AN IMPROVED PROCESS FOR THE PREPARATION OF APREPIT ANT

Field of the invention

The present invention relates to an improved process for the preparation of

Aprepitant of formula (I) and its intermediates. More particularly, the present invention relates to a method for the preparation of 3-(5)-(4-fluorophenyl)-4-benzyl-2- morpholinone of Formula (III) or its salts thereof by reacting N-benzyl- (5)-(4- fluorophenyl) glycine of formula (II) with 1,2-dibromoethane in presence of an organic base.

Background of the invention

Aprepitant of formula (I) is a selective high-affinity antagonist of human substance P/neurokinin 1 (NKi) receptors, is chemically known as 5-[[(2R,3S)-2-[(lR)- l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl) -4-moφholinyl]methyl]- l,2-dihydro-3H-l,2,4-triazol-3-one.

Aprepitant is useful in the treatment of chemotherapy-induced nausea and vomiting, and is commercially available in the market under the brand name Emend â„¢ as 80 mg or 125 mg capsules.

US Patent No. 5,719,147 discloses the process for the preparation of compound of formula (III) by reacting N-benzyl-(S)-(4-fluorophenyl) glycine of formula (II) with 1,2-dibromoethane in presence of an organic base such as N,N- diisopropylethylamine and using N, N-dimethylformamide as a solvent. In this process the distillation of N, N-dimethylformamide is very difficult and the yield of the product is very low. Thus this process is not suitable for commercial scale production.

US Patent No. 6,177,564 claims a process for the preparation of a compound of formula (III) which comprises: (a) treating 4-fluorobenzaldehyde with sodium metabisulfite in a first solvent followed by reaction with a cyanide source selected from sodium cyanide and potassium cyanide, and the reaction is conducted at a temperature range of about 10 to about 50 ⁰ C, to give l-cyano-l-(4-fluorophenyl)methanol (b) followed by treating l-cyano-l-(4-fluorophenyl)methanol with N-benzylethanolamine which is reacted at a temperature range of about 10 to about 50 ⁰ C to give its corresponding amino derivative (c) followed by treating the corresponding amino derivative with a strong acid in a second solvent to give N-benzyl-3-(S)-(4- fluorophenyl)-l,4-oxazin-2-one.This process is not preferred in industrial scale because it involves more number of steps and uses a cyanide source which is hazardous.

Chiral 3-(4-fluorophenyl)-l,4-oxazin-2-one derivatives are important intermediates and useful in making therapeutic agents such as Aprepitant. Therefore, there is a need for development of a process for the preparation of N-benzyl-3-(4- fluoro-phenyl)-l,4-oxazin-2-one, which is readily amenable to scale-up.

Hence we focused our research to simplify the process for the preparation of compound of formula (III) in the absence of N,N-dimethylformamide to obviate the problems associated with the prior art process.

Object of the invention

The main object of the present invention is to provide a process for the preparation of compound of formula (III), which is simple, economical and commercially viable.

Another object of the present invention is to provide a process for the preparation of compound of formula (III), which would be easy to implement on commercial scale and which can avoid the use of toxic solvent like N, N- dimethylformamide.

Still another object of the present invention is to provide a process for the preparation of compound of formula (III) in high yield and very high purity.

Summary of the invention

Accordingly, the present invention provides an improved process for the preparation of 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone of Formula (IN) or its salts which comprises reacting N-benzyl-(S)-(4-fluorophenyl) glycine of formula (II) with 1,2 dibromoethane in the presence of an organic base and in absence of any additional solvent to obtain 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone of formula (III) or its acid addition salt. The above process is illustrated in the Scheme A.

III

Scheme A

Detailed description of the invention

In an embodiment of the present invention, 1,2-dibromoethane is used as a reactant as well as solvent in the preparation of 3-(iS)-(4-fIuorophenyl)-4-benzyl-2- morpholinone of Formula (III) or its salts. In this step the use of solvent like N ₁ N- dimethylformamide (DMF) as disclosed in prior art processes is avoided. The use of high boiling solvent N,N-dimethylformamide is not preferable in industrial scale since it requires high temperature for distillation and further this solvent is not environmental friendly. The present invention avoids the use of such high boiling solvents and conducts the reaction only in 1,2-dibromoethane for the preparation of compound of formula (III).

In another embodiment of the present invention the organic base used for the preparation of compound of formula (III) includes but not limited to triethylamine, diethylamine, dimethylamine, NN-diethylmethylamine, NN-diethyl aniline, N ₁ N- diethylethylenediamine, or NN-diisopropylethylamine, diisopropylethylamine, dimethylaminopyridine, N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4- methylpyridine, pyridine; most preferably, N,N-diisopropylethylamine.

In yet another embodiment of the present invention, the compound of formula (III) is isolated as its acid addition salt by reacting the compound of formula (HI) with an acid. More preferably the compound of formula (III) is converted to hydrochloride salt by reacting with HCl gas or HCl gas dissolved in solvent like alcohol (isopropyl alcohol, ethanol and the like), ester, ketone, ether and the like, further the acid addition salt is converted into its free base in presence of a base preferably sodium bicarbonate and a solvent preferably toluene, ethyl acetate and dichloromethane.

In yet another embodiment of the present invention, 3-(5)-(4-fluorophenyl)-4-

! benzyl-2-morpholinone of Formula (III) is converted to aprepitant of formula I by process known in the art or by following the steps given below,

a) 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone of Formula (III) was reduced using a reducing agent, which is selected from the group consisting of diisobutyl aluminum hydride, lithium aluminum hydride, lithium tri(sec-

butyl)-borohydride (L-Selectride.) in presence of an organic solvent selected from the group comprising of tetrahydrofuran, ether, isopropyl ether, dioxane, methyl tertiarybutyl ether, and the like to obtain Lactol;

b) The obtained Lactol was condensed with 3,5-bis(trifluoromethyl)benzoyl chloride in the presence of solvent. After completion of the reaction, the reaction mass was quenched with aqueous solution of sodium perborate in toluene or isopropyl ether to obtain (2R-cis)-2-[[l-[3,5-bis(trifluoromethyl)- phenyl]-ethenyl]oxy]-3-(4-fluoro-phenyl)-4-(phenylmethyl)moÏ †holine (APT-I);

c) (2R-cis)-2-[[l-[3,5-bis(trifluoromethyl)-phenyl]-ethenyl]oxy ]-3-(4-fluoro- phenyl)-4-(phenylmethyl)morpholine (APT-I) was optionally converted into its acid addition salt and further converted back into free base by using alkali in toluene or ethyl acetate or dichloromethane;

d) APT-I was converted into 2R-cis(-2-[[l-[3,5-bis(trifluoromethyl)-phenyl]- ethenyl]oxy]-3-(4-fluoro-p'henyl)-4-(phenylmethyl)-morpholin e (APT-2) by using dimethyl titanocene (DMT)) in presence of solvent selected from toluene, tetrahydrofuran or a mixture there of;

e) APT-2 was reduced to [2R-[2a(R*),3a]]-2-[l-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine (APT-3) using suitable reducing agents preferably Palladium/carbon, palladium oxide and the like;

f) APT-3 was optionally converted into acid addition salt preferably sulphonic acid salt where the sulphonic acid salt is selected from the group consisting of camphor sulphonic acid, benzene sulphonic acid, naphthalene-2-sulfonic acid, paratoluene sulphonic acid most preferably camphor sulphonic acid;

g) APT-3 or its acid addition salt was condensed with N-methyl carboxy-2-

I chloro acetamidrazone to obtain APT-4; and

h) APT-4 was cyclised to obtain aprepitant where the cyclisation is carried out in the presence of xylene or mixture of xylene:DMF in presence of alkali carbonate preferably sodium carbonate.

The above process is illustrated in the Scheme B.

III Lactol APT l

Toluene I DMT

APT-3

APT-3 CSA salt APT-2

Cl

DMF/KXO, ^{^} V ^f NH,NHCOOMe ^{+ cι} CN

^N \

,NH

MeO ₂ C' Methanol

I

Scheme B

In the above process can be carried out by isolating the intermediates or insitu manner.

In the present invention the starting materials are either commercially available or prepared according to the literature available in the prior art.

The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.

Example 1

Process for the preparation N-benzyl-4-fluorophenyl morpholinone hydrochloride

(III): N,N-diisopropylethylamine (7.23 g) was added into a mixture of N-benzyl-(S)-

4-fluorophenyl glycine (5 g) and l,2dibromoethane (36.23g) and stirred the contents at 30 ⁰ C. The reaction mass was heated up to 90 ⁰ C and maintained till the completion of reaction. After the completion of reaction, unreacted 1,2-dibromoethane was distilled out completely under vacuum. Ethyl acetate and brine solution was added to the concentrated mass and stirred. Layers were separated and aqueous layer was again extracted with ethyl acetate and the combined organic extracts were washed with water, brine and dried over sodium sulfate. Ethyl acetate was completely distilled under vacuum at 40°C and fresh ethyl acetate was added followed by 0.5g of charcoal, stirred for 30minutes and filtered through celite. To the filtrate IPA.HC1 (4.2mL) was added at 0 ⁰ C, followed by optional seeding with title compound and stirred. The solid obtained was filtered washed with ethyl acetate and dried under vacuum at 60 ⁰ C to yield 2.75 g (dry weight) of N-benzyl-4-fluorophenyl morpholinone hydrochloride with a HPLC purity of more than 90-98 %.

Example 2

Process for the preparation of (2R-cis)-2-[[l-[3,5-bis(trifluoromethyl)-phenyl]- ethenyl]oxy]-3-(4-fluoro-phenyl)-4-(phenylmethyl)-morpholine .HCl: (APT-l.HCl)

N-benzyl-4-fluorophenyl morpholinone hydrochloride (6Og) was made into freebase using 100ml of 5% sodium bicarbonate solution in presence of solvent ethyl acetate. N- benzyl-4-fluorophenyl morpholinone freebase in toluene was cooled to -8O ⁰ C to -6O ⁰ C and L-Selectride (252ml) was added slowly by maintaining the same temperature. After completion of reaction, 3,5-bis (trifluoromethyl) benzoyl chloride (57.8g) was added to the reaction mass and stirred the contents at the same temperature till the completion of reaction. After the completion of reaction, the reaction mass was quenched into mixture of 500ml of sodium perborate solutipn and 100ml of toluene or IPE at 0 ⁰ C and the reaction mass was stirred for lhr at 0-25 ⁰ C. Organic layer was separated and washed with waterl20ml, brinel20ml and dried over sodium sulphate and distilled out the solvent to get the crude APT-I base.

Crude base was dissolved in IPE: heptane (1 : 1) (600ml) and cooled to 0 ⁰ C and concentrated HCl (36ml) was added till pH=2. Solid precipitates out was stirred for lhr at 0 ⁰ C, filtered and washed with heptane or toluene 200ml. Dried the solid under vacuum at 30 ⁰ C for lOhrs to give (2R-cis)-2-[[l-[3,5-bis (trifluoromethyl)-phenyl]- ethenyl] oxy]-3-(4-fluoro-phenyl)-4-(phenylmethyl)-morpholine. HCl.

Dry weight-90-lOOg

Yield-95%

Purity-94%

Example 3

Process for preparation of 2R-cis)-2-[[l-[3,5-bis(trifluoromethyl)-phenyl]- ethenyl]oxy]-3-(4-fluoro-phenyl)-4-(phenylmethyl)-morpholine :(APT-2)

APT-I hydrochloride (5Og) was charged in to a mixture of toluene and sodium bicarbonate solution and stirred. _^ Organic layer was separated, washed with 5% sodium bicarbonate solution, water, brine and concentrated the organic layer to obtain APT-I freebase. APT-I freebase was dissolved in THF, DMT > in toluene (1600 mL) was added under nitrogen. The reaction mass was heated to 70°C-73°C for about 5 hours. After completion of the reaction, the reaction mass was brought down to room temperature 12.5g sodium bicarbonate, 200ml of methanol and 7.5ml of water were added to the reaction mass and the temperature was raised to 40°C-45°C and allowed to stir for 14 hours at the same temp. The reaction mass was cooled to 25-35 ⁰ C and filtered the byproduct and washed with heptane (200ml) the filtrate was collected and distilled completely under vacuum at 45°C. 250ml of heptane was added to the distillate and washed with water (100mlx2), brine solution (100ml) and distilled off the solvent completely to get the crude APT-2. 250ml methanol was added to the crude and heated to 40 to 50 ⁰ C then 12.5ml of water was added to the reaction mass. It was maintained at the same temp for 30min and cooled to room temperature and stirred forlhr. The crystalline APT-2 was stirred at 5 to 10 ⁰ C for 2-3 hours filtered, washed with methanol/water (7:3) and dried. Wt=25g Purity=99%

Example 4

Process for preparation of [2R-[2a(R*),3a]]-2-[l-[3,5- bis(trifluoromethyI)phenyl]ethoxy]-3-(4-fluorophenyl)-morpho line 4-camphor sulphonate salt: (STG-3)

APT-2 (1Og) was dissolved in 100 mL of ethanol /ethyl acetate (1 : 1) and hydrogenated using 2.5g of 5% Pd/C at room temperature. After the completion of reaction, the reaction mass was filtered through hyflow bed. The filtrate was distilled out completely and flushed with methyl tert-butyl ether (MTBE). A solution of APT-3 in MTBE: heptane (1 :2) was added to a solution of (R)(-) camphor sulphonic acid (3.15g) in (1 :2)

MTBE: heptane and stirred. The obtained APT-3 camphor sulphonic acid salt was filtered and washed with heptane.

Wt=7.5g

Purity=97% Yield=60%

Example 5

APT-3 camphor sulphonic acid salt (3g) was taken in a mixture of DMF (12 mL) and potassium carbonate (0.16 g), a solution of 1.05 g of N-methyl carboxy-2- chloroacetamidrazone in DMF (12mL) was added to the reaction mass and stirred till the completion of reaction. After completion of reaction, 30 mL of water and 6OmL of

MTBE were added and stirred, the organic layer was separated washed with water, sodium bicarbonate solution and finally with brine solution. The organic layer was concentrated and distilled to get crude APT-4 which was dissolved in Xylene and kept for further reaction.

Example 6

Process for the preparation 5-[2(R)-[l(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]- 3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-l, 2,4-triazol-3-one :

APT-4 was dissolved in xylene and heated the reaction mass to 135 to 140 ⁰ C for about 5 hours. After completion of reaction the reaction mass was cooled to 30 ⁰ C. The solid was filtered and washed with 300 mL of heptane to get APT-5 as crude. Wet wt=75g

Alternate process for APT-5:

APT-4 was dissolved in 3V of xylene:DMF (2.5:0.5) and 0.25g sodium carbonate was added to the reaction mass and heated to 120 to 130 ⁰ C for 3 hours. After completion of reaction the reaction mass was cooled to 30 ⁰ C and 20 mL of ethyl acetate was added. *

The pH of organic layer was adjusted to 6 with dil.HCl (1 :10). The organic layer was washed with water followed by brine. Charcoal (0.05 g) was added to the organic layer, stirred, filtered through hyflow and distilled to the syrupy mass. Heptane (30 mL) was added to the mass and heated to 50 ⁰ C. and stirred. The mass was cooled to 30 ⁰ C and filtered and washed the wet cake with hexane .Wet wt=0.6g.

0.6g of crude aprepitant and 6 mL of ethyl acetate: methanol (1.5:0.15) was stirred, heated to reflux for dissolution and cooled to 50 ⁰ C. 18mL of hexane was added slowly for 30 minutes and stirred for 30hours. The reaction mass cooled to room temperature and stirred for 2hours. The solid was filtered and washed with hexane. The solid was dried under vacuum for 8hours.

Wt=0.35g

Purity: 99.5 % Yiled=50-60%

Purification:

Crude aprepitant (75 g), 750 mL of methanol and 25% charcoal were added and heated to 50 ⁰ C and stirred for 30 minutes. The reaction mass was filtered through hyflow and washed with 12V of hot methanol. The reaction mass was cooled to 30 ⁰ C and water was added slowly for about 30 minutes. The solid was stirred for 2 hours and cooled to 20 ⁰ C and stirred for 30minutes. The solid was filtered and washed with chilled methanol: water (1 : 1) 2 V. The solid was dried under vacuum at 50 ⁰ C for δhours.

Wt=50-65g

Purity=99.6% Yield=50-60%

Second Purification of Aprepitant using MDC: Methanol: Heptane

Crude aprepitant (0.6 g) and 6 mL of MDC: Methanol (1.5:0.15) were stirred and heated to reflux for dissolution for 1 hour and cooled to 50 ⁰ C. Heptane (18 mL) was added slowly for 30 minutes at the same temp and stirred for 30 hours. The reaction mass was cooled to room temperature and stirred for 2 hours. The solid was filtered and washed with heptane. The solid was dried under vacuum for 8 hours Wt=0.35g Purity: 99.5 % Yield=50-60%

Synthesis of starting materials

Process for the preparation of N-methylcarboxy-2-cholroacetamidrazone:

A solution of 5 g chloroacetonitrile in 35 mL of methanol was cooled to 0 ⁰ C. 0.105 g of sodiummethoxide was added and stirred at same temperature for 15min. The reaction mass was stirred at room temperature for 30 min. Acetic acid (0.1 1ml) and then 5g (64.9mmol) of methyl hydrazinocarboxylate were added to the reaction mass and stirred for 30 min at room temperature. The reaction mass cooled to 0 ⁰ C and filtered the solid. The obtained solid was washed with 5V of IPA: water (8:2) to get the crude. The obtained crude was recrystallized by dissolving in acetonitrile 20V at 70 ⁰ C and cooling down to 10 ⁰ C to get white solid of the title compound. Wt=2.5g Yield =50% The prepared compound was stored at 5°C underdark.

Process for the preparation of Dimethyl Titanocene.(DMT)

Titanocene dichloride (120 g) and toluene (10V) was cooled to -10 ⁰ C to 0 ⁰ C. Methyl magnesium chloride (406 mL) was added drop wise into the reaction mass maintaining the temperature below 0 ⁰ C. The reaction mass was stirred for 2 hours at -10 ⁰ C to 0 ⁰ C.

It was then quenched into 6% chilled ammonium chloride solution (10V) maintaining the temperature below 10 ⁰ C. Toluene layer was separated and washed with water,

brine solution and separated the organic layer. The organic layer was distilled under high vacuum (2 mm) at temperature below 30°C and prepared dimethyl Titanocene in toluene is stored below 5°C.