FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: AN IMPROVED, INDUSTRIALLY SAFE AND ECONOMICAL PROCESS FOR THE PREPARATION OF BENZOXAZOLE OF FORMULA I; A KEY INTERMEDIATE FOR THE PREPARATION OF MK-4305
2. APPLICANT:

(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: ARCH HOUSE,
541 A, MAROL MAROSHI ROAD, ANDHERI (E) MUMBAI, 400059, INDIA
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE: An improved, Industrially safe and Economical process for the preparation of Benzoxazole of formula I; a key intermediate for the preparation of MK-4305

FIELD OF TECHNOLOGY: Disclosed herein is an improved process for the preparation of Benzoxazole of formula I; a key intermediate for the preparation of MK-4305 via an advanced intermediate of formula II depicted herein above. The process comprises using economical, industrially safe and commercially available starting materials using novel chemistry to synthesize benzoxazoles thereby making the process of manufacture of key intermediate of formula I economical and industrially safe which intern makes the process for making advanced intermediate of Formula II of MK-4305 economical and industrially safe.
Disclosed herein is a process comprising novel chemistry for the formation of benzoxazole of formula I comprising contacting compound of formula IV with a novel raw material for the instant invention of formula V replacing polymerisable and industrially unsafe methyl vinyl ketone of formula VI in presence of a simple alkali base replacing costlier DBU of the formula VII as reported therein in the prior art.


The novel and inventive process disclosed herein is described herein below:
Present invention provides technical improvement over the existing state of the art through novel chemistry comprising use of non polymeriasable, industrially safe and commercially available raw materials which not only makes the process efficient in respect of industrial safety but also reduces the cost of the process at-least by 1.8 times.

The new chemistry disclosed herein for the synthesis of benzoxazole leads to the successful realization of a suitable route to synthesize MK-4305 on commercial scale.

BACKGROUND OF THE INVENTION: MK-4305 (Suvorexant) is a dual orexin receptor antagonist developed by Merck & Co used against sleeping disorder with the intension of treating insomnia. It is not currently approved for commercial use, but it has completed three Phase III trials.
Insomnia is characterized by difficulty in initiating or maintaining sleep, waking early or finding sleep non-restorative. Merck's investigational dual orexin receptor antagonist MK-4305, is found to be significantly more effective in improving overall sleep efficiency in patients with primary insomnia. Key structural features of MK-4305 includes a 1,4-diazepane ring system with a chiral methyl substituent at 7-position, with the ring nitrogen atoms bearing benzoxazole and aromatic moieties as represented herein below.

Benzoxazole of the formula I is a key intermediate for the preparation of molecule like MK-4305 via an advanced intermediate of formula II commercially called as amine hydrochloride. In simple words Benzoxazole of the formula I is a cyclisation precursor of compound of formula II.
Key intermediates and their key steps for preparation of MK-4305 are described herein below:

The salient feature steps involved in the preparation of MK-4305 are:
1. Preparation of cyclisation precursor also referred as benzoxazole of formula I hereinabove and herein below.
2. Preparation of diazepam ring system.
3. Coupling of diazepam ring system with triazole derivative.
The improved process disclosed herein has addressed the issues associated with the process for the preparation of cyclisation precursor of formula I.
Organic Process Research & Development, 2011, 15, 367-375 discloses two different processes for the preparation of cyclisation precursor benzoxazole of formula I under the heading of Medicinal Chemistry Approach represented as scheme lhaving overall 9 steps as decribed herein below:

A reported drawback associated with this process is that this process is successful only on multigram quantities of cyclisation precursor of formula I termed as benzoxazole. Secondly Aza-Michael reaction comprising the reaction of methyl vinyl ketone and Boc ethylene diamine resulted into lower yield due the formation of dimer of methyl vinyl ketone as a byproduct indicating that methyl vinyl ketone owing to unsaturation is susceptible to undergo the polymerization. Moreover preparative chiral HPLC was used for the resolution purpose which is not handy and feasible at commercial scale, extensive use of protecting groups and the product required chromatographic purification as it remained contaminated with

byproducts. The said process affords 12% overall yield of cyclisation precursor of formula I. Although the said Organic Process Research & Development, 2011, 15, 367-375 as a priot art process discloses the disadvantage of using methyl vinyl ketone as a starting material for the preparation of compound of Formula I as it undergoes dimerisation but it does not indicate, teach or motivate a person skilled in the art about substitution of methyl vinyl ketone by any other raw material that can replace methyl vinyl ketone for the same purpose. Another issue related to the process disclosed therein in the said prior art is the commercial nonavailability. Fyrthermore the said raw material is unstable and has to be stored at a low temperature.
Another process as disclosed in Organic Process Research & Development, 2011, 15, 367-375 is a large scale manufacturing process under the heading of proposed process chemistry approach to the preparation of cyclisation precursor of formula I termed as benzoxazole, represented as scheme 2 therein and described herein below:

Drawback associated with the above process is the use of same polymerisable methyl vinyl ketone and its commercially unavailability and its use making the process industrially unsafe. And uneconomical.
US20110195957A1 discloses Aza Michael reaction under the scheme E therein in the said prior art and described herein below comprising the use of methyl vinyl ketone.


Drawback associated with the above process is again the use of polymerisable methyl vinyl ketone however. Other problem is its commercial unavailability and its use making the process industrially unsafe as it has to be stored and used at low temperature.
DRAWBACKS ASSOCIATED WITH PRIOR ART PROCESS:
1. One major drawback associated with this process is use of methyl vinyl ketone
(MVK) which owing to unsaturation function is susceptible to polymerization.
2. Use of expensive DBU as a base; the current cost at the time of filing the
instant patent application is Rs.5500/kg.
3. Methyl vinyl ketone is not easily available on commercial scale.
4. Methyl vinyl ketone also requires low temperature storage at about 2-8°C, therefore, industrially unsafe and not user friendly.
All the processes disclosed therein in the prior art comprises use of methyl vinyl ketone as a starting material for the preparation of compound of Formula I. None of the processes disclosed therein in the prior art indicate, teach or motivate a person skilled in the art use of any other alternate substitute for methyl vinyl ketone which can be used for the preparation of compound of Formula I replacing the commercially unavailable, industrially unsafe, uneconomical and polymerisable methyl vinyl ketone.
In view of above it is desirable to develop a process for the preparation of Formula I which is a key intermediate for the preparation of drug molecule MK-4305 wherein use of methyl vinyl ketone and uneconomical base DBU are replaced by

industrially safe and economical substitutes. Disclosed herein is a process comprising novel chemistry comprising novel raw materials for the preparation of cyclisation precursor of formula I termed as bezoxazoleas described herein below.

Due diligence of the prior art references in a unity manner or by combining the pieces of information from all the references does not indicate, teach or motivate a person skilled in the art:
- to substitute methyl vinyl ketone of formula VI which is industrially unsafe as requires for storage and handling low temperature and unsuitable as owing to presence of unsaturation functionality has tendency to undergo polymerisation resulting in low yield and polymeric byproduct which makes the process uneconomical and complex and commercially unavailable raw material with a suitable alternate substitute 4-chloro-2-butanone of formula V which owing to absence of unsaturation does not undergo polymerization and is also stored and handled at ambient temperature thus gives good yield without any chance of polymer as a byproduct thus making the process simple, industrially safe and economical.
- Furthermore, with this said novel substitute the reaction is carried out in the presence of a simple base replacing expensive DBU making the process further economical.
The said process has many advantages over the prior art as mentioned herein after in the specification.

1) The present invention is not only improvement over the prior art processes addressing the issues but also provides an economical and industrially viable process hence beneficial to the industry.
2) The process under the present invention is a novel process for the preparation of cyclisation precursor of formula I referred as bezoxazole hereinbefore and hereinafter comprising the use of 4-chloro-2-butanone of formula V as a novel raw material for the instant invention which is easily available and owing to absence of any unsaturation functionality non susceptible to the polymerization.

3) Use of ordinary alkali base replacing costly DBU during the preparation of cyclisation precursor of formula I comprising the reaction of compound of formula D as shown hereinabove and compound of formula V.
4) The process under the present invention is 1.8 times cheaper compared to processes disclosed therein in the prior art.
5) Eliminates aza-Michael reaction from the entire process.
6) All the process disclosed in the prior art can be conveniently modified by replacing polymerisable methyl vinyl ketone by 4-chloro-2-butanone of formula V and thus providing all the three process as improved versions over the known ones.
7) The use of compound of Formula V replacing methyl vinyl ketone makes the process industrially safe and does not require storage of said substitute at low temperature.
OBJECT OF THE INVENTION:

First aspect of the invention is to provide an improved, industrially safe and economical process for the preparation of cyclisation precursor of the formula I, a key intermediate for the preparation of MK-4305.
Second aspect of the invention is to provide a process for the preparation of cyclisation precursor of formula I comprising the use of industrially safe and commercially available raw materials.
Third aspect of the invention is to provide an improved and industrially viable process for the preparation of cyclisation precursor of the formula I comprising the use of industrially safe, commercially available and non polymerisable alternate to polymerisable and industrially unsafe methyl vinyl ketone used in the prior art.
Fourth aspect of the invention is to provide an economical process for the preparation of cyclisation precursor of the formula I comprising the use of an ordinary base replacing costlier DBU known in the prior art.
Fifth aspect of the invention is the preparation of MK-4305 using an advanced intermediate of formula II prepared by using the cyclisation precursor based on the novel process disclosed herein.
SUMMARY OF THE INVENTION:
Disclosed herein is novel chemistry for the preparation of benzoxazole of formula I comprising contacting compound of formula IV with a newly used raw material of formula V for the said reaction replacing polymerisable methyl vinyl ketone of formula VI in the presence of simple alkali base replacing costlier DBU of the formula VII as reported therein in the prior art.
Present invention is not only technical improvement over the existing state of the art that involves novel chemistry comprising use of industrially safe, non polymeriasable and commercially available raw materials which gives higher yield without the formation of polymeric byproduct as an impurity which reduces the cost of the process at-least by 1.8 times.



The said chemical reaction can be depicted as given herein below:
The novel industrially safe and economical process disclosed herein for the preparation of benzoxazole of Formula I provides a industrially safe and viable and economical route to synthesize MK-4305 on commercial scale as the 4-chloro-2-butanone used as a raw material for the preparation of Benzoxazole of Formula I is abundantly available on commercial scale compared to methyl vinyl ketone used in the prior art for the same purpose which is not easily available on commercial scale.
DETAILED DESCREPTION OF THE INVENTION:

Disclosed herein is an efficient, economical and industrially safe and viable process for the preparation of cyclisation precursor of formula I, a key intermediate used for the preparation of an advanced intermediate of formula II which intern is used for the preparation of MK-4305.

The word contact, contacted or contacting used hereinbefore and hereinafter means adding, reacting, stirring, refluxing, mixing and the like.
The present invention relates to novel chemistry for the synthesis of benzoxazole of Formula I which leads to the successful realization of a industrially safe, viable and economical route to synthesize MK-4305 on commercial scale. The instant disclousure may be formulated as the provision of an alternative process for the preparation of bezoxazole of the formula I which addresses the problems and issues of the process disclosed therein in the prior art for the preparation of said intermediate compound used for the preparation of drug molecule MK-4305.
The process disclosed herein comprises use of simple and commercially available raw materials for the preparation of cyclisation precursor of formula I as described herein below:


In an embodiment the compound of the formula D(secondary amine) shown in the scheme herein above is prepared by any of the process available in the art. The compound of formula D is then subsequently contacted with 4-chloro butanone- 2 of formula V in the presence of an ordinary base in a reaction medium resulting in the formation of compound of formula I.
In another embodiment disclosed herein is a process to prepare Aza-Michael reaction product comprising contacting 4-chloro butanone- 2 of formula V with Boc protected amino (or suitably protected) amino compound in the presence of an ordinary base in a reaction medium as depicted herein below in the scheme:

The said Aza-Michael reaction product is subsequently converted finally into MK-4305 by the process known in the art.
The ordinary base used in both the embodiments described hereinabove is an alkali metal based base selected from group comprising hydroxides, carbonates, bicarbonates.
The reaction medium for the reactions described in both the embodiments described hereinabove is a solvent that will not inhibit the progress of the reaction. Preferably the solvent is acetonitrile.
The present invention can be best understood by the way of following example which comprises the use of 4-chloro-2-butanone as a novel reactant reacting with

secondary amine of formula D made by any of the process reported in prior art in presence of an ordinary base like sodium hydroxide.
PREPARATION OF BENZOXAZOLE OF FORMULA I: 190.g of secondary amine of formula D diluted in 3.4 It of acetonitrile is added the solution of l0 Msodium hydroxide to adjust the pH of 11.0 at the ambient temperature followed by the slow addition of 4-chloro-2-butanone at about ambient temperature. The reaction mass is stirred till the completion of the reaction. The reaction mass is then quenched slowly with water, the product precipitated is filtered off and washed with water. Product is dried under vacuum to get 190 g of compound of formula I.

CLAIMS:
We claim:
1. A process for the preparation of compound of formula I

comprising contacting compound of formula IV with compound of formula V in presence of a base

2. The process of claim 1 wherein base is selected from the group comprising alkali metal based hydroxides, carbonates, bicarbonates and mixture thereof.
3. The process of claim 2 wherein base is sodium hydroxide.
4. The compound of Formula I prepared by the process according to claim 1 is used for the preparation of MK-4305 by any standard process disclosed in the art.