DESC:FIELD OF THE INVENTION
[0001] The present invention generally relates to a chemical process. Specifically, the present invention relates to an cost effective and industrially scalable continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I),

(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
[0002] 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.
[0003] 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.
[0004] WO2011048425 discloses a continuous process for the production of beta-keto esters of formula (6) by claisen condensation using an alkali metal or alkaline earth metal amide base. In particular, discloses a continuous process for the production of certain pharmaceutically useful intermediate compound, (5R)-1,1- dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate.

(6)
[0005] CN112430197A discloses a continuous flow process for synthesizing 3-oxo-5-hydroxy-6-cyanocaproic acid tert-butyl ester, which takes metal lithium and diisopropylamine as raw materials.
[0006] 4701/DELNP/2006 discloses a process for preparing a lithium amide composition in which in a first step lithium metal is brought into contact with ammonia to form lithium bronze and in a second step the lithium bronze is reacted with a 1.3-diene or an arytolefin in the presence of a solvent.
[0007] 315/MUMNP/2015 discloses a use of lithium amide in liquid ammonia as a base to produce an enolate from at least one ester starting material in a crossed Claisen condensation reaction.
[0008] Various available prior art process for preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoateuse more base equivalents which leads to many side reactions and hence, the process becomes tedious and results in less pure desired products.
[0009] There is, therefore, an unmet need to develop a commercially viable and industrially scalable continuous 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
[0010] The main objective of the present invention is to provide a simple and industrially scalable continuous flow process for preparation of tert-butyl 5-hydroxy-3-oxohexanoate compounds (Atorvastatin and Rosuvastatin intermediate).
[0011] Another objective of the present invention is to provide a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compounds which utilizes lower equivalent of base and relevant reagents.
[0012] Another objective of the present invention is to provide a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compounds which results in reduced impurities.
[0013] Another objective of the present invention is to provide a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compounds with lesser time cycle.
[0014] Another objective of the present invention is to provide a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoatecompoundswhich is faster, cost effective and less impurity formation.
[0015] Yet another objective of the present invention is to provide a continuous flow 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
[0016] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0017] The present invention generally relates to a chemical process. Specifically, the present invention relates to an cost effective and industrially scalable continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoatecompound of formula (I),

(I)
wherein: R1 is CN, halogen or O-protecting group.
[0018] In one aspect, the present invention provides a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I),

(I)
R1 is CN, halogen or O-protecting groups;
wherein the process comprising the steps of:
(a) providing a lithium amide solution at a flow rate in the range of 1.0 ml/min to 25 ml/min and a tert-butyl acetate(TBA)solution at a flow rate in the range of 1.0 ml/min to 25 ml/min into a first microchannel reactor zone at a temperature in the range of -60°C to 10°C at a pressure in the range of 1 milli bar to 100 bar for a residence time in the range of 10 seconds to 50 seconds to obtain an enolate compound of formula (1);

(1)
(b) passing the compound of formula (1) to a second microchannel reactor zoneand contacting a compound of formula (2), wherein: R1 is CN, halogen or O-protecting groups;

(2)
at a flow rate in the range of1.0 ml/min to 25 ml/min in the temperature range of -60°C to 10°C at a pressure in the range of 1 millibar to 100 bar for the residence time in the range of 10 seconds to 50 seconds to obtain a compound of formula (3);

(c) passing the compound of formula (3) to a third microchannel reactor zone and contacting with a solution of HCl at a flow rate in the range of 1.0 ml/min to 25 ml/min at a temperature in the range of -60°C to 10°C at a pressure in the range of 1millibar to 100barfor the residence time in the range of 10 seconds to 50 seconds to obtain a reaction mass; and
(d) passing the reaction mass to a hydrophobic membrane cartridge at a temperature in the range of 25°C to 35°C at a pressure in the range of 1millibar to 100barto obtain the compound of formula (I).
[0019] In another aspect, the present invention provides a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I),

(I)
R1 is CN, halogen or O-protecting groups;
wherein: the process comprising the steps of:
(a) providing an enolate compound of formula (1) and a premix solution of a compound of formula (4) or a compound of formula (5);

at a flow rate in the range of 1.0 ml/min to 25 ml/min into the microchannel reactor zone at a temperature in the range of -60°C to 10°C at a pressure in the range of 1millibar to 100 bar for a residence time in the range of 10 seconds to 50 seconds to obtain a compound of formula (3a);

(b) quenching the compound of formula (3a) in HCl to obtain the compound of formula (I).
[0020] In one more aspect of the present invention, the lithium amide solution is prepared by the steps of (a) reacting liquid ammonia and lithium metal in a solvent under argon atmosphere at a temperature in a range of -50 to -60°C to obtain a reaction mass of lithium amide solution; and (b) optionally adding a solution of styrene in MTBE to the reaction mass at a temperature in a range of -50 to -60°C to obtain the lithium amide solution.
[0021] In another aspect of the present invention, the enolate compound of formula (1)is prepared by the steps of (a) reacting liquid ammonia and lithium metal in a solvent under argon atmosphere at a temperature in a range of -50 to -60°C to obtain a reaction mass; (b) optionally adding a solution of styrene in MTBE to the reaction mass at a temperature in a range of -50 to -60°C to obtain a lithium amide solution; and (c) adding a solution of tert-butyl acetate in MTBE at a temperature in the range of -50 to -60°C to obtain the enolate compound of formula (1).
[0022] In another aspect of the present invention, the solvent used in the preparation of the lithium amide solution and enolate compound of formula (I) 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 or mixture thereof and the like.
[0023] In another aspect, the present invention relates to a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) as shown in the following General scheme-1.

wherein: R1 is CN, halogen or O-protecting groups.
[0024] 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 General scheme-2.

wherein: R1 is CN, halogen or O-protecting groups.
[0025] 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
[0026] 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.
[0027] 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.”
[0028] 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.
[0029] 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.
[0030] 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 the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
[0031] 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.
[0032] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0033] 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.
[0034] 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.
[0035] 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 particular 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.
[0036] 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.
[0037] 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.
[0038] The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.
[0039] 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.
[0040] The present invention provides a process for preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) comprising the steps of:
a) providing a lithium amide solution and a tert-butyl acetate(TBA) solution into a first microchannel reactor zone under condition to obtain an enolate compound of formula (1);

(1)
b) passing the compound of formula (1) to a second microchannel reactor zone and contacting a compound of formula (2), wherein: R1 is CN, halogen or O-protecting groups

(2)
under condition to obtain a compound of formula (3);

c) passing the compound of formula (3) to a third microchannel reactor zone and contacting with a solution of HCl under condition to obtain a reaction mass; and
d) passing the reaction mass to a hydrophobic membrane cartridge under condition to obtain the compound of formula (I).

(I)
wherein R1 is CN, halogen or O-protecting groups.

[0041] In an embodiment of the present invention, the lithium amide solution and a tert-butyl acetate(TBA) solution in step a) are provided at a flow rate in the range of 1.0 ml/min to 25 ml/min into the first microchannel reactor zone. The condition in step a) includes a temperature in the range of -60°C to 10°C at a pressure in the range of 1 milli bar to 100 bar for a residence time in the range of 10 seconds to 50 seconds.
[0042] In an embodiment of the present invention, the condition in step b) includes a flow rate in the range of 1.0 ml/min to 25 ml/min at a temperature in the range of -60°C to 10°C at a pressure in the range of 1 millibar to 100 bar for the residence time in the range of 10 seconds to 50 seconds.
[0043] In an embodiment of the present invention, the condition in step c) includes a flow rate in the range of 1.0 ml/min to 25 ml/min at a temperature in the range of -60°C to 10°C at a pressure in the range of 1 millibar to 100 bar for the residence time in the range of 10 seconds to 50 seconds.
[0044] In an embodiment of the present invention, the condition in step d) includes a temperature in the range of 25°C to 35°C at a pressure in the range of 1 millibar to 100 bar.
[0045] In another embodiment, the present invention provides a continuous flow process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) comprising the steps of:
a) providing an enolate compound of formula (1) and a premix solution of a compound of formula (4) or a compound of formula (5)

into the microchannel reactor zone under condition to obtain a compound of formula (3a);

(b) quenching the compound of formula (3a) in HCl to obtain the compound of formula (I).
[0046] In another embodiment, the enolate compound of formula (1) and a premix solution of a compound of formula (4) or a compound of formula (5) are provided into the microchannel reactor zone at a flow rate in the range of 1.0 ml/min to 25 ml/min.
[0047] In another embodiment, the condition in step a) includes a temperature in the range of -60°C to 10°C at a pressure in the range of 1 millibar to 100 bar for a residence time in the range of 10 seconds to 50 seconds.
[0048] In another embodiment, the lithium amide solution is prepared by the steps of: a) reacting liquid ammonia and lithium metal in a solvent under argon atmosphere at a temperature in a range of -50 to -60°C to obtain a reaction mass of lithium amide solution; and (b) adding a solution of styrene in MTBE to the reaction mass at a temperature in a range of -50 to -60°C to obtain the lithium amide solution.
[0049] In another embodiment, the enolate compound of formula (1) is prepared by the steps of: a) reacting liquid ammonia and lithium metal in a solvent under argon atmosphere at a temperature in a range of -50 to -60°C to obtain a reaction mass; b) adding a solution of styrene in MTBE to the reaction mass at a temperature in a range of -50 to -60°C to obtain a lithium amide solution; and c) adding a solution of tert-butyl acetate in MTBE at a temperature in the range of -50 to -60°C to obtain the enolate compound of formula (1).
[0050] In another embodiment, the solvent selected from a group consisting of 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 and hexanes or mixture thereof.
[0051] In certain embodiment, the present invention relates to a process for the preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I),

(I)
R1 is CN, halogen or O-protecting groups;
wherein the process comprising the steps of:
(a) providing a lithium amide solution at a flow rate of 8.0 ml/min and a tert-butyl acetate (TBA) solution at a flow rate of 2.0 ml/min into a first microchannel reactor zone at a temperature in the range of -20°C to -10°C at 60 bar pressure for a residence time of 15 seconds to obtain an enolate compound of formula (1);

(1)
(b) passing the compound of formula (1) to a second microchannel reactor zoneand contacting a compound of formula (2), wherein: R1 is CN, halogen or O-protecting groups;

(2)
at a flow rate of 2.0 ml/min in the temperature range of -10°C to 0°C at a 60 bar pressure for the residence time of 15seconds to obtain a compound of formula (3);

(c) passing the compound of formula (3)to a third microchannel reactor zone and contacting with a solution of HCl at a flow rate of 6.0 ml/min at a temperature in the range of -10°C to 0°C at 60 bar pressure for the residence time of 15 seconds to obtain a reaction mass; and
(d) passing the reaction mass to a hydrophobic membrane cartridge at a temperature in the range of 25°C to 35°C at 3.0 bar pressure to obtain the compound of formula (I).
[0052] In another 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:

(I)
wherein: R1 is CN, halogen or O-protecting groups;
(a) providing an enolate compound of formula (1) and a premix solution of a compound of formula (4);

at a flow rate of 3.0 ml/min into the microchannel reactor zone at a temperature in the range of 10°C to 0°C at 60 bar pressure for a residence time of 15 seconds to obtain a compound of formula (3a);

(b) quenching the compound of formula (3a) in HCl to obtain the compound of formula (I).
[0053] In another 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:

(I)
wherein: R1 is CN, halogen or O-protecting groups;
(a) providing an enolate compound of formula (1) and a premix solution of a compound of formula (5);

at a flow rate of 3.0 ml/min into the microchannel reactor zone at a temperature in the range of 10°C to 0°C at 60bar pressure for a residence time of 15seconds to obtain a compound of formula (3a);

(b) quenching the compound of formula (3a) in HCl to obtain the compound of formula (I).
[0054] In another embodiment, the present invention relates to a continuous flow process for preparation of (R)-tert-butyl 5-hydroxy-3-oxohexanoate comprising the step of:
.
[0055] In another embodiment, the present invention relates to a continuous flow process for preparation of (R)-tert-butyl 5-hydroxy-3-oxohexanoate comprising the step of:
.
[0056] 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.
[0057] 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.
[0058] In an embodiment, the process of the present invention utilizes low equivalent lithium and tert-butyl acetate to obtain the final compounds.
[0059] 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.
[0060] 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.
[0061] According to the process of the present invention, the tert-butyl acetate self-condensation impurity, t-butyl acetoacetate was reduced significantly.
[0062] In another embodiment, the process of the present invention is faster and cost effective process.
[0063] 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.
[0064] 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 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
[0065] 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

Step-1: Preparation of Lithium amide solution:
[0066] Charged tert-butyl methyl ether (300 ml) under argon atmosphere in a RB flask and added slowly liquid ammonia (300 ml) and lithium metal (9.27 g) at -50 to -60°C. The reaction mass was stirred for 10 min at -50 to -60°C and slowly added a solution of styrene (77 g) in MTBE (115 ml) at -50 to -60°C and stirred the reaction mass for 30 minutes at -50 to -60°C to obtain lithium amide solution.
Step-2: Preparation of TBA solution:
[0067] Charged tert-butyl methyl ether (130 ml) under argon atmosphere and added TBA (170ml) at 25 to 35°C and the reaction mass was stirred for 10 minutes to obtain tert-butyl acetate (TBA) solution.
Step-3: Preparation of (R)-ethyl 4-cyano-3-hydroxybutanoate solution:
[0068] Charged tert-butyl methyl ether (120 ml) under argon atmosphere and added (R)-ethyl 4-cyano-3-hydroxybutanoate (100 g) at 25 to 35°C and the reaction mass was stirred for 10 minutes at 25 to 35°C to obtain (R)-ethyl 4-cyano-3-hydroxybutanoate solution.
Step-4: Preparation of Enolate solution:
[0069] The Lithium amide solution at a flow rate of 8.0 ml/min obtained in step-1 and the TBA solution at a flow rate of 3.0 ml/min obtained in step-2 were pumped into the microchannel reactor-1 at the temperature of -20°C to -10°C at 60 bar pressure for the residence time of 20 seconds. Outlet of microchannel reactor-1 is connected to microchannel reactor-2.
Step-5: Preparation compound (3b) solution:
[0070] (R)-Ethyl 4-cyano-3-hydroxybutanoate at a flow rate of 2.2 ml/min obtained in step (3) was pumped into the microchannel reactor -2 and contacted with the enolate solution obtained in step-4 at the temperature of -10°C to 0°C at 60bar pressure for the residence time of 15sec. Outlet of microchannel reactor -2 is connected microchannel reactor -3.
Step-6: Quenching of reaction mass:
[0071] 6N Hydrochloric acid solution at a flow rate of 5.0 ml/min was pumped into the microchannel reactor -3 at a temperature of -10°C to 0°C at 40bar pressure for the residence time of 30 seconds. Out let is connected to hydrophobic membrane cartridge.
Step-7: Separation of the reaction mass:
[0072] The reaction mass obtained in Step (6) was pumped into the hydrophobic membrane cartridge at a temperature of 25°C to 35°C at 3.0 bar pressure to obtain organic layer.
Step-8: Distillation:
[0073] The organic layer obtained was distilled under reduced pressure at 40-45°C in falling film evaporator to obtain the title compound. Yield: 140 g; HPLC purity: 99 %.
Example 2: Preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate:

Step-1: Preparation of Enolate solution:
[0074] In RB flask, charged tert-butyl methyl ether (300 ml) under argon atmosphere and added slowly liquid ammonia (300 ml) and Lithium metal (5.2 g) at -50 to -60°C. The reaction mass was stirred for 10 min at -50 to -60°C and slowly added a solution of styrene (44 g) in MTBE (52 ml) at -50 to -60°C. Stirred the reaction mixture for 15 to 20 minutes at -50 to -60°C and slowly added a solution of TBA (100 ml) in MTBE (100ml) at -50 to -60°C. Stirred the reaction mass for 15 to 20 minutes at -50 to -60°C to obtain enolate solution.
Step-2: Preparation of Premix solution:
[0075] In RB flask, charged MTBE (120 ml) and (R)-ethyl 4-cyano-3-hydroxybutanoate (100 g). The reaction mixture was cooled to -10 to -15°C and slowly added 3M methyl magnesium chloride solution (230 ml) in THF at -10 to -15°C. Stirred the reaction mass for 30 to 60 min at -10 to -15°C to obtain the premix solution.
Step-3: Preparation compound (3c) solution:
[0076] The enolate solution obtained in Step (1) at a flow rate of 4.0 ml/min and the premix solution obtained in step (2) at a flow rate of 1.0ml/min were pumped into the microchannel reactor -1 at a temperature of -10°C to 0°C at 60 bar pressure for the residence time of 10seconds to obtain the reaction mass.
Step-4: Quenching of reaction mass
[0077] The reaction mass obtained in step (3) was quenched into a RBF containing 6N HCl (1000 ml) at below 25°C and separated the organic layer. The organic layer was distilled under reduced pressure at 40-45°C in falling film evaporator to obtain the title compound. Yield: 140.6 g; HPLC purity: 99 %.
Example 3: Preparation of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate

Step-1: Preparation of Enolate solution:
[0078] In RB flask, charged tert-butyl methyl ether (144 ml) and DIPA (156 g). Added slowly (7.94 g) lithium metal at 25-35°C and a solution of Styrene (72 ml) in THF (128 ml) at 35-45°C. Stirred the reaction mass for 1-2hours at 35-40°C and cooled the reaction mass to -40 to -45°C. Added TBA (1500 ml) at -40 to -45°C and stirred the reaction mass for 15 minutes at -40 to -45°C to obtain enolate solution.
Step-2: Preparation of Premix solution:
[0079] Charged(R)-ethyl 4-cyano-3-hydroxybutanoate (100 g) and MgCl2 at 25-35°C into RB flask. Stirred the reaction mass at 90-95°C for 1-2 hrs and cooled the reaction mass to 40-45°C. Added THF (225 ml) and stirred for 15-30 minutes to obtain premix solution.
Step-3: Preparation of compound (3c) solution:
[0080] The Enolate solution obtained in Step (1) at a flow rate of 4.2 ml/min and the premix solution obtained in step (2) at a flow rate of 2.1ml/min were pumped into the microchannel reactor -1 at a temperature of -10°C to 0°C at 30bar pressure for the residence time of 30 seconds to obtain the reaction mass.
Step-4: Quenching of reaction mass
[0081] The reaction mass obtained in step (3) was quenched into a RBF containing 6N HCl (1000 ml)at below 25°C and separated the organic layer. The organic layer was distilled under reduced pressure at 40-45°C in falling film evaporator to obtain the title compound. Yield: 141 g; HPLC purity: 99 %.
[0082] 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.
[0083] 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.


,CLAIMS:1. A process for preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) comprising the steps of:
a) providing a lithium amide solution and a tert-butyl acetate(TBA) solution into a first microchannel reactor zone under condition to obtain an enolate compound of formula (1);

(1)
b) passing the compound of formula (1) to a second microchannel reactor zone and contacting a compound of formula (2), wherein: R1 is CN, halogen or O-protecting groups

(2)
under condition to obtain a compound of formula (3);

(3)
c) passing the compound of formula (3) to a third microchannel reactor zone and contacting with a solution of HCl under condition to obtain a reaction mass; and
d) passing the reaction mass to a hydrophobic membrane cartridge under condition to obtain the compound of formula (I)

(I)
wherein R1 is CN, halogen or O-protecting groups.
2. The process as claimed in claim 1, wherein the lithium amide solution and a tert-butyl acetate(TBA) solution in step a) are provided at a flow rate in the range of 1.0 ml/min to 25 ml/min into the first microchannel reactor zone.
3. The process as claimed in claim 1, wherein the condition in step a) includes a temperature in the range of -60°C to 10°C at a pressure in the range of 1 milli bar to 100 bar for a residence time in the range of 10 seconds to 50 seconds.
4. The process as claimed in claim 1, wherein the condition in step b) includes a flow rate in the range of 1.0 ml/min to 25 ml/min at a temperature in the range of -60°C to 10°C at a pressure in the range of 1 millibar to 100 bar for the residence time in the range of 10 seconds to 50 seconds.
5. The process as claimed in claim 1, wherein the condition in step c) includes a flow rate in the range of 1.0 ml/min to 25 ml/min at a temperature in the range of -60°C to 10°C at a pressure in the range of 1 millibar to 100 bar for the residence time in the range of 10 seconds to 50 seconds.
6. The process as claimed in claim 1, wherein the condition in step d) includes a temperature in the range of 25°C to 35°C at a pressure in the range of 1 millibar to 100 bar.
7. A process for preparation of tert-butyl 5-hydroxy-3-oxohexanoate compound of formula (I) comprising the steps of:
a) providing an enolate compound of formula (1) and a premix solution of a compound of formula (4) or a compound of formula (5)

into the microchannel reactor zone under condition to obtain a compound of formula (3a);

(b) quenching the compound of formula (3a) in HCl to obtain the compound of formula (I).
8. The process as claimed in claim 7, wherein the enolate compound of formula (1) and a premix solution of a compound of formula (4) or a compound of formula (5) are provided into the microchannel reactor zone at a flow rate in the range of 1.0 ml/min to 25 ml/min.
9. The process as claimed in claim 7, wherein the condition in step a) includes a temperature in the range of -60°C to 10°C at a pressure in the range of 1 millibar to 100 bar for a residence time in the range of 10 seconds to 50 seconds.
10. The process as claimed in claim 1, wherein the lithium amide solution is prepared by the steps of:
a) reacting liquid ammonia and lithium metal in a solvent under argon atmosphere at a temperature in a range of -50 to -60°C to obtain a reaction mass of lithium amide solution; and
(b) adding a solution of styrene in MTBE to the reaction mass at a temperature in a range of -50 to -60°C to obtain the lithium amide solution.
11. The process as claimed in claim 1, wherein the enolate compound of formula (1) is prepared by the steps of:
a) reacting liquid ammonia and lithium metal in a solvent under argon atmosphere at a temperature in a range of -50 to -60°C to obtain a reaction mass;
b) adding a solution of styrene in MTBE to the reaction mass at a temperature in a range of -50 to -60°C to obtain a lithium amide solution; and
c) adding a solution of tert-butyl acetate in MTBE at a temperature in the range of -50 to -60°C to obtain the enolate compound of formula (1).
12. The process as claimed in 10 to 11, wherein the solvent selected from a group consisting of 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 and hexanes or mixture thereof.