FORM 2
THE PATENT ACT 1970
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A process for the preparation of aprepitant and similar compounds.
2. APPLICANT(S)
(a) NAME: Emcure Pharmaceuticals Ltd
(b) NATIONALITY: an Indian Company
(b) ADDRESS: P-1, IT-BT Park
MIDC Phase-2, Hinjwadi, Pune-411057, INDIA
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
This invention relates to a process for the manufacture of aprepitant and similar compounds of higher yield and purity with ease of manufacturing due to use of a novel catalyst. Aprepitant is a member of the class of drug molecules that target the NK-1 receptors in central nervous system and other tissues. These molecules are indicated for the treatment of acute and delayed chemotherapy induced nausea and vomiting and for postoperative nausea and vomiting.
Aprepitant and similar compounds have been synthesized in the known art through various methods. Several of the currently used synthesis schemes have limitations in that solvents and catalysts used are not eco-friendly and industrially economical. They also have problems with respect to scale-up and work-up of the current processes. These factors lead to formation of impurities that can limit the use of the final products in pharmaceutical compositions.
It is known to the skilled person in organic chemical synthesis that in order to obtain highly pure final products, it is a good strategy to avoid formation of byproducts than develop purification methods to remove impurities from the final products. The principal object of this invention relates to an improved method of preparation of aprepitant molecules for use in pharmaceutical compositions with improved impurity profiles for the impurities due to byproducts formed during the preparation. Another object of this invention relates to the use of new catalysts (buffering agents) previously not used in this type of synthesis and new chemistry that significantly increases the utility of the invention in industrial applications.
Aprepitant is prepared by various methods as known in the prior art. In this invention, a novel process for the preparation of aprepitant is disclosed having several advantages over the existing processes. It is disclosed in WO 2009/001203 patent application that to prepare aprepitant by condensing (5) and (6) bases like potassium carbonate (K2C03). There are used in the prior art

different bases for this step in the synthesis of aprepitant. Similar methods is also disclose in WO 2007/044829 patent application.
Accordingly, the invention is disclosed in the general Scheme 1 with a generic reaction sequence for the preparation of aprepitant. As an example of the utility of the invention, Na2HP04 is used as a catalyst in condensation of (5) with (6) leading to formation of aprepitant. Other buffering agent like Na2HP04'2H20, NaH2P04*2H20, Na3P04'12H20, K2HP04, KH2P04, K3P04*H20, (NH4)2HP04) NaOAc (sodium acetate), and Tris-Buffer may be used in this step with superior or similar yield and purity of the product. This scheme can also be used for the preparation of fosaprepitant compounds.
In Scheme 1 in the first step, the lactol (1) is condensed with (2) (1-(1-bromoethyl)-3,5-bis(trifluromethyl)benzene) in the presence of a solvent like DMF in alkaline condition maintained by NaOH at low temperature. This is an inventive step in that the low temperatures of -5 to o °C lead to more than 95% completion of the reaction without any impurities in the product (3) as detected by HPLC. In the second step, compound (3) is treated with 10% Pd-C in methanol for debezylation of (3) leading to formation of the racemic compound (4). The racemic compound (4) is resolved into required chiral isomer (5) with known methods using reagents as indicated. In the next step, compound (5) is condensed with (6) (3-chloromethyl-1,2,4-triazolin-5-one) in the presence of a buffering agent like Na2HP04 at temperature between 15 to 85 °C leading to formation of aprepitant of higher yield and purity. In this step, different buffering agents as listed in Table 1 may be used without loss of efficiency of the reaction to form compounds of formula (6). The same method can also be used to preparation fosaprepitant molecules.

As depicted in Table 1, several buffering agents or combination thereof may be used as catalysts in condensation of compound (5) with (6) leading to the formation of aprepitant, fosaprepitant or similar compounds with higher yield and purity-Table 1: Reaction time required for % yield of compound (6) using different buffering agents.

Reaction Temp (°C)
▼ Reaction
( n Time
Buffer Agent ▼
10
Na2HP04-2H20 Disodiumhydrogen phosphate dihydrate 25-30 - 96.82

70-75 96.27 -
NaH2P04*2H20 Sodium dihydrogen phosphate dihydrate 25-30 - ND

70-75 93.00 -
Na3P04*l2H20 Trisodium phosphate dodecahydrate 25-30 - 93.33

70-75 94.00 -
K2HP04 Dipotassium hydrogen phosphate 25-30 - 87.20

70-75 90.03 -
KH2P04 Potassium dihydrogen phosphate 25-30 - ND

70-75 95.06 -
K3P04-H20 Potassium phosphate monohydrate 25-30 - 96.11

70-75 92.81
(NH4)2HP04 Ammonium phosphate 25-30 - 96.34

70-75 96.64 -
NaOAc Sodium acetate 25-30 - 95.91

70-75 95.93 -
Tris-Buffer 2-Amino-2-
hydroxymethyl-
propane-1,3-diol 25-30 - 93.00

70-75 92.55 -

The invention detailed above is illustrated with the following examples for the purpose showing the utility of the invention. Examples below do not restrict the invention in any way from broader application of the reaction chemistry to prepare aprepitant, fosaprepitant, and similar molecules. The teaching of this invention can also be used in the preparation of the organic molecules where triazoles are condensed with imide heterocyclic ring structures.
Example 1: preparation of compound of formula (3)
To dimethyl formamide (749 mL) add compound of formula (1) (107gm) at room temperature and stir for 15 min. Cool the mixture to -5 to 0 °C and slowly add NaOH over 2 h. Stir the reaction mass for at -5 to 0 °C for 20 min. Then add compound of formula (2) (191.53 gm) and run the reaction for up to 3 h at -5 to 0 °C until (1) content NMT 2% by HPLC. After completion of reaction add toluene (535 mL) with stirring at 5 °C, then charge with DM water (749 mL) at 10 °C. Partition the compound (3) in toluene layer, and wash toluene layer with 2% sodium chloride solution (1926 mL), repeat several cycles to increase the purity. Distill out toluene under vacuum below 70 °C. Cleanse (3) with methanol at room temperature. Remove methanol under vacuum and dry the product at 40 to 45 °C. This product has purity of NLT 95% by HPLC with yield of about 70%.
Example 2: preparation of compound of formula (4)
To methanol (500 mL) in a clean autoclave add compound (3) (100 gm) at room temperature and stir for 30 min. To this solution, add 20 gm of 10% wet Pd/C under nitrogen at 25-30 °C. Run the reaction under 10 kg of hydrogen pressure for 7 h at 40-50°C until (3) content NMT 2% by HPLC. After the completion of the reaction, cool the reaction mass to 25-30 °C and filter the reaction mass through hyflo bed under nitrogen atmosphere at 25-30 °C, wash with 100 mL of methanol. Then filter the reaction mass through 0.45-micron paper at 25-30 °C and distill out methanol at 50-55 °C under vacuum to get compound of formula (4), which is used directly in further steps.

Example 3: preparation of compound of formula (5)
a) To a solution of compound (4) obtained by Example 2 in 205 mL of methanol, add L (-) camphor sulfonic acid solution (dissolve 48.5 gm L (-) camphor sulphonic acid in 125 mL methanol) within 45 to 75 min at 25 to 30 °C and stir for 30 min at 25 to 30°C. Cool the reaction mass to 0 to 5 °C and maintain for 2 h at 0 to 5 °C. Filter the reaction mass, wash with 40 mL chilled methanol and dry at 50 to 55 °C under vacuum (650 to 700 mm of Hg) for 4 h till LOD is less than 2.0 % and SQR between +22° and +28° to get 39 to 52 gm of the intermediate compound.
b) Stir the reaction mass of 135 mL dichloromethane, 135 mL water and 45 gm of the intermediate compound obtained by step a) at 25 to 30°C for 15-20 min. Add 30 % sodium carbonate solution slowly and adjust pH of the reaction mass between 8-10 at 25 to 30 °C (dissolve 11.3 gm sodium carbonate in 29 mL water at 25 to 30 °C). After pH adjustment, stir the reaction mass for 30 min at 25 to 30 °C, settle the reaction mass and separate the organic & aqueous layers, repeat several cycles of extraction of compound into organic layer (270 mL). Wash organic layer with 90 mL of water, twice and distill out dichloromethane completely under vacuum (600 to 700 mm of Hg) at 40 to 50 °C. Charge 175.5 mL DMF into above reaction mass at 25 to 30 °C and stir for 15 min at 25 to 30 °C. Cool the reaction mass to 0 to 5 °C, charge 2.98 gm potassium carbonate at 0 to 5 °C and maintain the reaction mass for 15 min at 0 to 5°C. Add 12.57 gm n-chlorosuccinamide slowly at 0 to 5 °C and stir the reaction mass for 15 min at 0 to 5 °C. Add 17.49 gm DBU slowly at 0 to 5°C and stir the reaction mass for 15 min at 0 to 5 °C. Raise the temperature of reaction mass to 25 to 30 °C and maintain for 2 h at 25 to 30 °C. After completion of reaction, cool the reaction mass to 0 to 5°C and add 146 mL water and 146 ml toluene slowly at 0 to 10°C. Raise the temperature of reaction mass to 25 to 30 °C and stir for 30 min at 25 to 30 °C. Settle and separate both the layers. Extract aqueous layer with 87.8 mL of toluene and wash combined organic layer with 87.8 mL of water. Distill out toluene under vacuum (600

to 700 mm of Hg) at 65 to 70°C to get 24 to 29 gm of oiiy intermediate compound. c) To a 130 mL methanol in a clean autoclave, add intermediate compound obtained by step b) at 25 to 30°C and stir for 30 min at 25 to 30 °C. Charge 2.6 gm wet 10 % Pd-C under nitrogen into autoclave at 25 to 30°C. Run the reaction under 5 Kg of hydrogen pressure for 4 h at 25-30 °C. Filter the reaction mass through hyflo bed under nitrogen gas at 25 to 30°C and distill out methanol completely under vacuum (600 to 700 mm of Hg) at 50 to 55 °C to get 23 to 26 gm of compound of formula (5) with >98% purity by HPLC.
Example 4: preparation of aprepitant and similar compounds by using Di-sodium hydrogen phosphate
To a solution of 100 gm of compound {6) in 400 mL of DMF, add 100 gm of disodium hydrogen phosphate and stir for 10-15 min at 25-30°C. Add solution of compound (5) (33.5 gm dissolved in 400 mL DMF) in the reaction at 25-30 °C and maintain for 7 h at 25-30 °C. After completion of the reaction, add 1600 mL of water into it and stir for 10-15 min. at 25-30 °C. Further, cool the reaction mass to 0-5 °C and maintain for 1 h at 0-5 °C. Filter the reaction mass, wash with 800 mL of water, thrice and dry at 50-55 °C to get 90 to 125gm crude aprepitant with >97% purity by HPLC.
Example 5: purification of aprepitant
Heat the reaction mixture of 100 gm of crude aprepitant and 2000 mL of methanol to 45 to 55 °C to get clear solution. Filter the reaction mass through 0.45-micron filter paper and distill out methanol completely under vacuum (600 to 700 mm of Hg) at 50 to 55°C. Cool the reaction mass to 25 to 30°C and charge 200 mL methanol and 500ml acetonitrile at 25 to 30°C to the above reaction mass. Heat the reaction mass to 60 to 65°C and stir for 60 min at 60 to 65 0C. Cool the reaction mixture slowly to 0 to 5°C and maintain for 60 min at 0

to 5°C, filter, wash with 100 mL filtered acetonitrile and dry the product at 50 to 55°C for 12.0hrs under vacuum (600 to 700 mm of Hg) to get 70 to 90 gm of pure aprepitant with >99% purity by HPLC.

5. CLAIMS
1. A process for the preparation of aprepitant, fosaprepitant and similar compounds, comprising the steps of
(a) reacting the compound of the formula (1) with compound of the formula (2) in the presence of an alkali in dimethyl formamide leading to formation of a compound of formula (3);

(b) debenzylation of a compound of formula (3) using an alcohol in the presence of palladium-carbon leading to the formation of compound of formula (4);


(c) isomeration of compound of formula (4) to compound of formula (5);


(d) condensation of compound of formula (5) with compound of formula (6) in the presence of a buffering agent in a solvent like dimethyl formamide at room temperature leading to formation of compound of formula (7).


2. A process for the preparation of a compound of the formula (7) as per claim 1, and said process having a buffering agent as catalyst in condensation of compounds of formulas (5) and (6) selected from the group comprising of Na2HPO42H20, NaH2P04'2H20, Na3P04*12H20, K2HP04, KH2P04, K3PO4H2O, (NH4)2HP04, NaOAc (sodium acetate), and tris-buffer.
3. A process for the manufacture of a compound of the formula (3) as per claim 1, and said method having reaction temperature between -5 to + 5 °C for condensation of compounds of formulas (1) and (2).
4. A pharmaceutical composition comprising an effective amount of a compound according to claim 1.
5. A pharmaceutical composition according to claim 1 in a unit dosage form.
6. A pharmaceutical composition according to claim 1 with a pharmaceutically acceptable carrier and/or an inactive compound and/or another active compound.
7. A process for preparation of a compound of formula (7) substantially as described with reference to the examples.