.25 55.43 0.10000 1.94 3.82217 18-29 23.25282 155.63 59.48 0.10000 0.75 3.68505 48.21 24.13086 410.16 61.72 0.14000 2.13 3.58516 67.12 24.81375 571.08 63.47 0.22000 15.92 3.48021 26.40 25.57449 224.59 65.42 0.20000 2 6 3.39358 48.57 26.23886 413.26 67.12 0.08000 0.70 3.32524 42.22 26.78805 359.17 68.52 0.18000 6.41 3-27101 13.93 27.24063 118.48 69.68 0.16000 0.87 3.23566 11.76 27.54406 100.02 70.45 0.16000 1.16 3.13628 27.93 28.43493 237.59 72.73 0.20000 3.48 3.01286 3.40 29.62588 28.91 75.78 0.40000 2JZ1 2.89613 13.82 30.84906 117.61 79.39 0.24000 2-26 2.86763 10.45 31.16334 88.93 80.38 0.16000 0.89 2.81503 7.56 31.76095 64.30 82-25 0.16000 1.28 2.70302 5.12 33.11412 43-53 86.49 0.48000 2.43 2.63801 8.98 33.95458 76.44 89.12 0.28000 2 0 2J4637 13.83 35.21582 117.63 93.08 0J2000 4-30 2.49972 2.16 35.89510 18.39 95.20 0.16000 0.81 2.44059 2.46 36.79550 20.95 98.03 0.48000 0.84 2.37115 3.15 37.91352 26.84 105.32 0.40000 122

-IX- TABLE 2

X-RAY POWDER DIFFRACTION PATTERN OF HIGHER MELTING CRYSTAL FORM OF COMPOUND 8

Used wavelength: K- Alpha 1

K-Alphal wavelength i (A): 1.54056

K-Alpha2 wavelength (A): 1.54439

K- Alpha2/K- Alpha 1 intensity ratio: 0.50000

K-Alpha ι wavelength (A): 1.54056

K-Beta wavelength (A) i: 1.39222

Peak search parameter ; set: As Measured Intensities

Peak positions defined by: Minimum of 2^nd derivative

Minimum peak tip width (°2Theta): 0.01

Minimum peak tip width (°2Theta): 1.00

Peak base width (*2Theta): 2.00

Minimum significance: 0.60 d-spacing Relative Angle Peak Background Tip Significance

Intensity- Height Width

(A) C2Theta) (counts) (counts) C2Theta)

13.48405 5.30 6.54964 56.38 25.65 0.06000

12.07892 0.96 7.31253 10.20 26.81 0.24000

8.12865 12.05 10.87515 128.25 30.81 0.12000

7.12847 9.19 12.40662 97.79 30.81 0.28000

6.77733 19.68 13.05216 209.52 30.81 0.10000

5.79835 23.18 15.26801 246.69 30.81 0.10000

5.59457 10.02 15.82765 106.70 30.81 0.10000

5.43035 5.47 16.30951 58.22 30.81 0.12000

5.28424 20.20 16.76367 215.06 30.81 0.16000

5.20591 14.88 17.01775 158.37 30.81 0.08000

4.75856 14.53 18.63121 154.64 30.81 0.20000

4 9266 47.28 1931054 503.31 30.81 0.12000

4.49915 28.76 19.71585 306.08 30.81 0-24000

4.44499 22.42 19.95852 238.62 30.81 0.08000

4.37607 15.75 20-27617 167.68 30.81 0.16000

4.25236 33.42 20.87255 355.77 30.81 0.10000

4.04597 91.58 21.95018 974.84 30.81 0.26000

3.83986 100.00 23.14423 1064.44 30.81 0.12000

3.80694 " 68.18 23.34715 725.79 30.81 0-20000

3.73497 50.03 23.80354 532.54 30.81 0.04000

3.71826 50.99 23.91211 542.71 30.81 0.08000

3.62906 42J3 24.50887 450.56 30.81 0.12000

3.56115 46.68 24.98372 496.87 30.81 0.16000

3J7597 19.34 26.37822 205.85 30.81 0.24000

3J3274 22.98 26.72668 244.58 30.81 0-20000

3.26746 15.91 27.27080 169J8 30.81 0.10000

3.15242 14.64 28.28635 155.79 30.81 0-20000

3.12625 17.01 28.52807 181.07 30.81 0.16000

2.99092 18.64 29.84323 198J9 30.81 0.16000

2.95299 16 J 9 30.24073 174.49 ^• 30.81 0-20000

2.89661 8.67 30.84376 9-L24 30.8.1 0.16000

2.81616 13.43 31.74786 142.92 30.81 0-20000

2.70326 16.94 33.11115 180.28 30.81 0.16000

2.64450 22.00 33.86872 234.21 30.81 ^• 0-20000

2^9388 1.L56 34.55021 133.66 30.81 0-32000

2.48018 7.51 36.18775 . 79.94 30.81 0.56000

2J8551 8.93 37.67677 95.11 30.81 0.48000

2-29733 8.64 39.18085 91.99 . 30.81 0.32000 TABLE 3

X-RAY POWDER DIFFRACTION PATTERN OF SODIUM SALT FORM I

Diffractometer system: 1 Generator settings: 45 kV, 40 mA Cu alpha 1.2 wavelengths: 1.54060, 1.54439 Ang Step size, sample time: 0.015 deg.0.20 s, 0.075 deg/s Monochrornator used: Yes Divergence slit Automatic (Irradiated sample length: 13.0 mm)

Analysis program number: Peak angle range: 2.007 -40.002 deg Range in D spacing: 2.25207-43.9723 Ang Peak position criterion: Top of smoothed data Cryst peak width range: 0.00 -2.00 deg Minimum peak significance: 0.75 Number of peaks in file: 29 (Alpha 1: 29, Amorphous: 0) Maximum intensity: 213. cts, 1065.8 cps

Peak Angle Tip width Peak Backg D-spac I/Imax Type Sign no (deg) (deg) (cts) (cts) (Ang) Al A2 Ot

1 2.3925 0.18 10. 2. 3S.8971 4.80 X X 1.66

2 4.7S00 0.18 24. 2. 18.5494 11.26 X X 1.32

3 7.1325 0.09 64. 5. 12.3837 30.02 X X 1.26

11.1550 0.24 12. 10. 7.9255 5.75 X X 0.91

5 12.S075 0.21 28. 10. 7.0155 13.18 X X 1.78

6 13.0400 0.24 15. 11. 6.7838 7.14 X X 0.98

7 13.8650 0.18 16. 12. 6.3819 7.51 X X 98

8 14.3400 0.18 14. 13. 6.1716 6.42 X X 76

9 15.7525 0.24 58. 14. 5.6212 27.10 X X 26

10 16.6075 0.12 49. 14. 5.3337 22.99 X X 79 1 18.8650 0.15 69. 17. 4.7002 32.32 X X 07 2 19.4400 0.24 135. 17. 4.5625 63.13 X X 50 3 19.9725 0.24 72. 18. 4.4420 33.89 X X 2.69 4 20.1275 0.24 55. 18. 4.4082 25.69 X X 2.09 5 21.5200 0.24 55. 18. 4.1260 25.69 X X 2.24 6 22.3250 0.18 213. IS. 3.9790 100.00 X X 3.09

1.10 7 23.9450 0.18 66. 20. 3.7133 ^"30.78 X X 8 24.4175 0.18 81. 20. 3.6425 38.00 X X 1.48 9 25.5200 0.24 74. 21. 3.4876 34.70 X X 1.95 0 26.4375 0.30 29. 22. 3.3686 13.68 X X 0.78 1 27.0825 0.36 41. 22. 3.2898 19.22 X X 2.19 2 27.8700 0.15 64. 23. 3.1986 30.02 X X 0.89 3 29.1500 0.24 38. 24. 3.0610 18.03 ^' X X 0.98

1.32 4 29.7975 0.24 40. 24. 2.9960 18.62 X X 5 31.0625 0.30 52. 25. 2.8768 24.32 X X 2.24 δ 32.3050 0.24 19. 26. 2.7689 9.08 X X 0.85 7 33.0S00 0.24 28. 26. 2.7058 13.18 X X 0.76 S 35.1775 0.30 18. 2£ . 2.5491 8.67 X X 1.48

1.07 9 37.2525 0.3. 22. 23. 2.4118 • 10.36 X TABLE 4

X-RAY POWDER DIFFRACTION PATTERN OF SALT FORM II

Used wavelength: K- Alpha 1

K-Alphal wavelength (A): 1.54056 K-Alpha2 wavelength (A): 1.54439 K-Alpha2/K- Alpha 1 intensity ratio: 0.50000 K-Alpha wavelength (A): 1.54056 K-Beta wavelength (A): 1.39222

Peak search parameter set: As Measured Intensities Peak positions defined by: Minimum of 2" derivative Minimum peak tip width (°2Theta): 0.01 Minimum peak tip width (°2Theta): 1.00 Peak base width (°2Theta): 2.00 Minimum significance: 0.60 d-spacing Relative Angle Peak Background Tip Significance Intensity Height Width

(A) (°2Theta) (counts) (counts) (°2Theta)

35.82893 8.67 2.46377 36.03 3.49 0.10000 1.93

18.33907 18.19 4.81450 75.62 10.96 0.12000 2.15

12.26294 38.96 7.20266 161.91 18.54 0.08000 1.03

6.95058 6.69 12.72546 27.82 31.65 0.32000 1.78

6.14649 13.18 14.39850 54.76 33.82 0.20000 1.66

5.60606 32.68 15.79500 135.83 35.62 0.36000 4.62

5.45420 41.63 16.23769 173.02 36.19 0.16000 1.89

4.87980 26.38 18.16433 109.66 38.69 0.16000 0.62

4.79870 35.44 18.47399 147.29 39.09 0.16000 0.72

4.66335 49.14 19.01506 204.25 39.79 0.16000 0.75

4.54978 45.01 19.49429 187.08 40.41 0.20000 1.71

4.32145 31.10 20.53518 129.25 41.75 0.20000 1.89

4.15071 39.71 2IJ8964 165.04 42.86 0.32000 7.24

4.08843 41.39 21.71943 172.00 43.29 0.16000 0.67

3.97518 100.00 22.34602 415.62 44.10 0.06000 0.89

3.85026 44.03 23.08082 183.00 45.05 0.24000 1.97

3.62884 40.85 24-51041 169.78 46.90 0.32000 5.04

3.50184 23.70 25.41391 98.50 48.06 0.32000 1.10

3.38949 23.12 26.27111 96.08 49.17 0.24000 1.16

3.30772 37.23 26.93259 154.74 50.03 0.28000 2.38

3.19224 23.08 27.92628 95.93 51.31 0.40000 2.06

3.09849 21.70 28.78921 90.21 52.43 0.12000 0.94

3.00403 17.38 29.71495 72.23 53.63 0.32000 1.03

2.91191 27.19 30.67771 113.01 54.87 0.12000 L32

2.73116 13.77 32.76326 57.23 57.57 0.20000 1.00

2.66996 11.36 33.53623 47.19 58.57 0.32000 0.98

2J7992 12.11 34.74314 50.31 60.13 0.48000 3.24

2.40848 4.88 37.30410 20.30 77.93 0.48000 2.01

2J5913 2.73 38.11415 1IJ5 93.75 0.16000 0.65

2J2909 5.89 38.62516 24.47 103.74 0.32000 1.31

Claims

WHAT IS CLAIMED IS:

1. A method of making a compound having the formula I:

wherein

Arl is (l) arylene or (2) heteroarylene, wherein arylene and heteroarylene are optionally substituted with from

1 to 4 groups selected from Ra; Ar2 is (1) ortho-substituted aryl or

(2) ortho-substituted heteroaryl, wherein said ortho substituent is selected from R; and aryl and heteroaryl are optionally further substituted with from 1-4 groups independently selected from R^a; X and Y are independently O, S, N-Rb, or CH2;

Z is O or S >; n is 0 to 3 •>

R is (1) C3-ioalkyl optionally substituted with 1-4 groups selected from halo and C3-6cycloalkyl,

(2) C3-ioalkenyl, or

(3) C3-8cycloalkyl;

R^a is (1) Ci-15 alkanoyl,

(2) C 1-15 alkyl,

(3) C2-15 alkenyl,

(4) C2-15 alkynyl,

(5) halo,

(6) OR^b,

(7) aryl, or

(8) heteroaryl, wherein said alkyl, alkenyl, alkynyl, and alkanoyl are optionally substituted with from 1-5 groups selected from R^c, and said aryl and heteroaryl optionally substituted with 1 to 5 groups selected from Rd, Rb is (1) hydrogen, (2) Ci-ioalkyl,

(3) C2-10alkenyl,

(4) C2-10alkynyl,

(5) aryl,

(6) heteroaryl, (7) aryl CMS alkyl,

(8) heteroaryl Ci-15 alkyl,

(9) Ci-15 alkanoyl,

(10) C3-8cycloalkyl, wherein alkyl, alkenyl, alkynyl are optionally substituted with one to four substituents independently selected from R^c, and cycloalkyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rd; or Rc -s (1) halo,

(2) aryl,

(3) heteroaryl,

(4) CN,

(5) NO2,

(6) OR^f,

(7) S(O)_mR^f, m = 0, 1 or 2, provided that R^f is not H

(8) NR^fR^f,

(9) NR^fCOR^f,

(10) NR^fCO2R^f,

(11) NR^fCON(R^f)2,

(12) NR^fSO2R^f, provided that Rf is not H,

(13) COR^f,

(14) CO2R^f,

(15) CON(Rf)₂,

(17) OCON(R^f)2, or

(18) C3-.8cycloa.kyI, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 3 groups of halo or Ci-6 alkyl;

Rd is (1) a group selected from Rc,

(2) C i-io alkyl,

(3) C2-10 alkenyl,

(4) C2-10 alkynyl,

(5) aryl Ci-ioalkyl, or

(6) heteroaryl Ci-io alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R^e;

Re is (1) halogen,

(2) amino,

(3) carboxy,

(4) Ci_4alkyl,

(5) Cι_4alkoxy,

(6) hydroxy,

(7) aryl,

(8) aryl Ci-4alkyl, or

(9) aryloxy;

Rf is (1) hydrogen,

(2) Ci-ioalkyl,

(3) C2-10alkenyl,

(4) C2-10alkynyl,

(5) aryl,

(6) heteroaryl,

(7) aryl Ci-15 alkyl,

(8) heteroaryl Ci-15 alkyl,

(9) Ci-15 alkanoyl,

(10) C3-8cycloalkyl; wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally substituted with one to four groups selected from R^e; comprising the steps of

(a) prov.dmg a compound C having the formula RgOOC-CH2- Arl-Y-CH2-(CH2)n-CH2-X-Ar2 , wherein Rg is a a tπalkylsilane group or a CI-15 alkyl group which is optionally substituted with an aryl group, a cycloalkyl group, a heterocyclic group, or a heteroaryl group, except that Rg is not unsubstituted methyl; and

(b) converting said compound C_ to an arylthiazohdinedione having Formula I.

2. The method as recited m Claim 1, wherein said step (b) of converting compound C to a compound having Formula I compπses the steps of (a) converting compound C to an alpha-halo ester, and (b) converting said alpha-halo ester to a compound having Formula I.

3. The method as recited in Claim 1, compπsing the steps of: (a) providing compound C as a carboxylic acid or salt, (b) converting the carboxylic acid or salt to an alpha-halo carboxylic acid or salt by halogenation of the carboxylic acid or salt to yield the alpha-halo carboxylic acid or salt, and (c) converting the alpha-halo carboxylic acid or salt to the thiazolidinedione having Formula I by reaction with thiourea.

4 A method of making a salt of 5-[3-(3-(2-propyl-4- phenoxyphenoxy)propoxy)phenyl]-2,4-thιazohdιnedιone compπsing the step of combining 5-[3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4- thiazolidinedione with about one equivalent of base.

5. The method as recited in Claim 4 wherein the salt is a sodium salt and the base is sodium hydroxide.

6. A sodium salt made by the method of Claim 5

7. A sodium salt made by the method of Claim 5 having the x- ray powder diffraction pattern of Table 3 or Figure 3.

8. A sodium salt made by the method of Claim 5 having the x-ray powder diffraction pattern of Table 4 or Figure 4.

9. A pharmaceutical composition comprising the sodium salt of Claim 7 and a pharmaceutically acceptable carrier.

10. A crystalline form of 5-[3-(3-(2-propyl-4- phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione having the x-ray powder diffraction of Table 1 or Figure 1.

11. A crystalline form of 5-[3-(3-(2-propyl-4- phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione having the x-ray powder diffraction spectrum of Table 2 or Figure 2.

12. A pharmaceutical composition comprising the crystalline form of 5-[3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione of Claim 11 and a pharmaceutically acceptable carrier.

13. A method of synthesizing 5-[3-(3-(2-propyl-4- phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione comprising the steps of providing Compound 5 of Scheme 3, and converting Compound 5 to 5-[3-(3-(2- propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione.

14. A method of synthesizing 5-[3-(3-(2-propyl-4- phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione as recited in Claim 12 comprising the steps of converting Compound 5 to an alpha halo compound and then converting the alpha halo compound to 5-[3-(3-(2-propyl-4- phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione.