FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION

"AN IMPROVED FOSAPREPITANT PROCESS"
Emcure Pharmaceuticals Limited, an Indian Company, registered under the Indian Company's Act 1957 and
having its Registered Office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH
IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of fosaprepitant
dimeglumine free from heavy metals and other associated impurities. Specifically, the
invention relates to a process for preparing fosaprepitant dimeglumine free from impurities
without isolating dibenzyl fosaprepitant.'
BACKGROUND OF THE INVENTION
Fosaprepitant dimeglumine (la) is chemically known as l-deoxy-l-(methylamino)-D- glucitol-
[3-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluoro phenyl)-4-
morpholinyl]methyl]-2,5-dihydro-5-oxo-lH-l,2,4-triazol-l-yl]phosphonate 2:1) (salt) and is administered intravenously as antiemetic drug. Fosaprepitant is a prodrug of aprepitant and acts in prevention of acute and delayed nausea and vomiting associated with chemotherapy treatment.
Fosaprepitant (I) Fosaprepitant dimeglumine (la)
Various inventors have synthesized fosaprepitant dimeglumine (la). However, the reported processes are prone to formation of impurities at various stages, especially during conversion of dibenzyl fosaprepitant (III) into fosaprepitant and purification of crude fosaprepitant. These associated impurities include aprepitant (II) & heavy metal used during deprotection of dibenzyl group.

The reported methods involve isolation of intermediates such as dibenzyl fosaprepitant (III), monobenzyl fosaprepitant (IV) or isolation and further purification of crude fosaprepitant dimeglumine (la). These reported prior art methods, due to substantial formation of impurities, •invariably give lower yields of the final product.
US 5,691,336 illustrates a process for preparation of fosaprepitant through the preparation of dibenzyl fosaprepitant or monobenzyl fosaprepitant by reacting aprepitant with tetrabenzyl pyrophosphate in presence of a sodium hexamethyldisilazane (NaHMDS) base in tetrahydrofuran (THF) followed by workup in diethyl ether. The intermediates, dibenzyl fosaprepitant or monobenzyl fosaprepitant were debenzylated to fosaprepitant (I) in presence of palladium catalyst. The disclosed process resulted in formation of dibenzyl fosaprepitant impurity to an extent of 0.8-20% and required additional steps to eliminate these impurities form the final product.
US 2007/0265442 describes a process for preparation of fosaprepitant dimeglumine by using monobenzyl fosaprepitant as an' intermediate. The deprotection of the monobenzyl fosaprepitant intermediate results in formation of fosaprepitant with impurities like aprepitant which require additional step to eliminate and hence lower the yield. Similarly the process disclosed in WO 2010018595 results in final product, fosaprepitant dimeglumine (la) associated with impurities like aprepitant, monobenzyl fosaprepitant, desfloro fosaprepitant and diastereomer of fosaprepitant.
WO 2011/045817 discloses a process for the preparation of fosaprepitant dimeglumine wherein, dibenzyl fosaprepitant is subjected to hydrogenation in the presence of palladium-carbon and N-methyl-D-glucamine. The obtained product fosaprepitant dimeglumine is associated with individual impurities like dibenzyl fosaprepitant.
WO 2012164576 discloses a process for reducing palladium content from fosaprepitant dimeglumine (la) by utilizing SiliaBond metal scavenger. However, the use of SiliaBond metal scavenger for reducing palladium content itself gives rise to impurity like aprepitant.

US 7,807,829 discloses a process for the preparation of fosaprepitant dimeglumine (la) by catalytic reduction of the corresponding mono-O-benzophosphate compound. After the catalytic reduction, the solution of fosaprepitant dimeglumine is treated with tri-n-butyl phosphine in order to eliminate the palladium from the product to get pure fosaprepitant dimeglumine free from metal impurities. The use of tri-n-butyl phosphine is very hazardous and toxic to human; and requires very specific precautions on large scale use.
Organic Process Research & Development (2011), 15(6), 1371-1376 describes a method for removal of palladium by utilizing a binary system containing a chelating agent in combination with either activated carbon or silica gel absorbents; and the said binary system produces in-situ metal scavenger and acts on metals present in the compound. However, the catalyst used here is uneconomical and is not completely eliminated from the final product.
WO 2010/034032 discloses purification process for peptidomimetic macrocycles free from heavy metals. The patent application uses multiple metal scavengers like thiophenol; however for complete elimination of the metals from the product, require profuse treatment of the product with metal scavengers; which leads to loss of yield and increase in the cost of process. WO 2013168176 provides a process for the preparation of fosaprepitant (I) and its salt. The process includes reaction of aprepitant (II) with tetrabenzyl pyrophosphate in presence of a hydride base to give dibenzyl fosaprepitant (III) after extracting the product in hydrocarbon solvent. Subsequently, dibenzyl fosaprepitant is converted to fosaprepitant (I) in presence of palladium-carbon and N-methyl-D-glucamine. However, it was observed that the product obtained at each stage, i.e. during formation of dibenzyl derivative, fosaprepitant and fosaprepitant dimeglumine (la), was associated with aprepitant (II) as impurity which was formed due to decomposition of phosphate bond. This leads to additional purification steps causing substantial yield loss for the final product.
From the prior art reference it can be concluded that none of the methods reported in the prior art are capable of providing satisfactory results in terms of impurities such as palladium, aprepitant (II), monobenzyl fosaprepitant, desfloro fosaprepitant, undesired diastereomer of fosaprepitant etc. which are associated with fosaprepitant or its intermediates. To address this

issue, the prior art methods suggest isolation, purification of each intermediate before conversion into final product which results in significant reduction in yield.
Thus, there is a need for a synthetic process which affords fosaprepitant dimeglumine having desired purity without isolating either the dibenzyl fosaprepitant or crude fosaprepitant dimeglumine or without use of SiliaBond metal scavengers or silica-gel chromatography. The present inventors have accordingly developed a simple, cost-effective, environment friendly process which gives fosaprepitant dimeglumine which is free from associated impurities and heavy metals. The present invention, due to significant enhancement in yield as against prior art methods, is commercially viable for large scale production of fosaprepitant dimeglumine.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved process for preparation of fosaprepitant dimeglumine (la) free from associated impurities and heavy metals like palladium without utilizing silica-gel chromatography or SiliaBond metal scavengers.
Another object of the present invention is to provide an improved process for preparation of fosaprepitant dimeglumine (la) without isolating dibenzyl fosaprepitant intermediate. -
Yet another object of the present invention is to provide a process for preparation of fosaprepitant dimeglumine free from palladium and other associated impurities such as aprepitant.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide a convenient process for the preparation of fosaprepitant dimeglumine which confirms to regulatory specification.
Another aspect of the present invention is to provide a process for preparation of fosaprepitant dimeglumine comprising,
a) treating aprepitant with tetra benzyl pyrophosphate (TBPP) and sodium hexamethyldisilazide (NaHMDS) in tetrahydrofuran; after completion of reaction, adding

the mass to a mixture of sodium dihydrogen phosphate buffer solution & ether solvent followed by separation and concentration of organic layer, addition of ether and hydrocarbon solvent to the residue to obtain a reaction mass containing dibenzyl fosaprepitant (II),
b) treating the slurry from step a) with N-methyl D-glucamine (N1V1.DG) and Pd-C under hydrogen pressure in solvent methanol, filtering the re'action mixture after completion of reaction; .......
c) adding resin metal scavenger to the filtrate from step b), stirring, followed by filtration and concentration of resulting filtrate,
d) adding alcohol or ketone solvent to the resulting residue from step c), followed by filtration of solid to give fosaprepitant dimeglumine having desired purity.
An aspect of the present invention relates to an improved process for preparation of fosaprepitant dimeglumine (la) without isolating dibenzyl fosaprepitant (III) intermediate or crude fosaprepitant dimeglumine.
Yet another aspect of the present invention is to provide an efficient, cost effective,
environment-friendly and industrially viable process comprising use of resin based metal
scavenger for preparation of fosaprepitant dimeglumine (la), which is free from palladium
metal impurity. ............
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have developed an improved process which overcomes the serious drawbacks of prior art, for preparation of fosaprepitant dimeglumine (la) without isolating the intermediate, dibenzyl fosaprepitant (III) or crude fosaprepitant dimeglumine. The prior art methods, which use silica for column chromatography or during any other stage of the process, cause breakage of the phosphate bond and give fosaprepitant dimeglumine with aprepitant (II)
i
impurity and other associated impurities like dibenzyl fosaprepitant (III), monobenzyl fosaprepitant (IV). Therefore, it was indeed necessary to eliminate these impurities during preparation of fosaprepitant dimeglumine (la).

One embodiment of the present invention comprises a process for fosaprepitant dimeglumine
without isolating dibenzyl fosaprepitant intermediates.
The process comprises four steps, (a), (b), (c) and (d).
Step (a): treatment of aprepitant with terra benzyl pyrophosphate (T.BPP) and NaHMDS in
solvent THF, after completion of reaction, quenching the reaction mixture into a mixture of
ether solvent and aqueous sodium dihydrogen phosphate, separation and concentration of
organic layer; addition of hydrocarbon and ether or ester solvent to the residue, cooling to 0-
15°C with stirring to obtain a slurry containing dibenzyl fosaprepitant (11)
Step (b): addition of methanol to the above slurry, further treatment of the clear solution with
N-methyl D-glucamine (NMDG) and Pd/C under hydrogen pressure in an autoclave, and after
completion of reaction, filtration of the reaction mixture;
Step (c): addition of methanol and resin metal scavenger, stirring, filtration, concentration of
the filtrate;
Step (d): addition of alcohol or ketone solvent to the above concentrated mixture, filtration of
the precipitated solid, and drying at temperature below 35°C to give fosaprepitant dimeglumine.

The ether solvent used in the step (a) was selected from the group of diethyl ether, diisopropyl
ether (DIPE), methyl tertiary butyl ether (MTBE), ethyl tert-butyl ether, di-tert-butyl ether,
diglyme, dimethoxyethane, dimethoxymethane and methoxyether, tertrahydropyran (THF), 1,4-
dioxane, while the ester solvent was selected from the group of ethyl acetate, isopropyl acetate,
butyl acetate etc.
The hydrocarbon used in the step (a) was selected from the group of pentanes, hexanes,
heptanes and cyclohexane.
The temperature for step (a) was in the range of O'to 35°C, preferably 5 to 15°C.
After addition of ether (or ester) and hydrocarbon solvent, cooling and stirring for 30 minutes,
it was observed that some supernatant liquid accompanied the solid, which was removed by
decantation or siphoning, optionally repeating the process for better results.
Step (b) comprised mixing the slurry obtained from step (a) with methanol and treatment with
N-methyl D-glucamine (NMDG)in presence of Pd/C under hydrogen pressure.
In step (b), the palladium-carbon was used in the range of 5% or 10 %. and hydrogen pressure
was set in the range of 0.1 to 0.5 kg/cm2.
In place of methanol, other alcoholic solvent such as ethanol or isopropyl alcohol also could be
used for the above reaction.
After completion of step (b), the reaction mixture was filtered.
In step (c), additional methanol was added to the filtrate so obtained, followed by addition of
resin metal scavenger. The reaction mass thus obtained was stirred at 25 to 35°C and filtered
through hyflo-bed. The resulting filtrate was concentrated under reduced pressure.
The prior art methods disclose use of 'SiliaBond Metal Scavenger' for elimination of palladium
from fosaprepitant or fosaprepitant dimeglumine. However, the said methods result in
formation of aprepitant impurity, which is formed due to breaking of bond between
phosphorous and nitrogen atoms, and which is very difficult to eliminate, especially in the final
stages of fosaprepitant preparation. Therefore, it was very essential to develop an efficient
method to eliminate the formation of aprepitant impurity. Hence, the present inventors
developed a method to eliminate palladium form fosaprepitant by utilizing resin based metal
scavengers which did not cause the breaking of bond between phosphorous and nitrogen atoms
in fosaprepitant.

Resins are broadly classified into two groups viz. natural and synthetic resins on basis of their origin Natural resins are hydrocarbon secretions observed in many plants, and such resins are used for a wide range of applications which range from perfume to the treatment of the bows for instruments such as violins and. cellos.
Synthetic resins, on the other hand, are usually polymeric materials that are produced through chemical syntheses. These resins, due to their chemical properties and associated uses, have immense application and commercial value and find use in numerous applications in variety of fields including pharmaceutical field.
In an embodiment wherein the resin'based .metal scavenger is selected from the list available in the market; the synthetic resins are classified as macro porous (MP) or macro porous fine (MP Fine).
The resin based metal scavenger as used in step (c) was selected from the group of sulfonic acid resins, triethylamine resins, carbonate resins, borohydride resins, cyanoborohydride resins, thiophenol resins, thiourea resins, sulfonyl chloride resins, diethanolamine resins, diisopropylethylamine resins, trisamine resins, sulfonylhydrazide resins, tribromide resins, merrifield resins, piperazine resins, trimercaptotriazine (TMT) resins and aminopolyhydroxy resins.
The present invention preferably utilizes 'thiophenol resin MP' which has a highly cross-linked polystyrene resin functionalized with a thiophenol end group and is a versatile, robust metal-scavenger for elimination of residual metals like palladium, platinum, ruthenium, tin, copper and mercury form the product. The thiophenol resin metal scavenger captures metal either from the solution or it form complex between chelating agent (thiophenol group) and metal; subsequently by conventional filtration, which offers efficient elimination of metal from the products.
Step (d) comprised of addition of alcohol or ketone solvent to the residue obtained in step (c), stirring at ambient temperature, filtration of the precipitated solid and drying under reduced pressure below35°C,to give pure fosaprepitant dimeglumine.
Optionally, from the precipitated solid, the solvent mixture was decanted or the supernatent liquid was siphoned to eliminate the impurities.
Fosaprepitant dimeglumine thus obtained possessesd desired purity wherein the associated impurities were well within the regulatory limits.'

Thus, the present invention provides a simple, economical and efficient method for preparing fosaprepitant dimeglumine with desired purity.
The present invention is an improved process for the preparation of fosaprepitant dimeglumine which has the following advantages over prior art methods:
• Use of silica gel chromatography or 'SiliaBond' metal scavengers is eliminated, which
- :. f ■ ■
avoid the formation of impurities like aprepitant, as reported in the prior art references;
• Filtration and isolation of dibenzyl fosaprepitant as disclosed in the prior art (e.g. WO
2010018595 ) is avoided. These steps would have increased the cost and batch-time,
especially on industrial scale.
Thus, the present invention based on the above advantages satisfies the need for developing an improved process for fosaprepitant which has minimum number of steps and is cost effective, environmental friendly and is applicable on industrial scale.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however should not to be construed to be limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive.. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention. The present invention is described herein below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
EXAMPLES:
Example 1: Preparation of fosaprepitant dimeglumine
Aprepitant (20 gm; 0.0374 mol), tetrabenzyl pyrophosphate (26 gm; 0.052 mol) and tetrahydrofuran (200 ml) were cooled to 5-10°C under nitrogen atmosphere and added NaHMDS (100 ml; 0.09 mol) was added. The reaction mass was stirred for about 60 minutes. Added sodium dihydrogen phosphate (600 ml) solution and MTBE (600 ml) and was stirred for 30 minutes; separate organic layer and washed with aqueous sodium bicarbonate (10%). The organic layer was treated with activated carbon, and filtrate concentrated completely; add ethyl acetate (70 ml) and cyclohexane (70 ml) and stirrer for 30 minutes, solid precipitates. The

supernatent liquid decanted, and add methanol (240 ml), N-Methyl D-glucamine (12.8 gm) and Pd/C (0.65 gm 10%) into autoclave along with reaction mixture, stirrer autoclave under hydrogen pressure (0.1 kg to 0.2 kg). After the completion of reaction, the suspension was filtered. To the filtrate, MTBE (20 ml), Thiophenol resin (2 gm) added and stirred for 2 hours. The reaction mass was filtered and washed with methanol and solvent was concentrated under reduced pressure. Further, dissolve residue in methanol (200 ml) and isopropyl alcohol (1000 ml) and stirred for 1 hour. The obtained solid was filtered and washed with methyl tertiary butyl ether (MTBE) and dried under reduced pressure to get pure fosaprepitant dimeglumine (la). Yield 18 gm.
Example 2: Preparation of fosaprepitant dimeglumine
Aprepitant (5 gm; 0.09 mol), tetrabenzyl pyrophosphate (6.5 gm; 0.0135 mol) and tetrahydrofuran (50 ml) were cooled to 5-10°C under nitrogen atmosphere and added NaHMDS (25 ml; 0.0225 mol) was added. The reaction mass was stirred for about 60 minutes. Added sodium dihydrogen phosphate (150 ml) solution and MTBE (150 ml) and was stirred for 30 minutes; separate organic layer and washed with aqueous sodium bicarbonate (10%). The organic layer was treated with activated carbon, and filtrate concentrated completely; add ethyl acetate (20 ml) and cyclohexane (20 ml) and stirrer for 30 minutes, solid precipitates. The supernatent liquid decanted, and add methanol (60 ml), N-Methyl D-glucamine (3.2 gm) and Pd/C (0.16 gm; 10%) into autoclave along with reaction mixture, stirrer autoclave under hydrogen pressure (0.1 kg to 0.2 kg). After the completion of reaction, the suspension was filtered. To the filtrate MTBE (20 ml), thiophenol resin (0.5 gm) added and stirred for 2 hours. The reaction mass was filtered and washed with methanol and solvent was concentrated under reduced pressure. Further, dissolve residue in methanol (50 ml) and isopropyl alcohol (250 ml) and stirred for 1 hour. The obtained' solid was filtered and washed with methyl tertiary butyl ether (MTBE) and dried under reduced pressure to get pure fosaprepitant dimeglumine (la). Yield 4.5 gm.
Example 3: Preparation of fosaprepitant dimeglumine
Aprepitant (100 gm; 0.187 mol), tetrabenzyl pyrophosphate (13.1 gm; 0.24 mol) and tetrahydrofuran (200 ml) were cooled to 5-10°C under nitrogen atmosphere and added

NaHMDS (500 ml; 0.467 mol) was added. The reaction mass was stirred for about 60 minutes. Added sodium dihydrogen phosphate (3000 ml) solution and MTBE (3000 ml) and was stirred for 30 minutes; separate organic layer and washed with aqueous sodium bicarbonate (10%). The organic layer was treated with activated carbon, and filtrate concentrated completely; add ethyl acetate (350 ml) and cyclohexane (350 ml) and stirrer for 30 minutes, solid precipitates. The supernatent liquid decanted, and add methanol (1200 ml), N-Methyl D-glucamine (63.8 gm) and Pd/C (3.25 gm; 10%) into autoclave along with reaction mixture, stirrer autoclave under hydrogen pressure (0.1 kg to 0.2 kg). After the completion of reaction, the suspension was filtered. To the filtrate MTBE (20 ml), thiophenol resin (10 gm) added and stirred for 2 hours. The reaction mass was filtered and washed with methanol and solvent was concentrated under reduced pressure. Further, dissolve residue in methanol (1000 ml) and isopropyl alcohol (5000 ml) and stirred for 1 hour. The obtained solid was filtered and washed with methyl tertiary butyl ether (MTBE) and dried under reduced pressure to get pure fosaprepitant dimeglumine (la). Yield 90 gm.
Example 4: Preparation of fosaprepitant dimeglumine
Aprepitant (100.2 gm; 0.187 mol), tetrabenzyl pyrophosphate (141.4 gm; 0.262 mol) and tetrahydrofuran (1000 ml) were cooled to 0- -10°C under nitrogen atmosphere and NaHMDS (500 ml; 0.467 mol) was added to the mixture. The reaction mass was stirred for about 60 minutes and completion of the reaction was monitored by HPLC. After completion, the mass was added to a mixture of 7% aqueous sodium bicarbonate solution and MTBE (3000 ml each). After stirring for about 30 minutes, organic layer was separated and washed with aqueous sodium bicarbonate (10%). Water (2000ml) was then added to the organic layer, followed by addition of 5% aqueous sodium bisulphate solution till pH of the reaction mass was between 4 and 6. The organic layer was separated, treated with activated carbon, filtered and filtrate was concentrated. MTBE (700 ml) was added'to the residue and the mass was stirred at 20-30°C, when solid precipitated out. Cyclohexane (300 ml) was added to the mass, and stirring was continued for 60 minutes. The stirred mass was allowed to settle and supernatant liquid portion was decanted from it. A mixture of ethyl acetate (350 ml) and cyclohexane (350 ml) was added to the decanted solid, followed by stirring, settling and decantation of liquid portion. The solid was mixed with methanol (1200 ml), charged into autoclave and N-Methyl D-glucamine (63.8

gm) and Pd/C (3.25 gm; 10%) were added. The reaction was continued with stirring under hydrogen pressure (0.5 kg to ,1.0 kg) at 25-30°C. After completion of reaction, the mass was filtered. Activated carbon and SP-thiophenol resin (10 gm) were added to the filtrate and stirred for 2 hours, followed by filtration. The filtrate was concentrated, and MeOH (1000ml) was added to it to get a clear solution, which was added to isopropyl alcohol (5000 ml) and stirred for 1 hour. The resulting mass was settled, supernatant liquid was decanted and isopropyl alcohol (1000 ml) and acetone (1000 ml) were added to the decanted solid. The mass was stirred at 25-30°C, filtered and the obtained solid was dried under vacuum to get pure fosaprepitant dimeglumine (la). Yield 88.5 gm.

CLAIMS ' .
We claim,
1. A process for preparation of fosaprepitant dimeglumine comprising;
a) treating aprepitant with tetra benzyl pyrophosphate (TBPP) and sodium hexamethyldisilazide (NaHMDS) in tetrahydrofuran; after completion of reaction, adding the mass to a mixture of buffer solution 'and organic solvent, followed by separation and concentration of organic layer, addition of solvent mixture to the residue to obtain a reaction mass containing dibenzyl fosaprepitant (II),
b) treating the reaction mixture from step a) with N-methyl D-glucamine (NMDG) and Pd-C under hydrogen pressure in solvent methanol, filtering the reaction mixture after completion of reaction;
c) adding resin metal scavenger to the filtrate from step b), stirring, followed by filtration and concentration of resulting filtrate.
d) adding alcohol or ketone 'solvent to the resulting residue from step c), followed by filtration of solid to give fosaprepitant dimeglumine having desired purity.

2. A process as claimed in claim la) wherein the buffer is sodium dihydrogen phosphate
3. A process as claimed in claim la) wherein the organic solvent is selected from the group of diethyl ether, diisopropyl ether (DIPE), methyl tertiary butyl ether (MTBE), ethyl tert-butyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyether, tertrahydropyran (THF), 1,4-dioxane.
4. A process as claimed in claim la) wherein the solvent mixture is selected from a mixture of hydrocarbon solvent with an ether or ester.
5. A process as claimed in claim lc) wherein resin metal scavenger is selected from the group of sulfonic acid resins, triethylamine resins, carbonate resins, borohydride resins, cyanoborohydride resins, thiophenol resins, thiourea resins, sulfonyl chloride resins, diethanolamine resins, diisopropylethylamine resins, trisamine resins, sulfonylhydrazide resins, tribromide resins, merrifield resins, piperazine resins, trimercaptotriazine (TMT) resins and aminopolyhydroxy resins, preferably thiophenol resins.
6. A process as claimed in claim 4 wherein the hydrocarbon is selected from the group of pentanes, hexanes, heptanes and cyclohexane,and mixtures thereof.

7. A process as claimed in claim 4 wherein the "ether is selected from the group of diethyl ether, diisopropyl ether (DIPE), methyl tertiary butyl ether (MTBE), ethyl tert-butyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyether, tertrahydropyran (THF), 1,4-dioxane, and mixtures thereof. ;
8. A process as claimed in claim 4 wherein the ester is selected from the group of ethyl acetate, isopropyl acetate, and butyl acetate.