CLIAMS:
1. A process for the preparation of a compound of formula (I);

Formula (I)
and its pharmaceutically acceptable salt; comprising the steps of:

step (1a): acetylating the compound 1 of the following formula:

by reaction with an acetylating agent selected from acetic anhydride (Ac2O) or acetyl chloride (CH3COCl) in the presence of a base selected from triethylamine (TEA), sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3) or potassium carbonate (K2CO3) in a solvent selected from n-heptane, n-hexane, toluene or cyclohexane at a temperature ranging from 0 °C to 30 °C to obtain a compound 2 of the following formula;

which is telescoped to next step without isolation;

step (1b): reacting in-situ the compound 2 obtained in step (1a), with a mixture of bis(pinacolato)diboron, chloro-1,5-cyclooctadiene-iridium dimer and dipyridyl in a solvent selected from n-heptane, n-hexane, toluene or cyclohexane at a temperature ranging from 95 °C to 100 °C to obtain a compound 3 of the following formula;

step (1c): reacting the compound 3 obtained in step (1b) with a compound 4 of the following formula:

in the presence of a reagent selected from palladium(II) acetate [Pd(OAc)2]- triphenylphosphine (PPh3) mixture, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)-palladium (II) or 1,1-bis (diphenylphosphino) ferrocene-dichloropalladium (II) complex with dichloromethane (DCM) in the presence of a base selected from sodium carbonate (Na2CO3) or potassium carbonate (K2CO3) in a solvent selected from toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) at a temperature ranging from 50 °C to 120 °C to obtain a compound 5 of the following formula;

step (1d): brominating the compound 5 obtained in step (1c) by reaction with hydrogen bromide (HBr) in acetic acid as a brominating agent in a solvent selected from toluene or dichloromethane (MDC) to obtain a compound 6 of the following formula;

step (1e): reacting the compound 6 obtained in step (1d) with compound 7;

(wherein TMS = trimethylsilyl);
in presence of a reagent selected from lithiumbis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) or potassium bis(trimethylsilyl)amide (KHMDS) in a solvent selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane at a temperature ranging from -70 to 0 °C under an atmosphere of nitrogen to obtain a compound 8 of the following formula;

which is subjected to next step without purification;
step (1f): oxidizing the compound 8 obtained in step (1e) using periodic acid (H5IO6) or sodium periodate (NaIO4) as an oxidising agent in the presence of a base selected from sodium hydroxide or potassium hydroxide in tetrahydrofuran at a temperature ranging from 25 °C to 30 °C to obtain a compound 9 of the following formula;

which is subjected to purification using ethyl acetate followed by addition of n-heptane;
step (1g): reacting the compound 9 obtained in step (1f) with a compound 10 of the following formula:

in presence of a reagent selected from sodium triacetoxyborohydride (STAB) prepared in situ or sodium cyanoborohydride in a solvent selected from acetonitrile acetic acid mixture, isopropyl alcohol (IPA), methanol, dichloromethane (MDC) or tetrahydrofuran (THF) at a temperature ranging from 25 °C to 65 °C to obtain the compound of formula (I); which is subjected to treatment with silicon thiol (SiThiol) in dichloromethane (MDC) to remove residual metals; and
step (1h): crystallizing the compound of formula (I) obtained in step 1(g) in the presence of acetone to obtain the compound of formula (I) with a purity of 95 -100 %; and
step (1i): reacting the compound of formula (I) obtained in step (1h) with an acid to obtain a pharmaceutically acceptable salt of the compound of formula (I).

2. The process according to claim 1, wherein the preparation of compound 4 used in step (1c) comprises the steps of:
step (2a): reacting compound A of the following formula;

with a reagent selected from thionyl chloride (SOCl2), phosphoryl chloride (POCl3), or oxalyl chloride [(COCl)2] in a solvent dichloromethane (MDC) or toluene at a temperature ranging from 35 °C to 90 °C to obtain a compound B of the following formula;

step (2b): reacting the compound B with a compound C, of the following formula;

in the presence of triethylamine (TEA) as a base in a solvent selected from dichloromethane or toluene at a temperature ranging from 0°C to 20 °C to obtain compound 4.

3. The process according to claim 1, wherein the preparation of compound 10 used in step (1g) comprises the steps of:
step (3a): reacting compound D of following formula;

with sodium nitrite (NaNO2) in the presence of acetic acid as a solvent at a temperature ranging from 25 °C to 30 °C to obtain a compound E of the following formula;

step (3b): reducing the compound E by reaction with platinum on carbon (Pt/C) in methanol at a temperature ranging from 20 °C to 40 °C to obtain compound 10.

4. The process according to claim 1, wherein in step (1a), the solvent is selected from n-heptane or n-hexane.

5. The process according to claim 1, wherein in step (1c), the solvent is selected from toluene or tetrahydrofuran.

6. The process according to claim 1, wherein in step (1d), the brominating agent is 33 % hydrogen bromide (HBr) in acetic acid.

7. The process according to claim 1, wherein in step (1g), the reagent used is sodium triacetoxyborohydride (STAB), which is prepared in-situ.

8. The process according to claim 1, wherein in step (1i), the pharmaceutically acceptable salt of compound of formula (I) is selected from acetic acid, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, trifluro acetic acid or tartaric acid salt.

9. The process according to claim 2, wherein in step (2a), the reagent is selected from thionyl chloride (SOCl2) or phosphoryl chloride (POCl3).

10. The process according to claim 2, wherein in step (2a) the solvent is dichloromethane (MDC).

11. The process according to claim 2, wherein in step (2a), the reaction is carried out at a temperature ranging from 40 oC to 45 oC.

12. The process according to claim 2, wherein in step (2b), the reaction is carried out at a temperature ranging from 0 oC to 5 oC.

13. The process according to claim 3, wherein in step (3b), the reaction is carried out at a temperature ranging from 25 oC to 30 oC. ,TagSPECI:FIELD OF INVENTION
The present invention relates to an improved process for the preparation of (R)-3-((3,5-dichloro-4’-(4-(trifluoromethyl)piperidine-1-carbonyl)-[1,1’-biphenyl]-4-yl)methyl)-1-(4-hydroxy-piperidin-1-yl)pyrrolidin-2-one (compound of formula (I)), which is an inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 enzyme (11- ß-HSD1), and hence, is useful in the treatment of diseases or disorders mediated by the modulation of 11ß-HSD1, such as diabetes, metabolic syndrome and other metabolic disorders.

BACKGROUND OF THE INVENTION
Glucocorticoids, such as cortisol, are steroid hormones produced by the adrenal cortex that regulates carbohydrate, fat and protein metabolism. Glucocorticoids, acts in the liver, adipose and muscle tissue, and cause their effect by binding to the glucocorticoid receptor. Glucocorticoids are also involved in the up-regulation of anti-inflammatory proteins in cell nucleus and down-regulation of the pro-inflammatory protein in cell cytosol. It has been reported that, over expression of glucocorticoid (cortisol) is associated with metabolic syndromes such as insulin resistance, visceral obesity, hypertension, and dyslipidemia (P. Alberts et al., Diabetologia, 2002, 45, 1528–1532).

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a member of short chain dehydrogenase superfamily of enzymes, which mainly catalyses the conversion of inactive glucocorticoid cortisone into its physiologically active form, cortisol. The key role of 11ß-HSD1 in the conversion of cortisone to cortisol has made it a potential target for the treatment of metabolic disorders.

Several compounds having 11ß-HSD1 inhibitory activity have been reported in the prior art, for example, BVT2733 (Swedish Orphan Biovitrum) and PF-877423 (Pfizer) (Hengmiao Cheng et al; Bioorganic & Medicinal Chemistry Letters, 2010, 20, 2897–2902). Illustratively, PCT Publication No. WO 2007/127688 (WO’688), describes biphenyl-4-yl- methyl- pyrrolidin-2-one derivatives including the compound namely (R)-3-((3,5-dichloro-4’-(4-(trifluoromethyl)piperidine-1-carbonyl)-[1,1’-biphenyl]-4-yl)methyl)-1-(4-hydroxy-piperidin-1-yl)pyrrolidin-2-one (hereinafter referred to as the compound of formula (I)). The biphenyl-4-yl- methyl- pyrrolidin-2-one derivatives described in WO’688 have 11ß-HSD1 antagonist activity. The said compound of Formula (I) is reported to be in developmental phase for type 2 diabetes and other metabolic disorders. WO’688 also describes a process for the preparation of the said compound of formula (I). However, the process for the preparation of compound of formula (I) reported in WO’688 have certain drawbacks, for instance, use of costly reagents such as carbontetrabromide or triphenylphospine, use of toxic solvents such as dimethoxyethane, difficulty in purification of intermediates and final product (i.e. the compound of Formula (I)). Moreover, the process of WO’688 provides the desired compound in reasonably lower yield. Thus, in view of the drawbacks of the process of WO’688 provided for the manufacture of the said compound of Formula (I), there is a need to provide an improved process for the synthesis of the said compound. It is particularly desirable to have an industrially viable process for the synthesis of the said compound.
In order to overcome the drawbacks associated with the prior art process, inventors of the present application have provided an improved, industrially viable and cost-effective process for the preparation of said compound (R)-3-((3,5-dichloro-4’-(4-(trifluoromethyl)piperidine-1-carbonyl)-[1,1’-biphenyl]-4-yl)methyl)-1-(4-hydroxy- piperidin-1-yl)pyrrolidin-2-one (represented by formula (I)).

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of (R)-3-((3,5-dichloro-4’-(4-(trifluoromethyl)piperidine-1-carbonyl)-[1,1’-biphenyl]-4-yl)methyl)-1-(4-hydroxy-piperidin-1-yl)pyrrolidin-2-one (the compound of formula (I)), or a pharmaceutically acceptable salt thereof.

The present invention relates to an improved process for the preparation of the compound of Formula (I) or a pharmaceutically acceptable salt thereof; which is industrially viable and cost-effective.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention relates to a process for the preparation of the compound of formula (I);

Formula (I)
and its pharmaceutically acceptable salt.

The compound of formula (I) described in PCT Publication WO’688, is an inhibitor of 11ß-HSD type 1 enzyme. WO’688 describes biphenyl-4-yl- methyl- pyrrolidin-2-one derivatives including the compound of Formula (I). The said compound is useful in the treatment of diseases or disorders selected from cognitive disorders and metabolic disorders such as diabetes, insulin resistance, visceral obesity and dyslipidemia.

Abbreviations, which may be used in the description of the schemes and in the examples that follow, include:
Ac2O Acetic anhydride;
CH3COCl Acetyl chloride;
DCM / MDC Dichloromethane;
DMF Dimethylformamide;
HBr Hydrogen bromide;
IPA Isopropyl alcohol;
K2CO3 Potassium carbonate;
KHMDS Potassium bis(trimethylsilyl)amide;
LiHMDS Lithiumbis(trimethylsilyl)amide;
Na2CO3 Sodium carbonate;
NaHCO3 Sodium bicarbonate;
NaHMDS Sodium bis(trimethylsilyl)amide;
NaBH4 Sodium borohydride;
Pt/C Platinum on carbon;
Pd(OAc)2 Palladium(II) acetate;
PPh3 Triphenylphosphine;
STAB Sodium triacetoxyborohydride;
SiThiol Silicon thiol;
TEA Triethylamine;
THF Tetrahydrofuran;
TMS Trimethylsilyl;
vol Volume;
min. Minute (s);
h Hour (s).
L Litre;

The present invention provides a process for the preparation of the compound of formula (I), as outlined in the following Scheme 1.

Scheme 1
According to the aspect of the present invention, the process for the preparation of a compound of formula (I) and its pharmaceutically acceptable salt comprises the steps of:

step (1a): acetylating the compound 1of the following formula;

by reaction with an acetylating agent selected from acetic anhydride (Ac2O) or acetyl chloride (CH3COCl) in the presence of a base selected from triethylamine (TEA), sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3) or potassium carbonate (K2CO3) in a solvent selected from n-heptane, n-hexane, toluene or cyclohexane at a temperature ranging from 0 °C to 30 °C to obtain a compound 2 of the following formula:

which is telescoped to next step without isolation;
step (1b): reacting in-situ the compound 2 with a mixture of bis(pinacolato)diboron, chloro-1,5-cyclooctadiene-iridium dimer and dipyridyl in a solvent selected from n-heptane, n-hexane, toluene or cyclohexane at a temperature ranging from 95 °C to 100 °C to obtain a compound 3 of the following formula;

step (1c): reacting the compound 3 as obtained in the step (1b) with compound 4;

in the presence of a reagent selected from palladium(II) acetate [Pd(OAc)2]- triphenylphosphine (PPh3) mixture, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)-palladium (II) or 1,1-bis (diphenylphosphino) ferrocene-dichloropalladium (II) complex with dichloromethane (DCM) in the presence of a base selected from sodium carbonate (Na2CO3) or potassium carbonate (K2CO3) in a solvent selected from toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) at a temperature ranging from 50 °C to 120 °C to obtain a compound 5 of the following formula;

step (1d): brominating the compound 5 as obtained in step (1c) by reacting it with hydrogen bromide (HBr) in acetic acid as a brominating agent in a solvent selected from toluene or dichloromethane (MDC) to obtain a compound 6 of the following formula;

step (1e): reacting the compound 6 as obtained in step (1d) with compound 7;

(wherein TMS = trimethylsilyl);
in presence of a reagent selected from lithiumbis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) or potassium bis(trimethylsilyl)amide (KHMDS) in a solvent selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane at a temperature ranging from -70 °C to 0 °C under an atmosphere of nitrogen to obtain a compound 8 of the following formula:

which is subjected to next step without purification;
step (1f): oxidizing the compound 8 as obtained in step (1e) using periodic acid (H5IO6) or sodium periodate (NaIO4) as an oxidising agent in the presence of a base selected from sodium hydroxide or potassium hydroxide in tetrahydrofuran at a temperature ranging from 25 °C to 30 °C to obtain a compound 9 of the following formula;

which is subjected to purification using ethyl acetate followed by addition of n-heptane;
step (1g): reacting the compound 9 as obtained in step (1f) with the compound 10 of the following formula;

in presence of a reagent selected from sodium triacetoxyborohydride (STAB) prepared in situ or sodium cyanoborohydride in a solvent selected from acetonitrile- acetic acid mixture, isopropyl alcohol (IPA), methanol, dichloromethane (MDC) or tetrahydrofuran (THF) at a temperature ranging from 25 °C to 65 °C to obtain the compound of formula (I);

Formula I
which is subjected to treatment with silicon thiol (SiThiol) in dichloromethane (MDC) to remove residual metals;
step (1h): crystallizing the compound of formula (I) obtained in step 1(g) in the presence of acetone to obtain the compound of formula (I) with a purity of 95 -100 %; and
step (1i): reacting the compound of formula (I) obtained in step (1h) with an acid to obtain a pharmaceutically acceptable salt of the compound of formula (I).

The compound 1 used in step (1a) of scheme 1 is commercially available or may be prepared by methods well-known in the art (da Costa, Jorge C. S. et al; Arkivoc, 2006, i, 128-133).
The preferred acetylating agent used in step (1a) of the process is acetic anhydride.
The base used in step (1a) is selected from triethylamine (TEA), sodium bicarbonate (NaHCO3) or sodium carbonate (Na2CO3). The preferred base is triethylamine (TEA).
The solvent used in step (1a) is n-heptane or n-hexane. The preferred solvent is n-heptane.
The preferred reagent used in step (1b) is n-heptane.
The preferred reagent used in step (1c) is palladium(II) acetate [Pd(OAc)2] - triphenylphosphine (PPh3) mixture or tetrakis(triphenylphosphine)palladium(0).
The solvent used in step (1c) is selected from toluene or tetrahydrofuran. The preferred solvent is toluene.
The brominating agent used in step (1d) is 33 % hydrogen bromide (HBr) in acetic acid.
The preferred reagent used in the step (1e) is selected from lithiumbis(trimethylsilyl)amide (LiHMDS) or sodium bis(trimethylsilyl)amide (NaHMDS).
The solvent used in the step (1e) is preferably tetrahydrofuran (THF) or dioxane.
The step (1e) is carried out at a preferred temperature ranging from -70 °C to -60 °C.
The compound 7 used in step (1e) is commercially available or may be prepared by methods well-known in the art (US7981918).
The preferred oxidising agent used in step (1f) is periodic acid (H5IO6).
The reagent used in step (1g) is sodium triacetoxyborohydride (STAB) which is prepared in-situ.
The preferred solvent used in step (1g) is a mixture of acetonitrile and acetic acid.
The step (1g) is preferably carried out at a temperature ranging from 60 °C to 65 °C.

The compound 4 used in the step (1c) of Scheme 1 is prepared by a process as depicted in the following Scheme 2.

Scheme 2

The process for the preparation of the compound 4 comprises the steps of:

step (2a): reacting a compound A of the following formula;

with a reagent selected from thionyl chloride (SOCl2), phosphoryl chloride (POCl3), or oxalyl chloride [(COCl)2] in a solvent selected from dichloromethane (MDC) or toluene at a temperature ranging from 35 °C to 90 °C to obtain a compound B of the following formula;

step (2b): reacting the compound B as obtained in step (2a) with compound C;

in the presence of triethylamine (TEA) as a base in a solvent selected from dichloromethane (MDC) or toluene at a temperature ranging from 0 °C to 20 °C to obtain the compound 4.
The reagent used in step (2a) is selected from thionyl chloride (SOCl2) or phosphoryl chloride (POCl3).
The solvent used in the step (2a) is dichloromethane (MDC).
The process of step (2a) is carried out at a temperature ranging from 40 °C to 45 °C.
The compound A used in step (2a) is commercially available or may be prepared by methods well-known in the art (Penn, John H et al; J. Org. Chem., 1993, 58, 8, 2128–2133).
The solvent used in the step (2b) is dichloromethane (MDC).
In step (2b) the reaction is carried out at a temperature ranging from 0 °C to 5 °C.

The compound 10 used in step (1g) of Scheme 1 is prepared by a process depicted in the following Scheme 3:

Scheme 3

The process for the preparation of compound 10 comprises the steps of:

step (3a): reacting compound D of the following formula:

with sodium nitrite (NaNO2) in the presence of acetic acid at a temperature ranging from 25 °C to 30 °C to obtain a compound E of the following formula:

step (3b): reducing the compound E as obtained in step (3a) by reaction with platinum on carbon (Pt/C) in methanol at a temperature ranging from 20 °C to 40 °C to obtain the compound 10.
The compound D used in step (3a) of scheme 3 is commercially available or may be prepared by methods well-known in the art (Hall, H. K., Jr., J. Am. Chem. Soc., 1958, 80, 23, 6412–6420).

In step (3b) the reaction is carried out at a temperature ranging from 25 °C to 30 °C.

The acid used in step (1i) is selected from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
The acid used in step (1i) is preferably selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, trifluro acetic acid or p-toluenesulfonic acid.
The acid used in step (1i) is more preferably selected from acetic acid, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid or tartaric acid.
Method to obtain pharmaceutically acceptable salts as described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19.
The improved process for the preparation of the compound of Formula (I) of the present invention is advantageous over the prior art in terms of its overall efficiency, and in particular, due to its cost effectiveness, time duration, suitability for industrial scale-up. Moreover, the process provides the compound of Formula (I) in higher yield.
In the improved process of present invention, the intermediate of compound of formula (I); the compound 2 of step (1a) is telescoped to next step without isolation. This eliminates the requirement of column purification thereby rendering the process cost effective and suitable for large scale application.
Further, the use of cost-effective and less toxic solvents such as toluene, tetrahydrofuran or dimethylformamide (DMF) in step (1c) of the Scheme 1 also renders present process cost effective and suitable for large scale application.
Also, the use of brominating agent 33 % hydrogen bromide (HBr) in acetic acid in step (1d) of Scheme 1 renders process simple, cost effective and substantially improves yield of the intermediate compound 6 thereby increasing overall yield of the final product.
In step (1g) of Scheme 1 use of STAB which is prepared In-situ improves yield of the end product and also makes process cost effective. Further, the treatment of compound of formula (I) with silicon thiol (SiThiol) removes residual metal impurities thereby improving the purity of said compound. The crystallization of the compound of Formula (I) carried out in step (1h) of Scheme 1 further improves the purity of the compound.
The process for the preparation of compound 4 in Scheme 2, avoids the use of costly reagents. The said process is carried out in two steps using cheaper reagents such as thionyl chloride SOCl2, phosphoryl chloride (POCl3) or oxalyl chloride [(COCl)2] which substantially improves the yield of compound 4 compared to the prior art process thereby improving overall yield of final product in cost effective manner.
The reagent platinum on carbon (Pt/C) used in step (3b) of Scheme 3 for preparation of the compound 10 substantially improves the yield of the compound 10 as compared to the prior art process. Moreover, the reagent platinum on carbon (Pt/C) used in step (3b) is recoverable which makes present process cost effective.

The details of the process of the invention are provided in the examples given below. The examples illustrate the practice of the preferred embodiments of the present invention which are given for illustrative purpose only and should not be construed to limit the scope of the invention.
Examples:
Example 1:
4-bromophenyl (4-(trifluoromethyl)piperidin-1-yl)methanone (Compound 4)
Part (a) - Intermediate: 4-Bromobenzoyl chloride (compound B)
Dichloromethane (5.0 L) and 4-bromobenzoic acid (1.0 kg) (compound A) were added to the reactor with constant stirring. To the stirred reaction mixture was added N, N-dimethylformamide (0.001 L) after 10 min. To the resulting mixture, thionyl chloride (1.5 L) was added drop wise over a period of 30 min. at 25-30 oC. The reaction mixture was heated to attain temperature between 40-45 oC and maintained at that temperature for 8-10 h. After completion of the reaction, the reaction mixture was cooled to a temperature between 35-40 oC and dichloromethane was distilled under vacuum below 40 °C. The reaction mixture was chased with 2.0 L of dichloromethane under vacuum below 40 °C and distilled under vacuum to remove the traces of solvent below 40 °C to yield a residue. The residue was dissolved in dichloromethane (5.0 L) and used for the next step without purification.
Yield: 1.0 - 1.08 w/w
Part (b) -Title compound: 4-bromophenyl (4-(trifluoromethyl)piperidin-1-yl) methanone (Compound 4)
To a cooled solution of dichloromethane (5.0 L) and 4-(trifluoromethyl)piperidine hydrochloride (1.0 kg) (compound C) was added triethylamine (5.0 L) drop wise over a period of 15-30 min. at 0-5 oC and resulting reaction mixture was maintained at 0-5 oC for 30 min. To this reaction mixture was added 1.1 kg of 4-Bromobenzoyl chloride (compound B) dissolved in dichloromethane (5.0 L) over a period of 1.5 - 2 h at 0-5 oC ensuring pH of reaction mixture is not lower than 8. The reaction mixture was maintained at 25-30 oC for 12-14 h. On completion of the reaction, the reaction mixture was quenched with water (5.0 L) having temperature less than 5 oC. The reaction mixture was stirred for 10-15 min. and allowed to settle for 15 min. The dichloromethane layer was separated and washed with 5.0 L of 10 % sodium carbonate solution and dried over 0.2 kg of anhydrous sodium sulphate. The solvent was completely distilled under vacuum at 40 oC and the residue was chased with n-heptane (1.0 L). To this residue was added 3.0 L of fresh n-heptane to make a slurry at 40-45 oC over the period of 30 min. The slurry of the reaction mixture was cooled to 5-10 oC and maintained at 5-10 oC for 30 min. The title compound was filtered, washed with 0.5 L of n-heptane and dried at 40-45 oC for 12-14 h.
Yield: 1.4-1.6 w/w, HPLC purity: 95 - 99 %
1H NMR (500 MHz, CDCl3): d ppm 7.59 (d, 2H), 7.31 (d, 2H), 4.82 (bs, 1H), 3.86 (bs, 1H), 3.02 (bd, 2H), 2.36 (m, 1H), 2.03 (bd, 2H), 1.64 (bs, 2H); MS(ES+): m/z 336.1 (M+1) +.

Example 2:
1-Aminopiperidin-1-ol (Compound 10)

Part (a) - Intermediate: N-Nitroso-4-hydroxypiperidine (compound E)

Water (7.5 L) and 1.0 kg of piperidin-4-ol (compound D) were added to a reactor with constant stirring at 20-30 oC. The resulting reaction mixture was cooled to a temperature between 5-10 oC. Sodium nitrite (1.36kg) was added to the reaction mixture with constant stirring at 5-10 oC. The reaction mixture was cooled to a temperature between 0-5 oC. Acetic acid (0.9 L) was added to the reaction mixture at a temperature between 0-5 oC. The reaction mixture was slowly heated to a temperature 25-30 oC and maintained at that temperature for 12-14 h. On completion of the reaction, the reaction mixture was cooled to a temperature between 15-20 oC. Sodium carbonate (0.9 kg) was added to the reaction mixture at 15-20 oC to adjust pH between 9-10. The reaction mixture was heated to a temperature 25-30 oC with constant stirring for 15-30 min. 4.0 L of ethyl acetate was added to the reaction mixture with stirring for 10-15 min. The reaction mixture was allowed to settle and aqueous and organic layer were separated. The aqueous layer was added back to the reactor to repeat extraction with ethyl acetate. All organic layers separated in extraction were combined together and dried with an anhydrous sodium sulphate (0.2 kg). The dried organic layer was added to the reactor with constant stirring. The solvent was completely distilled under vacuum at a temperature below 40 oC to obtain the title compound (compound B).
Yield: 1.0-1.1 w/w; GC purity: 98 - 99 %;
1H NMR (500 MHz, CDCl3): d ppm 4.52 (bs, 1H), 3.31 (m, 1H), 2.91 (bs, 1H), 2.15 (bs, 2H), 1.67 (m, 2H), 1.44 (m, 2H); MS(ES+): m/z 131.2 (M+1) +.

Part (b) – Title compound: 1-Aminopiperidin-1-ol (Compound 10)

Methanol (10.0 L) and N-nitroso-4-hydroxypiperidine (1.0 kg) (compound E as per example 2) was added into a reactor with constant stirring. The resulting reaction mixture was cooled to a temperature between 5-10 oC. 0.2 kg of 5 % platinum on carbon (Pt/C) suspended in methanol (5.0 L) was added to the reaction mixture at 20-25 oC. The reaction mixture was flushed twice with 2 kg/cm2 nitrogen at 20-25 °C and then flushed twice with 2 kg/cm2 hydrogen at 20-25 °C. Hydrogen gas was purged through the reaction mixture at a pressure of 8-10 kg/cm2. The reaction mixture was maintained at a temperature 30-35 °C for 30-45 min. On completion of the reaction, the reaction mixture was filtered through celite bed, filter bed washed with 2.5 L of methanol and filtrate taken into the reactor. Methanol was distilled from the filtrate under vacuum at a temperature below 45 °C to afford title compound of formula 10.
Yield: 0.70-0.85 w/w; GC purity: 75 - 85 %;
1H NMR (500 MHz, CDCl3): d ppm 4.52 (bs, 1H), 3.31 (m, 1H), 2.91 (bs, 1H), 2.15 (bs, 2H), 1.67 (m, 2H), 1.44 (m, 2H); MS(ES+): m/z 117.2 (M+1) +.

Example 3:
2,6-dichlorobenzyl acetate (compound 2)
n-Heptane (6.0 L) was taken in a reactor and the temperature was maintained at 25-30 oC. To this solvent, the compound 1 (2,6-dichlorobenzyl alcohol) (1.0 kg) was added with constant stirring under an atmosphere of nitrogen. The reaction mixture was cooled to a temperature between 0-5 oC and 1.5 L of triethylamine was added with continuous stirring. Acetic anhydride (0.87 L) was added slowly over a period of 45-60 min. to the reaction mixture while maintaining the reaction temperature between 0-5 oC and ensuring that the pH was not lower than 8. After the addition was complete, the reaction mixture was stirred continuously for 12-15 h at room temperature. On completion of the reaction, ice cold water (4.0 L) was added to the reaction mixture at 0-5 oC over a period of 15-30 min. The reaction mixture was stirred continuously for 15-30 min and then allowed to settle. The aqueous layer was separated and n-heptane layer was collected. To this n-heptane layer, 5 % sodium bicarbonate solution (1.0 L) was added with stirring for 15-30 min. The reaction mixture was allowed to settle and aqueous layer was separated. The separated n-heptane layer was again subjected to treatment with 5 % sodium bicarbonate solution until the pH was adjusted between 7-8. The organic layer was separated and used for the next step.
1H NMR (500 MHz, CDCl3): d ppm 7.38 (d, 2H), 7.34 (dd, 1H), 5.38 (s, 2H), 2.10 (s, 3H), 1.35 (s, 12H); MS(ES+): m/z 220 (M+1) +

Example 4:
2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (compound 3)
To a solution of 2,6-dichlorobenzyl acetate (compound 2 as per example 3) in 6.0 L of n-heptane from the previous stage was added bis(pinacolato)diboron (1.27 kg) with constant stirring at 25-30 oC. To a resulting reaction mixture was added chloro-1,5-cyclooctadiene-iridium dimer (0.021 kg) and 2,2’-dipyridyl (0.015kg) with stirring at temperature 25-30 oC. The reaction mixture was heated to a temperature 95-100 oC and maintained at 95-100 oC for 12-16 h. On completion of the reaction, the reaction mixture was cooled to a temperature 25-30 oC. Ethyl acetate (5.0 L) was added to the reaction mixture and reaction mixture was cooled to a temperature 10-15 oC. 1N HCl (5.3 L) was added to the reaction mixture at 10-15 oC over the period of 3-4 h and reaction mixture was stirred for 15-30 min. The reaction mixture was filtered through celite bed and filter bed was washed with 0.5 L of n-heptane. Filtrate was added back to the reactor to drain aqueous layer. Organic layer was collected and dried with anhydrous sodium sulphate (0.2kg). The organic layer was distilled under vacuum at a temperature below 55 oC and the mass was cooled to a temperature 25-30 oC. 1.5 L of ethanol was added to the mass with stirring for 15-20 min. at a temperature 25-30 oC. The mass was cooled to a temperature 10-15 oC and constantly stirred for 15-30 min. to obtain the title compound. The compound was filtered, washed with 0.5 L of chilled ethanol and dried at 50-60 oC.
Yield: 1.3-1.4 w/w; HPLC purity: 90 - 97 %;
1H NMR (500 MHz, CDCl3): d ppm 7.38 (d, 2H), 7.34 (dd, 1H), 5.38 (s, 2H), 2.10 (s, 3H), 1.35 (s, 12H); MS(ES+): m/z 220 (M+1) +.

Example 5:
(3,5-dichloro-4'-(4-(trifluoromethyl)piperidine-1-carbonyl)biphenyl-4-yl)methyl acetate (compound 5)
To a reactor was added toluene (8.0 L), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (1.0 kg) (compound 3 as per example 4) and 1.05 kg of (4-bromophenyl)(4-(trifluoromethyl)piperidin-1-yl)methanone (compound of example 1) in presence of a nitrogen. To the resulting reaction mixture, was added 2.4 L of water at 25-30 oC with stirring for 10-15 min. Triphenylphosphine (0.18 kg), potassium carbonate (0.61 kg) and palladium acetate (0.033 kg) was added to the reaction mixture at 25-30 oC. The resulting reaction mixture was heated to a temperature 80-85 oC and the reaction mixture was maintained at 80-85 oC for 10-12 h. On completion of the reaction, the reaction mixture was cooled to a temperature 25-30 oC and filtered through a celite bed (1 kg). The celite bed was washed with 1 L of toluene, filtrate was allowed to settle for 15-20 min and the aqueous layer was separated. 1 N HCl (4.5 L) was added to a toluene layer with stirring for 15-30 min. The reaction mixture was allowed to settle for 15 min. and aqueous and toluene layer were separated. The toluene layer was subjected again to a treatment with 1N HCl (4.5 L). 5 % sodium bicarbonate (3.5 L) was added to the toluene layer with stirring for 15-30 min. The toluene layer was separated, dried over anhydrous sodium sulphate (0.2 kg), the solvent was distilled out from the toluene layer below 50 °C under vacuum and chased with n-heptane (4.0 L) at temperature below 50 °C. To the resulting mixture, was added n- heptane (4.0 L) at 25-30 °C with stirring for 30-45 min. The resulting slurry was filtered, filter bed washed with n-heptane (1.25 L) and dried at 50-60 oC to obtain the title compound.
Yield: 1.35-1.45 w/w; HPLC purity: 75 % at 225 nm and 90 - 95 % at 275 nm;
1H NMR (500 MHz, CDCl3): d ppm 7.62 (d, 2H, J = 8.5Hz), 7.58 (s, 2H), 7.53 (d, 2H, J = 8.5Hz), 5.43 (s, 2H), 4.86 (bs, 1H), 3.93 (bs, 1H), 3.07 (bs, 1H), 2.82 (bs, 1H), 2.37 (m, 1H), 2.14 (s, 3H), 2.03 (bd, 2H), 1.63 (bd, 2H); MS(ES+): m/z 375.2 (M+1) +

Example 6:
(4'-(bromomethyl)-3',5'-dichlorobiphenyl-4-yl)(4-(trifluoromethyl) piperidin-1-yl)methanone (compound 6)
Acetic acid (3.0 L) and (3,5-dichloro-4'-(4-(trifluoromethyl)piperidine-1-carbonyl)biphenyl-4-yl)methyl acetate (1.0 kg) (compound 5 as per example 5) was added to a reactor with stirring at a temperature 25-30 °C. The resulting reaction mixture was cooled to a temperature 15-20 °C. 1.57 L of ~30 % HBr in acetic acid was slowly added to the reaction mixture over a period of 0.45-1.0 h at a temperature of 15-20 °C. The reaction mixture was heated to a temperature of 25-30 °C and maintained at that temperature for 14-16 h. On completion of the reaction, toluene (6.0 L) was added to the reaction mixture at 25-30 °C and the reaction mixture was maintained at 25-30 °C for 15-20 min. The reaction mixture was cooled to a temperature 0-5 °C, 6.0 L of cold water was added to the reaction mixture with constant stirring for 15-20 min. at 0-5 °C and then the temperature of reaction mixture was slowly raised to 15-20 °C. The reaction mixture was filtered through celite bed, filtrate was collected and allowed to settle for 15-30 min. The aqueous layer was separated and toluene layer was collected. The aqueous layer was subjected to extraction with toluene. All separated toluene layers were combined and washed twice with 10 % sodium carbonate solution (2.5 L) to adjust pH between 7-8 and dried over anhydrous sodium sulphate (0.2 kg). The solvent was distilled under vacuum at temperature below 50 °C and chased twice with n-heptane (3.0 L) at temperature below 50 °C. A mixture of n-heptane (4.5 L) and ethyl acetate (0.5 L) was added to the residue at 15-20 °C and maintained at 15-20 °C for 30-45 min. The resulting title compound was filtered and dried at 50-60 °C for 12-14 h.
Yield: 0.8-0.9 w/w; HPLC purity: ~83 % at 225 nm and ~95 % at 275 nm;
1H NMR (300 MHz, CDCl3): d ppm 7.61 (d, 2H, J = 8.5Hz), 7.57 (s, 2H), 7.52 (d, 2H, J = 8.5Hz), 4.81(s, 2H), 3.92 (bs, 1H), 3.07 (bs, 1H), 2.82 (bs, 1H), 2.38 (m, 1H), 2.02 (bd, 2H), 1.69 (bs, 2H), 1.64 (bs, 1H); MS(ES+): m/z 494.1 (M+1) +.

Example 7:
(3R,5S)-3-((3,5-dichloro-4'-(4-(trifluoromethyl)piperidine-1-carbonyl)biphenyl-4-yl)methyl)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (compound 8)

8.0 L of tetrahydrofuran was added to a reactor with stirring in presence of nitrogen. To this solution was added 0.49 kg of (S)-5-((trimethylsilyloxy)methyl)dihydrofuran-2(3H)-one (compound 7) at temperature 25-30 °C. The resulting reaction mixture was cooled to a temperature -65 to -60 °C. In a separate reactor (4'-(bromomethyl)-3',5'-dichlorobiphenyl-4-yl)(4-(trifluoromethyl)piperidin-1-yl)methanone (1 kg) (compound 6 as per example 6) was dissolved in tetrahydrofuran (4.0 L) in the presence of nitrogen and resulting solution was slowly added to the reaction mixture over a period of 45-60 min. at a temperature -65 to -60 °C. The reaction mixture was stirred for 15-20 min. at temperature -65 to -60 °C. 20 % lithium hexamethyldisilazide in a mixture of tetrahydrofuran and ethyl benzene (2.7 L) was added to the reaction mixture over the period of 1.0–1.5 h at a temperature -65 to -60 °C. The reaction mixture was maintained at -65 to -60 °C for 45-60 min. On completion of the reaction, the reaction mixture was warmed up to -30 °C. 30 % phosphoric acid (4.0 L) was added to the reaction mixture followed by continuous stirring for 45-60 min at temperature 25-30 °C. The reaction mixture was maintained at 25-30 °C for 3.0-3.5 h. Ethyl acetate (2.0 L) was added to the reaction mixture at 25-30 °C with constant stirring for 10-15 min and then the reaction mixture was allowed to settle. The aqueous layer was separated and organic layer was collected. 5 % Sodium bicarbonate solution (5.0 L) was added to the organic layer with stirring for 15-20 min. to adjust pH to neutral. The reaction mixture was washed with 10 % sodium chloride (5.0 L) with stirring for 15-20 min. and allowed to settle. The aqueous layer was separated and organic layer was collected. The organic layer was subjected to a wash with 10 % sodium chloride solution (5.0 L), the aqueous layer was separated and the organic layer was dried. The ethyl acetate was distilled under vacuum at temperature below 40 °C and residue chased with tetrahydrofuran (5.0 L) below 40 °C. The residue was dissolved in tetrahydrofuran (8.0 L) in the presence of nitrogen and organic layer containing the title compound was taken to next step.
Yield: 1-1.05 w/w; HPLC purity 80 - 85 % at 225 nm and 80 - 86 % at 275 nm.
1H NMR (500 MHz, CDCl3): d ppm 7.61 (d, 2H, J = 8Hz), 7.57 (s, 2H), 7.52 (d, 2H, J = 8Hz), 4.75 (m, 2H), 3.95 (dd, 1H, J = 2.5 & 12Hz), 3.67 (dd, 1H, J = 4 & 12Hz), 3.52(dd, 1H, J = 4 & 12Hz), 3.34 (m, 1H), 3.27 (m, 1H), 3.07 (bs, 1H), 2.82 (bs, 1H),
2.36 (m, 1H), 2.30 (m, 1H), 2.24 (m, 2H), 2.02 (bs, 1H), 1.91 (bs, 1H), 1.73 (bs, 2H), 1.63 (bs, 1H); MS(ES+): m/z 530.2 (M+1) +.

Example 8:
(R)-3-((3,5-dichloro-4'-(4-(trifluoromethyl)piperidine-1-carbonyl)biphenyl-4-yl)methyl)-5-hydroxydihydrofuran-2(3H)-one (compound 9)

1.0 kg of (3R,5S)-3-((3,5-dichloro-4'-(4-(trifluoromethyl)piperidine-1-carbonyl) biphenyl-4-yl)methyl)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (compound 8 as per example 7),as a solution in 8.0 L of tetrahydrofuran was added to a reactor with constant stirring at 25-30 °C. To this solution was added tetrahydrofuran (1.0 L). Sodium hydroxide (0.15 kg) in 1.89 L of water was added to the resulting reaction mixture at 25-30 °C and the reaction mixture was maintained at 25 °C to 30 °C for 0.45-1.0 h. Periodic acid (0.51 kg) in 3.0 L of water was added to the reactor over a period of 0.5-1.0 h at 25-30 °C. The reaction mixture was maintained at 30-35 °C for 0.45-1.0 h. On completion of the reaction, reaction mixture was diluted with 10.0 L of ethyl acetate. 1N hydrochloric acid (5.0 L) was added drop wise to the reaction mixture over a period of 15-30 min. at 25-30 °C with stirring for 15-30 min. The reaction mixture was allowed to settle for 15 min. and aqueous and organic layer were separated. The aqueous layer was subjected to extraction with ethyl acetate (2.0 L). The organic layer was washed with 10 % sodium metabisulphite solution (5.0 L) and allowed to settle for 10-15 min. Organic layer was collected and aqueous layer was separated. The organic layer was subjected twice for washing with 10 % sodium chloride (5.0 L) and dried over anhydrous sodium sulphate (0.5 kg). Solvent was distilled from organic layer and chased twice with n-heptane (3.0 L) under high vacuum below 45 °C for 1-1.5 h to obtain a residue. The residue was dissolved in ethyl acetate (2.0 L) and 4.0 L of n-heptane was added over the period of 30 min. at 40-45 °C. The resulting mixture was maintained at 40-45 °C for 30 min. The mixture was cooled to 5-10 °C and maintained at that temperature for 45-60 min. The mixture was filtered and filter bed was washed with 1.0 L mixture of 33 % ethyl acetate and 66 % n-heptane. The filtrate was dried at 40-45 °C for 12-16 h to obtain the title compound.
Yield: 0.75-0.85 w/w; HPLC purity: 88 - 92 % at 225 and 275 nm.
1H NMR (500 MHz, CDCl3): d ppm 7.59 (d, 2H), 7.50 (s, 2H), 7.50 (d, 2H), 5.89 (d, 2H), 4.85 (bs, 1H), 3.93 (bs, 1H), 3.61 (m, 1H), 3.42 (m, 1H), 3.18 (m, 1H), 3.08 (bs, 1H), 2.83 (bs, 1H), 2.38 (m, 2H), 2.19 (m, 1H), 2.06 (bd, 2H), 1.66 (bs, 2H); MS(ES+): m/z 516.1 (M+1) +.
Example 9:
(R)-3-((3,5-dichloro-4'-(4-(trifluoromethyl)piperidine-1-carbonyl)biphenyl-4-yl) methyl)-1-(4-hydroxypiperidin-1-yl)pyrrolidin-2-one (compound of formula I)

0.4 kg of 1-aminopiperidin-1-ol (compound 10 as per example 2) was dissolved in 9.0 L of acetonitrile and added to a reactor A. The resulting reaction mixture was maintained at 25-30 °C. 1.0 kg of (R)-3-((3,5-dichloro-4'-(4-(trifluoromethyl)piperidine-1-carbonyl)biphenyl-4-yl)methyl)-5-hydroxydihydrofuran-2(3H)-one (compound 9 as per example 8) was added to the reaction mixture in presence of nitrogen at 25-30 °C. To the resulting reaction mixture was added 3.0 L of acetic acid and the reaction mixture was maintained at 25-30 °C for 2-3 h. In a separate reactor B, acetonitrile (6.0 L) and powdered sodium borohydride (NaBH4) (0.23 kg) was added in presence of nitrogen and the resulting reaction mixture was cooled to a temperature of -5 to 0 °C. To the reaction mixture of reactor B, acetic acid (1.0 L) was added drop wise over the period of 1-2 h at temperature -5 to 0 °C. To the reaction mixture of reactor B was added the reaction mixture of reactor A at 0-5 °C over the period of 1-2 h. The temperature of resulting reaction mixture was increased to 60-65 °C and maintained at that temperature for 1-2 h. On completion of the reaction, the solvent was distilled under vacuum at temperature below 40 °C. The reaction mixture was cooled to a temperature 15-20 °C and diluted with dichloromethane (10 L). Water (5.0 L) was added to the reaction mixture with stirring for 15-20 min. at 15-20 °C. The reaction mixture was allowed to settle and the aqueous and organic layers were separated. The organic layer was taken in the reactor, water (5.0 L) was added to the organic layer with stirring for 10-15 min. and allowed to settle to separate organic and aqueous layer. To the organic layer was added 5 % sodium carbonate solution (5.0 L) and methanol (2 L) with stirring for 5 min. The resulting mixture was allowed to settle for 15-20 min. and the organic layer was separated. The organic layer was added back to the reactor and subjected to treatment with 10 % sodium chloride (5.0 L). To the resulting reaction mixture was added methanol (1.5 L) with stirring for 5 min. and the reaction mixture was allowed to settle for 25-30 min. to separate aqueous and organic layer. The organic layer was subjected again to extraction with 10 % sodium chloride and methanol. The resulting organic layer was dried over 0.2 kg of anhydrous sodium sulphate. To the dried organic layer was added activated carbon (0.1 kg) and SiThiol (0.1 kg) with stirring for 45-60 min. The resulting reaction mixture was filtered through celite bed and the filter bed was washed with dichloromethane (2 L). The solvent dichloromethane was distilled under vacuum below 35 °C to obtain a residue. The residue was diluted in acetone (5.0 L) at 30-35 °C and was heated to 40-45 °C. Solvent was distilled and the residue was chased thrice with acetone (3.0 L). The residue was diluted in acetone (3 L), heated to 50-55 °C and maintained at 50-55 °C for 2 h. The resulting mixture was cooled to a temperature 35-40 °C over a period of 1-2 h and maintained at 25-30 °C for 12-16 h. The reaction mixture was filtered and filter bed washed with 1.0 L of chilled acetone. The reaction mixture was dried in vacuum at 45-50 °C for 12-16 h to obtain the title compound. The title compound was further subjected to jet milling process.
Yield: 0.4-0.6 w/w; HPLC purity: 97 %; Chiral purity: 95 % ee;
1H NMR (500 MHz, CDCl3): d ppm 7.61 (d, 2H, J = 8.5), 7.54 (s, 2H), 7.51 (d, 2H, J = 8.5), 4.86 (bs, 1H), 3.93 (bs, 1H), 3.81 (m, 1H), 3.52 (m, 2H), 3.38 (dd, 1H, J = 4.4 & 16.2), 3.15(m, 1H), 3.14 (m, 1H), 3.13 (m, 3H), 3.08 (m, 1H), 2.94 (m, 2H), 2.83 (bs, 1H), 2.37 (m, 1H), 2.05 (m, 4H), 1.95 (m, 2H), 1.80 (m, 2H), 1.57 (bs, 2H); MS(ES+): m/z 598.2 (M+1) +.