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1. WO2014203045 - A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE

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A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE- HEXANOATE

Field of Invention:

The present invention relates to a process of preparation of an intermediate useful for the preparation of statins more particularly the present invention relates to an eco-friendly and cost effective process for the preparation of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate [I].

The present invention describes an eco-friendly and cost effective process for the synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate [I].

Background of the Invention:

tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate [I] [CAS No. 124752-23-4] is key intermediate for the preparation of statins such as Atorvastatin (Tetrahedron 63, 2007, 8124 -8134), Cerivastatin (Journal of Labeled Compounds and Radiopharmaceuticals, 49, 2006 311-319), Fluvastatin [WO2007125547; US 4739073], Pitavastatin [WO2007/132482; US2012/22102 Al, WO2010/77062 A2; WO2012/63254 Al ; EP 304063; Tetrahedron Letters, 1993, 34, 513 - 516; Bulletin of the Chemical Society of Japan, 1995, 68, 364 - 372] and Rosuvastatin [WO2007/125547 A2; WO2011/132172 Al ; EP 521471]. Statins are used for treatment of hypercholesterolemia, which reduces the LDL cholesterol levels by inhibiting activity of HMG-CoA reductase enzyme, which is involved in the synthesis of cholesterol in liver.


Compound [I] is generally obtained by various methods of oxidation of teri-butyl 2-((4R,65)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [compound II] and are discussed in details hereinafter. In addition, various methods for synthesis of compound [II] are also elaborated below.


A) tert-butyl2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [compound II]

US patent Number 5278313 describes a process for synthesis of compound [II]

(Schemel). In the said process, (5)-methyl 4-chloro-3-hydroxybutanoate has been obtained in only 70% yield through whole cell enzymatic reduction of methyl 4-chloro-3-oxobutanoate, which has a necessity of special equipment such as fermenters as well as other microbial facilities such as sterile area, autoclaves, incubator for growing seed culture, etc.

(S)-methyl 4-chloro-3-hydroxybutanoate upon reaction with tert-butyl acetate in presence of LiHMDS or LDA at -78°C, yielded (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate, which was further transformed to corresponding diol through syn selective reduction in presence of methoxydiethyl borane/sodium borohydride at -78°C. The diol thus obtained was converted to compound [II] .

The overall yield for this process is low and required special equipment such as fermenters, etc and in addition to that, this process is not cost effective due to use of costly reagent such as methoxydiethyl borane.

Moreover, methoxydiethylborane is highly pyrophoric (Encyclopedia for organic synthesis, editor in chief L. Paquette; 2, 5304; Published by John and Wiley Sons;

Organic Process Research & Development 2006, 10, 1292-1295) and hence safety is a major concern.


Scheme 1

EP 1282719 B1 (PCT application WO 01/85975 A1 ) discloses a process for synthesis of compound (3R, 5S)-tert-bvXy\ 3,5,6-trihydroxyhexanoate from (S)-tert-butyl-5,6-dihydroxy-3-oxohexanoate through a) asymmetric hydrogenation in presence of a chiral catalyst e.g. di-mu-chlorobis-[(p-cymene)chlororuthenium(II)] along with an auxiliary such as (1S, 2S)-(+)-N- (4-toluenesulfonyl)-1,2-diphenylethylenediamine as ligand, which gave desired product only in 70% diastereomeric excess (de); b) Whole cell enzymatic reduction of (S)-tert- butyl 5,6-dihydroxy-3-oxohexanoate to obtain compound (3R, 5S)-tert-butyl 3,5,6-trihydroxyhexanoate in 99% de (80% yield).

It is needless to mention that it has necessity of fermenter and other microbiological equipment (Scheme 2).

Moreover, conversion of ( 3R,5S)-tert-butyl 6-acetoxy-3,5-dihydroxyhexanoate to tert-butyl 2-((4R,65)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was accomplished in only 25% yield and also required the flash chromatography for isolation of desired product.

Thus, overall yield for this process is poor and process is not operation friendly especially at large scale hence cannot be considered feasible for commercial manufacturing.


Scheme 2

EP1317440 Bl (PCT Application WO 02/06266 A1) has disclosed the process for synthesis of compound [II] from 6-chloro-2,4,6-trideoxy-D-erythro-hexose (Scheme 3) .

In the said patent application 6-chloro-2,4,6-trideoxy-D-erythro-hexose was converted to (4R, 65)-4-hydroxy-6-chloromethyl-tetrahydropyran-2one with excess of bromine in presence of potassium bicarbonate, which liberates environmentally undesired gas i.e. carbon dioxide.

Moreover, starting material i.e. 6-chloro-2,4,6-trideoxy-D-erythro-hexose is not commercially available and conversion efficiency of starting material at large scale towards (4R, 65)-4-hydroxy-6-chloromethyl-tetrahydropyran-2-one is only 67%.

Scheme 3

US Patent No. 6689591 B2 has demonstrated the whole cell enzymatic reduction of tert-butyl 6-chloro-3,5-dioxohexanoate to compound [II] (Scheme 4).

In the said process, whole cell enzymatic reduction is not specific; yield for desired product is only 34% and other partially reduced products are also obtained.

Hence, further purification is required for obtaining the desired compound. Thus, this process is not suitable for commercial scale.


Scheme 4

Tatsuya et al (Tetrahedron Letters; 34, 1993,513 - 516) has reported synthesis of compound [I] from derivative of L-tartatric acid (Scheme 5).

In the said process, tartaric acid di-isopropyl ester is doubly protected by tert-butyldimethylsilyl group, which was reacted with dianion of teri-butyl acetoacetate to give β, δ-diketo ester compound.

β,δ-diketo ester was reacted with 2 equivalent of diisobutylaluminium hydride (which is a pyrophoric reagent) to afford P-hydroxy,8-keto ester in only 60% yield.

This process is not industrially viable as overall yield is very low and also because of use of costly and pyrophoric reagents/chemicals.


Scheme 5

US7205418 (PCT application WO03/053950A1) has described the process for synthesis of compound [II] from (S)-tert-butyl-3,4-epoxybutanoate (Scheme 6).

The overall yield for this process is very low and moreover, it required the diastereomeric separation of tert-butyl 2-(6-(iodomethyl)-2-oxo-1,3-dioxan-4-yl)acetate by flash chromatography.

Since overall requirement of title compound is very high, any operation involving flash chromatography will tend to render the process commercially unviable.


Scheme 6

Fengali et al (Tetrahedron: Asymmetry 17; 2006; 2907-2913) has reported the process for synthesis of compound [II] from racemic epichlorohydrin (Scheme 7).

In this process, racemic epichlorohydrin was converted to corresponding nitrile intermediate through reaction with sodium cyanide; nitrile intermediate thus obtained was further resolved through lipase catalyzed stereo-selective esterification to obtain (5)-4-(benzyloxy)-3-hydroxybutanenitrile and (R)-1-(benzyloxy)-3-cyanopropan-22yl acetate;

separation of desired product i.e. (S)-4-(benzyloxy)-3-hydroxybutanenitrile having 98% de (40% yield) was done by column chromatography.

Needless to mention a commodity chemical like compound [I] cannot be manufactured by such a laboratory method, which involved number of steps.


Scheme 7

Bode et al (Organic letters, 2002, 4, 619-621) has reported diastereomer- specific hydrolysis of 1,3-diol-acetonides (Scheme 8).

In this publication, duration of the reaction for diastereomer- specific hydrolysis of 1,3, diol-acetonides is reported to be 4 h, however, in our hand it was observed that hardly any reaction took place in 4 h, which made it non-reproducible.

In addition to that, separation of desired product is achieved by flash chromatography and it is needless to mention that any process which involved flash chromatography would render the process to be commercially unviable.

Hence, additional innovation needs to be put in for making the process industrially viable.

Scheme 8

CN 101613341A has reported the process for synthesis of compound [II] (Scheme

9).

In the same patent application tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate was synthesized through Blaise condensation of (5)-4-chloro-3-hydorxy-butanenitrile with zinc enolate of tert butyl bromo acetate.

In the literature, synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate was reported through Blaise condensation of silyl protected (5)-4-chloro-3-(trimethylsilyl)oxy-butanenitrile with zinc enolate of tert butyl bromo acetate, in good yield (Synthesis 2004, 16, 2629-2632). Thus, protection of hydroxy group in (5)-4-chloro-3-hydorxy-butanenitrile is imperative.

In the said Chinese patent application, in claim 7, it was mentioned that solvent used for conversion of tert-butyl (5)-6-chloro-5-hydroxy-3-oxohexanoate to (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate is anyone or mixture of more than one from tetrahydrofuran, ether, methanol, ethanol, n-propanol, /so-propanol and ethylene glycol.

However, in enablement the only example using mixture of solvent was that of THF-methanol (Experimental section, Example 4: The preparation of (R,5)-6-chloro-3,5- dihydroxyhexanoate) and same outcome was expected in other individual or mixture of solvents.

Claim 8 of CN 101613341A mentioned that reduction was carried out by any one or mixture of more than one reducing agents such as sodium borohydride, potassium borohydride, lithium aluminum hydride, diethylmethoxy borane, triethyl borane and tributyl borane.

It implies that either any one of the reducing agents or a mixture of the same can be employed. From reaction mechanism it is very much clear that diethylmethoxy borane, triethyl borane and tributyl borane form the six membered complex between optically active hydroxyl and carbonyl group, which gets reduced by sodium borohydride, signifying that individually diethylmethoxy borane, triethyl borane and tributyl borane are not reducing agents

Moreover, in claims 12 and 13 (Experimental section, Example 4: The preparation of (R,S)-6-chloro-3,5-dihydroxyhexanoate), it is mentioned that reduction should be carried out in temperature range -80 °C to -60 °C, implying that reaction would not work beyond this temperature range i.e. it would work in the temperature window of -80 °C to -60 °C only.

Summarizing, the teachings of the application are not workable.

Wolberg et al (Angewandte Chemie International Edition, 2000, 4306) has reported that diastereomeric excess for syn selective reduction using mixture of diethyl methoxy borane/sodium borohydride of compound [VI] gave 93% de for compound [VIII], which required further re-crystallization to obtain compound [VIII] in 99% de and 70% yield.

Thus, all the reported methods for stereo-selective hydride reduction of compound [VI] were achieved through mixture of trialkyl borane or diethyl methoxy borane & sodium borohydride in THF, at -78°C. As mentioned earlier, trialkyl borane or diethyl methoxy borane are pyrophoric in nature; in addition to that anhydrous THF is costly and moreover, reaction required large dilution.

Hence, there is need for developing efficient, environment friendly, cost effective and green process for stereo-selective reduction compound [VI].

B) The process of Oxidation of compound [II] to compound [I] has been discussed in following literature processes.

1) Swern oxidation (US4970313; Tetrahedron Letters, 1990, 2545

Synthetic Communications, 2003, 2275 - 2284).

2) Parrkh-Doering oxidation (J. Am. Chem. Soc, 1967, 89, 5505-5507)

3) TEMPO/NaOCl oxidization (EP2351762)

4) Trichloroisocyanuric acid/ TEMPO (CN 101747313A)

5) Oxidation of compound [II] to compound [I] through IBX [CN101475558A].

It would be evident that most of the reported methods are not "green" and

environmentally benign; none of the reported methods use molecular oxygen as oxidizing agent in presence of metal catalyst/co-catalyst.

Object of the present invention:

An object of the present invention is to overcome the drawbacks of the prior art.

Another object of the present invention is to provide a process for the preparation of tert-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate [I].

Yet another object of the present invention is to provide an efficient and cost effective process for the synthesis of teri-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate [I].

Yet another object of the present invention is to provide an environment friendly and green process for the synthesis of tert-butyl (3R,55)-6-oxo-3,5-dihydrdxy-3,5-0-isopropylidene-hexanoate [I].

Summary of the present invention:

An aspect of the present invention provides a process for synthesis of teri-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate of compound [I]

from (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI]


Comprising steps of:

a) reducing compound [VI] with sodium borohydride to yield compound [VIII] having at least 80% de(diastereomeric excess) in aqueous micellar aggregate at 0-5°C;

b) converting compound [VIII] to compound [XII] through reaction of 2,2- dimethoxy propane in presence of D-10-camphor sulfonic acid in acetone;

c) converting compound [XII] to optically pure compound [XI] in presence of tetra n-butyl ammonium acetate in presence of any polar aprotic solvent at 95°C and crystallization from n-heptane;

d) converting compound [XI] to compound [II] in presence of base in methanol as solvent;

e) converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

Another aspect of the present invention provides a process for synthesis of tert- butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate of compound

from (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI]


Comprising steps of:

a) reducing compound [VI] with sodium borohydride to yield compound [VIII] having at least 30 % de in aqueous micellar aggregate at 0-5°C;

b) converting diastereomeric excess compound [VIII] to diastereomeric excess compound [XII] through reaction of 2,2-dimethoxy propane in presence of D- 10-camphor sulfonic acid in acetone;

converting compound [XII] to optically pure compound [IX] through selective hydrolysis of undesired isomer in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane at 20 °C, followed by separation of compound [IX] through selective extraction with n-hexane from crude product

[IX]·

Yet another aspect of the present invention provides a process for synthesis of tert-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate of compound [I]

from (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI]


Comprising steps of:

a. reducing compound [VI] with sodium borohydride to yield compound [VIII] having at least 30 % de in aqueous micellar aggregate at 0-5°C; b. converting compound [VIII] to optically pure compound [IX] through selective ketal formation with 2,2-dimethoxy propane in presence of D-10-camphor sulfonic acid in dichloromethane, followed by separation of compound [IX] through selective extraction with n- hexane from crude product [IX]

c. converting compound [IX] to optically pure compound [XI] in presence of tetra n-butyl ammonium acetate in presence of polar aprotic solvent at 95°C and crystallization from n-heptane; d. converting compound [XI] to compound [II] in presence of base in methanol as solvent;

e. converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

yet another aspect of the present invention provides a process for synthesis of tert-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate of compound [I]

from 4-chloro-3-((alkylsilyl)oxy)butanal [V]


Comprising steps of:

a) reacting compound [V] with Reformatsky reagent of compound [IV] in presence of an organic solvent to obtain compound [VII] ;

b) treating compound [VII] with tetra-butylammonium fluoride in THF to obtain compound [VIII] ;

c) converting diastereomeric excess compound [VIII] to diastereomeric excess compound [XII] through reaction of 2,2-dimethoxy propane in presence of D- 10-camphor sulfonic acid in acetone.

d) Converting compound [XII] to optically pure compound [IX] having at least 98% de through selective hydrolysis of undesired isomer in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane at 25°C, followed by separation of compound [IX] through selective extraction with n-hexane from crude product [IX] .

Yet another aspect of the present invention provides a process for synthesis of tert-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate of compound [I]

from 4-chloro-3-((alkylsilyl)oxy)butanal [V]

Comprising steps of:

a. reacting compound [V] with Reformatsky reagent of compound [IV] in an organic solvent to obtain compound [VII] ;

b. treating compound [VII] with tetra-butyl ammonium fluoride in THF to obtain compound [VIII] ;

c. converting compound [VIII] to compound [IX] having at least 98% de through selective ketal formation with 2,2-dimethoxy propane in presence of D-10-camphor sulfonic acid in dichloromethane, followed by separation of compound [IX] through selective extraction with n- hexane from crude product [IX] ;

d. converting optically pure compound [IX] to compound [XI] in presence of tetra n-butyl ammonium acetate in presence of polar aprotic solvent at 95 °C;

e. converting compound [XI] to compound [II] in presence of base in methanol as solvent;

f. Compound [II] was converted to optically pure compound [I] in presence of Cu (Salt)/diimine ligands/TEMPO/02 as oxidization system in organic solvent at 30-50°C.

Another aspect of the present invention provides a process for synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate of compound [I]

From diasteromeric excess tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XIII]


Comprising steps of:

a) Converting compound [XIII] to optically pure compound [XI] having at least 98 % de through selective hydrolysis of undesired isomer in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane at 25°C, followed by separation of compound [XI] ;

b) Converting compound [XI] to compound [II] in presence of base in methanol as solvent;

c) Converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

Yet another aspect of the present invention provides a process for synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate of compound [I]

From diasteromeric excess (de) tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2- dimethyl-1,3-dioxan-4-yl)acetate [II]


Comprising of step:

a) Converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

Brief description of the accompanying drawings:

Figure 1 illustrates the initial rate of hydrolysis of anti-isomer of compound [XII]; for other derivatives similar trend has been observed.

Detail description of the present invention:

Schematic representation for present process for synthesis of compound [I] was shown in Scheme A:

1) Stereo selective reduction of compound [VI] to obtain diastereomeric excess compound [VIII]

Compound [VI] was synthesized as per reported procedure (Synthesis 2004, 16,

2629 - 2632).

Parsad "Syn" reduction (Tet Lett.1987,28,155) i.e. combination of diethyl methoxy borane/sodium borohydride as reducing agent is generally used for obtaining syn 1,3 diol.

Wolberg et al (Angewandte Chemie International Edition, 2000, 4306) reported

Parsad "Syn" reduction in THF on compound [VI], employing diethyl methoxy borane/sodium borohydride to obtain compound [VIII] in 93% de at -78°C.

As mentioned earlier, reduction using diethyl methoxy borane or triethyl borane is not only costly, but requires special safety precautions since the reagents are pyrophoric in nature. In addition, stereoselectivity depends to a large extent on reaction temperature viz. -78 °C. Moreover, sodium borohydride reductions in THF sometimes lead to explosions due to presence of peroxide in THF. Thus, there is a significant probability that reaction can go out of hand at large scale synthesis.

Apparently, triethyl borane or methoxy diethyl borane are known to form six membered cyclic complexes (Scheme B), which on reduction in THF give syn selectivity (Tet Lett.19%1 , 28, 155).


Scheme B:

Ketone reduction in aqueous micellar aggregates has been well reported (Ind. Eng.

Chem. Res. 2007, 46, 1923-1927; JOC, 2004, 69, 8224-8230; JOC, 2004, 69, 8231-8238; Organic Letters 2004, 22, 4133-4136). Although, in presence of chiral surfactants stereoselective reduction of ketone was reported, however, enantiomeric excess for corresponding hydroxyl compound was very poor (Organic Letters 2004, 22, 4133-4136; Langmuir 2005, 21, 10398-10404).

In addition regio- selective reduction of α,β-unsaturated ketone to achieve 1,2 reduction as well as 1,4 reduction in achiral aqueous micellar aggregates has also been reported (Ind. Eng. Chem. Res. 2007, 46, 1923-1927).

As per our knowledge, there are no literature reports, wherein stereo-selective reduction of carbonyl compound with sodium borohydride in aqueous achiral micellar aggregates

has been performed to obtain chiral alcohol, having such a high degree of induction and which has a synthetic utility.

In an embodiment of the present invention, there is provides the synthesis of diastereomerically excess (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] through stereo-selective reduction of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI] by sodium borohydride in aqueous micellar aggregates obtained from 1) anionic surfactant such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate and sodium dihexyl sulfosuccinate Or 2) cationic surfactant such as benzalkonium chloride and cetyl trimethyl ammonium bromide Or 3) amphoteric surfactant such as lecithin, which is further converted into compound [I].

In one another step of the method, the (3R,55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (VIII) is condensed with2,2-dimethoxy propane to form tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (IX) in presence of (D)-camphor- 10-sulphonic acid. The said reaction is carried out in chlorinated solvents, such as chloroform, dichloromethane. Preferably this reaction is carried out in dichloromethane. The reaction is carried out in a temperature of mixture at 40 °C. Moreover, selective separation of compound [IX] from crude product containing compound [IX] and compound [X] is achieved through selective extraction with n-hexane in more than 80% isolated yield and having 99% de. The formation of compound during reaction is identified using advanced analytical techniques such as Gas Chromatography.

In one another step of the method, tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate(IX) is reacted with tetrabutyl ammonium acetate in a solvent to form tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate(XI). This reaction is carried out in a solvent. The solvent is selected from N-methyl pyrrolidone (NMP), Ν,Ν-dimethylformamide, and dimethylsulfoxide. This reaction is carried out at higher reaction mixture. The favorable range for this reaction is 80 to 150°C. The achieved product can be recrystallized from which from n-hexane, n-heptane or similar solvents.

In one another step of the method, (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester (XI) is reacted with base in methanol to form tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [II]. The base can be selected from sodium carbonate, potassium carbonate, and lithium carbonate. The progress of the reaction can be studied using TLC and GC techniques.

In another step of this process, the tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate is oxidized to tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate [I] using TEMPO as an oxidizing agent in presence of copper salt, diimine ligands and solvent or mixture of solvents thereof. The copper salt can be used from CuCl, CuBr, CuCl2, CuSO4, Cu(OTf) and Cu(OTf)2. The diimine ligands can be used from a group comprising pyridine, phenanthroline, bipyridyl, bipyridine, DABCO and pybox; preferably bipyridyl in organic solvent selected from a group comprising dichloromethane, acetonitrile or mixture of dichloromethane/acetonitrile. This reaction is monitored on GLC, which normally shows 90% conversion for desired product.

Surprisingly, present inventors found that sodium borohydride reduction of compound [VI] in achiral micellar aggregates gave diasteromeric excess of compound [VTII] and the results are summarized in Table 1.

It is well known that during synthesis of pharmaceutical intermediates/products, approximately 80% waste generated, was mainly due to organic solvents, which results into higher E-factor (C& EN, 2013, 91, 22-23).

Thus, this finding has shown the tremendous improvement over the prior art, improving the cost effectiveness, elimination of hazards and moreover low E-factor due to elimination of solvents at this stage.


Result and observation:

When compound [VI] was attempted to reduce with sodium borohydride in water, it was observed that no corresponding compound [VIII] was obtained and starting material was recovered as such.

When non-ionic surfactant such as "Poloxamers 188" was used as amphiphilizing compound, obtained product was equimolar mixture of Syn and anti- isomer of compound [VIII] and in case of cationic amphiphilizing compounds i.e. benzalkonium chloride and cetyl trimethyl ammonium bromide as micellar forming agent, >30% de for compound [VIII] was obtained.

Surprisingly, with anionic surfactants as amphiphilizing agents, diasteromeric excess (de) for compound [VIII] was found to be constantly >80% de at reaction temperature 0-5°C.

When anionic surfactant i.e. sodium lauryl sulfate was used (40% w/w to substrate), diasteromeric excess for compound [VIII] was found to be constantly >82% de. It was also observed that when surfactant concentration was used 20 % w/w or 60% w/w of substrate, diasteromeric excess for compound [VIII] was decreased to 32% de and 33% de respectively.

When, temperature of reaction was enhanced to 20-25°C from 0-5 °C it was observed that diasteromeric excess for compound [VIII] was decreased to 0% de from 82 % de.

In case of sodium alkyl sulfosuccinate such as sodium dioctyl sulfosuccinate and sodium dihexyl sulfosuccinate, diasteromeric excess for compound [VIII] was increased to 92% de and 88% respectively.

It could be summarized from the study that variation in product distribution is function of 1) nature of surfactant, 2) ratio of surfactant to substrate, 3) reaction temperature and 4) agitation speed.

Presumably, high chiral induction in case of anionic surfactants was due to neighboring chiral center present in the molecule and during reduction some sort of complex could be forming to give syn selective reduction in high diasteromeric excess.

2) Selective ketal formation of syn isomer of compound [VIII] to obtain optically pure compound

[IX]

In another embodiment of the present invention there is provided a selective ketalisation of desired isomer i.e. (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] from mixture of two diastereomer i.e. (3R,55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate and (3S,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate in equal proportion or excess of desired isomer to obtain optically pure tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [IX], followed by isolation by extraction, which is further converted into compound [I].

Compound [VIII] was converted to optically pure compound [IX] (99% de) through selective ketalization with 2, 2 -dimethoxy propane (1 mole equivalent with respect to desired diastereomer) in presence of acid such as D-10-camphor sulphonic acid or PTSA in organic solvent such as dichloromethane.

In general, the (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (VIII) is condensed with2,2-dimethoxy propane to form tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (IX) in presence of (D)-camphor-10-sulphonic acid. The said reaction is carried out in chlorinated solvents, such as chloroform, dichloromethane. Preferably this reaction is carried out in dichloromethane. The reaction is carried out in a temperature of mixture at 40 °C. Moreover, selective separation of compound [IX] from crude product containing compound [IX] and compound [X] was achieved through selective extraction with n-hexane in more than 80% isolated yield and having 99% de. The formation of compound during reaction is identified using advanced analytical techniques such as Gas Chromatography.

) Selective hydrolysis of diastereomeric excess compound [XIII] to obtain optically pure compound [XI]


In yet another embodiment of the present invention selective hydrolysis of undesired isomer i.e. tert-butyl 2-((4S,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate from the diastereomeric mixture of tert-butyl 2-((4S,6S)-6-(acetoxymethyl)-2,2-dimethyl- 1,3-dioxan-4-yl)acetate and tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3- dioxan-4-yl)acetate to obtain optically puret tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2- dimethyl-1,3-dioxan-4-yl)acetate, which is further converted into compound [I].

Compound [VIII] obtained by various methods as mentioned earlier was converted to corresponding compound [XII] through non-selective ketalization with large excess of 2,2 -dimethoxy propane in presence of D-10-camphor sulphonic acid. Obtained compound was converted to corresponding compound [XIII] as per reported process using tetra n-butyl ammonium acetate in NMP as solvent.

Selective hydrolysis of only one isomer was achieved when compound [XIII] was subjected to hydrolysis in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane.

When compound [XIII] having 90% de (syn: anti; 95:5), was subjected to selective hydrolysis in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane to obtain compound [XI] in 99% de it required 48h, meaning, rate of hydrolysis of the undesired isomer i.e. anft'-isomer is very slow.

In literature selective ketal hydrolysis of diasteromeric excess compound [XII] has been reported (Organic letters, 2002, 4, 619-621). However, it was observed that rate of hydrolysis of undesired isomer of compound [XII] was very slow (Figure 1) than that reported in the literature and separation of desired compound was achieved by flash chromatography.

On the other hand selective hydroxylation of compound [XII] in biphasic mixture of dichloromethane and 2 N aqueous solution of acid at temperature 20-25°C required 24 h.

Separation of desired ketal compound i.e. compound [IX] from crude product was achieved through selective extraction with non-polar solvent such as n-hexane.

4) Process for synthesis of compound [VIII] through Reformatsky reaction between compound [V] and compound [IV]

In another embodiment of the present invention synthesis of (55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] through reaction between (5)-4-chloro-3- ((trialkylsilyl)oxy)butanal [V] and Reformatsky reagent of bromo / iodo acetic acid alkyl ester [IV], which is further converted into compound [I].

Compound [V] was obtained by di-i'sobutyl aluminum hydride reduction of compound [III] in presence of dichloromethane in 80% isolated yield. It was observed that reduction of compound [III] to compound [V] in toluene does not go to completion even after 24 h.

Compound [VII] was obtained through Reformatsky reaction between silyl protected compounds [V] and Reformatsky reagents.

A Reformatsky reagent was obtained by reaction of zinc dust with tert-butyl bromoacetate, tert butyl iodoacetate, ethylboromoacetate and ethyliodoacetate in THF as solvent.

Compound [VII] was obtained in 80% isolated yield by reaction between compound [V] and Reformatsky reagent of tert-butyl bromoacetate in THF at 65 °C reaction temperature.

It is observed that activation of zinc dust for obtaining Reformatsky reagent of tert-butyl bromoacetate is done either with trimethyl silyl chloride or 2,2 dibromoethane.

When, Reformatsky reagent of ethyl iodoacetate is used for synthesis of compound [VII], it is observed that reaction goes to completion at 0-5°C and compound [VII] is obtained in 85% isolated yield.

However, reaction of Reformatsky reagent of tert-butyl iodoacetate with compound [V] did not initiate at 0-5 °C, but when same reaction mixture is heated to 65 °C for 24h, compound [VII] is obtained in 65% isolated yield.

Reaction of trimethylsilyl protected compound [V] with Reformatsky reagent of tert-butyl bromoacetate gave racemic compound [VII] in 80% yield and when TBDMS protected compound [V] is reacted with Reformatsky reagent of tert-butyl bromoacetate it gives more anti compound [VII] than syn compound [VII] in 80% chemical yield.

Compound [VII] was converted to compound [VIII] in presence of tetrabutyl ammonium fluoride in THF.

5) Aerial oxidation of Compound [II] to compound [I]

Yet another embodiment of the present invention Synthesis of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate [I] by aerial oxidation of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [II] in presence of TEMPO/Cu (I) amine complex catalyst.

Prior arts have suggested various catalytic systems which have been developed from both Cu (I) salts as well as Cu (II) salts for aerial oxidation along with diimine ligands.

Diimine ligands are selected from pyridine, phenanthroline, bipyridine, DABCO and pybox (Bisoxazoline ligand).

Cu (I) as well as Cu(II) salt have been selected from CuCl, CuBr, CuCl2, CuSo4, Cu(OTf) and Cu(OTf)2.

In addition to that effect of additive such as N-methylimidazole (NMI), potassium ieri-butoxide, di-tert-butyl azodicarboxylate (DBAD) and DBU has been also studied (Chem. Rev. 2004, 104, 3037-3058; Nature protocols; 2012; 1161).

Apparently, it is very difficult to design one universal catalytic system which would work for oxidation of all types of alcohols to corresponding carbonyl compounds. Because various factors such as 1) valence state of copper salt; 2) nature of solvent; 3) additive; 4) nature of ligand and 5) temperature are to be varied for designing such type of systems.

Hence, to develop a successful industrial process, one needs to study the relationship between these variables through innovative experimentation. Moreover, one needs to understand the impact of these variables on yield, impurities and isolation process.

Thus, initially oxidation of compound [II] was carried out as per Sheldon's catalytic system i.e. ((byp) CuBr2/TEMPO/KOtBu/O2) (J. Org. Chem. 2002, 67, 6718-6724) in acetonitrile/water as solvent at 25°C. It was observed that reaction was sluggish and starting material did not go to completion to desired product even after 24h. Similar result was obtained by replacing potassium teri-butoxide with DBU, even though reaction mixture was heated to 50°C.

When oxidation of compound [II] was carried out in 10 mol% catalytic system as reported by Hoover and Stahl i.e .CuCl/bpy/TEMPO/ O2/b ase in acetonitrile/DCM as a solvent, only 52% conversion for desired product was obtained.

Thus, a novel oxidation catalytic system for oxidation of compound [II] was invented by employing stoichiometric amount of CuCl/bipyridine/TEMPO with bubbling

O2 in acetonitrile/DCM mixture, which gave compound [I] in 88 % yield. Taking this lead further, optimization of variables was carried out.

When 30 mol % of catalytic system i.e. CuCl/bipyridine/TEMPO was used for oxidation of compound [II] to compound [I] conversion was around 88% in 12 h and when the reaction is carried out in 10 mol % of catalytic system in conversion towards the formation of compound [I] is around 90% in 24 h. It is also observed that reaction is very clean and no additional impurities are formed up to 90% conversions to desired product, as per GC analysis.

However, when reaction is carried out in only DCM as solvent using 10 mol % of catalytic system it is not completed but when stoichiometric amount of CuCl is used and other co-catalyst such bipyridine, TEMPO is 20 mol %, it is observed that conversion is complete.

The present invention is now illustrated by way of non-limiting examples:

Example 1: Process for synthesis of (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile [III]


To a solution of (S)-4-chloro-3-hydroxy butanenitrile (52.5 g) in THF (150 mL) was added trimethyl silyl chloride (57.2 g) under inert atmosphere at 25 °C. The resulting reaction mixture was stirred for 10 min at 20°C. A solution of triethyl amine (53.4 g) in THF (100 mL) was added to above reaction mixture by maintaining reaction temperature below 40 °C. To the resulting reaction mixture catalytic amount of sodium iodide was added and stirred further for 5 h at 40°C. Reaction was monitored on GC as well TLC for complete conversion of starting material. After cooling to 0 °C, a 21% aqueous solution of sodium chloride (500 mL) was added and extracted with ethyl acetate (2 X 300 mL).

Combined organic layer was dried with anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain (S)-4-chloro-3-((trimethylsilyl) oxy)butanenitrile as light brown liquid (84.0 g, 99%).

GC analysis conditions:

Gas Chromatographic system:

Instrument : Gas Chromatograph.

Column : DB-5, length: 30 metre. , Dia.: 0.53mm, 5.0μm Capillary

Column.

Detector : Flame Ionization Detector.

Carrier gas : Nitrogen.

Gas Chromatograph parameters:

Carrier gas pressure : 5.0 psi

Detector Temperature : 260°C

Injector Temperature : 220°C

Split Ratio : 1: 10

Injection volume : 0.2 μL

Approximate retention time for (5)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile is about 8.3 min.

Approximate retention time for f5)-4-chloro-3-hydroxy butyronitrile is about 7.0 min.

NMR for (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile: 1H-NMR (CDCl3) δ 0.19 (S, 9H), 2.58-2.75 (m, 2H), 3.44-3.55 (m, 2H), 4.08-4.12 (1H, m), 13C- δ 0.01, 24.2, 46.6, 68.5, 116.9.

IR: 691, 844, 1110, 1253, 1361, 1445, 2254, 2960 cm-1

Example 2: Process for synthesis of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI]

To a suspension of zinc dust (32.0 g) in THF (400 mL) was slowly added solution of trimethyl silyl chloride (1.8 mL) in THF (10 mL) in inert atmosphere and stirred for 10-15 min at 25°C. A solution of methane sulfonic acid (1.8 mL) in THF (10 mL) was added at 25 °C and further stirred for 15 min. Reaction mixture was slowly heated to reflux temperature (63-65 °C) and at this temperature, a solution of (5)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile (43.8 g) in THF (200 mL) was slowly added and stirred for 30 min, after which solution of tert-butyl bromoacetate (66.5 g) in THF (100 mL) was added slowly such that a gentle reflux was maintained and stirred further for 2 h at 65 °C. After cooling to 0 °C, 2N aqueous solution of hydrochloric acid (100 mL) was slowly added and stirred for 1 h at 0 °C, after which, organic volatile material was removed under reduced pressure and residue was extracted with ethyl acetate (3 X 200 mL). Combined organic layer was washed first with 10% aqueous solution of sodium bicarbonate (210 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate as light brown oil (53.0 g).

NMR (Some enol form exist) : 1H NMR (400MHZ, CDCl3) : δ 1.47 (9H), 2.86 (t, 2H), 3.20 (t, 2H), 3.40 (s, 2H), 3.54-3.6 (m, 2H), 4.29-4.32 (t, 1H); 13C-NMR: δ 27.9, 46.4, 48.3, 51.1, 67.3, 82.5, 166.0, 202.7; IR: 747, 1045, 1582, 1712, 1731, 3444 cm-1; m/z: (ESI): calculated 236.08 & 238.08 observed 237.08 & 239.08

Example 3: Process for synthesis of (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] using methoxy diethyl borane and sodium borohydride in THF


To a solution of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (16 g) in THF (160 mL) was added methanol (16 mL) under inert atmosphere at 25°C. Methoxy diethyl borane in THF (25 mL) was added slowly at 25°C to the above reaction mixture and stirred for 1 h at 25°C. After cooling to -78 °C, sodium borohydride (2.83 g) was added in 5-6 portions at -78 °C and stirred for 4 h at this temperature. Reaction was monitored on TLC for complete conversion of starting material, after which reaction was quenched by slow addition of 30% aqueous solution of hydrogen peroxide (65 mL) at -78 °C and stirred for 1 h. Organic volatile material was removed under reduced pressure and residue was extracted with ethyl acetate (3 X 50 mL). Combined organic layer was washed with 10% aqueous solution of sodium bisulfite (170 mL) at 0 °C. The organic layer was separated and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain (JR,55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (17 g, 97% de) as light brown oil. Diastereomeric excess was determined by converting it to corresponding acetonide as per procedure given in example 10.

NMR of OR,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate: 1H NMR

(400MHz, CDCl3): δ1.47 (9H), 1.72 (t, 2H), 2.4(d, 2H), 3.52-3.65 (m, 2H), 4.10-4.13 (t, 1H), 4.29-4.32 (t, 1H). 13C-NMR: δ 28.0, 39.3, 42.0, 49.0, 68.1, 70.4, 81.6, 172.3

Example 4: Process for synthesis of diastereomeric excess (3R ,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] in aqueous micellar solution (benzalkonium chloride as surfactant) using sodium borohydride at 0-5 °C.

To a mixture of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (5 g) in water (95 mL) was added 50% aqueous solution of benzalkonium chloride (5 mL). After

cooling to 0 °c, sodium borohydride (1 g) was added in portions and stirred for 14 h at 0 °C. Completion of reaction was monitored on TLC and after completion of reaction ethyl acetate (125 ml) was added and stirred for 10 min. Organic layer was separated and washed with 10% aqueous solution of hydrochloric acid (25 mL). Organic layer was separated and dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give crude product (JR,55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (5.1 g, 36% de) as yellow oil. Diastereomeric excess was determined by converting it to corresponding acetonide as per procedure given in example 10.

Example 5: Process for synthesis of racemic product (5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VII] in aqueous micellar solution (Poloxomer 188 as surfactant) using sodium borohydride at 0 -5°C.

To a mixture of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (3 g) in water (50 mL) was added Poloxomer 188 (1.0 g). After cooling to 0°C, sodium borohydride (0.2 g) was added in portions and stirred for 14 h at 0°C. Completion of reaction was monitored on TLC and after completion of reaction, ethyl acetate (125 ml) was added and stirred for 10 min. Organic layer was separated and washed with 10% aqueous solution of hydrochloric acid (25 mL). Organic layer was separated and dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give racemic product (55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (3.1 g) as yellow oil. Diastereomeric excess was determined by converting to corresponding acetonide as per procedure given in example 10.

Example 6: Process for synthesis of diastereomeric excess (3/f,55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] in aqueous micellar solution (Sodium lauryl sulfate as surfactant) using sodium borohydride at 0-5 °C.

To a mixture of (5)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (15 g) in water

(200 mL) was added sodium lauryl sulfate (6 g). After cooling to 0 °C, sodium borohydride (3 g) was added in portions and stirred for 14 h at 0 °C. Completion of reaction was monitored on TLC and after completion of reaction ethyl acetate (250 ml) was added and stirred for 10 min. Organic layer was separated and washed with 10%

aqueous solution of hydrochloric acid (25 mL). Organic layer was separated and dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give crude product (3R,5S)-tert- butyl 6-chloro-3,5-dihydroxyhexanoate ( 14 g, 83% de) as yellow oil. Diastereomeric excess was determined by converting to corresponding acetonide as per procedure given in example 10.

Example 7: Process for synthesis of diastereomeric excess (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] in aqueous micellar solution (dioctyl sodium sulfosuccinate) using sodium borohydride at 0-5 °C.

To a mixture of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (7.0 g) in water (175 mL) was added dioctyl sodium sulfosuccinate (2.8 g). After cooling to 0 °C, sodium borohydride (1.4 g) was added in portions and stirred for 14 h at 0 °C. Completion of reaction was monitored on TLC and after completion of reaction ethyl acetate (200 mL) was added and stirred for 10 min. Organic layer was separated and washed with 10% aqueous solution of hydrochloric acid (40 mL). Organic layer was separated and dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give crude product (3R,5S)-tert- butyl 6-chloro-3,5-dihydroxyhexanoate (7.1 g, 92% de) as yellow oil. Diastereomeric excess was determined by converting to corresponding acetonide as per procedure given in example 10.

Example 8: Process for synthesis of diastereomeric excess (3/f,55)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] in aqueous micellar solution (dihexyl sodium sulfosuccinate) using sodium borohydride at 0-5 °C.

To a mixture of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (5.0 g) in water (150 mL) was added dihexyl sodium sulfosuccinate (80% solution in water, 2.5 mL). After cooling to 0 °C, sodium borohydride (1.0 g) was added in portions and stirred for 14 h at 0 °C. Completion of reaction was monitored on TLC and after completion of reaction ethyl acetate (175 mL) was added and stirred for 10 min. Organic layer was separated and washed with 10% aqueous solution of hydrochloric acid (30 mL). Organic layer was separated and dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give crude product (3R,5S)-tert-butyl 6-chloro- 3,5-dihydroxyhexanoate (4.8 g, 88% de) as yellow oil. Diastereomeric excess was determined by converting it to corresponding acetonide as per procedure given in example 10.

Example 9: Process for synthesis of diastereomeric excess (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] in micellar solution (Lecithin) using sodium borohydride at 0-5 °C.

To a mixture of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (2.5 g) in water (7.5 mL) was added lecithin (1.0 g). After cooling to 0 °C, sodium borohydride (0.5 g) was added in portions and stirred for 14 h at 0 °C. Completion of reaction was monitored on TLC and after completion of reaction ethyl acetate (100 ml) was added and stirred for 10 min. Organic layer was separated and washed with 10% aqueous solution of hydrochloric acid (25 mL). Organic layer was separated and dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give crude product (3R,5S)-tert- butyl 6-chloro-3,5-dihydroxyhexanoate (2.4 g, 48% de) as yellow oil. Diastereomeric excess was determined by converting to corresponding acetonide as per procedure given in example 10.

Example 10: Process for synthesis of tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [IX]


To a solution of (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (45 g) in acetone (135 mL) was added 2,2-dimethoxy propane (135 mL). Reaction mass was stirred at 25 °C for 15 min and (D)-camphor-10-sulphonic acid (4.5 g) was added. It was slowly heated to 48-50 °C. and was stirred for 6.0 h at 48 °C. Organic volatile matter was removed under reduced pressure. Crude product was added to 10 % sodium bicarbonate solution (45 mL) and extracted with n-hexane (3 x 230 mL). Combined ethyl acetate layer was dried over anhydrous magnesium sulfate, filter and concentrated under reduced pressure to obtain crude product as viscous oil. (47.8 g, 90.9 % yield and 99% de).

GC analysis conditions:

Gas Chromatographic system:

Instrument : Gas Chromatograph.

Column : DB-5, length: 30 mtr. , Dia.: 0.53mm, 5.0μm Capillary Column.

Detector : Flame Ionization Detector.

Carrier gas : Nitrogen.

Gas Chromatograph parameters:

Carrier gas pressure : 5.0 psi

Detector Temperature : 260°C

Injector Temperature : 220°C

Split Ratio : 1: 10

Injection volume : 0.2 μL

Approximate retention time for (tert-butyl 2-((4S,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate is about 30.6 min.1

Approximate retention time for (tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate is about 31.0 min.

1H NMR (400MHZ, CDCl3) : 1.37 (s, 2H), 1.40 (s, 2H), 1.47 (9H), 1.72 (d, 2H), 2.31-2.37 (dd, 1H), 2.43-2.49 (dd, 1H), 3.39-3.43 (dd, 1H), 3.50-3.54(m, 1H), 4.02-4.10 (m, 1H), 4.22-4.32 (m, 1H); 13C-NMR: δ 19.7, 24.5, 24.6, 28.0, 29.8, 33.9, 42.5, 47.0, 65.8, 69.1, 80.7, 99.2, 170.0; m/z (ESI) calculated: 278.18 & 180.18; observed : 279.18 & 181.18; IR: 846, 953, 1162, 1368, 1731, 2982 cm-1.

Example 11: Process for synthesis of disastereomeric excess tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XII]

To a solution of (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (5 g, 67% de) in acetone (25 mL) was added 2,2-dimethoxy propane (25 mL). Reaction mass was stirred at 25 °C for 15 min and (D)-camphor-10-sulphonic acid 1.0 g was added. It was slowly heated to 48-50 °C. and was stirred for 6.0 h at 48 °C. Organic volatile matter was removed under reduced pressure. Crude product was added to 10 % sodium bicarbonate solution (15 mL) and extracted with n-hexane (3 x 25 mL). Combined n-hexane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain crude product as viscous oil (4.8 g, 64% de).

Example 12: Selective hydrolysis of diastereomeric excess tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XII] to obtain optically pure tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [IX].

To a solution of diastereomeric excess tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (20 g) in dichloromethane (300 mL) was added 2 N aqueous hydrochloric acid (6 mL) and resulting biphasic reaction mixture was stirred for 24 h at 20 °C. Sample from organic layer was analyzed at various time intervals. After complete hydrolysis of undesired isomer i.e. tert-butyl 2-((4S,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate, organic phase was separated and concentrated under reduce pressure to obtain crude product. Crude product was suspended in mixture of acetone/water (50:50) and stirred for 15 min, which was further extracted with n-hexane to obtain pure tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate as brown oil (14.4 g, 99.23% de).

Example 13: Selective ketal formation of diastereomeric excess of (3R ,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII] with 2,2-dimethoxy propane to obtain tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [IX].

To a solution of diastereomeric excess (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (7.3 g, 46 % de) in dichloromethane (120 mL) was added 2,2-dimethoxy propane (2.3 g) and (D)-camphor-10-sulphonic acid (0.7 g) was added. The reaction mixture was stirred for 3 h at 40 °C. Conversion for selective ketal formation was monitored on chiral GC. After completion of reaction, dichlormethane layer was washed with 10 % sodium bicarbonate solution . Organic layer was dried over sodium sulphate, filtered and concentrated to obtain crude product. Crude product was suspended in mixture of acetone/water (50:50) and stirred for 15 min, which was further extracted with ft-hexane to obtain pure teri-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (4.3 g, 96 % de ) as brown oil.

Example 14: Process for synthesis of tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XI].


To a solution of tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 g) in NMP (300 mL) was added tetra butyl ammonium acetate (30 g) at 25°C. Resulting reaction mixture was heated to 95°C and stirred for 24 h. After cooling to room temperature, water (450 mL) was added and then extracted with n-heptane (3 X 150 mL). To the combined organic layer was added activated charcoal (1 g) and stirred for 5 h, filtered the activated charcoal and filtrate was concentrated to obtained crude product, which was further recrystallized from n-heptane to obtain off white solid material (7.2g, 99.2% GC purity and 99.5% de).

Gas Chromatographic system:

Instrument : Gas Chromatograph equipped with FID detector.

Column : DB-5, length: 30 mtr. , Dia.: 0.53mm, 5.0μm Capillary Column.

Detector : Flame Ionization Detector.

Carrier gas : Nitrogen.

Gas Chomatograph parameters:

Carrier gas pressure : 8.0 psi.

Detector Temperature : 280°C

Injector Temperature : 280°C

Injection volume : 0.2 μL

Split ratio : 1:25

Retention time: Approximate retention time for compound [XI] is about 12.0 min.

Example 15: Process for synthesis of diasteromeric excess tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XIII].

To a solution of tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 g, 60% de) in NMP (300 mL) was added tetra butyl ammonium acetate (30 g) at 25°C. Resulting reaction mixture was heated to 85°C and stirred for 24 h. After cooling to room temperature, water (450 mL) was added and then extracted with n-heptane (3 X 150 mL). To the combined organic layer was added activated charcoal (1 g) and stirred for 5 h, filtered off the activated charcoal and filtrate was concentrated to obtained product as off white solid material (7.2g, 65% de).

Example 16: Selective hydrolysis of diasteromeric excess tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XIII] to obtain pure tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XI]

To a solution of tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (2 g, 65 % de) in dichloromethane was added the solution of 2 N aqueous solution of hydrochloric acid and resulting biphasic mixture was stirred at 25°C for 48 h. After completion of reaction organic layer was separated and dried over sodium sulphate, filtered and concentrated to obtain crude product, which was further purified through flash chromatography to obtain optically pure compound (99.99% de)

Example 17: Process for synthesis of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [II]


To a solution of (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester (22.65 g, 75 mmole) in methanol (250 ml) was added powdered anhydrous potassium carbonate (5.17 g, 37.5 mmole) in one portion. The resulting heterogeneous solution was stirred vigorously for 30 minutes to complete the hydrolysis. The progress of the reaction was followed by TLC and GC analysis. The solution was filtered through a Buchner funnel and concentrated on a rotary evaporator at room temperature under reduced pressure. The residue was dissolved in water (250 ml) and extracted with ether (3*200 ml). The combined organic layers were washed with water (150 ml), brine (150 ml), dried over MgSO4, filtered and concentrated on a rotary evaporator to furnish the title compound as light yellow oil (19.2 g) in 98% yield.

Example 18: Process for synthesis of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate [I]


A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of acetonitrile. 2-2' Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25°C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40°C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product.

Example 19: Process for synthesis of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate [I]

A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of dichlorome thane. 2-2' Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25°C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40°C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product.

Example 20: Synthesis of 2-((tert-butyldimethylsilyl)oxy)-3-chloropropanenitrile from 4-chloro-3-hydroxybutanenitrile [V]


To a reactor equipped with overhead stirrer, thermopocket and nitrogen inlet was charged 4-chloro-3-hydroxybutanenitrile (28.9 g, 0.24 mol) followed by DMF (500 mL) at 25-30°C. Tert-butyl dimethylsilyl chloride (TBDMSCl) (40.0 g, 0.26 mol) was added to it and stirred for 15 min at 25-30°C. A solution of imidazole (25.0 g, 0.36 mol) and DMAP (14.7 g, 0.36 mol) in DMF (100 mL) was added to the above solution at 25°C and stirred for 4h. On completion of reaction (monitored by TLC: 40% ethyl acetate: cyclohexane), water (300 mL) was added and extracted with di-iso-propyl ether (2x 150 mL). The combined organic layer was washed with 10% HCl aq. soln. (200 mL), separated and dried over anhydrous magnesium sulfate (20.0 g). Filtration and evaporation of solvent from filtrate afforded product as clear, colorless oil. (50.0 g).

IR: 2956, 2931, 2858, 2254, 1472, 1256 cm-1

1H NMR (CDCl3, 400 MHz): δ 0.14-0.17 (d, 6H), 0.92 (s, 9H), 2.63-2.75 (m, 2H), 3.47-3.58 (m, 2H), 4.10-4.14 (m, 1H);

13C NMR (CDCI3, 100 MHz): δ -4.7, 17.9, 24.1, 25.6, 46.5, 68.5, 116.8

Example 21: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-4-chlorobutanal from 2-((tert-butyldimethylsilyl)oxy)-3-chloropropanenitrile [V]


To a reactor equipped with overhead stirrer, thermopocket and nitrogen inlet was charged 2-((tert-butyldimethylsilyl)oxy)-3-chloropropanenitrile (24.0 g, 0.11 mol) followed by DCM (150 mL) at 25-30°C. The solution was cooled to -65°C and DIBAL-H (1M in toluene, 130.0 mL, 0.13 mol) was added dropwise. After complete addition, the reaction mass was stirred at this temperature for lh and subsequently, the reaction mass was allowed to attain a temperature of -30°C and stirred at this temperature for 4h. The reaction mass was again cooled to -65°C and 20% aq. HCl solution (150 mL) was added carefully so as to maintain temperature of the reaction mass within -30°C. After addition, the reaction mass was extracted with ethyl acetate (2x 750 mL) and organic layer washed with 30% aq. sodium bicarbonate solution (220 mL). Any solid that appeared at this stage was filtered off though a Celite bed and filtrate was dried over anhydrous magnesium sulfate (20.0 g). Filtration, followed by evaporation of solvent from filtrate afforded 3-((tert-butyldimethylsilyl)oxy)-4-chlorobutanal (19.0 g) as yellow oil.

1H NMR (CDCI3, 400 MHz): δ 0.08-0.09 (m, 6H), 0.80-0.86 (m, 9H), 1.54-1.66 (m, 2H), 3.58-3.81 (m, 2H), 4.01-4.04 (m, 1H), 9.67 (s, 1H).

13C NMR (CDCI3, 100 MHz): δ -2.7, 18.1, 19.5, 26.1, 48.8, 68.1, 201.8.

Example 22: Process for synthesis of tert-butyl 5-((tert-butyldimethylsilyl)oxy)-6-chloro-3-hydroxyhexanoate [VII]


To a reactor equipped with overhead stirrer, thermopocket and nitrogen inlet was charged zinc dust (2.2 g, 0.03 mol) followed by dry THF (20 mL) at 25-30°C. The suspension was stirred and trimethylsilyl chloride (0.3 mL, 0.003 mol) was added. After stirring at 25-30°C for 15 min, the reaction mass was heated up to 65°C and a solution of 3-((tert-butyldimethylsilyl)oxy)-4-chlorobutanal (5.0 g, 0.02 mol) and tert-butyl bromoacetate (6.0 mL, 0.04 mol) in dry THF (30 mL) was added to it dropwise. The resultant reaction mass was stirred at 65°C for 4-5 h and cooled to 25-30°C. On cooling, 10% aq. HQ solution (50 mL) was added to it and extracted with ethyl acetate (2x 50 mL). Combined organic layer was evaporated to obtain crude product which was purified and isolated by column chromatography (silica gel 100-200 mesh size; eluent: 5% ethyl acetate: n-hexane) to give pure tert-butyl 5-((tert-butyldimethylsilyl)oxy)-6-chloro-3-hydroxyhexanoate (4.3 g) as a pale yellow oil.

1H NMR (CDCI3, 400 MHz): δ 0.02-0.12 (m, 6H), 0.90-0.94 (m,9H), 1.23-1.27 (t, 2H), 1.45-1.47 (d, 9H), 1.76 (s, 1H), 2.04 (s, 1H), 2.25 (s, 1H), 3.35 (s, 1H), 3.48-3.55 (m, 1H), 4.08-4.16 (m, 1H)

Example 23: Process for synthesis of tert-butyl 5-((tert-butyldimethylsilyl)oxy)-6-chloro-3-hydroxyhexanoate [VII]


To a reactor equipped with overhead stirrer, thermopocket and nitrogen inlet was charged zinc dust (6.0 g, 0.09 mol) followed by dry THF (30 mL) at 25-30°C. The suspension was stirred and trimethylsilyl chloride (1.0 mL, 0.007 mol) was added. After stirring at 25-30°C for 15 min, the reaction mass was heated up to 65°C and a solution of 3-((tert-butyldimethylsilyl)oxy)-4-chlorobutanal (8.0 g, 0.04 mol) and tert-butyl iodoacetate (27.0 g, 0.11 mol) in dry THF (50 mL) was added to it dropwise. The resultant reaction mass was stirred at 65°C for 4-5h and cooled to 25-30°C. On cooling, 10% aq. HCl solution (50 mL) was added to it and extracted with ethyl acetate (2x 50 mL). Combined organic layer was evaporated to obtain crude product which was purified and isolated by column chromatography (silica gel 100-200 mesh size; eluent: 30% ethyl acetate: n-hexane) to give pure tert-butyl 5-((tert-butyldimethylsilyl)oxy)-6-chloro-3-hydroxyhexanoate (3.5 g) as a yellow oil.

1H NMR (CDCI3, 400 MHz): δ 0.02-0.12 (m, 6H), 0.90-0.94 (m,9H), 1.23-1.27 (t, 2H), 1.45-1.47 (d, 9H), 1.76 (s, 1H), 2.04 (s, 1H), 2.25 (s, 1H), 3.35 (s, 1H), 3.48-3.55 (m, 1H), 4.08-4.16 (m, 1H)

Example 24: Process for synthesis of tert-butyl 6-chloro-3,5-dihydroxyhexanoate [VIII]


To a reactor equipped with overhead stirrer, thermopocket and nitrogen inlet was charged pure tert-butyl 5-((tert-butyldimethylsilyl)oxy)-6-chloro-3-hydroxyhexanoate (3.0 g, 0.08 mol) followed by dry THF (75 mL) at 25-30°C. The reaction mass was cooled to 0°C and tetra butyl ammonium fluoride (TBAF, 1.0 M in THF) (9.4 mL, 0.09 mol) was added and stirred for 5h. After heating to 25-30°C, the reaction mass was washed with 10% sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2x 50 mL). Washing with water (100 mL), separation of organic layer, and evaporation of solvent gave tert-butyl 6-chloro-3,5-dihydroxyhexanoate (2.1 g) as a yellow oil.

Example 25: Process for preparation of (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl (Pitavastatin intermediate)

To a solution of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-1,3- dioxan-4-yl)acetate (2.7 g) in 46 ml of dimethylsulfoxide was added triphenyl[2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-ylmethyl)- phosphonium]bromide (5 g) and potassium carbonate (2.88 g). The reaction mixture was heated to 70°C and stirred for 3 hours at 70°C. After completion of reaction, reaction was quenched with water and extracted with ethyl acetate (3 X 50 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated to obtain crude product, which was further re-crystallized from methanol to obtain desired product as solid material (5 g).

Example 26: Process for synthesis of (3S,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate with tetramethylammonium triacetoxyborohydride

(S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (1 g, dissolved in 5 mL anhydrous acetonitrile) was added dropwise to a solution of tetramethylammonium triacetoxyborohydride (8 g,) in anhydrous acetonitrile/acetic acid (30 mL, 50:50 v/v) at 0 °C. After stirring at this temperature for five hours, aq. sodium potassium tartrate (35 mL, 0.5 mol) was added drop wise, and the mixture was warmed to room temperature. Saturated aq. Sodium carbonate (70 mL) was added, and the mixture was extracted with ethyl acetate four times. The unified organic phases were washed with saturated aq. Sodium carbonate and brine, dried over MgSO4 , and the solvent was evaporated under reduced pressure. The crude product was obtained in quantitative yield Crystallization from isohexane/ethyl acetate gave title compound (3S,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate colorless crystals (m.p. 73.3 ± 75.0 8C) in 70%.

Example 27: Process for synthesis of tert-butyl 2-((4S,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate


To a solution of (3S,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (1.5 g) in acetone (35 mL) was added 2,2-dimethoxy propane (35 mL). Reaction mass was stirred at 25 °C for 15 min and (D)-camphor-10-sulphonic acid 0.5 g was added. It was slowly heated to 48-50 °C. and was stirred for 6.0 h at 48 °C. Or ganic volatile matter was removed under reduced pressure. Crude product was added to 10 % bicarbonate solution (15 mL) and extracted with ethyl acetate (3x5 mL). Combined ethyl acetate layer was dried over anhydrous magnesium sulfate, filter and concentrated under reduced pressure to obtain crude product as viscous oil. (1.2 g, 97% de by GC analysis).

1H NMR (400MHZ, CDCl3) : δ 1.37 (s, 2H), 1.40 (s, 2H), 1.47 (9H), 1.72 (d, 2H), 2.31-2.37 (dd, 1H), 2.43-2.49 (dd, 1H), 3.39-3.43 (dd, 1H), 3.50-3.54(m, 1H), 4.02-4.10 (m, 1H), 4.22-4.32 (m, 1H); 13C-NMR: δ 19.7, 24.5, 24.6, 28.0, 29.8, 33.9, 42.5, 47.0, 65.8, 69.1, 80.7, 99.2, 170.0; m/z (ESI) calculated: 278.18 & 180.18; observed : 279.18 & 181.18; IR: 846, 953, 1162, 1368, 1731, 2982 cm-1.

Example 28: Process for synthesis of tert-butyl 2-((4s,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [XI].


To a solution of tert-butyl 2-((4S,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (2 g) in NMP (50 mL) was added tetra butyl ammonium acetate (5 g) at 25°C. Resulting reaction mixture was heated to 85°C and stirred for 24 h. After cooling to room temperature, water (150 mL) was added and then extracted with n-heptane (3 X 50 mL). To the combined organic layer was added activated charcoal (1 g) and stirred for 5 h, filter the activated charcoal and filtrate was concentrated to obtained product as off white solid material (1.1 g, 99.2% GC purity by GC analysis).