WO2006138328A1

WO2006138328A1 - Process for the production of antidiabetic oxazolidinediones

Info

Publication number: WO2006138328A1
Application number: PCT/US2006/023064
Authority: WO
Inventors: Dalian Zhao
Original assignee: Merck & Co., Inc.
Priority date: 2005-06-14
Filing date: 2006-06-13
Publication date: 2006-12-28

Abstract

The present invention provides a convergent process for the preparation of a family of antidiabetic phenoxy-substituted phenoxybenzyl oxazolidinediones shown as structure I. The compounds are selective PPAR gamma partial agonists (SPPARM's), which are useful in the treatment of type 2 diabetes.

Description

TITLE OF THE INVENTION

PROCESS FOR THE PRODUCTION OF ANTIDIABETIC OXAZOLIDINEDIONES

FIELD OF THE INVENTION

The present invention relates to an improved process for the manufacture of pharmaceutically active compounds for the treatment of type 2 diabetes and other diseases that are modulated by PPAR gamma agonists, including hyperglycemia, obesity, dyslipidemia, and the metabolic condition. The compounds are selective PPAR gamma partial agonists (also known as a SPPARgM's or SPP ARM's).

BACKGROUND OF THE INVENTION

Type 2 diabetes is a serious medical problem. There is an ongoing need for new treatments that are more effective and that have fewer side effects. PPAR gamma full agonists, such as rosiglitazone and pioglitazone, are insulin sensitizers and are useful in treating hyperglycemia that occurs in type 2 diabetes without risk of hypoglycemia. The use of PPAR gamma agonists causes side effects that make them less desirable for many patients, such as weight gain and edema. A newer class of PPAR gamma agonists comprises compounds that are are potent selective ligands for the PPAR gamma receptor but are partial agonists in transactivation assays. The compounds are effective in reducing hyperglycemia in animal studies, with little or no edema and weight gain, and are often described as selective PPAR gamma modulators (SPPARM's or SPPARgM's).

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of antidiabetic oxazolidinediones of the general structure shown in formula I:

I

In the compounds of Formula I, X is halogen, and Ri and R₂ are independently selected from the group consisting of hydrogen and Ci-C₃ alkyl, wherein Ci-C₃ alkyl is optionally substituted with 1-3 F. The present invention also provides structurally novel intermediates useful in the disclosed process. The compounds can be made having either the (R) or (S)-configuration at the stereogenic center to which R₂ is connected; generally, compounds with the (Reconfiguration are the more active of the two stereoisomers.

The class of compounds described by Formula I which are made by the process disclosed herein are potent PPAR ligands that in vitro are generally PPARγ partial agonists. The compounds are useful in the treatment of PPAR modulated diseases, including type 2 diabetes, hyperglycemia, insulin resistance, and diabetic dyslipidemia. They may also be useful in delaying the onset of type 2 diabetes in patients who are in a pre-diabetic state, such as patients who have impaired glucose tolerance. They may also be used in combination with other antidiabetic compounds, such as DPP-IV inhibitors (sitagliptin, vildagliptin, or saxagliptin), sulfonylureas, metformin, GLP-I, GLP-I analogs (e.g. exenatide), meglitinides (e.g. nateglinide), GPR40 agonists, and GPR120 agonists. They may also be administered with compounds that are useful in improving a patient's lipid profile, such as statins, ACAT inhibitors, CETP inhibitors, fibrates, PPAR alpha agonists, niacin, and niacin receptor agonists. CETP inhibitors include torcetrapib and the compounds described in WO2005/100298 and WO2006/014413. Combinations of the drugs of formula I with other drugs can be administered concomitantly or as a fixed dose combination.

The compounds of Formula I were previously described in WO2005/070905. The compounds in WO2005/070905, including Compound Ia synthesized in Example 1 herein, were prepared by a different process.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 provides a characteristic X-ray powder diffraction pattern of the crystalline anhydrous compound (5R)-5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl-l,3- oxazolidine-2,4-dione made by the process described in Example 1.

FIGURE 2 provides a characteristic thermogravimetric analysis (TGA) curve of the crystalline anhydrous compound (5R)-5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl- l,3-oxazolidine-2,4-dione made by the process described in Example 1.

FIGURE 3 provides a characteristic differential scanning calorimetry (DSC) curve of the crystalline anhydrous compound (5R)-5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl- 1 ,3-oxazolidine-2,4-dione made by the process described in Example 1.

FIGURE 4 provides a characteristic solid state carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline anhydrous compound of (5R)-5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-niethyl-l,3-oxazolidine-2,4-dione made by the process described in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula I are produced by reacting a compound of formula II with a compound of Formula IH,

π wherein Y in Formula II is either (a) a halogen atom, or (b) selected from the group consisting of -OH, -OC(=O)Ci-C₃ alkyl, and -OCC=O)OC₁-C₃ alkyl, wherein the C₁-C₃ alkyl groups are optionally substituted with 1-3 fluorine atoms, and Z in the compound of Formula III (an oxazolidinedione) is selected from the other of the two groups that are described above as selections (a) and (b) for Y, so that one of Y and Z is (a) and the other is (b):

m

In the compounds of formula II and HI, X is a halogen atom, and R₁ and R₂ are each independently selected from the group consisting of hydrogen and C₁-C₃ alkyl, wherein C₁-C₃ alkyl is optionally substituted with 1-3 F.

Reactions between compounds of formula II and compounds of formula HI are generally accomplished in the presence of suitable catalysts, solvents, and bases so that II and IH are coupled to form compound I. Reactions are carried out under suitable conditions for a chemical reaction to take place. Such conditions include suitable temperature, exclusion of air or use of inert atmosphere, and agitation or lack of agitation.

This process is a convergent synthesis of the compound of formula I by first synthesizing or obtaining the intermediates II and HI and then coupling them in the final step. The process involves the preparation of a diaryl ether (the compound of formula II) and an oxazolidinedione (formula HT). These two compounds are then combined to create the compound of formula I.

The invention has numerous embodiments, summarized below. In the description and claims herein, alkyl groups are either linear or branched, unless otherwise defined.

One embodiment of the invention comprises a process for making the compound of formula I in which X is selected from F, Cl, Br, and I, and Ri and R₂ are independently selected from the group consisting OfC]-C₃ alkyl, wherein Ci-C₃ alkyl is optionally substituted with 1-3 F.

An embodiment of the invention comprises the reaction of the compound of formula II with the compound of formula DI, wherein in the compound of formula II:

X is selected from F, Cl, Br, and I;

R] is selected from H and Ci-C₃ alkyl, wherein Ci-C₃ alkyl is optionally substituted with 1-3 F; and Y is selected from the group consisting of -OH, -OC(=O)C_rC₃ alkyl, and -OC(O)OCi-

C₃ alkyl, wherein said Ci-C₃ alkyl groups are optionally substituted with 1-3 fluorine atoms; and wherein in the compound of formula IH,

Z is selected from F, Cl, Br, and I; and

R₂ is selected from the group consisting of H and Q-C₃ alkyl, wherein Ci-C₃ alkyl is optionally substituted with 1-3 F.

The compounds of formula II and El are reacted in the presence of appropriate catalyst(s), solvent(s), and base(s), and under conditions that are sufficient for a chemical reaction or a series of chemical reactions to occur to yield a compound of Formula I.

Another embodiment of the invention comprises a process for making the compounds of formula I in which X, Ri and R₂ are as described above, in which a compound of formula π is reacted with a compound of formula HI, wherein in the compound of formula II, X is selected from F, Cl, Br, and I;

Ri is selected from H and C_rC₃ alkyl, wherein Ci-C₃ alkyl is optionally substituted with 1-3 F; and

Y is selected from F, Cl, Br, and I; and wherein in the compound of formula in, Z is selected from the group consisting of -OH, -OC(=O)d-C₃ alkyl, and -OC(=O)OC]-C₃ alkyl, wherein the Ci-C₃ alkyl groups are optionally substituted with 1-3 fluorines; and

R₂ is selected from the group consisting of H and C]-C₃ alkyl, wherein Ci-C₃ alkyl is optionally substituted with 1-3 fluorine atoms. The compounds of formula II and HI are reacted in the presence of appropriate catalyst(s), solvent(s), and base(s), and under conditions such that a chemical reaction or a series of chemical reactions occurs to yield a compound of Formula I.

In preferred embodiments of the processes described above, the group X of Formula I and π is Cl.

In embodiments of the processes described above, the group Ri of formula I and II is selected from Ci-C₃ alkyl. In preferred embodiments of the processes described above, the group Ri of formula I and II is n-propyl.

In embodiments of the processes described above, the group R₂ of formula I and IH is selected from Ci-C₃ alkyl. Ih preferred embodiments of the processes described above, the group R₂ of formula I and IH is methyl.

In embodiments of the processes described above, the group Z of formula DI or the group

Y of formula II is Br or I, and the other of Z and Y is as defined previously.

Y of formula II is -OH, and the other of Z and Y is as defined previously.

In embodiments of the processes described above, one of the groups Y of formula II and Z of formula IH is -OH; and the other of the groups Y of formula π and Z of formula HI is Br or I.

In embodiments of the processes described above, the group Z of formula DI is Br or I; and the group Y ofFormula ll is -OH.

In embodiments of the processes described above, the group Y of formula π is Br or I, and the group Z of formula IH is -OH. In preferred embodiments of the process of making compounds of formula I, X of formula I and II is Cl; Ri of formula I and II is C_rC₃ alkyl (and especially n-propyl); Y of formula II is -OH; Z of formula HI is Br or I (and especially Br); and R₂ of formula I and IH is Ci-C₃ alkyl (and especially methyl).

Suitable catalysts are generally transition metal catalysts. In some embodiments, the catalyst comprises copper or palladium. In some embodiments, the transition metal catalyst is a Cu(I) or Pd(O) catalyst. In some embodiments, the catalyst comprises a Cu(I) halogen salt. In some embodiments, the catalyst comprises CuI.

In preferred embodiments, compounds of formula II and IU are reacted in the presence of a copper(I) catalyst, a solvent, a solubilizing agent such as 2,2,6,6-tetramethylheptane-3,5-dione, and at least one carbonate base. The reaction is conducted under conditions suitable to bring about a chemical transformation of compounds of formula II and IH to a compound of formula I. Either enantiomer (i.e. R or S) at the 5-position of the oxazolidinedione ring is made by this process. The R enantiomer is in general more active and is preferred. Racemates can also be made by starting with R² at a racemic center.

The process for making the compounds can additionally include product purification or separation steps such as filtration, crystallization, distillation, and the like, and may also include other methods of improving the relative proportion of one enantiomer over the other.

Structures of specific compounds and synthetic methods for making the compounds are disclosed in the Examples.

One series of steps of the process involves the preparation of a diaryl ether of structural formula II:

π

One way in which compounds of formula π can be prepared is through an aromatic substitution reaction in which an aryl-halide is reacted with an appropriate phenol. Further reactions, such as a Claisen rearrangement, can be utilized in order to obtain structural variations and placement of pendant groups on the aryl rings. Further treatments can include hydrogenation or substitution reactions involving the pendant groups in order to obtain appropriate or desired functionality.

Another series of steps in the process involves the preparation of oxazolidinediones of formula HI:

m

One way in which these compounds can be prepared is to react a cyanohydrin compound with an appropriate ring generating compound such as a chlorosulfonylisocyanate. It is possible for the reaction to be stereospecifϊc with auxiliary reagents or ligands that make it sterospecifϊc, but the reaction generally produces a racemic mixture. Enantiomeric resolution can be obtained using standard methods well-known in the practice of organic chemistry, such as crystallization in the presence of an enantiomerically enriched or entantiomerically pure compound.

The final step (or steps) in the process involves the reaction of a compound of formula II with a compound of formula HI in the presence of appropriate catalysts, solvents, and/or other reaction auxiliaries. One way in which this reaction can be accomplished is via an Ullmann condensation reaction, in which an aryl-halide is reacted with a phenol to generate a diaryl ether. These types of reactions are generally conducted under basic conditions, with a transition metal catalyst, commonly Pd or Cu, and in the presence of a polar solvent.

While traditionally Ullmann condensations were carried out under rather harsh conditions with low to moderate yields, a recent publication demonstrated an efficient and much milder set of conditions (Organic Letters, Vol. 4, No. 9, 1623-1626 (2002)). As described, a copper-halide catalyst and carbonate salts are combined with 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) in order to create a highly active and inexpensive catalyst that reacts with a wide variety of phenols and aryl halides. Suitable solvents for this type of condensation reaction include acetonitrile, NMP, DMF, DMSO, and mixtures thereof. Reactions are generally conducted at elevated temperatures, both in order to increase the solubility of the metal catalyst as well as to remove reaction byproducts such as water. Acetonitrile is especially useful as a solvent for this reaction because of the boiling point and ability to easily remove water from the reaction mixture. The preferred temperature is at the boiling point of acetonitrile (82°C). In general, the temperature is in the range of 70⁰C-110°C. Base choice is also important for these reactions. Bases can generally be chosen from carbonates, hydroxides, and other basic compounds. In particular, Cs₂CO₃ has been shown to be a very effective base for Ullmann type condensation reactions. While Cs₂CO₃ is a very efficient base, it is also heavy, expensive, and hydroscopic. Reactions conducted with K₂CO₃ proceed much more slowly, but K₂CO₃ is less expensive, lighter, and less hydroscopic than Cs₂CO₃. A mixture Of Cs₂CO₃ and K₂CO₃ is a particularly useful base combination because the reaction proceeds more quickly than with K₂CO₃ alone, while simultaneously mitigating some of the disadvantages of using Cs₂CO₃ alone. Representative experimental procedures utilizing the novel process are described below.

EXAMPLES

The following examples are provided to illustrate the invention and are not to be construed as limiting the invention in any manner. The scope of the invention is defined by the appended claims.

A process for making one specific compound is generally depicted in Scheme I below. Other claimed compounds can be made by obvious modifications of this scheme.

Scheme I

Step 1 : Fluoride displacement Step 5: Step 2: Allylation Cyanation

Step 3: Claisen rearrangement Step 6: Oxazolidinedione formation Step 4: Hydrogenation i Step 7: Optical resolution: 99% ee

Intermediate 1

Step 1. Fluoride Displacement

Hydroquinone (253g, 2.30 mol, 4 equiv.), potassium tert-butoxide (272 g, 2.30 mol, 4 equiv.), chlorofluorobenzene (75 g, 0.574 mol, 1 equiv.), and DMSO (1500 mL) were placed in a 3L 4-neck round bottom flask fitted with reflux condenser and mechanical stirrer. The mixture was heated to 140⁰C and then aged at 140⁰C for 24h.

The reaction mixture was cooled to room temperature and partitioned between 6% NaHCO₃ solution (1500 mL) and MTBE (1500 mL). The aqueous layer was back extracted with MTBE (IX 1500 mL). The organic layers were combined and washed with 6% NaHCO₃ soln (3 X 1500 mL).

Step 1. Alternate Method: Fluoride Displacement with Crown Ether

Hydroquinone (78.8g, 716 mmol, 4 equiv.), potassium tert-butoxide (84.6g, 716 mmol, 4 equiv.), 18- crown-6 (47.3g, 179 mmol, 1 equiv), l-chloro-4-fluorobenzene (23.3g, 179 mmol, 1 equiv.), and DMSO (350 mL) were combined in a IL 3-neck flask fitted with a reflux condenser and a mechanical stirrer. The reaction was heated to an internal temperature of 100⁰C with an oil bath at 110⁰C, and allowed to react for 72 hours. The reaction mixture was then cooled to room temperature and partitioned between water (400 mL) and n-heptane (400 mL). The aqueous layer was extracted with MTBE (2 X 400 mL), and then the organic layers were combined and washed with 6% NaHCO₃ solution (3 X 400 mL). The two aqueous layers were then back extracted with MTBE (3 X 350 mL). All of the organic layers were combined and washed with 6% NaHCO₃ (3 X 350 mL).

Step 2. Allylation

AlIyI Bromide, K₂CO₃, acetone reflux

To a crude solution of the product from step 1 in acetone (4 mL/g starting material) at room temperature was added K₂CO₃ and allyl bromide, and the resulting slurry was heated to 60 ⁰C. After 12-16 hrs at 60 ⁰C the reaction was checked for completeness by HPLC, cooled to room temperature, and filtered through a plug of solca-floc. The collected inorganics were washed with acetone (2 mL/g) and the filtrates were combined. The solvent was switched in vacuo to toluene :heptane (1:3, 3.8 mL/g) and the resulting crude solution was used in step 3 (Claisen rearrangement) without further purification.

Intermediate 2: 4-(4-chlorophenoxy)-2-propylphenol

Step 3. Claisen Rearrangement

To a crude solution of the product of step 2 in toluene:heptane (1:3, 3.8 mL/g) at 0 ⁰C under nitrogen was slowly added IM Et₂AlCl in heptane over 60 minutes via a dropping funnel. The reaction was warmed to room temperature over 2-4 hrs, and then was checked for remaining starting material by HPLC.

The reaction was cooled to 0 ⁰C, then with vigorous stirring was slowly quenched, dropwise, with 6N HCl over 30 minutes to 1 hour. The resulting thick slurry was stirred rapidly, allowed to warm to room temperature (internal temperature), and then the mixture was filtered and the collected precipitate washed with a mixture (1:7) of toluene :heptane (5 mL/g). The crude product solution was used in step 4 (hydrogenation) without further purification. Step 4. Hydrogenation

The crude allyl phenol from step 3 in toluene/heptane was concentrated to an oil in vacuo and dissolved in toluene (3.5 mL/g). To the crude solution was added Wilkinson's catalyst (1 mol%) and the reaction was hydrogenated under 45 psi of hydrogen at 40 ⁰C for 18 h. The reaction was then cooled to room temperature.

Intermediate 3

Step 5. Cyanation

In a 2-liter 3-neck flask equipped with an overhead stirrer were added under nitrogen 3- bromophenylacetone (84.0 g, 394 mmol, 99% purity) and dichloromethane (985 ml, 11.7 ml/g). To the resulting solution was added TMSCN (78.2 g, 105 ml, 788 mmol, 2.0 equiv) in one portion. Zinc iodide (12.6 g, 39.4 mmol, 0.1 equiv) was then added over a few minutes, keeping the temperature of the mixture at 19-25 ⁰C with a cold bath. The reaction mixture was aged at 25 ⁰C using a warm water bath until completion of the reaction (4-5 h, <1 assay % starting material by HPLC). The reaction mixture was then cooled to 15 ⁰C and quenched with 2 N HCl (197 ml, 394 mmol, 1.0 equiv) keeping the temperature of the reaction mixture below 20⁰C, followed by addition of water (200 ml). The biphasic mixture was transferred to a 2 L separatory funnel and the layers were separated. The organic layer was washed with water (2 x 250 ml). The solvent was removed by evaporation and then MeCN (400 ml) was added. The solution was cooled to 0⁰C and IN HCl (400 ml) was added, keeping the temperature of the mixture below 20 ⁰C. The mixture was allowed to warm to room temperature and aged until the deprotection of the cyanohydrin was complete. Toluene was added (200 ml), followed by sat. aqueous NaCl (30 ml). The layers were separated and the top organic layer was washed with aqueous NaCl (5 wt%, 2 x 200 ml). The organic layer was then concentrated to form a slurry which was triturated in 3:7 toluene /heptane (200 ml) at ambient temperature for a few hours. The slurry was filtered and the cake was washed with 1:9 toluene/heptane (100 ml) followed by heptane (100 ml). The solid was dried under partial vacuum under a flow of nitrogen.

Intermediate 4

Step 6. Oxazolidinedione Formation

The cyanohydrin from step 5 (76.0 g, 312 mmol, 98.5 wt%) and toluene (380 ml) were added under nitrogen to a 1 -liter 3 -neck flask equipped with an overhead stirrer. Chlorosulfonylisocyanate (48.6 g, 343 mmol, 1.1 equiv.) was added to the solution over a few minutes, keeping the temperature of the solution below 35 ⁰C, and the reaction was aged at 20-35 ⁰C for 1 h. The triethylamine (34.7 g, 343 mmol, 1.1 equiv.) was then added, keeping the temperature below 35 ⁰C and the resulting mixture was aged at 20-35 ⁰C for 2 h. The mixture was then heated to reflux until the conversion was complete by HPLC (1 h, release of gas occurs at >95 ⁰C). The solvent was switched to ethanol via concentration, flushed with EtOH, and the volume of the solution was adjusted to 600 ml. Concentrated HCl (60 ml, 2.3 equiv.) was added and the mixture was heated to reflux until the conversion to the oxazolidinedione was complete by HPLC (12 h). The solvent was switched to EtOAc (500 ml total volume) via concentration and dilution with EtOAc. While keeping the reaction temperature below 30 ⁰C, water (150 ml) was added. The layers were separated and the organic layer was washed with aqueous NaHCO₃ (1-2 wt%, 120 ml) and aqueous NaCl (2 wt%, 120 ml). The organic layer was dried via partial distillation and the final volume was adjusted to 500 mL. The crude oxazolidinedione solution can be used without further purification.

Step 7. Optical Resolution

To a crude solution of racemic oxazolidinedione intermediate (72.3 g, 255 mmol) in EtOAc (500 ml) as obtained in step 6 was added (S)-α-methylbenzylamine (30.9 g, 32.8 ml, 255 mmol, 1.0 equiv) over 20 minutes at ambient temperature. The mixture was seeded with optically pure oxazolidinedione (70 mg) from previous preparations halfway through the addition of the methylbenzylamine. The resulting slurry was aged at 50⁰C for 5 h and cooled to ambient temperature for a few hours. The slurry was filtered and the wet cake was washed with EtOAc (2 x 50 ml) followed by 1 : 1 EtO Ac/Heptane (50 ml). The solid was dried under partial vacuum with a flow of nitrogen to give 41.6 g of optically enriched oxazolidinedione (97 % ee).

The methylbenzylamine salt (40.5 g) can be reslurried in EtOAc (180 ml) as previously described to increase the optical purity to 99% ee (No wash is applied to the wet cake).

To a slurry of MBA salt (5.0 g, 12.3 mmol, 99% ee) in EtOAc (30 ml) at ambient temperature was added IN HCl (14 ml) and the biphasic mixture was stirred for a few minutes. The layers were separated and the organic layer was washed with water (3 x 6 ml). The organic layer can be dried via azeotropic removal of water to give a crude solution of the oxazolidinedione or evaporated to yield the crude product as an oil which solidifies upon standing.

Example 1: Synthesis of (5R)-5-{3-F4-(4-chlorophenoxyV2-propylphenoxy]benzyl)-5-methyl-1.3- oxazolidine-2,4-dione fCompound Ia). Synthesis:

To a solution of oxazolidinedione (intermediate 4, 3.5 g, 12.3 mmol, 1.0 equiv.) in acetonitrile (28 ml, 8 ml/g) were successively added chlorophenoxyphenol (intermediate 2, 3.6 g, 13.5 mmol, 1.1 equiv.), 2,2,6,6-tetramethylheptane-3,5-dione (2.3g, 13.5 mmol, 1.0 equiv.), Cs₂CO₃ (6.4 g, 19.7 mmol, 1.6 equiv.), and K₂CO₃ (2.7 g, 19.7 mmol, 1.6 equiv.). The reaction mixture was degassed under partial vacuum under an atmosphere of nitrogen. Copper iodide (1.2 g, 6.2 mmol, 0.5 equiv.) was added and the reaction mixture was degassed again. The flask was equipped with a reflux condenser and the reaction mixture was heated to reflux for 30 h, at which point the reaction was >99% complete by HPLC. The reaction mixture was cooled to ambient temperature, diluted with isopropanol (35 ml), and then filtered through solka-floc (rinsing with 15 ml isopropanol). The organic layer was washed with saturated aqueous NH₄Cl followed by water, and the solvent was removed.

Purification step 1:

A slurry of oxazolidinedione (larger scale) from example 1 (2.95 Kg, 99.2 wt%, 99.7

A%, 85-87% ee, 6.29 mol) in isopropanol (4.4 L, 1.5 L/Kg) and ra-heptane (8.8 L, 3 L/Kg) in a 50-L 3- neck round bottom flask was heated to 78 ⁰C until the material dissolved. The mixture was then cooled to 64 ⁰C and n-heptane (10.3 L, 3.5 L/Kg) was added slowly over 30 min (Temp range: 78 to 64⁰C).

Pre-prepared seed of the oxazolidinedione (93.3 g, 98.9 wt%, 98.6 %ee) was then added and the reaction was allowed to cool to 26⁰C over 4 hours. Additional n-heptane (3.5 mL/g) was added over 2 hours.

The resulting slurry was stirred at room temperature overnight. The product slurry was filtered, washed with isopropanolrn-heptane (1:13.4, 11.7 L, 4

L/Kg) and «-heptane (5.9 L, 2 L/Kg), and then dried briefly. A portion of the material was separated and dried. Chiral analysis showed 96.1% ee.

The crude, solvent-wet cake (3.6 Kg, 71.7 wt%) was then slurried in isopropanol (3.9 L,

1.5 L/Kg) and «-heptane (7.8 L, 3 L/Kg) and heated to 67⁰C until dissolution of solids was complete. n-Heptane (9.1 L, 3.5 L/Kg) was then added over 30 min., the mixture was seeded with pre-prepared oxazolidinedione (60.8 g, 98.9 wt%, 98.6 %ee), and the resulting slurry was cooled to 26 ⁰C over 3.5 hours. R-Heptane (9.1 L. 3.5 L/Kg) was then added over 1 hour and the mixture was aged overnight at room temperature. The batch was then filtered and washed with isopropanol/n-heptane (10.4 L, 1:13.4, 4

L/Kg), then ?z-heptane (5.2 L/ 2 L/Kg) and dried under a stream of nitrogen. Chiral analysis showed 98.9% ee.

Purification step 2: Recrvstallization

To a 12 L, 3-neck flask, was charged the recrystallized oxazolidinedione (2.07 Kg, 98.9 wt%, 98.9% ee), isopropanol (2.6 L), and w-heptane (2.6 L), and the mixture was heated to dissolution (57 ⁰C). To a secondary vessel was added «-heptane (29 L) followed by seed material of pre- prepared oxazolidinedione (255 g, 98.9 wt%, 98.6 %ee), and the resulting mixture was stirred rapidly. The product solution (at 60 ⁰C) was then added to this vessel via an in-line filter over 18-20 min. The resulting slurry was stirred at rt overnight then filtered, washed with n-heptane (6.3 L), and dried under a stream of nitrogen. Chiral analysis showed 99.6% ee.

Purification step 3: particle size

A filtered solution of oxazolidinedione (2.1 Kg) in isopropanol (2.6 L, 1.25 L/Kg) and n- heptane (2.6 L, 1.25 L/Kg) at 60 ⁰C was added over 30-45 min to a stirred slurry of pre-prepared oxazolidinedione seed (250 g, 98.9 wt%, 98.6 %ee) in heptane (28.9 L, 13.75 L/Kg) at 18-22° C. The resulting slurry was aged for several hours at 18-22 ⁰C and filtered. The cake was washed with heptane (6.3 L, 3 L/Kg) and was dried for several hours under a stream of nitrogen.

The product is a crystalline, anhydrous compound. The crystalline anhydrous compound has properties that make it advantageous for use as an active pharmaceutical ingredient (API) in pharmaceutical compositions, including stability, ease of purification, ease of processing, stability, and low hygroscopicity.

Pharmaceutical compositions comprising (5R)-5-{3-[4-(4-chlorophenoxy)-2- propylphenoxy]benzyl}-5-methyl-l,3-oxazolidine-2,4-dione as the drug substance (API) comprise the crystalline anhydrous compound made by the method of Example 1 in a detectable amount. The pharmaceutical compositions further comprise one or more pharmaceutically acceptable carriers or excipients. The amount of crystalline anhydrous compound in the drug substance (API) can be quantified by the use of physical methods such as X-ray powder diffraction (XRPD), solid-state fluorine- 19 magic- angle spinning (MAS) nuclear magnetic resonance spectroscopy, solid-state carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared spectroscopy, and Raman spectroscopy. In one embodiment, about 5% to about 100% by weight of the crystalline anhydrous compound is present in the drug substance. In a second embodiment, about 10% to about 100% by weight of the crystalline anhydrous compound is present in the drug substance. In a third embodiment, about 25% to about 100% by weight of the crystalline anhydrous compound is present in the drug substance. In a fourth embodiment, about 50% to about 100% by weight of the crystalline anhydrous compound is present in the drug substance. In a fifth embodiment, about 75% to about 100% by weight of the crystalline anhydrous compound is present in the drug substance. In a sixth embodiment, substantially all of the drug substance (API) is the crystalline anhydrous compound, i.e., the API is substantially phase pure crystalline anhydrous compound. The pharmaceutical compositions described above may be used in the treatment or control of clinical conditions for which a PPAR gamma agonist is indicated, by the method of administering to a patient in need of such treatment or control a therapeutically effective amount of (5R)- 5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl-l,3-oxazolidine-2,4-dione comprising the crystalline anhydrous compound made in Example 1. Such clinical conditions include Type 2 diabetes, hyperglycemia, obesity, dyslipidemia, and metabolic syndrome. A "patient" is a mammal, including humans. The patient is most often a human patient.

EXAMPLE 2 Exemplary 480 mg fill formulations that provide 25 mg and 150 mg doses in a standard gelatin capsule (576 mg) are shown below. Amounts of the components are in mg. These are made by combining and mixing the dry components and then transferring 480 mg to each capsule.

Components 25 me Dose 150 mg Dose

Compound of Ex. 1 25.0 mg 150.0 mg

Lactose monohydrate (Diluent) 417.6 282iO

Croscarmellose sodium (Disintegrant) 2 244..00 24.0

Colloidal Silicon Dioxide (Glidant) 1.4 9.6

Talc (Glidant) 9.6 9.6

Sodium Lauryl Sulfate (Surfactant) 2.4 4.8

CHARACTERIZATION OF THE PRODUCT PREPARED IN EXAMPLE 1

X-rav Powder Diffraction (XRPD)

FIGURE 1 provides a characteristic X-ray powder diffraction pattern of the crystalline anhydrous compound (5R)-5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl-l,3- oxazolidine-2,4-dione made by the process described in Example 1. The X-ray powder diffraction spectrum was generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console. A PW3373/00 ceramic Cu LFF X-ray tube K-Alpha radiation was used as the source. The X- ray powder diffraction spectrum was recorded at ambient temperature (CuKa radiation, 2° to 40° (2Θ), steps of 0.0167°, 5.08 sec per step). Cu K-α of wavelength 1.54187A was used for the d-spacing calculation. The crystalline anhydrous compound is characterized by XRPD peaks at 17.6°, 7.0°, and 3.5°. It is further characterized by XRPD peaks at 10.6°, 12.7°, and 14.0°.

Peaks d-spacinq

17.6 5.039 7.0 12.628

3.5 25.245

10.6 8.346

12.7 6.970

14.0 6.326

14.9 5.946

16.1 5.505

19.0 4.671

Thermogravimetry Curve

FIGURE 2 provides a characteristic thermogravimetric (TG) analysis curve of the crystalline anhydrous compound (5R)-5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl- l,3-oxazolidine-2,4-dione made by the process described in Example 1. The thermogravimetric (TG) analysis curve was obtained under a nitrogen flow at a heating rate of 10°C/min on a Perkin Elmer TGA- 7 instrument and confirms that the crystalline compound is anhydrous.

Differential Scanning Calorimetry Curve

The DSC curve of the crystalline anhydrous compound form of (5R)-5-{3-[4-(4- chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl-l,3-oxazolidine-2,4-dione made by the process described in Example 1 was obtained on a TA Instruments DSC-2910 differential scanning calorimeter at a heating rate of 10°C/min under N₂ flow. The sample was heated in a closed pan. The DSC curve is shown in FIGURE 3. The crystalline anhydrous compound exhibits an endotherm at 107.7 ⁰C, with an onset at 106.3 ⁰C.

Solid-state Carbon-13 CPMAS NMR Spectrum

In addition to the X-ray powder diffraction patterns described above, the crystalline anhydrous compound form of (5R)-5-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]benzyl}-5-methyl-l,3- oxazolidine-2,4-dione made by the process described in Example 1 was further characterized by its solid- state carbon-13 nuclear magnetic resonance (NMR) spectra. The solid-state carbon-13 NMR spectra were obtained on a Bruker DSX 500WB NMR system using a Bruker 4 mm H/X/Y CPMAS probe. The carbon-13 NMR spectra utilized proton/carbon- 13 cross-polarization magic-angle spinning with variable- amplitude cross polarization, total sideband suppression, and SPINAL decoupling at 10OkHz. The samples were spun at 10.0 kHz, and a total of 1024 scans were collected with a recycle delay of 3 seconds. A line broadening of 10 Hz was applied to the spectra before FT was performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03 p.p.m.) as a secondary reference.

FIGURE 4 shows the solid-state carbon- 13 CPMAS NMR spectrum of the crystalline anhydrous compound of compound Ia. The crystalline anhydrous compound exhibits characteristic signals with chemical shift values of 120.0, 87.5, and 20.7 p.p.m. Further characteristic of the crystalline anhydrous compound are the signals with chemical shift values of 14.6, 158.1, and 42.9 p.p.m. The crystalline anhydrous compound is even further characterized by signals with chemical shift values of 25.9, 152.8, and 124.9 p.p.m.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound of structural formula I:

wherein Ri and R₂ are each independently selected from the group consisting of H and C₁-C₃ alkyl, wherein Ci-C₃ alkyl is optionally substituted with 1-3 fluorine atoms; and X is selected from the group consisting of F, Cl, Br, and I; comprising reacting a compound of formula II:

π

with a compound of formula HI:

m

wherein Y and Z are each selected from (a) the group consisting of -OH, -OC(=O)Ci-C₃ alkyl, and -OC(=O)OC_rC₃ alkyl wherein the Ci-C₃ alkyl groups are optionally substituted with 1-3 fluorines, and (b) the group consisting of F, Cl, Br, and I; provided that when Y is selected from (a) then Z is selected from (b), and when Y is selected from (b) then Z is selected from (a); wherein the compounds of formula II and HI are reacted in the presence of a base, an organic solvent, and a catalyst so that a chemical reaction or series of chemical reactions occurs to yield a compound of formula I.

2. The process of Claim 1 wherein the catalyst comprises copper or palladium.

3. The process of Claim 1, comprising reacting a compound of formula π, wherein

Y is selected from the group consisting of F, Cl, Br, and I; with a compound of formula IH, wherein Z is selected from the group consisting of -OH, -OCC=O)C₁-C₃ alkyl, and -OCC=O)OC₁-C₃ alkyl, wherein the C₁-C₃ alkyl groups are optionally substituted with 1-3 fluorine atoms; wherein compounds II and IE are combined in the presence of a base, an organic solvent, and a copper or palladium catalyst under conditions such that a chemical reaction occurs to yield a compound of formula I.

4. The process of Claim 1, comprising reacting a compound of formula π, wherein

Y is selected from the group consisting of -OH, -OCC=O)C₁-C₃ alkyl, and -OCC=O)OC₁-C₃ alkyl, wherein the Ci-C₃ alkyl groups are optionally substituted with 1-3 fluorine atoms; with a compound of formula IH, wherein Z is selected from the group consisting of F, Cl, Br, and I; wherein compounds II and III are combined in the presence of a base, an organic solvent, and a copper or palladium catalyst under conditions such that a chemical reaction occurs to yield a compound of formula I.

5. The process of claim 1 , wherein the catalyst is a Cu(I) or Pd(O) catalyst.

6. The process of claim 1, wherein the catalyst comprises a Cu(I) halogen salt.

7. The process of claim 1, wherein the catalyst comprises CuI.

8. The process of claim 1, wherein the organic solvent is selected from the group consisting of acetonitrile, DMF, DMSO, and NMP, or a mixture thereof.

9. The process of claim 1, wherein the organic solvent is acetonitrile.

10. The process of claim 1, wherein the reaction further comprises 2,2,6,6- tetramethylheptane-3,5-dione.

11. The process of claim 1, wherein the base is selected from carbonate salts, hydroxide salts, and other inorganic and organic bases.

12. The process of claim 1, wherein the base comprises potassium carbonate, cesium carbonate, or a mixture thereof.

13. The process of claim 1 wherein the catalyst comprises CuI, the organic solvent is acetonitrile, the base is a mixture of cesium carbonate and potassium carbonate, and the reaction further comprises 2,2,6,6-tetramethylheptane-3,5-dione.

14. The process of Claim 1 wherein the compound of structural formula I has formula Ia:

Ia

wherein in the compounds of formula II and HI, Rl is n-propyl; R.2 is methyl; X is Cl; Y is -OH; and Z is Br or I.

15. The process of Claim 14, comprising reacting a compound of formula II and a compound of formula HI, wherein Z is Br, in a mixture comprising acetonitrile, CuI, potassium carbonate, and cesium carbonate.

16. The process of Claim 15, said mixture further comprising 2,2,6,6- tetramethylheptane-3,5-dione.

17. The compound of structural formula HI:

m wherein Z is selected from the group consisting of halogen -OH, -OC(=O)C_rC₃ alkyl, and -OC(=O)OC_r C₃ alkyl, wherein the Ci-C₃ alkyl group is optionally substituted with 1-3 fluorine atoms; and

R₂ is selected from the group consisting of H and C]-C₃ alkyl, wherein C₁-C₃ alkyl is optionally substituted with 1-3 fluorine atoms.

18. The compound of Claim 17, wherein Z is I, Cl, Br, or F; and R₂ is methyl.

19. The compound of claim 17, wherein Z is Br; and R₂ is methyl.

20. The compound of claim 17, wherein Z is -OH; and R₂ is methyl.

21. A compound having Formula Ia:

Ia characterized as being an anhydrous crystalline compound.

22. The compound of Claim 21, characterized as being an anhydrous crystalline compound having one or more spectral characteristics selected from an X-ray powder diffraction pattern, a thermogravimetric (TG) analysis curve, a differential scanning calorimetry (DSC) curve, and a solid- state carbon- 13 CPMAS nuclear magnetic resonance spectrum.

23. The anhydrous crystalline compound of Claim 22, characterized by XRPD peaks (2Θ) at 17.6°, 7.0°, and 3.5°.

24. The anhydrous crystalline compound of Claim 22, characterized by XRPD peaks

(2Θ) at 10.6°, 12.7°, and 14.0°.

25. The anhydrous crystalline compound of Claim 22, characterized by XRPD peaks (2Θ) at 17.6°, 7.0°, 3.5°, 10.6°, 12.7°, and 14.0°.

26. The anhydrous crystalline compound of Claim 22, characterized by peaks in the solid-state carbon-13 CPMAS NMR spectrum having chemical shift values at 120.0, 87.5, and 20.7 p.p.m.

27. The anhydrous crystalline compound of Claim 22, characterized by peaks in the solid-state carbon-13 CPMAS NMR spectrum having chemical shift values at 14.6, 158.1, and 42.9 p.p.m.

28. The anhydrous crystalline compound of Claim 22, characterized by peaks in the solid-state carbon-13 CPMAS NMR spectrum having chemical shift values at 25.9, 152.8, and 124.9 p.p.m.

29. The anhydrous crystalline compound of Claim 22, characterized by peaks in the solid-state carbon-13 CPMAS NMR spectrum having chemical shift values at 120.0, 87.5, 20.7, 14.6, 158.1, 42.9, 25.9, 152.8, and 124.9 p.p.m.

30. The anhydrous crystalline compound of Claim 22, characterized by an endotherm in the DSC at 107.7 ⁰C with an onset at 106.3 ⁰C.

31. A pharmaceutical composition comprising the anhydrous crystalline compound of Claim 22.