DESC:FIELD OF THE INVENTION
The present invention generally relates to a chemical process. Specifically, the present invention relates to a cost effective and industrially scalable process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I),

Formula (I)
wherein: R1 is CN, halogen or O-protecting group.
The tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) is the key intermediate for the preparation of atorvastatin and rosuvastatin.

BACKGROUND OF THE INVENTION
Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

HMG CoA reductase inhibitors are pharmaceutically active compounds used for inhibition of cholesterol biosynthesis. A group of compounds called 'statins' comprising lovastatin, simvastatin, mevastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin and fluvastatin that show antilipidemic activity. By inhibiting this enzyme, cholesterol and LDL-cholesterol production is decreased by statins. Statins also increase the number of LDL receptors on liver cells, which enhances the uptake and breakdown of LDL-cholesterol.

USRE39333E1 discloses a process for producing a 5-hydroxy-3- oxopentanoic acid derivative of formula (IV) which comprises treating a 3- hydroxypropionic acid derivative with a Grignard reagent or a magnesium halide followed by reaction with an acetic acid ester in the presence of a lithium amide at a temperature not below -20 °C

formula (IV)
EP1394157B1 discloses a process of reacting an acetic acid ester and a 3- hydroxypropionic acid chloro derivative at a temperature of not less than -30 °C, in the presence of a Grignard reagent or a magnesium halide followed by the addition of a lithium amide, to afford a 5-hydroxy-3-oxopentanoic acid chloro derivative.

EP2874992B1 discloses a process for crossed claisen condensation reactions promoted by lithium in liquid ammonia wherein at least one ester starting material is a ß-hydroxy ester.

Various available prior art process for preparation of (R)-tert-butyl 6- cyano-5-hydroxy-3-oxohexanoate use more base equivalents which leads to many side reactions and hence, the process becomes tedious and results in less pure desired products.

There is, therefore, an unmet need to develop a commercially viable and industrially scalable process for preparation of tert-butyl 5-hydroxy-3- oxohexanoate which is faster, yields high pure product and utilizes reduced amount of base.

OBJECTS OF THE INVENTION
The main objective of the present invention is to provide a simple and industrially scalable process for preparation of tert-butyl 5-hydroxy-3- oxohexanoate compounds (Atorvastatin and Rosuvastatin intermediate).
Another objective of the present invention is to provide an improved process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compounds which utilizes low amount of base.
Another objective of the present invention is to provide a process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compounds which results in reduced impurities.
Another objective of the present invention is to provide a process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compounds which is faster, cost effective and less impurity formation.
Yet another objective of the present invention is to provide a process for the preparation of Atorvastatin or Rosuvastatin using tert-butyl -5-hydroxy-3- oxohexanoate compound prepared according to the present invention.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I), wherein the process comprising the steps of:

(I)
R1 is CN, halogen, or O-protecting groups;
(a) reacting a compound of formula (A), wherein: R1 is CN, halogen, or O-protecting groups;

(A)
with methyl magnesium chloride or magnesium chloride in a solvent to obtain a premix solution of compound of formula (C) or (D),

(C)

(D)
(b) reacting tert-butyl acetate with lithium / alkali metals such as sodium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene, and the like in a solvent to obtain tert-butyl enolate solution; and
(c) reacting the premix solution of compound of formula (C) or (C1) with the tertbutyl enolate solution to obtain the compound of formula (I).
In another aspect of the present invention, the solvent used in the step (a) and (b) of the process is selected from ether solvents such as tert-butyl methyl ether (MTBE), tetrahydrofuran (THF), monoglyme, diglyme, and chlorinated solvents such as dichloromethane, dichloroethane, tetrachloromethane, trichloroethylene, perchloroethylene and toluene, cylcohexane, hexanes and mixture thereof.
In another aspect of the present invention, the base used in the process is selected from ammonia, diisopropylamine, and HMDS.
In another aspect, the present invention relates to a process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) as shown in the following scheme.

wherein: R1 is CN, halogen, or O-protecting groups.
In another aspect, the present invention relates to a process of preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) as shown in the following scheme.

wherein: R1 is CN, halogen, or O-protecting groups.
Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.

Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”

As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within 15 the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.

All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.

It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method, or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.

Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.

The term, “O-protecting groups” as used herein refers to O-benzyl, p-methoxy-O-benzyl, p-nitro-O-benzyl, O-tosyl, O-mesyl and the like.
In a general embodiment, the present invention relates to a process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I),

wherein: R1 is CN, halogen, or O-protecting groups;
wherein the process comprising the steps of: (a) reacting a compound of formula (A), wherein: R1 is CN, halogen or O-protecting groups;

with methyl magnesium chloride or magnesium chloride in a solvent to obtain a premix solution of compound of formula (C) or (D),

(C)

(D)
(b) reacting tert-butyl acetate with lithium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene and the like in a solvent to obtain tert-butyl enolate solution,
(c) reacting the premix solution of compound of formula (C) or (D) with the tertbutyl enolate solution to obtain the compound of formula (I).
In an embodiment, the present invention relates to a process for preparation of (R)-tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) comprising the step of:

(a) reacting a compound of formula (A) (wherein R1 is CN or halogen or O-protecting group) with methyl magnesium chloride or magnesium chloride in a solvent to obtain a premix solution comprising a compound of formula (C) or (D);
(b) reacting tert-butyl acetate with lithium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene, and the like in a solvent to obtain tert-butyl enolate solution; and
(c) reacting the premix solution comprising the compound of formula (C) or (D) with the tert-butyl enolate solution in a solvent to obtain the (R)-tert-butyl 5- hydroxy-3-oxohexanoate compound of formula (I) (wherein R1 is CN or halogen).

In an embodiment, the present invention relates to a process for preparation of (S)-tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) comprising the step of:

(a) reacting a compound of formula (A) (wherein R1 is CN or halogen or O-protecting group) with methyl magnesium chloride or magnesium chloride in a solvent to obtain a premix solution comprising a compound of formula (C) or (D);
(b) reacting tert-butyl acetate with lithium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene, and the like in a solvent to obtain tert-butyl enolate solution,
(c) reacting the premix solution comprising the compound of formula (C) or (D) with the tert-butyl enolate solution in a solvent to obtain the (S)-tert-butyl 5- hydroxy-3-oxohexanoate compound of formula (I) (wherein R1 is CN or halogen).

In an embodiment, the present invention relates to a process for preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate comprising the step of:

(a) reacting (R)-ethyl 4-cyano-3-hydroxybutanoate with methyl magnesium chloride in a solvent to obtain a premix solution comprising a compound of C1;
(b) reacting tert-butyl acetate with lithium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene and the like in a solvent to obtain tert-butyl enolate solution,
(c) reacting the premix solution comprising the compound of C1 with the tert-butyl enolate solution in a solvent to obtain the of (R)-tert-butyl 6-cyano-5- hydroxy-3-oxohexanoate.

In an embodiment, the present invention relates to a process for preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate comprising the step of:

(a) reacting (R)-ethyl 4-cyano-3-hydroxybutanoate with magnesium chloride in a solvent to obtain a premix solution comprising a compound of D1;
(b) reacting tert-butyl acetate with lithium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene and the like in a solvent to obtain tert-butyl enolate solution,
(c) reacting the premix solution comprising the compound of D1 with the tert-butyl enolate solution in a solvent to obtain the of (R)-tert-butyl 6-cyano-5- hydroxy-3-oxohexanoate.

In another embodiment, the present invention relates to a process for preparation of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate comprising the step of:

(a) reacting (S)-ethyl 4-chloro-3-hydroxybutanoate with methyl magnesium chloride in a solvent to obtain a premix solution comprising a compound of C2;
(b) reacting tert-butyl acetate with lithium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene, and the like in a solvent to obtain tert-butyl enolate solution,
(c) reacting the premix solution comprising the compound of C2 with the tert-butyl enolate solution in a solvent to obtain the of (S)-tert-butyl 6-chloro-5- hydroxy-3-oxohexanoate.

In another embodiment, the present invention relates to a process for preparation of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate comprising the step of:

(a) reacting (S)-ethyl 4-chloro-3-hydroxybutanoate with magnesium chloride in a solvent to obtain a premix solution comprising a compound of D2;
(b) reacting tert-butyl acetate with lithium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene, and the like in a solvent to obtain tert-butyl enolate solution,
(c) reacting the premix solution comprising the compound of D2 with the tert-butyl enolate solution in a solvent to obtain the of (S)-tert-butyl 6-chloro-5- hydroxy-3-oxohexanoate.

In an embodiment of the present invention, the solvent used in the preparation of premix solution is ether solvent selected from tert-butyl methyl ether (MTBE), and tetrahydrofuran (THF); chlorinated solvent selected from dichloromethane, dichloroethane, tetrachloromethane, trichloroethylene, and perchloroethylene; toluene, hexanes, cyclohenane and mixture thereof. Preferably, the solvent is tert-butyl methyl ether (MTBE), tetrahydrofuran (THF) or toluene, hexanes, cyclohexane or mixture thereof.

In an embodiment of the present invention, the solvent used in the preparation of tert-butyl ethonate solution is ether solvent selected from tert-butyl methyl ether (MTBE), and tetrahydrofuran (THF) or chlorinated solvent selected from dichloromethane, dichloroethane, tetrachloromethane, trichloroethylene, perchloroethylene and mixture thereof. Preferably, the solvent is tert-butyl methyl ether (MTBE), tetrahydrofuran (THF), toluene, hexanes, cyclohexane or mixture thereof.

In an embodiment of the present invention, the base used in the preparation of tert-butyl ethonate solution is liquid ammonia, diisopropylamine, or hexamethyldisilazane (HMDS).

In an embodiment, the process of the present invention utilizes low equivalent lithium and tert-butyl acetate to obtain the final compounds.

In another embodiment of the present invention, the lithium was used in less than three equivalents in the instant process to obtain the final compounds.

In another embodiment of the present invention, the tert-butyl acetate was used in less than three equivalents in the instant process to obtain the final compounds.

According to the process of the present invention, the tert-butyl acetate self-condensation impurity, t-butyl acetoacetate was reduced significantly.

In another embodiment, the process of the present invention is faster and cost-effective process.

While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions, or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.

EXAMPLES
The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.
Example 1: Preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate

To tetrahydrofuran (50 ml) at room temperature was added (R)-ethyl 4- cyano-3-hydroxybutanoate (25 g). Cooled the reaction mass to 0 to 5°C slowly and added 2.0M Methyl magnesium chloride (79.5 ml) solution in tetrahydrofuran at 0 to 5°C. The mixture was stirred for 1-2 hrs at 0 to 5°C to obtain a premix solution. In separate round bottom flask, tert-butyl methyl ether (50 ml) and THF (25 ml) were charged under argon condition. To the solution, charged DIPA at 25 to 30°C slowly and added Lithium metal (3.2 g) at 25 to 30°C. The reaction mass temperature was raised to 30 to 35°C and added slowly styrene solution and stirred for 20 min at 45 to 55°C. Slowly added t-butyl acetate at -65 to -50°C and stirred for 20 min at -50 to -60°C to obtain t-butyl acetate enolate solution. Added the premix solution to the t-butyl acetate enolate solution at -45 to -40°C and stirred for 1-3 hours at -40 to -35°C. The reaction mass was quenched with 6N HCl solution and the organic layer was separated. The organic layer was distilled under reduced pressure to obtain a title product. Yield: 34.8 g (96.3 %).
Example 2: Preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate

In RB flask charged tetrahydrofuran (50 ml) and (R)-ethyl 4-cyano-3- hydroxybutanoate (25 g) at room temperature. The reaction mass was cooled to 0 to 5°C and slowly added 2.0M Methyl magnesium chloride (79.5 ml) solution in tetrahydrofuran at 0 to 5°C. The reaction mixture was stirred for 1-2 hrs at 0 to 5°C to get pre mix solution. In another RB flask, charged tert-butyl methyl ether under argon condition and added liquid ammonia at -50 to -60°C slowly and Lithium metal (3.2 g) at -50 to -60°C. The reaction mass was stirred for 10 min at -50 to -60°C, slowly added styrene at -50 to -60°C and stirred for 20 min at -50 to -60°C. Slowly added t-butyl acetate (50.6 g) at -50 to -60°C to the reaction mixture and stirred for 20 min at -50 to -60°C to obtain t-butyl acetate enolate solution. Added the premix solution to the t-butyl acetate enolate solution at -60 to -70°C and stirred for 1-2 hrs at -60 to -70°C. The reaction mass was quenched with 6N HCl solution and separated organic layer. The organic layer was distilled under reduced pressure to obtain the title product. Yield 34.2 g (94, 6%), Purity (98 %, assay 95 %, tert-butyl acetoacetate ~ 1.0 %)
Example 3: Preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate

The Tetrahydrofuran (50 ml) was charged to RB flask at room temperature and added (R)-ethyl 4-cyano-3-hydroxybutanoate (25 g). The reaction mass was cooled to 0 to 5°C and slowly added 2.0M methyl magnesium chloride (79.5 ml) solution in tetrahydrofuran at 0 to 5°C. The reaction mixture was stired for 1-2 hrs at 0 to 5°C to get pre mix solution. In another RB flask, charged Toluene (90 ml) under argon condition and slowly add Li metal (3.2 g) at room temperature. The reaction mass was cooled to -50 to -60°C and added anhydrous liquid ammonia (30 g) at -50 to -60°C, stirred for 20 to 30 min at -50 to -60°C. Lithium bronze was observed. The reaction mass temperature was raised to 25-30°C and once the ammonia completely evocated reaction mass temperature raised to 70- 80°C. The reaction mixture was stirred for 5 to 6 hours at 70-80°C and cooled the reaction mass to -50 to -60°C. Added anhydrous liquid ammonia (30 g) at -50 to -60°C and stirred for 20-30 min. Slowly added t-butyl acetate (50.6 g) at -50 to -60°C and stirred for 20 min at -50 to -60°C to obtain t-butyl acetate enolate solution. Added the premix solution to the t-butyl acetate enolate solution at -60 to -70°C and the mixture was stirred for 5 to 6 hours at -60 to -70°C. The reaction mass was quenched with 6N HCl solution and separated organic layer. The organic layer was distilled under reduced pressure to obtain the title compound. Yield: 33.8g (93.5%).
Example 4: Preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate

Charged (R)-ethyl 4-cyano-3-hydroxybutanoate (25 g) and MgCl2 (6.2 g) into RB flask and heated the reaction mass to 90 to 95°Cunder stirring for 2 to 3 hrs. The reaction mass was cooled to room temperature. Obtained foamy solid was dissolved in 50 ml THF to get pre-mix solution. In another RB flask, tertbutyl methyl ether (25 ml) and THF (25 ml) were charged under argon condition, charged DIPA (60 g) at 25 to 30°C slowly and added Lithium metal (3.2 g) at 25 to 30°C. The reaction mass temperature was raised to 30 to 35°C and slowly added styrene (30 g) solution in THF (38 ml) at 35 to 45°C and stirred for 20 min at 35 to 45°C. Slowly added t-butyl acetate (48.5 g) at -45 to -50°C and stirred for 20 min at -45 to -50°C to obtain t-butyl acetate enolate solution. Added the premix solution to the t-butyl acetate enolate solution at -45 to -40°C and stirred the mixture for 2 to 3 hrs at -40 to -35°C. The reaction mass was quenched with 6N HCl solution and separated the organic layer. The organic layer was distilled under reduced pressure to obtain the title compound. Yield: 34.2 g. (99.1%).
Characterization: IR data of the starting material, (R)-ethyl 4-cyano-3- hydroxybutanoate is 1722.78 cm-1 (C=O stretching); and 3455.75cm-1 (O-H stretching). IR data of foamy solid (premix with magnesium chloride) is 1685.88 cm-1 (C=O stretching) and 3287.12 cm-1 (O-H stretching). The foamy solid (premix with magnesium chloride) is insoluble in tert-butyl methyl ether (MTBE), whereas (R)-ethyl 4-cyano-3-hydroxybutanoate is soluble in tert-butyl methyl ether (MTBE).
Example 5: Preparation of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate

The tetrahydrofuran (50 ml) were charged to RB flask at room temperature and added (S)-ethyl 4-chloro-3-hydroxybutanoate (25 g). The reaction mass was cooled to 0 to 5°C and slowly added 2.0M Methyl magnesium chloride (75.72 ml) solution in tetrahydrofuran at 0 to 5°C. The reaction mixture was stirred for 1-2 hrs at 0 to 5°C to obtain premix solution. In another RB, the tetrahydrofuran (65 ml) was charged under argon condition, collect liquid ammonia (45 g) at -50 to -60°C and slowly added Lithium metal (2.6 g) at -50 to - 60°C. The reaction mass was stirred for 10 min at -50 to -60°C and slowly added styrene (20.5 g) at -50 to -60°C and stir for 20 min at -50 to -60°C. Slowly added t-butyl acetate (43.6 g) at -50 to -60°C and stirred for 20 min at -50 to -60°C to obtain t-butyl acetate enolate solution. Add the premix solution to the t-butyl acetate enolate solution at -60 to -70°C and stirred for 2 to 3 hrs at -60 to -70°C. The reaction mass was quenched with 6N HCl solution and separated the organic layer. The organic layer was distilled under reduced pressure to obtain the title compound. Yield: 35.2 g (96.1%).

Example 6: Preparation of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate

Charged (S)-ethyl 4-chloro-3-hydroxybutanoate (25 g) and MgCl2 (5.65 g) in RB flask and heated the reaction mass to 100 to 110°C under stirring for 2 to 3 hrs. The reaction mass was cooled to room temperature. Obtained foamy solid was dissolved in 50 ml THF to get pre mix solution. In another RB flask, the tert-butyl methyl ether (25 ml) and THF (25 ml) were charged under argon condition, and added DIPA (41.3 g) at 25 to 30°C slowly and added Lithium metal (2.82 g) at 25 to 30°C. The reaction mass temperature was raised to 30 to 35°C. Slowly added styrene (23.12 g) solution in THF (38 ml) at 35 to 45°C and stirred for 20 min at 35 to 45°C. Slowly added t-butyl acetate (43.53 g) at -45 to -50°C and stirred for 20 min at -45 to -50°C to obtain t-butyl acetate enolate solution. Added the premix solution to the t-butyl acetate enolate solution at -45 to -40°C and stirred for 2-3 hrs at -40 to -35°C. The reaction mass was quenched with 6N HCl solution and separated organic layer. The organic layer was distilled under reduced pressure to obtain the title product. Yield: 34.86 g (98.2%).

A skilled artisan will appreciate that the quantity and type of each ingredient can be used in different combinations or singly. All such variations and combinations would be falling within the scope of present disclosure.

The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

ADVANTAGES OF THE PRESENT INVENTION
The present invention provides a process for preparation of tert-butyl 5- hydroxy-3-oxohexanoate compounds which advantageously utilizes low equivalent of lithium and base.

The present invention provides a process for preparation of tert-butyl 5- hydroxy-3-oxohexanoate compounds which advantageously reduces the impurity.

The present invention provides a process for preparation of tert-butyl 5- hydroxy-3-oxohexanoate compounds which is faster and cost-effective.

,CLAIMS:1. A process for the preparation of compound of formula (I)

(I)
wherein R1 is CN, halogen, or O-protecting groups;
(a) reacting a compound of formula (A), wherein: R1 is CN, halogen, or O-protecting groups;

(A)
with methyl magnesium chloride or magnesium chloride in a solvent to obtain a premix solution of compound of formula (C) or (D),

(C)

(D)
(b) reacting tert-butyl acetate with lithium / alkali metals such as sodium in presence of a base and optionally electron transfer reagents such as styrene, isoprene, naphthalene, and the like in a solvent to obtain tert-butyl enolate solution; and
(c) reacting the premix solution of compound of formula (C) or (D) with the tertbutyl enolate solution to obtain the compound of formula (I).

2. The process as claimed in claim 1, wherein tert-butyl acetate reacts with Li/LiqNH3 or Li/DIPA and optionally electron transfer reagents such as styrene, isoprene, naphthalene, and the like in THF to obtain tert-butyl enolate solution.