FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"NOVEL PROCESS FOR SYNTHESIS OF A (NEUROKININ-1) RECEPTOR
ANTAGONIST"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field of the Invention:
The present invention relates to a process for the preparation of a neurokinin-1 receptor
antagonist.
In particular the invention relates to novel key intermediates used in synthesis of
Aprepitant and processes for preparation thereof.
Background and prior art:

Aprepitant, chemically described as 5-[[(2/?,3S)-2-[(l/?)-l-[3,5-

bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-l,2-dihydro-3//-l,2,4-triazol-3-one, is a substance P(neuarokinin 1) receptor antagonist. Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal.

It is useful for prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) and for prevention of postoperative nausea and vomiting.

Aprepitant was first disclosed in US patent 5,719,147. The patent also provides a process for the preparation of aprepitant which involves reacting (S)-3-(4-fluorophenyl)-4-(phenylmethyl)-2-morphoIinone with L-selectriderM, treating the reaction mixture with 3,5-bis(trifluoromethyl)benzoyl chloride, and further isolating (2R-cis)-3,5-
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bis(trifluoromethyl)-benzeneacetic acid 3-(4-fIuorophenyl)-4(phenylmethyl)-morpholinyl
ester using flash chromatography. The compound thus obtained is treated with dimethyl
titanocene in toluene to yield (2R-cis)-2-[[l-[3,5-bis(trifluoromethyl)phenyl-
ethenyl]oxy]-3-(4-fluorophenyl)-4(phenylmethyl) morpholine, which is further converted
to [2R[2a(R*),3a]]-2-[ 1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-
fluorophenyl)morpholine 4-methylbenzenesulfonate salt. The salt is finally treated with N-methylcarboxy-2-chloroactamidrazone in presence of aqueous ammonium chloride and cylizing the resulting compound in xylene to obtain Aprepitant.
This process requires isolation by flash chromatography, which is expensive technique and not feasible on industrial scale.
WO 03/089429A1 application describes a process for preparation of aprepitant by reacting hydrochloride salt of (2R, 2-alpha-R, 3a)-2-[l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-l,4-oxazine with amidrazone in presence of inorganic base and aprotic solvent, followed by cyclization at 140-150°C. There are various patents related to process of preparation of intermediates, which are cited here as follows.
US6096742A discloses preparation of [2R-[2a(R*),3a]]-2-[l-[3,5-
bis(Trifluoromethyl)phenyl] ethoxy]-3-(4-fiuorophenyl)morpholine, an intermediate
useful in the preparation of Aprepitant by reducing (2R-cis)-2-[[l-[3.5-
bis(trifluoromethyl)-phenyl] ethenyl] oxy]-3-(4-fluorophenyl)-4-
(phenylmethyl)mopholine with 10% Pd/C and hydrogen.
US6469164B2 claims (2R, 2-alpha-R)-4-benzyl-2-[l-[3,5-
bis(trifluoromethyl)phenyl]ethoxy-l,4-oxazin-3-one, an intermediate in the preparation of substance P(neurokinin 1) receptor antagonist. The process involves coupling of activated 4-benzyl-2-hydroxy-l,4-oxazin-3-one with (R)-l-[3,5-bis(trifluoromethyl)phenyl]ethan-l-ol in the presence of Lewis acid (boron trifluoride etherate).
US6504066B1 claims process for the preparation of (R)-l-(3,5-
bis(trifluoromethyl)phenyl)ethan-l-ol by treating 1 -(3,5-
bis(trifluoromethyl)phenyl)ethane-l-one with bis(pentamethylcyclopentadienyl)rhodium
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chloride or with bis(4-isopropyl-toluenyl)ruthenium chloride) and (S,R)-cis-l-amino-2-hydroxy-indane in presence of isopropanol.
The method is tedious as it involves use of rhodium or ruthenium catalyst, which is not readily available and very expensive.
US6395898B1 claims the process for preparation of (2R-2-alpha-R, 3a)-2- [l-(3,5-bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluorophenyl)-l,4-oxazine, which is an intermediate in the synthesis of substance P (neurokinin-1) receptor antagonists. The process involves reduction of 3-(4-fluoro-phenyl)-4-(l-phenyl-ethyl)-morpholin-2-one followed by activation with trichloroacetonitrile to give 2,2,2-trichloro-acetimidic acid 3-(4-fluoro-phenyl)-4-(l-phenyl-ethyl)-morpholin-2-yl ester. This compound is then coupled with 1-(3,5-Bis-trifluoromethyl-phenyl)-ethanol in presence of a Lewis acid followed by hydrogenation to form 2-[l-(3,5-bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-morpholine (trans-glycoside), which is converted to cis-glycoside by dehydrogenation followed by hydrogenation.
Zhao, M. M. et. al. J. Org. Chem. 2002, 67, 6743-6747 describes synthesis of Aprepitant
by condensing 2-[l-(3,5-bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-
morpholine (cis-glycoside) obtained from the method described in US6395898B1, with 5-chloromethyl-2,4-dihydro-[l,2,4]triazol-3-one in presence of K2C03 and dimethyl formamide.
The scheme can be collectively represented as shown below in scheme 1 SCHEME 1
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As described in the prior art, various methods are developed for the preparation of Aprepitant and its intermediates. The present invention is an attempt to provide improved process for the preparation of Aprepitant involving the use of novel intermediates. The process is cost effective, simple and utilizes readily available reagents.
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Objects of the invention
The object of present invention is to provide a novel process for chiral synthesis of
Aprepitant.
Another object of present invention is to provide a process for the preparation of
Aprepitant involving use of novel intermediates and their preparation.
Yet another object of the invention is to provide improved process for the stereoselective
synthesis of intermediate 3,5-Bis(trifluoromethyl)phenyl ethane-1-ol, to provide desired
stereoselective isomer in high yields and purity.
Detailed description of the invention
In one aspect, present invention provides improved process for the synthesis of Aprepitant, which involves the use of a key intermediate (A) of formula

(A)
The stereogenic centers are indicated by asterisk (*), which may be present in S or R
configuration.
Further the present invention provides a process for the synthesis of the key intermediate
(A) which involves the use of novel intermediates of formula (I), (II) and (III).
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*^N.
(I)

The process can be schematically represented as shown in scheme 2,
SCHEME 2


X> * -V
Fluorobenzene Oxalyl Chloride
(4-Fluoro-phenyl)-oxo-acetic acid ethyl ester

wherein it comprises the following steps:
(i) Fluorobenzene is added to ethyl oxalyl chloride in presence of methylene dichloride and aluminium trichloride to isolate (4-Fluoro-phenyl)-oxo-acetic acid ethyl ester. It is further condensed with phenyl ethylamine in a suitable solvent in presence of dehydrating
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agent, most preferably, titanium tetrachloride to get novel intermediate (I) in higher yield. The solvent used in the process is preferably selected from toluene, hexane, benzene, diethyl ether, chloroform and ethylacetate.
(ii) Intermediate (I) is further reduced catalytically or using a suitable reducing agent, such as Raney nickel, to obtain intermediate II in high yields. Intermediate (II) is further condensed with bromoethanol in a suitable organic solvent, preferably acetonitrile, dimethylformamide, 1,4-dioxane, tetrahydrofuran, acetone, and in presence of a base in aprotic polar solvent to isolate intermediate III.
(iii) Intermediate (III) thus obtained is further cyclized in presence of a suitable acid, preferably acetic acid at suitable temperature to get compound (A).

Xylene
Aprepitant ■*
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In another aspect the invention provides a process for the preparation of Aprepitant, using compound (A) as prepared by scheme II, wherein compound (A) is reduced using suitable reducing agent, such as Lithium tri-sec-butyl borohydride (L-selectride™) or di(iso-butyl)lithium hydride) (DIBAL-H) to 3-(4-Fluoro-phenyI)-4-(l-phenylethyl)-2-morpholinol. The compound is further converted to Aprepitant as shown in scheme 3, Scheme 3

wherein the process comprises following steps:
At a suitable temperature trifluoroacetic anhydride is added to slurry of 3-(4-Fluoro-phenyl)-4-(l-phenylethyl)-2-morpholinol in an organic solvent in anhydrous conditions and in presence of suitable Lewis acid preferably selected from boron trifluoride etherate, trimethylsiiyl trifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride and the like. The organic solvent used in the process is preferably selected from acetonitrile, dimethylformamide, ethyl acetate, tetrahydrofuran, toluene and dichloromethane.
To the reaction mixture, 3,5-Bis(trifluoromethyl)phenyl-l-ethanol (compound (IV)) is added, followed by slow addition of alkali, preferably sodium hydroxide at a suitable temperature. Compound (V) is isolated in suitable solvent, such as C1-C4 primary, secondary and tertiary alcohols, water and mixtures thereof, most preferably methanol, ethanol, isopropanol, n-propanol, n-butanol and water. Compound (V) is subjected to hydrogenation using a suitable catalyst such as palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica and palladium hydroxide on carbon to form 2-[l-(3,5-bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-morpholine. It is treated with gaseous hydrogen chloride to form its hydrochloride salt (VI).
Compound (VI) thus obtained is condensed with N-methylcarboxy-2-chloroacetamidrazone to get an intermediate (VII), which is further cyclized in presence of suitable solvent, preferably xylene at ambient temperature to give Aprepitant.
In a further aspect the present invention provides an improved process for preparation of compound (IV), from 3,5-bis-trifluoromethyl acetophenone through the preparation of diazabicyclo octane (hereafter referred to as DABCO) complex using oxazaborolidine catalyst as shown below:
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3,5-bis-trifluoromethyl S^BisflnfluoromethyOphenyl
acetophenone DABCO Complex (|v)
3,5-bis-trifluoromethyl acetophenone dissolved in a suitable solvent, preferably tetrahydrofuran and reduced using oxazaborolidine catalyst at a suitable temperature. The catalyst is prepared by purging borane gas in previously prepared solution of S(-)-diphenyl prolinol and tetrahyhdrofuran. Borane gas used is prepared by adding boron trifluoride etherate to the mixture of sodium borohydrate and diglyme. The reaction mixture is then treated with DABCO solution to form DABCO complex. DABCO complex is optionally isolated in a suitable non-polar organic solvent. The pH of the complex is adjusted, preferably in the range of 4-5, using suitable organic or inorganic acid such as hydrochloric acid to liberate desired stereoisomer of 3,5-bis(trifluoromethyl)phenyl-l-ethanol (IV). The stereoisomer is an important intermediate useful in the preparation of Aprepitant.
The process is advantageous over prior art as it provides stereoselective synthesis of compound (IV). It is more simple, as it involves formation of in situ oxazaborolidine catalyst resulting in desired stereoisomer with higher yield and greater enantiomeric excess.
This invention covers all the stereoisomeric forms of phenylethylamine and novel intermediates (I), (II), and (III); compound A, 3-(4-Fluoro-phenyl)-4-(l-phenylethyl)-morpholin-2-ol, and compounds (V) to (VII), which have at least one stereogenic center.
Examples
Example 1
Preparation of (4-Fluoro-phenyl)-oxo-acetic acid ethyl ester
In a round bottom flask fluorobenzene (111.79 gm), aluminium trichloride (194.9 gm)
and methylene dichloride (700 ml) were charged. The mixture thus obtained was cooled.
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To this ethyl oxalyl chloride (100 gm) was added. The reaction mixture was stirred at 10°C, till completion of reaction. The reaction mixture was quenched in dilute hydrochloric acid (325 ml). The mixture was extracted in methylene dichloride (200 ml X 3). The organic layer was concentrated to get (4-fluoro-phenyl)-oxo-acetic acid ethyl ester (125 gm).
Example 2
Preparation of (4-Fluoro-phenyn-(l-phenyl-ethylamino)-acetic acid ethyl ester Toluene (400 ml) was added to the mixture of (4-fluoro-phenyl)-oxo-acetic acid ethyl ester (20 gm), S(-)-phenyl ethylamine (37 gm) and titanium tetrachloride (19.34 gm) and the mixture was stirred for 16 hours. After completion of the reaction, the reaction mass was concentrated to get (4-Fluoro-phenyl)-(l-phenyl-ethylimino)-acetic acid ethyl ester (18 gm). It was further dissolved in methanol (300 ml) and subjected to reduction under hydrogen pressure (70 psi) at room temperature using Raney nickel as a catalyst to form (4-fluoro-phenyl)-(l-phenyl-ethylamino)-acetic acid ethyl ester (5 gm).
Example 3
Preparation of (4-Fluoro-phenyl)-r(2-hydroxy-ethyn-(l-phenyl-ethyl)-amino]-
acetic acid ethyl ester
The compound obtained in example 2 was added to N,N-diisopropylethylamine (22 gm)
and 2-bromoethanol (38.4 gm) in dimethylformamide (100 ml). The reaction mixture was
heated at 80 to 85°C. After completion of the reaction, the reaction mixture was cooled to
room temperature and water (100 ml) was added. The mixture was extracted with ethyl
acetate (75 ml X 2). The separated organic layer was washed with water (100 ml X 2) and
concentrated under vacuum to get (4-fluoro-phenyl)-[(2-hydroxy-ethyl)-(l-phenyl-ethyl)-
amino]-acetic acid ethyl ester (8 gm).
Example 4
Preparation of 3-(4-Fluoro-phenyl)-4-(l-phenyl-ethyl)-morpholin-2-one
Acetic acid (20 ml) was added to (4-fluoro-phenyl)-[(2-hydroxy-ethyl)-(l-phenyl-ethyl)-
amino]-acetic acid ethyl ester (20 gm) and the reaction mixture was heated to 50 - 60°C.
After completion of the reaction the reaction mixture was cooled to room temperature and
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water (100 ml) was added. The solution was extracted with toluene (100ml X 2). The combined organic layer was washed with 5% Na2C03 solution (100 ml X 2) followed by water (2 X 100 ml). The organic layer was concentrated under vacuum to get 3-(4-Fluoro-phenyl)-4-(l-phenyl-ethyl)-morpholin-2-one (16 gm).
The compound was treated with concentrated hydrochloric acid (6.5 ml) in a mixture of toluene:hexane (20:180 ml) to form crystalline hydrochloride salt of 3-(4-Fluoro-phenyl)-4-(l-phenyl-ethyl)-morpholin-2-one. (Yield: 18 gm).
Example 5
Preparation of 3-(4-Fluoro-phenyl)-4-( 1 -phenyl-ethyl)-morpholin-2-ol
The mixture of 3-(4-fluoro-phenyl)-4-(l-phenyI-ethyl)-morpholin-2-one hydrochloride
salt (10 gm), toluene (40 ml) and saturated aqueous NaHC03 (35 ml) was stirred until
solid dissolves. The residual moisture was removed by azeotropic distillation.
tetrahydrofuran (25 ml) was added and mixture was cooled to -20°C. Gradually added
1.5M di(iso-butyl)lithium hydride) (DIBAL-H) (20.8 ml) in toluene over period of about
20 hrs. The mixture was stirred for 30 minutes and quenched into saturated aqueous
Rochelle salt (25 ml) at 0 - 20°C with stirring mixture. The organic layer was separated,
washed with 1:1 water: brine solution and partially concentrated for further use.
Example 6
Preparation of DABCO complex
To a round bottom flask tetrahydrofuran (800 ml) and S(-)-diphenyl prolinol (5 gm) was charged under argon and cooled to -5 to -10°C. In another round bottom flask boron trifluoride etherate (350 gm) was added to the mixture of NaBH4 (68.17 gm) and diglyme (350 ml) in one hour. Borane gas generated was purged in previously prepared solution of S(-)-diphenyl prolinol at -5 to -10°C to form oxazaborolidine catalyst. The reaction mixture was heated to 60°C for 3 hours. The mixture was again cooled to -5 to -10°C. To the catalyst thus obtained, 3,5-bis trifluoromethyl acetophenone (100 gm) dissolved in tetrahydrofuran was added by dropping funnel at -5 to -10°C to form l-(3,5-bis-trifluoromethyl-phenyl)-ethanol. After completion of the reaction, the reaction mixture was quenched into dilute hydrochloric acid and extracted with heptane (500ml X 2). Further washed with brine solution (500 ml). To the solution of 3,5-bis trifluoromethyl
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alcohol, DABCO (25 gm) was added, partially concentrated and cooled to 0°C to form crystalline DABCO complex (85 gm).
Example 7
Preparation of l-(3,5-Bis-trifluoromethyl-phenyl)-ethanol
To the DABCO complex obtained in example 6, ethyl acetate (425 ml) and water (425
ml) was added and stirred for 15 minutes. The pH of the solution was adjusted between 4-
5, using concentrated hydrochloric acid. Organic layer was separated and washings of
brine solution were given till neutral pH and the solution was concentrated to obtain 1-
(3,5-Bis-trifluoromethyl-phenyl)-ethanol (51 gm).
Example 8
Preparation of 2-[l-(3,5-Bis-trifluoromethvl-phenyn-ethoxy]-3-(4-fluoro-phenyl)-4-( 1 -phenyl-ethvP-morpholine
Trifluoroacetic anhydride (101.44 gm) was added to the reaction mass obtained in example 5, at 5°C. The temperature was raised to 25°C and boron trifluoride etherate (41.15 gm) was added dropwise followed by addition of l-(3,5-bis-trifluoromethyl-phenyl)-ethanol (118.38 gm) in acetonitrile (50%). The mixture was aged for 4 hours at temperature less than 25°C and then NaOH (5M) was added by maintaining the temperature below 27°C followed by addition of 3,7-dimethyl-3-ocatnol (228.94 gm). The resulting mixture was distilled at atmospheric pressure. To this water (240 ml) and heptane (385 ml) was added and mixture was warmed to 45 to 50°C. Organic layer was separated, washed with water and diluted with heptane. The solution thus obtained was dried via azeotropic distillation. The distillate was cooled to room temperature and seeded with R,R-distereoisomer. The reaction mass was cooled to -10°C and potassium tertiary butoxide (35.22 gm) was added. The mixture was aged for 8 hours at -12 to -7°C. Acetic acid (29 gm) was added followed by addition of 5% NaHC03 at 50°C. The organic layer was concentrated via distillation and cooled gradually to -10°C. 2-[l-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-4-(l-phenyl-ethyl)-morpholine (110 gm) thus obtained was washed with cold heptane.
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Example 9
2-[l-(3,5-Bis4rifluoromethyl-phenyl)-ethoxy1-3-(4-fluoro-phenyl)-morpholine hydrochloride salt
2-[l-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-4-(l-phenyl-ethyl)-morpholine (10 gm) was dissolved in methanol (100 ml) and to this solution 10% Pd/C catalyst (0.5 gm) was added. Stirr the reaction mixture under 70 psi hydrogen pressure and the solution was filtered. To the filtrate gaseous hydrogen chloride was passed. The compound obtained was recrystallised using methyl isobutyl ketone (70 ml) to get 2-[l-(3,5-bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-morpholine hydrochloride salt (6 gm). This salt was treated with N-methylcarboxy-2-chloroacetamidrazone (2.27 gm), and further cyclized in xylene (40 ml) to yield Aprepitant (4 gm).
Dated this 1st day of October 2007

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