FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
NOVEL PROCESS FOR THE SYNTHESIS OF APREPITANT AND FOSAPREPITANT AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
PANACEA BIOTEC LIMITED,
an Indian Company incorporated under the Companies Act 1956 B-l Ext. A-27, Mohan Co-operative Industrial Estate, Mathura Road,
New Delhi-110 044,
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention is related to the field of synthetic chemistry. It is related to novel process of synthesis of 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1.2dihydro-3H-l,2,4-triazol-3-one (Aprepitant) and [3-{[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl}-5-oxo-2H-l,2,4-triazol-l-yl]phosphonic acid (Fosaprepitant) and pharmaceutically acceptable salts thereof
BACKGROUND:
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Aprepitant is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(triflnoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-l,2dihydro-3H-'l,2,4-triazol-3-one and is represented by the following structural formula:


Aprepitant is a substance P (neurokinin-1) receptor antagonist useful in the treatment of chemotherapy-induced nausea and vomiting, and is commercially available in the market under the brand name EMENDTM as 80 mg or 125 mg capsules.
Fosaprepitant is chemically known as [3-{[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl}-5-oxo-2H-l,2,4-triazol-l-yl]phosphonic acid and has the structure shown as Formula V

Fosaprepitant dimeglumine is an antiemetic drug, administered intravenously. It is a prodrug of aprepitant. Fosaprepitant dimeglumine is chemically known as l-Deoxy-l-(methylamino)-D-glucitol[3-[[(2R3S)-2-[(lR)-143,5bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl] methyl]-2,5-dihydro-5-oxo-lH-1.2,4triazol-l-yl] phosphonate (2:1) (salt) and is structurally represented as follows:

Aprepitant was first disclosed in EP 0734381 Bl and is currently being marketed as a treatment for chemotherapy-induced nausea and vomiting under the trade name Emend®. In EP 0734381

Bl a synthetic route for this compound and a series of other morpholine derivatives is described. U.S. Patent Nos. 5,719,147 and 5,637.699 disclose a process for the preparation of aprepitant which involves condensation of 2(R)-(l-(R)-3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenylmorpholine with N-methyicarboxy-2-chloroacetamidrazone in the presence of the base N.N-diisopropylethylamine and the solvent acetonitrile. Subsequent processing by flash chromatography using methylene chloride/methanol/ammonium hydroxide as an eluant in a ratio of 50:1:0.1 provided 2(R)-(l-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(SH4-fluoro)phenyl-4-(N-methylcarboxy acetamidrazono)-morpholine, which was further refluxed in xylene and purified by flash chromatography using a 50:1:0.1 ratio of methylene chloride/methanol/ ammonium hydroxide as the eluant to afford aprepitant.
However, the disclosed processes for these compounds suffer from lengthy syntheses and low product purity.
In EP 0748320 Bl the structure of fosaprepitant is disclosed. The preparation is based on appropriate phosphoryl transfer to aprepitant, optionally followed by removal of the phosphoryl protecting groups.
In WO 99065900 Al an improved process for the introduction of the l,2,4-triazolin-5-on-yl-methyl side chain by using 3-chloromethyl-l,2,4-triazolin-5-one as alkylating agent at ambient temperature is described.
International Application Publication No. WO 01/96315 Al discloses the preparation of aprepitant by condensation of 3-chloromethyl-l,2,4-triazolin-5-one with 2-(R)-(l-(R)-(3,5-bistrifluoromethyl) phenyl) ethoxy) 3-(S)-(4-fluorophenyl)morpholine(R)-camphor sulfonic acid salt in the presence of potassium carbonate and N, N-dimethylformamide. Alternatively, aprepitant was prepared by condensation of 3-chloromethy 1-1,2.4-triazolin-5-one with 2-(R)-(l-(R)-(3,5bistrifluoromethyl)phenyl)ethoxy)3-(S)-(4-fluoropheny!)morpholine paratoluenesulfonic acid salt in the presence of the base N.N-diisopropylethylamine and N,N-dimethylformamide. In another alternative, aprepitant was prepared by condensation of 3-chloromethyl-l,2,4-triazolin-5-one with 2-(R)-(l-(R)-(3,5-bistrifluoromethyl)phenyl)ethoxy)3-(S)-(4-fluorophenyl)morpholine

para toluenesulfonic acid salt at 21-23° C in the presence of the base potassium carbonate and N, N-dimelhylformamide.
International Application Publication No. WO 03/089429 Al discloses the preparation of aprepitant which involves condensation of the hydrochloride salt of (2R,2-cis-R, 3S)-2-[l-[3,5-bis (trifluoromethyl) phenyl]ethoxy-3-(4-fluorophenyl)-l,4-oxazine with amidrazone in presence of potassium carbonate and the organic-solvents toluene and dimethylsulfoxide to give an intermediate, which on cyclization at 140° C affords aprepitant.
U.S. Patent No. 5,691.336 (the '336 patent) describes morpholine compounds including fosaprepitant and its pharmaceutically acceptable salts thereof. The '336 patent exemplifies the process for the preparation of fosaprepitant dimeglumine.
International Application Publication No. WO2006060110 A2 describes the process for the preparation of fosaprepitant dimeglumine by conversion of aprepitant to monobenzyl ester fosaprepitant and then subsequently converting to fosaprepitant dimeglumine.
In summary, some of the disadvantages of the foregoing processes include: i) the purity of the isolated aprepitant is low, thereby requiring additional steps like flash chromatography, which is industrially not feasible, to obtain a pharmaceutically acceptable substance; ii) the chemical yield of aprepitant is low; iii) high temperature reactions are involved; iv) a lengthy time cycle is required: and v) expensive reagents are used.
None of the above mentioned prior arts disclose the improved process according to the present invention. The present invention provides an improved, commercially viable and industrially advantageous process for the synthesis of Aprepitant and its pharmaceutically acceptable salts and thereby its extension for the preparation of fosaprepitant and its pharmaceutically acceptable salts thereof that involves milder reaction conditions and high reaction efficiency. The intermediates and the final end products obtained through the improved processes of this

invention are obtained in a superior yield and high purity. Further the reaction time is dramatically reduced by following the improved process according to the present invention.
SUMMARY OF THE INVENTION
The present invention relates to improved, commercially viable and industrially advantageous processes for the synthesis of Aprepitant and Fosaprepitant and pharmaceutically acceptable salts thereof.

which comprises:
(i) reacting a compound of Formula II

with a compound of Formula III
In one aspect, the present invention provides a process for the preparation of Aprepitant, represented by the Formula I


in the presence of suitable reagents and a solvent to obtain a compound of formula (IV); and

(ii) converting the compound of formula (IV) to compound of formula I.
In another aspect, the present invention provides a process for the preparation of compound of formula I

which comprises:
cyclizing a compound of Formula IV


in the presence of MIBIC and heptane.
In yet another aspect, the present invention provides a process for the preparation of compound of formula V and its pharmaceutically acceptable salts.

which comprises:

with a compound of Formula III
(i) reacting a compound of Formula II



in the presence of suitable reagents and a solvent to obtain a compound of formula (IV); and
(ii) cyclizing the compound of formula (IV) to compound of formula I.

(iii) converting the compound of formula (I) to compound of formula (V) or its pharmaceutically acceptable salts thereof
These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to limit the scope of the subject matter.

DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides a process for the preparation of Aprepitant, represented by the Formula I

which comprises:

with a compound of Formula III
(i) reacting a compound of Formula II

in the presence of suitable reagents and a solvent to obtain a compound of formula (IV); and


(ii) cyclizing the compound of formula (IV) to obtain compound of formula I.
The details of the above embodiment are given below:
Step (i) involves reacting a compound of Formula II with a compound of Formula III in the
presence of suitable reagents and a solvent to obtain a compound of formula (IV).
The suitable reagent used in the above step is selected from an inorganic base selected from the
group comprising: sodium carbonate, cesium carbonate, sodium hydroxide, potassium
hydroxide, potassium carbonate and the like. More particularly, the preferred inorganic base is
potassium carbonate.
The solvent used in the above step (i) is selected from an organic solvent, preferably, a polar
aprotic solvent, As used herein, the term "polar aprotic solvent" refers to a solvent that neither
donates or accepts protons, and is, for example, selected from the group comprising: N,N-
dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP),
acetonitrile (MeCN), N,N-dimethylacetamide (DMAC) and hexamethyl phosphoramide
(HMPA). More particularly, the solvent is N,N-dimethyl form amide (DMF).
The temperature for carrying out the reaction of Step (i) is in the range of 25-30°C.
In an embodiment, the step (i) involves reacting a compound of Formula II with a compound of
Formula III in the presence of potassium carbonate and N(N-dimethylformamide (DMF) at 25-
30°C to obtain a compound of formula (IV).
The compound of formula (II) used as the starting material in step (i) may be obtained in
accordance with the International patent application numbers WO01/94324 Al and
US20020052494 Al. or using modifications thereof. The starting material can be used directly or

following purifications. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
Step (ii) involves cyclizing the compound of formula (IV) to obtain compound of formula (I) The cyclization reaction of step (ii) is carried out in the presence of methyl isobutyl ketone (MIBK) and a solvent.
The solvent used in the above step is selected from the group comprising but not limited to heptane, cyclohexane and the like.

which comprises:
cyclizing a compound of Formula IV

in the presence of MIBK and heptane.
In a preferred embodiment, the present invention provides a process for the preparation of compound of formula I

In yet another embodiment, the present invention provides a process for the preparation of compound of formula V and its pharmaceutically acceptable salts

which comprises:

with a compound of Formula III

(i) reacting a compound of Formula II
in the presence of suitable reagents and a solvent to obtain a compound of formula (IV): and


(ii) cyclizing the compound of formula (IV) to obtain a compound of formula I; and

(iii) converting the compound of formula (I) to compound of formula (V)
In a preferred embodiment, the present invention provides a process for the preparation of compound of formula V or its pharmaceutic ally acceptable salts


(i) reacting a compound of Formula II

with a compound of Formula III

in the presence of potassium carbonate and N.N-dimethyl formamide to obtain a compound of formula (IV); and

(ii) cyclizing the compound of formula (IV) in the presence of methyl isobutyl ketone (MIBK) and heptane to obtain a compound of formula I; and


(in) converting the compound of formula (I) to compound of formula (V) or its pharmaceutically acceptable salts thereof.
In an embodiment, the present invention provides a process for the preparation of compound of formula V and its pharmaceutically acceptable salts, wherein the pharmaceutically acceptable salt is a compound of formula (VI)

The step (iii) of the above reaction involves converting the compound of formula (I) to (V). The said conversion may be carried out by processes known in the art or using the processes disclosed in European patent number EP 0748320 Bl, U.S. Patent No. US 5,691336 and International Application Publication No. WO2006060110 A2 or using modifications thereof. The preparation of fosaprepitant and fosaprepitant dimeglumine is disclosed herein with reference to the reference examples 1 and 2.

The use of methyl isobutyl ketone (MIBK) according to the processes of the present invention is advantageous over the prior known xylenes with respect to quality and color of the intermediates and end product obtained. Further, the processes of the present invention are characterized by reduced number of operations involved in discoloring the intermediates and final material. The color index of the intermediates and final material can be determined using techniques known in the art.
The general reaction scheme of the above embodiment of the instant invention can be schematically represented as scheme-A:

EXAMPLES:
The invention is farther described by reference to the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1: Preparation of 2(R)-[l-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy]-3(S)-(4-fluoro) phenyl-4-(2-(N-methylcarboxy acetamidrazono)morpholine
Dimethyl formamide (400 ml) is charged in to a round bottom flask at 25-30°C. and [2R.3S]-2[lR-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine. HC1 is added and stirred for 10-15 minutes at 25-30°C. Potassium carbonate (29.11 g) is added lot-wise in 10-15 minutes and stirred for 10-15 minutes. The reaction mass is cooled to 15-20°C. N-methylcarbonyl-2-chloroacetarnidrazonoe (16.78 g dissolved in 60.0 ml of dimethyl formamide) is added drop-wise at 15-20°C and later the reaction mass is allowed to return to 25-30°C.The reaction mixture is maintained for 4-5 hours at 25-30°C.
Water (480 ml) is charged in another round bottom flask at 25-30°C and the reaction mass is added drop-wise from the other round bottom flask and maintained for 30-45 minutes at 25-30°C. The reaction mass is filtered and the wet cake obtained is washed with water (80 ml) and suck dried for 15-30 minutes. The wet material is unloaded and charged into the round bottom flask at 25-30°C and water (240 ml) is added and stirred for 15-30 minutes. The wet material is unloaded and charged in to a round bottom flask and water is added and stirred for 15-30 minutes. The reaction mass is filtered and the wet cake is washed with water (80 ml) and suck dried for 15-30 minutes. (Output: 44 g; Yield: 1.1 w/w; Purity: 90.18%)
Example -2: Preparation of crude Aprepitant
Methyl isobutyl ketone (250 ml) is charged in to a round bottom flask at 25-30°C and 2(R)-[1-(R)-3.5-bis(trifluoromethyI)phenyl)ethoxy]-3(S)-(4-fIuoro)phenyI-4-(2-(N-methylcarboxy acetamidrazono) morpholine (125 g) is added and the reaction mass is heated to reflux at 115-120°C. The reaction mass is maintained to 10-12 hours at 115-120°C. The reaction mass is allowed to cool to 15-20° and Heptane (375 ml) is added in 10-15 minutes followed by maintenance of the reaction mass for 3-4 hours at 15-20°C. The reaction mass is filtered and the wet cake is washed with Heptane (250ml) and suck dried for 30 minutes. The material is unloaded and dried for 4-6 hours under vacuum at 50-55°C. (Output: 85 g; Yield: 0.68 w/w; Purity: 99%)

Example-3: Preparation of Aprepitant
Methanol (530 ml) is charged in to a round bottom flask at 25-30°C, crude aprepitant (obtained
from example 2) (53.0 g) is added and heated to 50-60°C and maintained for 10-15 minutes at
50-60°C to get a clear solution. The reaction mass is allowed to cool to 45-50°C and active
charcoal (10.6 g) is added at 45-50°C. The reaction mass is maintained for 15-20 minutes at 45-
50°C and the mass is filtered through Celite and washed with methanol (106 g).
The above filtrate is charges in to a round bottom flask and heated to 45-501 6C. Active charcoal
(5.3 g) is added at 45-50°C and maintained for 15-20 minutes at that temperature. The mass is
filtered through Celite and washed with methanol (106 ml).
The above reaction mass is charged in to a round bottom flask and water (265 ml) is added in 15-
30 minutes at 20-25°C and maintained for 5-10 minutes at that temperature. The mass is filtered
and the wet cake is washed with methanol; water (132 ml of methanol and 88 ml of water) and
suck dried for 30-40 minutes and the material is dried at 50-55°C for 10-12 hours to get pure
aprepitant.
(Output: 41.7g; Yield: 078 w/w; Purity: 99.77%)
Reference example 1: Preparation of fosaprepitant
DMSO (10 ml) was taken under stirring and sodium hydroxide (0.19 g) was added at ambient temperature. Aprepitant (0.5 g) was added and stirred for 30 minutes to get clear solution. Tetra benzyl pyrophosphate (0.5 g) was added under stirring. The clear solution was stirred for 30 minutes at 25-30°C. After completion of reaction (aprepitant < 20 %), the reaction mass was cooled to 10-15 °C. Water (20 ml) was added slowly under stirring over 20-30 minutes and stirred for 5 minutes and toluene (10 ml) was added under stirring and stirred for 30 minutes. The layers were separated and the toluene layer was washed with (2x 20 ml) water and (2x 20 ml) saturated sodium bi-carbonate solution. The toluene layer was dried over 1.0 g anhydrous sodium sulphate and concentrated under vacuum at ambient temperature to give yellow colored oil. (Yield-0.62 g; 83.5% theory)

Reference example 2: Preparation of fosaprepitant dimeglumine
Dibenzyl Fosaprepitant (50 g) was dissolved in methanol (1.0 liter). The reaction mixture was
subjected to the hydrogenation using Pd/C catalyst and monitored the reaction by HPLC till its
completion. The reaction mixture was filtered and residue washed with methanol containing N-
methyl-D-glucamine. The clear filtrate of methanol was added slowly to Isopropyl alcohol,
filtered the precipitated slurry and dried under vacuum to get pure fosaprepitant dimeglumine
salt.
(Yield - 47 (75%), HPLC Purity 99.7%)

We claim:
1. A process for the preparation of Aprepitant, represented by the Formula I

which comprises:

with a compound of Formula ITT
(i) reacting a compound of Formula II

in the presence of suitable reagents and a solvent to obtain a compound of formula (IV); and


(ii) cyclizing the compound of formula (IV) in the presence of methyl isobutyl ketone (MIBK) and a solvent to obtain compound of formula I.
2. A process according to claim 1. wherein the suitable reagents used in step (i) is an inorganic base selected from the group comprising: sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and potassium carbonate.
3. A process according to claim 2, wherein the suitable reagent is potassium carbonate.
4. A process according to claim 1, wherein the solvent used in step (i) is selected from the group comprising: N.N-dimethylformamide (DMF). dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP); acetonitrile' (MeCN). N,N-dimethylacetamide (DMAC) and hexamethyl phosphoramide (HMPA).
5. A process according to claim 4, wherein the solvent is N,N-dimethylformamide (DMF).
6. A process according to claim 1, wherein the solvent used in step (ii) is selected from the group comprising: heptane and cyclohexane.
7. A process for the preparation of compound of formula I


which comprises:
cyclizing a compound of Formula IV

in the presence of MIBK and heptane.

which comprises;
8. A process for the preparation of compound of formula V or its pharmaceutic ally acceptable salts

(i) reacting a compound of Formula II

with a compound of Formula III

in the presence of potassium carbonate and N,N-dimethyl formamide to obtain a compound of formula (IV); and

(ii) cyclizing the compound of formula (IV) in the presence of methyl isobutyl ketone (MIBK) and heptane to obtain a compound of formula I: and


(iii) converting the compound of formula (I) to compound of formula (V) or its pharmaceutically acceptable salts thereof,
9. A process according to claim 8, wherein the pharmaceutically acceptable salt of compound of formula (V) is a compound of formula (VI)