WO2008126075A1

WO2008126075A1 - Process for preparing montelukast and salts thereof using optically impure 2-(2-(3(s)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol

Info

Publication number: WO2008126075A1
Application number: PCT/IL2008/000484
Authority: WO
Inventors: Michal Noiman; Ada Salman; Inna Levin; Oded Arad; Joseph Kaspi; Alex Weisman; Yael Gafni
Original assignee: Chemagis Ltd.
Priority date: 2007-04-12
Filing date: 2008-04-09
Publication date: 2008-10-23

Abstract

A process for preparing montelukast and salts thereof using an optically impure 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3-(hydroxylpropyl)phenyl)-2 propanol as starting material, which contains the (R)-enantiomer impurity in the range of greater than 0.5% to about 8.0% by weight, is disclosed. The process described herein using an optically impure material results in the final product, montelukast sodium, in optical purity of greater than 99.7% enantiomeric excess.

Description

PROCESS FOR PREPARING MONTELUKAST AND SALTS THEREOF USING

OPTICALLY IMPURE 2-(2-(3(S)-(3-(7-CHLORO-2-

OUINOLINYL)ETHENYL)PHENYL)-B-HYDROXYPROPYL)PHENYL-I-

PROPANOL

TECHNICAL FIELD

[0001] The present invention relates to the field of organic chemistry and, more particularly, to a process for preparing montelukast and salts thereof using optically impure 2-(2-(3 (S)-(3 -(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3 -(hydroxypropyl)phenyl)-2 propanol (II) as starting material.

BACKGROUND

[0002] Montelukast sodium, (R)-(E)- 1-(((1 -(3 -(2-(7-chloro-2-quinolinyl)- ethenyl)phenyl)-3 -(2-(I -hydroxy- 1 -methylethyl)phenyl)propyl)thio)methyl)- cyclopropaneacetic acid sodium salt is a leukotriene antagonist, and is thus useful as an anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis and is marketed in the United States and other countries by Merck & Co. Inc. under the trade name Singulair®.

[0003] Montelukast sodium is represented by the structural formula (I) below:

[0004] Montelukast sodium possesses one chiral carbon center, and a racemic form of montelukast sodium contains equal amounts of the two enantiomeric forms, i.e., the S and R optical isomers. The biologically active form of montelukast sodium is the R stereoisomer. Since the biological activity of the two enantiomers can be different, it is imperative that the amount of the S stereoisomer in the commercial product be controlled to within acceptable limits, as required by the various national drug regulatory agencies (e.g., the FDA). The ICH (The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) is a body common to the health authorities of the US, the European Union and Japan. Its aim is to harmonize the regulation pertaining to human drugs in these countries. These regulations are also accepted by many other countries as "common practice".

[0005] The relevant ICH guideline is "Impurities in New Drug Substances Q3 A (R2)," second revision, issued in October 2006. For any drug substance, this guideline states that any impurity present at a level of 0.05% or above must be reported. The structure of any impurity present at a level of 0.10% or more must be determined. For impurities present at a level of 0.15% or more, a toxicological qualification to assess its risk to humans is required. Accordingly, the amount of the S optical isomer of montelukast should be lower than 0.15%.

[0006] Montelukast sodium was first disclosed in European Patent No. EP 480 717 (EP '717). The synthesis of montelukast sodium is depicted in Scheme 1 below and involves reacting compound (II) with methanesulfonyl chloride (MsCl) to obtain the mesylate alcohol, compound (III). Compound (III) then is coupled with methyl l-(mercapto- methyl)cyclopropane acetate, compound (IV), to afford the montelukast methyl ester, compound (V). Subsequently, compound (V) is hydrolyzed to form montelukast free acid, compound (VI). Treatment of compound (VI) with aqueous sodium hydroxide affords montelukast sodium salt, compound (I), which is isolated by freeze drying.

Scheme 1

IV

[0007] U.S. Patent No. 5,614,632 (U.S. '632) discloses a method of preparing crystalline montelukast sodium salt. The dilithium dianion of l-(mercaptomethyl)cyclopropaneacetic acid, compound (VII), is prepared using n-butyl lithium, which reacts with compound (III) to afford a solution of montelukast acid in ethyl acetate. Reaction of the montelukast acid with dicyclohexylamine affords solid montelukast dicyclohexylamine salt, compound (IX), which subsequently is converted into crystalline montelukast sodium.

[0008] In both EP '717 and U.S. '632, the reduction of the 3-oxo to the 3-hydroxy functionality is performed using a chiral reducing agent, diisopinocamphylchloroborane, to afford compound (II) having an enantiomeric excess (ee) >99%. This reduction is disclosed in U.S. Patent No. 5,545,758 (U.S. '758) in example 2 and shown in Scheme 2, below.

Scheme 2

diisopinocamphyl

chloroborane

HA [0009] The above synthetic procedures for preparing (R)-montelukast sodium, containing acceptable levels of impurities allowed by national or regional regulatory authorities, involves the use of optically pure compound (II). Accordingly, the optical purity (as measured by %ee) of compound (II) needed for preparing an optically pure (R)-montelukast acid or salt thereof, as previously synthesized, typically has been >99.0%. Anything less was considered an optically impure compound (II) which was thought not to produce (R)- montelukast in an acceptable optical purity.

[0010] It has been stated, for example in Organic Chemistry by Robert T. Morrison and Robert N. Boyd, 3rd Edition, edited by Allyn and Bacon (1975) at page 126, that "enantiomers have identical physical properties, except for the direction of rotation of the plane of polarized light," and "enantiomers have identical chemical properties except toward optically active reagents". As a result, the two enantiomers are not supposed to be separated on the basis of their solubility in organic solvents because their solubilities are identical. There are several options for purifying optically impure compound (II) which include separation of enantiomers via differential absorption, chiral recognition, biochemical processes, kinetic resolution, and/or deracemization, selective formation of a desired enantiomer over the undesired one, and the like. These procedures require extensive efforts and are time consuming.

[0011] Thus, a need exists for an improved process which selectively forms the desired (R)-enantiomer of montelukast sodium, containing less than 0.15% by weight of the undesired (S)-enantiomer using optically impure compound (II) as starting material without having to resort to difficult separation techniques.

SUMMARY

[0012] Disclosed herein is a process for preparing montelukast sodium using an optically impure intermediate, compound (II), which affords montelukast sodium (I) having an acceptable optically purity, i.e., containing less than 0.15% by weight of the (S)-enantiomer.

[0013] According to one embodiment of the present invention, there is provided a process for producing pure (R)-montelukast and salts thereof having an enantiomeric excess (ee) above 99.7%, prepared from optically impure compound (II) containing the (R)- enantiomer in the range of greater than 0.5% up to about 8% by weight. [0014] The process comprises the steps of:

(a) reacting optically impure compound (II) with methanesulfonyl chloride to form 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)- ethenyl)- phenyl)-3-

(methanesulfonyloxypropyl)phenyl)-2 propanol, compound (III), wherein compound (II) has an enantiomeric excess of about 84 to 99%;

(b) reacting compound (III) with l-(mercaptomethyl)cyclopropaneacetic acid, compound (VII), or a salt thereof to form montelukast acid, compound (VI), or a salt thereof;

(c) converting compound (VI), or a salt thereof, using an organic amine of formula NR₁R₂R₃ to form the montelukast ammonium salt, compound (IX);

(d) isolating compound (IX); and

(e) optionally converting compound (IX) to montelukast sodium (I), wherein R₁, R₂, and R₃ are independently selected from the group consisting of hydrogen, C_1-15 alkyl, and aryl, with the proviso that no more than two OfR₁, R₂, and R₃ can be hydrogen, and the resulting compound (I) or compound (IX) has an enantiomeric excess of at least 99.7%.

[0015] In some embodiments, step (a), comprises: i) reacting optically impure compound (II), a base, and methanesulfonyl chloride in an organic solvent to form a suspension comprising compound (III); and ii) separating the suspension to obtain a filtrate comprising compound (III).

[0016] In some embodiments, step (b) comprises: i) reacting compound (VII) with a base in an organic solvent, which optionally comprises a co-solvent, to form a dianion of compound (VII); ii) reacting the dianion of compound (VII) with compound (III) to form a salt of compound (VI); iii) adding an organic solvent, water, and an acid; and iv) separating the organic layer comprising compound (VI).

[0017] In some embodiments, step (c) comprises adding an organic amine to a solution of compound (VI) in an organic solvent to form compound (IX).

[0018] In some embodiments, step (d) comprises isolating compound (IX). In a preferred embodiment, compound (IX) is isolated by filtration.

[0019] In some embodiments, step (d) comprises purifying compound (IX) by crystallizing from an organic solvent. [0020] In some embodiments, step (e) comprises: i) admixing compound (IX), an acid, an organic solvent, and water to form an aqueous layer and an organic layer, comprising compound (VI); ii) separating the organic layer from the aqueous layer; iii) washing the organic layer with water; iv) evaporating a portion of the organic solvent to form a concentrated mixture; v) adding a base and water to the concentrated mixture to form an aqueous layer, comprising compound (I), and an organic layer; vi) separating the aqueous layer, comprising compound (I); and vii) isolating compound (I).

DETAILED DESCRIPTION

[0021] Surprisingly, it now has been discovered that an optically impure compound (II) can be used to prepare an optically pure (R)-montelukast acid or salt thereof, wherein the resulting (R)-montelukast acid or salt thereof contains less than 0.15% by weight of (S)- enantiomer of montelukast acid or a salt thereof.

[0022] The present invention provides a process for preparing montelukast acid or a salt thereof from optically impure compound (II), as shown in Scheme 3.

Scheme 3

VII R₁R₂R₃N

montelukast acid (Vl) montelukast ammonium salt (IX)

montelukast ammonium salt (IX) montelukast sodium (I)

[0023] The term "enantiomeric excess", as used herein, is the percent excess of one enantiomer compared to the other enantiomer, and can be calculated using the following equation: percent enantiomeric excess = ((R-S) / (R+S)) x 100 = %(R*) - %(S*) wherein R and S are the number of moles of each enantiomer in the mixture, and R* and S* are the respective mole fractions of the enantiomers in the mixture.

[0024] The term "optically impure", as used herein, refers to a compound having from 84% to 99% enantiomeric excess.

[0025] The term "optically pure", as used herein, refers to a compound having an enantiomeric excess equal or greater than 99%.

[0026] The term "alkyl," as used herein, means straight chained and branched hydrocarbon groups containing from 1 to 20 carbon atoms, typically methyl, ethyl, propyl and straight chained and branched butyl groups. The term "alkyl" also includes "bridged alkyl," i.e., a C₆-C₁₆ bicyclic or polycyclic hydrocarbon group, for example, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or decahydronaphthyl. Alkyl groups optionally can be substituted, for example, with hydroxy (OH), halo, aryl, heteroaryl, amino, and sulfonyl.

[0027] The term "aryl," as used herein, means a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, C_1-6 alkyl, OCF₃, NO₂, CN, NC, CO₂H, and OC_1-6 alkyl. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like.

[0028] The process for preparing montelukast or a salt thereof preferably includes the steps of:

(a) reacting optically impure compound (II) and methanesulfonyl chloride to form compound (III);

(b) reacting compound (III) with a dianion of compound (VII) to form a salt of compound (VI);

(c) converting the salt of compound (VI) using an organic amine of formula NR₁R₂R₃ wherein, R₁, R₂ and R₃ are independently selected from the group consisting of hydrogen, alkyl, and aryl, with the proviso that that not more than two OfR₁, R₂, and R₃ can be hydrogen, to form a montelukast ammonium salt, compound (XI);

(d) isolating compound (IX); and

(e) optionally converting compound (IX) to montelukast sodium (I).

[0029] Step (a) comprises the steps of: i) reacting optically impure compound (II), a base, and methanesulfonyl chloride in an organic solvent to form a suspension comprising compound (III); and ii) separating the suspension to obtain a filtrate comprising compound (III).

[0030] The organic solvent of step (i) is selected from the group consisting of toluene, xylenes, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, and mixtures thereof. Preferably, the organic solvent is THF.

[0031] The base of step (i) typically is an organic amine. Non-limiting examples of suitable organic amines for use as a base in step (a) include triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylaniline, and mixtures thereof. In a preferred embodiment, the base is DIPEA. [0032] Step (b) comprises the steps of: i) reacting compound (VII) with a base in an organic solvent, which optionally comprises a co-solvent, to form a dianion of compound (VII); ii) reacting the dianion of compound (VII) with compound (III) to form a salt of compound (VI); iii) adding an organic solvent, water, and an acid; and iv) separating the organic layer comprising compound (VI).

[0033] In various embodiments, the organic solvent of step (i) is selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), 2-methyl- tetrahydrofuran, acetonitrile, acetone or a mixture thereof. In a preferred embodiment, the organic solvent is NMP.

[0034] The co-solvent of step (i) is water. The co-solvent can be present in a volume/volume ratio of about 1 to about 10% v/v of the solvent. In a preferred embodiment, the amount of co-solvent is from about 4% v/v to about 6% v/v, based on the total volume of the mixture.

[0035] In several embodiments, the base of step (i) is selected from the group consisting of lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. In a preferred embodiment, the base is sodium hydroxide. The amount of base used in step (i) is at least about 1.1 moles per mole of compound (VII). The amount of base can be about 1.3 to about 2.5 moles base per mole compound (VII), about 1.7 to about 2.2 moles base per mole compound (VII), or about 1.9 to about 2.1 moles base per mole compound (VII).

[0036] In some embodiments, the organic solvent of step (iii) comprises methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene or a mixture thereof. In a preferred embodiment, the organic solvent is toluene.

[0037] The acid used in step (iii) can be an inorganic acid or an organic acid. In preferred embodiments, the acid is an organic acid, such as acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid or a mixture thereof. Preferably, the organic acid comprises tartaric acid. [0038] Step (c) comprises adding an organic amine to a solution of compound (VI) in an organic solvent to form compound (IX).

[0039] The organic amine can be any amine of formula NR₁R₂R₃, wherein R₁, R₂, and R₃ are as defined above, and include primary, secondary and tertiary amines, e.g., amines where no more than two OfR₁, R₂, and R₃ are hydrogen. The organic amine is selected from the group consisting of cyclohexyl amine, cyclopentylamine, cycloheptylamine, cyclooctylamine, cyclododecylamine, and phenethylamine. In a preferred embodiment, the organic amine is cyclooctylamine.

[0040] The organic solvent can be any organic solvent compatible with the reaction, and is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene, and mixtures thereof. In a preferred embodiment, the organic solvent is toluene.

[0041] Step (d) comprises isolating compound (IX). In a preferred embodiment, compound (IX) is isolated by filtration.

[0042] In an embodiment of the present invention, compound (IX) is optionally purified by crystallizing compound (IX) from an organic solvent. The organic solvent typically is methanol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, toluene, xylenes, and mixtures thereof. In a preferred embodiment, the organic solvent for crystallization comprises toluene. In some embodiments, the organic solvent further comprises up to about 5% methanol. In a preferred embodiment, the organic solvent comprises 0.5% methanol.

[0043] Step (e) optionally comprises the steps of: i) admixing compound (IX), an acid, and an organic solvent to form compound (VI) in a biphasic system of a first organic layer and a first aqueous layer; ii) separating the first organic layer, comprising compound (VI), from the first aqueous layer; iii) washing the first organic layer with water; iv) evaporating a portion of the organic solvent to form a concentrated mixture; v) adding a base and water to the concentrated mixture of step (iv) to form a second aqueous layer, comprising compound (I), and a second organic layer; vi) separating the second aqueous layer from the second organic layer; and vii) isolating compound (I) from the second aqueous layer.

[0044] The organic solvent of step (i) can be any organic solvent compatible with the conditions of step (i) of step (e). In preferred embodiments, the organic solvent is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene, and mixtures thereof. In a preferred embodiment, the organic solvent is ethyl acetate.

[0045] The acid used of step (i) typically is an organic acid. Suitable organic acids include acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid, and mixtures thereof. Preferably, the organic acid is tartaric acid.

[0046] The base of step (v) comprises sodium hydroxide.

[0047] Isolating compound (I) in the aqueous layer of step (vii) can be via precipitation, crystallization, spray-drying, filtration, evaporation, chromatography, and the like. In a preferred embodiment, compound (I) is isolated from the aqueous layer by spray-drying.

[0048] The enantiomeric excess of compound (I) obtained via the present process herein typically is greater than 99.7%, greater than 99.8% or greater than 99.9%.

[0049] The present process results in pure compound (I) comprising total impurities (e.g., any compound that is different from the chemical entity defined as the new drug substance and represented by structural formula (I)) in amounts less than about 0.5% by weight. In preferred embodiments, the amount of impurities is less than about 0.2% by weight.

[0050] Reference is now made to the following examples, which together with the above description illustrate the invention in a non-limiting fashion. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples. EXAMPLES

Preparation of Montelukast Sodium (I)

[0051] Step 1 : Preparation of compound (III): A three-necked flask equipped with a thermometer, a nitrogen inlet, and a magnetic stirrer was charged at room temperature with (S)-compound (II) having 8.0% by weight of R-compound (II) as an impurity (9.34 g, 0.0205 moles) and anhydrous THF (50 mL). The mixture was stirred and cooled to about - 20°C. DIPEA (5.04 mL, 0.0291 moles) was added in portions, followed by the addition of methanesulfonyl chloride (1.93 mL, 0.0249 moles), also in portions. The resulting mixture was stirred at a temperature of about -20°C for about 16 hours. A sample was withdrawn and checked by HPLC to monitor for reaction completion. The sample contained about 6% of the starting material (compound (H)). The cold suspension containing the product, compound (III), was filtered at -20°C, and the resulting cake was washed with cold anhydrous THF. The filtrate containing compound (III) was used as is in the next step.

[0052] Step 2: Preparation of compound (IX): A three-necked flask equipped with a thermometer, a nitrogen inlet, and a magnetic stirrer was charged at room temperature with compound (VII) (6.41 g, 0.0408 moles) and NMP (50 mL). The mixture was stirred under a nitrogen atmosphere to obtain a solution. 50% NaOH (w/w) solution (4.73 ml, 0.0902 moles) were added in portions at room temperature. The reaction mixture was stirred for 1 hour at room temperature to afford a suspension. A solution of compound (III), prepared in Step 1, in THF (about 50 mL), was maintained at about -20°C and added in portions to the dianion mixture of compound (VII) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. Reaction completion was checked by HPLC. Toluene (133 mL) and brine (133 mL) were added to the reaction mixture in portions at room temperature, and the resulting solution was stirred for 1 hour. Then, the layers were separated, and the organic layer was washed with brine (133 mL). The layers were separated again. A tartaric acid solution (87 mL of 0.5 M solution) was added to the organic layer, and the layers were separated. The organic layer was washed with water (43 mL) and again the layers were separated. To the organic layer was added cyclooctylamine (3.19 ml, 0.0233 moles) in portions at room temperature. The mixture was heated to reflux and maintained at reflux in order to remove the water by azeotropic distillation. Toluene (40 ml) was distilled out at atmospheric pressure. The mixture was cooled to room temperature and the resulting solution was seeded with crystalline montelukast cyclooctylammonium salt. Stirring was maintained at room temperature to afford a suspension, which was filtered off to obtain a cake. The cake was washed with toluene and dried at 40°C in vacuum to afford 7.6 g of dry crude (R)-montelukast cyclooctylammonium salt in 52% yield containing 2.0% by weight of the (S) isomer. The HPLC purity of (R)-montelukast cyclooctylammonium salt was 99.3%. The crude montelukast cyclooctylammonium salt was crystallized twice from toluene containing about 0.5% by volume methanol to afford 5.9 g of dry crystalline (R)-montelukast cyclooctylammonium salt in 78% yield with 99.7% HPLC purity and less than 0.1% by weight of the (S) isomer.

[0053] Step 3: Preparation of montelukast sodium (I): A three-necked flask equipped with a thermometer, a nitrogen inlet, and a magnetic stirrer was charged with crystalline montelukast cyclooctylammonium salt (5.9 g) and ethyl acetate (90 mL). The mixture was stirred, then tartaric acid solution (15 mL of a 0.5M solution) was added. After stirring at room temperature for 30 minutes, a two-phase system was formed. The layers were separated, and the organic layer (containing compound (I)) was washed three times with water (65 mL), then concentrated by evaporation to about half of its volume. A solution of NaOH (0.136 g solid NaOH in 25 mL water) was added in portions to the organic phase, and the resulting layers were separated. The aqueous layer (containing compound (I)) was spray-dried to obtain about 5.0 g of compound (I) having an HPLC purity of 99.7% and less than 0.1% by weight of the impure (S) isomer.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing montelukast or a salt thereof, comprising:

(a) reacting optically impure compound (II) with methanesulfonyl chloride to form compound (III);

(b) reacting compound (III) with compound (VII) or a salt thereof to form compound (VI) or a salt thereof;

(c) converting compound (VI) or a salt thereof using an organic amine of formula NR₁R₂R₃ to form a montelukast ammonium salt, compound (IX);

(d) isolating compound (IX); and

(e) optionally converting compound (IX) to montelukast sodium (I), wherein R₁, R₂, and R₃ are each independently selected from the group consisting of hydrogen, C_1-15 alkyl, and aryl, with the proviso that no more than two OfR₁, R₂, and R₃ can be hydrogen, and wherein the optically impure compound (II) has an enantiomeric excess of about 84% to 99% and the montelukast sodium (I) or compound (IX) has an enantiomeric excess of at least 99.7%.

2. The process of claim 1, wherein the enantiomeric excess of compound (II) is from about 97% to 99%.

3. The process of claim 1, wherein step (a) is performed in the presence of a base and an organic solvent.

4. The process of claim 3, wherein the organic solvent comprises toluene, xylenes, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or a mixture thereof.

5. The process of claim 4, wherein the organic solvent comprises tetrahydrofuran.

6. The process of claim 3, wherein the base comprises triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, N,N- diisopropylethylamine , N,N-dimethylaniline or a mixture thereof.

7. The process of claim 6, wherein the base comprises N,N- diisopropylethylamine.

8. The process of claim 1, wherein compound (VII) comprises a dianion and wherein the dianion of compound (VII) is formed by reacting compound (VII) with a base in an organic solvent.

9. The process of claim 8, wherein the base comprises lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or a mixture thereof.

10. The process of claim 9, wherein the base comprises sodium hydroxide.

11. The process of claim 8, wherein the organic solvent comprises N₅N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone or a mixture thereof.

12. The process of claim 11, wherein the organic solvent comprises N-methyl-2- pyrrolidone.

13. The process of claim 1 , wherein the organic amine of step (c) comprises cyclohexylamine, cyclopentylamine, cycloheptylamine, cyclooctylamine, cyclododecylamine, or phenethylamine.

14. The process claim 13, wherein the organic amine comprises cyclooctylamine.

15. The process of claim 1 , wherein compound (IX) is isolated by filtration.

16. The process of claim 1, wherein compound (IX) is purified by crystallization from an organic solvent.

17. The process of claim 16, wherein the organic solvent comprises methanol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, toluene, xylenes or a mixture thereof.

18. The process of claim 17, wherein the organic solvent comprises toluene.

19. The process of claim 18, wherein the organic solvent comprises toluene and up to about 5% (v/v) methanol.

20. The process of claim 18, wherein the organic solvent comprises toluene and about 0.5% (v/v) methanol.

21. The process of claim 3, wherein step (e) optionally comprises: (i) admixing compound (IX), an acid, and an organic solvent to form compound (VI) in a biphasic system of a first organic layer and a first aqueous layer;

(ii) separating the first organic layer, comprising compound (VI), from the first aqueous layer;

(iii) washing the first organic layer with water;

(iv) evaporating a portion of the organic solvent to form a concentrated mixture;

(v) adding a base and water to the concentrated mixture of step (iv) to form a second aqueous layer, comprising compound (I), and a second organic layer; and

(vi) separating the second aqueous layer from the second organic layer; and (vii) isolating compound (I) from the second aqueous layer.

22. The process of claim 21 , wherein the acid of step (i) comprises acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid or a mixture thereof.

23. The process of claim 22, wherein the acid of step (i) comprises tartaric acid.

24. The process of claim 21, wherein the organic solvent of step (i) is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene and mixtures thereof.

25. The process of claim 24, wherein the organic solvent of step (i) comprises ethyl acetate.

26. The process of claim 21 , wherein the base of step (v) comprises sodium hydroxide.