FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of sacubitril intermediates. More particularly, the present invention relates to a process for the preparation of sacubitril intermediates involving an unprecedented copper-catalyzed reductive cross-coupling and triflic acid mediated N-benzyl deprotection of lactam intermediates.

BACKGROUND AND PRIOR ART OF THE INVENTION
Sacubitril is an antihypertensive drug. It is a prodrug neprilysin inhibitor used in combination with valsartan and marketed under the brand name Entresto. The combination drug is used for the treatment to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. Sacubitril is activated to sacubitrilat (LBQ657) by de-ethylation (via esterases mediated enzymatic hydrolysis), which inhibits the enzyme responsible for the degradation of atrial and brain natriuretic peptide, two blood-pressure lowering peptides that work mainly by reducing blood volume. Chemically, sacubitril is known as 4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid having molecular formula C24H29NO5.

SACUBITRIL
Several synthetic protocols are known to prepare sacubitril. Almost all processes known in the prior art involve the Grignard reagent coupling reaction for the preparation of key lactam derived intermediates.
PCT application WO2008083967A2 filed by Novartis on 10th Jan 2008 discloses the coupling of (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (alkyl-tosylate) with aryl bromide using 2 equiv of CuCN and pre-prepared Grignard reagent (from 4 equiv of aryl bromide and 4.5 equiv of magnesium metal at elevated temperatures (60 oC)) followed benzyl protection of the free lactam nitrogen to deliver the key sacubitril intermediate (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one.

Another PCT application WO2009090251 filed by Novartis on 16th Jan 2009 discloses the preparation of sacubitril intermediate, (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one through the coupling of (S)-5-(iodomethyl)pyrrolidin-2-one (alkyl iodide) with pre-prepared Grignard Reagent (from 4.0 equiv of aryl bromide and 4.5 equiv of magnesium metal at elevated temperatures (60 oC)) using TMEDA and Fe(III)-catalyst followed by benzyl protection.
However, these processes suffer from problems such as the generation of Grignard reagent from alkyl-bromide and magnesium metal, which need to use low-flashpoint Et2O as a solvent, and other solvents like THF failed to generate the complete Grignard reagent. If THF used in this process, the elevated temperature is needed (60°C) for several hours. In addition, the Grignard reagent was prepared in a separate step. Moreover, CuCN, aryl-bromide, and magnesium metal were used in excess amounts (4-8 equiv). These processes also suffer from the side reaction, which generates a homo-coupling product of aryl bromide.
Therefore, thus, there is a need in the art to develop a process which may avoid these problems and does not involve the pre-generation of Grignard reagent — the process which may provide simple and cost-effective synthetic protocol.

OBJECTIVES OF THE INVENTION
The main objective of the present invention is to provide a simple, cost-effective process for the preparation of sacubitril intermediates.

ABBREVIATIONS:
CuCN: Copper(I) cyanide
TMEDA: Tetramethylethylenediamine
THF: Tetrahydrofuran
CuI: Copper(I) iodide
DPPM: (1,1-bis(diphenylphosphino)methane)
LiOMe: Lithium Methoxide
LiHMDS: Lithium hexamethyldisilazide
DMSO: Dimethyl sulfoxide
DMF: Dimethylformamide
CuCl: Copper(I) chloride
Cu(OTf)2: Copper(II) triflate
Cu(OAc)2: Copper(II) acetate
LiOMe: Lithium Methoxide
LiCl: Lithium chloride
LiI: Lithium Iodide
LiOtBu: Lithium tert-butoxide
TMEDA: Tetramethylethylenediamine
PPh3: Triphenylphosphine
DPPP: 1,3-Bis(diphenylphosphino)propane
DPPE: 1,2-Bis(diphenylphosphino)ethane
DPPB: 1,4-Bis(diphenylphosphino)butane
Pd/C: Palladium on carbon
Pd(OH)2/C: Palladium hydroxide on carbon
Pt/C: Platinum on carbon

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of sacubitril intermediates involving an unprecedented copper-catalyzed reductive cross-coupling and triflic acid-mediated N-benzyl deprotection of lactam intermediates.

The process involves an unprecedented copper-catalyzed reductive cross-coupling of (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one of formula (6) and aryl bromide intermediate of formula (7) and triflic acid-mediated N-benzyl deprotection of (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9) intermediate.
The process comprising the steps of:
i) esterifying the L-pyroglutamic acid of formula (1) in the presence of 98% sulfuric acid and an alcohol at a temperature in the range of 25-35°C for a period of 1-12 hr in a solvent to afford a compound ethyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2) or methyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2a);
ii) protecting the -N of ethyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2) or methyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2a) obtained from step (i) by using benzyl bromide in presence of a strong base at a temperature in a range of 0-30°C for a period of 2-6 hr in a solvent to afford (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate of formula (3) or (3a);
iii) treating the (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate of formula (3) or (3a) compound obtained from step (ii) with sodium borohydride at a temperature in a range of 0-30°C for a period of 2-3 hr in a suitable solvent to afford compound (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one of formula (4);
iv) tosylating the (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one of formula (4) obtained from step (iii) by using 4-toluenesulfonyl chloride in presence of triethylamine base at a temperature in the range of 25-30°C for a period of 5 to 12 hr in a suitable solvent to afford (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate of formula (5);
v) treating the compound (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate of formula (5) obtained from step (iv) with sodium iodide at reflux temperature in the range of 60 to 90 oC for a period of 2-4 hr in a suitable solvent to obtain (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one of formula (6);
vi) treating the compound (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (5) obtained from step (iv) or (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one (6) obtained from step (v) with biphenyl bromide (7) in the presence of coupling catalyst at a temperature in the range of 25-35°C for a period of 30 min in a suitable solvent to afford compound (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8);
vii) methylating the compound (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8) obtained from step (vi) by using methyl iodide in the presence of LiHMDS at a temperature in the range of -75-35°C for a period of 20-24 hr in a suitable solvent to afford (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9);
viii) debenzylating the compound (3R,5S)-5-([1,1'-Biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9) obtained from step (vii) by using debenzylating catalyst at a temperature in the range of 50-200°C under microwave radiation or without microwave for a period of 10-60 min in a suitable solvent to afford key intermediate (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-3-methylpyrrolidin-2-one of formula (10) for the synthesis of sacubitril.
In an embodiment of the present invention wherein said alcohol used in step (i) is selected from the group consisting of methanol or ethanol alone or in combination therefrom.

In an embodiment of the present invention, said base used in step (ii) is selected from the group consisting of Sodium hydride, potassium carbonate, cesium carbonate, butyl lithium, lithium diisopropyl amide, alone or in combination therefrom.
In another embodiment of the present invention, said coupling catalyst used in step vi) is selected from the group consisting of Grignard reagent, CuI, CuCl, Cu(OTf)2, Cu(OAc)2, LiOMe, LiCl, LiI, LiOtBu, TMEDA, PPh3,DPPP, DPPE, DPPB and DPPM alone or in combination therefrom.
In yet another embodiment of the present invention, said coupling catalyst used in step vi) is selected from the the group consisting of CuI, LiOMe andDPPM alone or in combination therefrom.
In yet another embodiment of the present invention, said debenzylating catalyst used in step viii) is selected from the group consisting of (H2, Pd/C), (H2, Pd(OH)2/C), (H2, Pt/C), (H2, Ni), (HCOOH, Pd/C), (HCOOH, Pd(OH)2/C), Na-Liq NH3, Li-Liq NH3, Ca-Liq NH3, Li or Na in amines, Li-naphthalenide, HBr/phase transfer catalyst, aqueous ceric ammonium nitrate, and triflic acid alone or in combination therefrom.
In yet another embodiment of the present invention, said debenzylating catalyst used in step viii) is triflic acid.
In yet another embodiment of the present invention, said solvents used in step i) to viii) are selected from the group consisting of acetone, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, water, sulfuric acid, deuterium oxide, methyl ethyl ketone, acetonitrile, dimethyl sulfoxide, Dimethylformamide, chloroform, pentane, hexane, benzene, toluene, octane, decane, dimethyl ether, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethyl ether, 2-metetrahydrofuran, 1,4-dioxane and diethyl ether and mixtures thereof.
In yet another embodiment of the present invention,the yield of the sacubitril intermediate as obtained in step viii) is in the range of 60 to 95%.

DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention provides a process for the preparation of sacubitril intermediates involving an unprecedented copper-catalyzed reductive cross-coupling and triflic acid-mediated N-benzyl deprotection of lactam intermediates.
The process is depicted below in Scheme-1:

SCHEME-1

The process involves an unprecedented copper-catalyzed reductive cross-coupling of (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one of formula (6) and aryl bromide of formula (7) intermediates and triflic acid mediated N-benzyl deprotection of (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9) intermediate. The process comprising the steps of:
i) esterifying the L-pyroglutamic acid of formula (1) in the presence of 98% sulfuric acid and an alcohol at a temperature in the range of 25-35°C for a period of 1-12 hr in a suitable solvent to afford compound ethyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2) or methyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2a);

ii) protecting the -N of ethyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2) or methyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2a) obtained from step(i) by using benzyl bromide in the presence of strong base at a temperature in the range of 0-30°C for a period of 2-6 hr in a suitable solvent to afford (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate of formula (3 or 3a);

iii) treating the (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate of formula (3 or 3a) compound obtained from step (ii) with sodium borohydride at a temperature in the range of 0-30°C for a period of 2-3 hr in a suitable solvent to afford compound (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one of formula (4);

iv) tosylating the (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one of formula (4) obtained from step (iii) by using 4-toluenesulfonyl chloride in presence of triethyl amine base at a temperature in the range of 25-30°C for a period of 5 to 12 hr in a suitable solvent to afford (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate of formula (5);

v) treating the compound (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate of formula (5) obtained from step (iv) with sodium iodide at reflux temperature in a range of 60 to 90 oC for a period of 2-4 hr in a suitable solvent to obtain (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one of formula (6);

vi) treating the compound (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (5) obtained from step (iv) or (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one (6) obtained from step (v) with biphenyl bromide (7) in the presence of coupling catalyst at a temperature in a range of 25-35°C for a period of 30 min in a suitable solvent to afford compound (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8);

vii) methylating of the compound (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8) obtained from step (vi) by using methyl iodide in the presence of LiHMDS at a temperature in a range of -75-35°C for a period of 20-24 hr in a suitable solvent to afford (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9);

viii) debenzylating the compound (3R,5S)-5-([1,1'-Biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9) obtained from step (vii) by using debenzylation catalyst at a temperature in a range of 50-200°C under microwave radiation or without microwave for a period of 10-60 min in a suitable solvent to afford key intermediate (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-3-methylpyrrolidin-2-one of formula (10) for the synthesis of sacubitril.

The yield of the step viii) of the above reaction is in the range of 60 to 95%.
In one aspect of the present invention suitable solvent used at step i) may include alcohol solvents, polar solvents, non-polar solvents, and mixtures thereof. Alcohol solvents may include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol. Polar solvents may include water, sulfuric acid, deuterium oxide, ethanol, methanol, acetone, isopropanol, methyl ethyl ketone, n-propanol, acetonitrile, DMSO, DMF, and mixtures thereof. Nonpolar solvents may include chloroform, pentane, hexane, benzene, toluene, octane, decane, dimethyl ether, dichloromethane, and mixtures thereof. In particularly useful embodiment, alcohol solvents are used, and more particularly, ethanol and methanol is used at step i).

In another aspect of the present invention, the suitable solvent used at step ii) may include ether solvent, polar solvent, non-polar solvent, and mixtures thereof. Ether solvents may include dry tetrahydrofuran, dimethyl ether, 2-me-tetrahydrofuran, 1,4-dioxane, diethyl ether, and mixtures thereof. Polar solvents may DMSO, DMF, and mixtures thereof. Nonpolar solvents may include chloroform, pentane, hexane, benzene, toluene, octane, decane, dimethyl ether, and mixtures thereof. In particularly useful embodiment, ether solvents are used, and more particularly tetrahydrofuran is used at step ii).

In still another aspect of the present invention, the base is selected from sodium hydride, potassium carbonate, cesium carbonate, butyl lithium, lithium diisopropyl amide, alone or in combination therefrom.

In still another aspect of the present invention, suitable solvent used at step iii) may include alcohol solvents, polar solvents, non-polar solvents, and mixtures thereof. Alcohol solvents may include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol. Polar solvents may include water, deuterium oxide, ethanol, methanol, isopropanol, n-propanol, acetonitrile, DMF, and mixtures thereof. Nonpolar solvents may include pentane, hexane, benzene, toluene, octane, decane, dimethyl ether, and mixtures thereof. In particularly useful embodiment, alcohol solvents are used and more particularly methanol is used at step iii).

In yet another aspect of the present invention, suitable solvent used at step iv) may include non-polar solvents. Nonpolar solvents may include chloroform, pentane, hexane, benzene, toluene, octane, decane, dimethyl ether, dichloromethane, 1,2-dichloroethane and mixtures thereof. In particularly useful embodiment, dichloromethane is used at step iv).

In still yet another aspect of the present invention, suitable solvent used at step v) may include acetone. In yet another useful embodiment of the present invention acetonitrile as a solvent is used at step v).

In still yet another aspect of the present invention solvent used at step vi) and vii) may include ether solvents. Ether solvents may include dry tetrahydrofuran, dimethyl ether, 2-me-tetrahydrofuran, 1,4-dioxane, diethyl ether, and mixtures thereof. In particularly useful embodiment, tetrahydrofuran is used as a solvent at step vi) and step vii).

Suitable coupling catalyst used at step vi) is selected from Grignard reagent, CuI/CuCl/Cu(OTf)2/Cu(OAc)2, Li salts LiOMe/LiCl/LiI/LiOtBu, additives TMEDA/PPh3/DPPP/DPPE/DPPB/DPPM alone or in combination. In particularly useful embodiment CuI/LiOMe/DPPM catalytic system is used at step vi.

In yet another useful embodiment of the present invention, the solvent used at step viii) may include alcohol solvents, polar solvents, non-polar solvents, and mixtures thereof. Alcohol solvents may include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol. Polar solvents may include water, sulfuric acid, deuterium oxide, ethanol, methanol, acetone, isopropanol, methyl ethyl ketone, n-propanol, acetonitrile, DMSO, DMF, and mixtures thereof. Nonpolar solvents may include chloroform, pentane, hexane, benzene, toluene, octane, decane, dimethyl ether, dichloromethane, and mixtures thereof. In particularly useful embodiment, non-polar solvents are used and more particularly toluene is used as a solvent at step viii).

Suitable debenzylation catalyst used at step viii) is selected from (H2, Pd/C), (H2, Pd(OH)2/C), (H2, Pt/C), (H2, Ni), (HCOOH, Pd/C), (HCOOH, Pd(OH)2/C), Na-Liq NH3, Li-Liq NH3, Ca-Liq NH3, Li or Na in amines, Li-naphthalenide, HBr/phase transfer catalyst, aqueous ceric ammonium nitrate, triflic acid, dialkyl azodicarboxylate alone or in combination therefrom. In particularly useful embodiment, triflic acid is used as a debenzylating agent at step viii).

Examples:
Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.

Example 1: Synthesis of ethyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2):
To a solution of L-pyroglutamic acid (1) (25 g, 0.193 mol) in ethanol (300mL) was added 98% sulfuric acid (0.1 to 0.4 mL). The resulting reaction mixture was stirred at 27 oC for 1 to 12 h. Sodium carbonate was added and the stirring was continued for an additional 1.0 h. The suspension was filtered and the filtrate was evaporated under reduced pressure to afford the ester 2 in 90-100% yield as a viscous oil. TLC: Rf = 0.6 (SiO2, 10% MeOH : CH2Cl2); 1H NMR (CDCl3, 400 MHz): d 4.38-4.08 (m, 3H), 2.49-2.21 (m, 3H), 2.10 (s, 1H), 1.22 (t, J = 7.32 Hz, 3H); 13C NMR (CDCl3, 101 MHz): d 178.4, 172.2, 61.5, 55.6, 29.3, 24.7, 14.0.
Example 2: Synthesis of ethyl (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate of formula (3):
To a 500 mL dry two-neck round bottom flask was added NaH (60% in mineral oil) (8.8 g, 0.221 mol) was dissolved in 150 mL of dry THF under argon atmosphere. The suspension was cooled to 0 oC then added ethyl (S)-5-oxopyrrolidine-2-carboxylate (2) (29 g, 0.184 mol) dissolved in 200 mL of above mentioned solvents and added drop wise to the resulting suspension. After the evolution of hydrogen gas is stopped then was added benzyl bromide (21 mL, 0.184 mol) drop wise. The resulting suspension was stirred for 2.0 to 6.0 h at 27 oC, after the reaction is over it was quenched with 150 mL of water extracted with 500 mL of EtOAc for three times. Resulting crude product was purified by column chromatography to afford (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate (3) in 85-100% yield. Rf = 0.5 (SiO2, 40% EtOAc:Hexane); 1H NMR (CDCl3, 500 MHz): d 7.36-7.26 (m, 3H), 7.22 (d, J = 7.25 Hz, 2H), 5.04 (d, J = 14.88 Hz, 1H), 4.14 (t, J = 6.87 Hz, 2H), 4.05-3.94 (m, 2H), 2.63-2.52 (m, 1H), 2.48-2.38 (m, 1H), 2.26 (m, 1H) , 2.12-2.01 (m, 1H), 1.25 (t, J = 7.25 Hz, 3H); 13CNMR (CDCl3, 125 MHz): d 175.1, 171.8, 135.9, 128.7, 128.5, 127.8, 61.4, 58.9, 45.6, 29.6, 22.8, 14.1.
Example 3: Synthesis of (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one of formula (4) :
To a solution of ethyl (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate (3) (20 g, 0.0809 mol) dissolved in methanol or ethanol was added NaBH4 (7.45 g, 0.2024 mol) portion wise at 0 °C carefully. The reaction was stirred at 27 oC for 2 h. Then the reaction mixture was quenched with acetone (300 mL) very carefully by maintaining reaction temp at 0 °C. Next, the reaction was concentrated to dry solid, diluted with brine and extracted with EtOAc concentrated and purified to afford (S)- 1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one (4) as white solid in 80-95% yield. Rf = 0.5 (SiO2, 10% MeOH:CH2Cl2); 1H NMR (CDCl3, 500 MHz): d 7.38-7.27 (m, 5H), 4.88 (d, J = 15.26 Hz, 1H), 4.25 (d, J = 14.50 Hz, 1H), 3.79 (dd, J = 11.63, 2.86 Hz, 1H), 3.48-3.60 (m, 2H), 2.52-2.66 (m, 1H), 2.43 (dd, J = 10.30, 5.72 Hz, 1H), 1.98-2.09 (m, 2H); 13C NMR (CDCl3, 125 MHz): d 176.2, 136.9, 128.8, 128.7, 127.9, 127.6, 62.5, 58.9, 44.8, 30.5, 30.0, 21.0.
Example 4: Synthesis of (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate of formula (5) :
To a stirred solution of (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one (4) (14 g, 0.062 mol) dissolved in dry CH2Cl2 was added Et3N (18.6 mL, 0.136 mol) followed by addition of DMAP (0.83 g, 0.00682 mol) and 4-toluenesulfonyl chloride (15.6 g, 0.0819 mol) added portion wise. The resulting solution was stirred at 27 oC until starting material was completely consumed on TLC. Then the reaction was quenched with Sat. aq. Solution of NH4Cl. The aqueous layer was extracted with CH2Cl2, combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (5) as white solid, (23 g, 94% yield). Rf = 0.6 (40% EtOAc:Hexane, 2 times run or 80% EtOAc:Hexane); 1H NMR (CDCl3, 500 MHz): d 7.75 (d, J = 8.39 Hz, 2H), 7.38 (d, J = 8.01 Hz, 2H), 7.35-7.25 (m, 3H), 7.15 (d, J = 6.87 Hz, 2H), 4.93 (d, J = 15.26 Hz, 1H), 4.05 (dd, J = 10.68, 3.81 Hz, 1H), 3.96 (dd, J = 10.68, 3.81 Hz, 1H), 3.81 (d, J = 15.26 Hz, 1H), 3.68-3.60 (m, 1H), 2.57-2.51 (m, 1H), 2.51-2.47 (m, 1H), 2.44-2.33 (m, 1H), 2.15-2.05 (m, 1H), 1.92-1.82 (m, 1H); 13C NMR (CDCl3, 125 MHz): d 175.0, 145.3, 136.1, 132.4, 130.1, 128.8, 128.0, 127.9, 127.7, 68.9, 55.4, 44.5, 29.7, 21.7, 21.1.
Example 5: Synthesis of (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one (6):
To a solution of (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (5) (23 g, 0.0582 mol) dissolved in dry acetonitrile was added NaI and refluxed at 90 oC for 4.0 h (monitored by TLC). After completion of reaction, it was directly concentrated on rota-vapour so that respective solvent was completely evaporated and diluted with H2O extracted with EtOAc, combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one (6) in 95% yield. Rf = 0.6 (40% EtOAc:Hexane); 1H NMR (CDCl3, 500 MHz): d 7.18-7.41 (m, 5H), 5.06 (d, J = 15.26 Hz, 1H), 3.95 (d, J = 15.26 Hz, 1H), 3.49-3.38 (m, 1H), 3.29 (dd, J = 10.68, 2.29 Hz, 1H), 3.23 (dd, J = 10.49, 6.29 Hz, 1H), 2.68-2.60 (m, 1H), 2.44 (ddd, J = 17.07, 10.78, 5.72 Hz, 1H), 2.23-2.11 (m, 1H), 1.87-1.79 (m, 1H); 13C NMR (CDCl3, 125 MHz): d 175.1, 136.0, 128.9, 128.1, 127.8, 56.4, 44.3, 29.8, 24.8, 10.7.
Example 6: Synthesis of (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8):
To a 100 mL two-neck round bottom flask was taken Magnesium powder (0.04 g, 0.0016 mol), activated by preheating it under vacuum with hot gun for 15 min. then cooled to 27 oC followed by addition of (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (5) (0.3 g, 0.00083 mol), LiOMe (0.031 g, 0.0083), DPPM (0.065 g, 0.00017 mol), CuI (0.015 g, 0.00008 mol) successively under argon atmosphere then 1.0 mL of dry THF was added followed by drop wise addition of biphenyl bromide dissolved in 1.0 mL of dry THF (minimum amount of solvent is used) and stirred at 27 oC for 30 min. reaction turns green in color. As soon as reaction is completed, it is immediately quenched with sat. aq. Solution of NH4Cl and diluted with CH2Cl2, DCE or EtOAc, aqueous layer was extracted with CH2Cl2, DCE or EtOAc and combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one (8) in 90% yield. Rf = 0.6 (40% EtOAc:Hexane); 1H NMR (CDCl3, 200 MHz): d 7.59-7.08 (m, 14H), 7.02 (d, J = 8.05 Hz, 2H), 5.03 (d, J = 15.10 Hz, 1H), 3.72-3.48 (m, 1H), 3.51-3.69 (m, 1H), 2.95 (dd, J = 13.45, 4.19 Hz, 1H), 2.51 (dd, J = 13.45, 8.60 Hz, 1H), 2.15-2.29 (m, 2H), 1.77-1.99 (m, 1H), 1.60-1.76 (m, 1H); 13C NMR (CDCl3, 50 MHz): d 175.3, 140.7, 139.7, 136.7, 136.1, 129.7, 128.9, 128.8, 128.1, 127.7, 127.3, 127.0, 58.0, 44.5, 38.8, 29.9, 23.8.
Example 7: Synthesis of (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8):
To a 100 mL two-neck round bottom flask was taken Magnesium powder (1.5 g, 0.0634 mol), activated by preheating it under vacuum with hot gun for 15 min. then cooled to 27 oC followed by addition of (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one (6) (10 g, 0.0317 mol), LiOMe (1.2 g, 0.0317), DPPM (2.2 g, 0.00634 mol), CuI (0.6 g, 0.00317 mol) successively under argon atmosphere then 8.0 mL of dry THF was added followed by drop wise addition of biphenyl bromide dissolved in 8 mL of dry THF (minimum amount of solvent is used) and stirred at 27 oC for 30 min. reaction turns green in color. As soon as reaction is completed, it is immediately quenched with sat. aq. Solution of NH4Cl and diluted with CH2Cl2, DCE or EtOAc, aqueous layer was extracted with CH2Cl2, DCE or EtOAc, combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one (8) in 85-95% yield. Rf = 0.6 (40% EtOAc:Hexane); 1H NMR (CDCl3, 200 MHz): d 7.59-7.08 (m, 14H), 7.02 (d, J = 8.05 Hz, 2H), 5.03 (d, J = 15.10 Hz, 1H), 3.72-3.48 (m, 1H), 3.51-3.69 (m, 1H), 2.95 (dd, J = 13.45, 4.19 Hz, 1H), 2.51 (dd, J = 13.45, 8.60 Hz, 1H), 2.15-2.29 (m, 2H), 1.77-1.99 (m, 1H), 1.60-1.76 (m, 1H); 13C NMR (CDCl3, 50 MHz): d 175.3, 140.7, 139.7, 136.7, 136.1, 129.7, 128.9, 128.8, 128.1, 127.7, 127.3, 127.0, 58.0, 44.5, 38.8, 29.9, 23.8.
Example 8: Synthesis of (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9):
To stirred solution of (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one (8) (9.4 g, 0.0278 mol) dissolved in dry THF, cooled to -78 oC was added LiHMDS (or other lithiating reagents such as KHMDS, LDA) (83 mL, 0.0834 mol) followed by addition of MeI (5 mL, 0.0834 mol) drop wise at same temperature then stirred at 27 oC for 24 h then quenched with sat. aq. solution of NH4Cl, aqueous layer extracted with EtOAc (500 mL), combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one (9) Rf = 0.5 (monomethylated), 0.6 (dimethylated) in 95% yield; 1H NMR (CDCl3, 400 MHz): d (mono-methylated) 7.58 (d, J = 7.63 Hz, 2H), 7.52 (m, J = 7.63 Hz, 2H), 7.47-7.40 (m, 2H), 7.39-7.28 (m, 4H), 7.23-7.28 (m, 2H), 7.14 (d, J = 7.63 Hz, 2H), 5.13 (d, J = 15.26 Hz, 1H), 4.00 (d, J = 15.26 Hz, 1H), 3.69-3.55 (m, 1H), 2.98 (dd, J = 13.73, 4.58 Hz, 1H), 2.64 (dd, J = 12.97, 8.39 Hz, 1H), 2.33-2.48 (m, 1H), 2.06 (ddd, J = 12.21, 9.16, 3.05 Hz, 1H), 1.57 (dt, J = 12.97, 8.39 Hz, 1H), 1.18 (d, J = 7.63 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d 177.6, 140.7, 139.7, 136.9, 136.5, 129.8, 128.9, 128.9, 128.2, 127.7, 127.4, 127.4, 127.1, 56.1, 44.7, 38.4, 35.1, 32., 16.7.
Example 9: Synthesis of (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-3-methylpyrrolidin-2-one of formula (10):
To a solution of (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one (9) (0.5 g, 0.001408 mol) dissolved in 4 mL of dry toluene (or other aromatic hydrocarbon solvents) followed by addition of triflic acid (0.49 mL, 0.00563 mol) then the reaction was treated in microwave or without microwave at 150 oC for 10 to 60 min. After completion of reaction it was quenched with solid NaHCO3 then little diluted with 2 mL of water and 5 mL of EtOAc, aqueous layer extracted with EtOAc, combined organic layer dried over Na2SO4, concentrated and purified by column chromatography to afford (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-3-methylpyrrolidin-2-one (10) in quantitative yield. Rf = 0.2 (70% EtOAc:Hexane); 1H NMR (CDCl3, 200 MHz): d 7.66 - 7.15 (m, 9H), 5.98 (br. s., 1H), 3.67-4.04 (m, 1H), 3.00-2.70 (m, 2H), 2.48 (d, J = 7.50 Hz, 1H), 2.11 (dd, J = 8.71, 3.64 Hz, 1H), 2.01-1.81 (m, 1H), 1.19 (d, J = 7.17 Hz, 3H); 13C NMR (CDCl3, 50 MHz): d 180.3, 140.7, 139.8, 136.7, 129.6, 128.8, 127.5, 127.3, 127.0, 53.4, 42.4, 35.2, 34.9, 16.3; HRMS (ESI): calcd for C18H20NO [M+H]+ 266.1539, found 266.1541.

ADVANTAGES OF THE INVENTION
• An unprecedented copper-catalyzed reductive cross-coupling is introduced and avoided excess Grignard reagent use in the process for the preparation of intermediate.
• This catalytic process is more operationally simple and cost-effective by using of CuI (0.1 equiv), DPPM (0.2 equiv) and cheaper additive LiOMe (1 equiv) compared to classical Grignard or Gillmann reagents.
• Unprecedented benzyl deprotection of N-lactam is disclosed for the first time, which avoids side reactions like racemization.
• Cost-effective and simple synthetic approach for the synthesis of sacubitril intermediates

CLAIMS:We claim,
1. A process for the preparation of sacubitril intermediates comprising the steps of:
i) esterifying L-pyroglutamic acid of formula (1) in the presence of 98% sulfuric acid and an alcohol at a temperature in a range of 25-35°C for a period of 1-12 hr in a solvent to afford a compound ethyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2) or methyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2a);
ii) protecting the -N of ethyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2) or methyl (S)-5-oxopyrrolidine-2-carboxylate of formula (2a) obtained from step (i) by using benzyl bromide in the presence of a strong base at a temperature in a range of 0-30°C for a period of 2-6 hr in a solvent to afford a compound (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate of formula (3) or (3a);
iii) treating the (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate of formula (3) or (3a) compound obtained from step (ii) with sodium borohydride at a temperature in a range of 0-30°C for a period of 2-3 hr in a solvent to afford a compound (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one of formula (4);
iv) tosylating the (S)-1-benzyl-5-(hydroxymethyl)pyrrolidine-2-one of formula (4) obtained from step (iii) by using 4-toluenesulfonyl chloride in the presence of triethylamine base at a temperature in a range of 25-30°C for a period of 5 to 12 hr in a solvent to afford a compound (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate of formula (5);
v) treating the compound (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate of formula (5) obtained from step (iv) with sodium iodide at reflux temperature in a range of 60 to 90 oC for a period of 2-4 hr in a solvent to afford a compound (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one of formula (6);
vi) treating the compound (S)-(1-benzyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (5) obtained from step (iv) or (S)-1-benzyl-5-(iodomethyl)pyrrolidin-2-one (6) obtained from step (v) with biphenyl bromide (7) in the presence of coupling catalyst at a temperature in a range of 25-35°C for a period of 30 min in a solvent to afford a compound (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8);
vii) methylating the compound (S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzylpyrrolidin-2-one of formula (8) obtained from step (vi) by using methyl iodide in the presence of LiHMDS at a temperature in a range of -75-35°C for a period of 20-24 hr in a solvent to afford a compound (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9);
viii) debenzylating the compound (3R,5S)-5-([1,1'-Biphenyl]-4-ylmethyl)-1-benzyl-3-methylpyrrolidin-2-one of formula (9) obtained from step (vii) by using debenzylating catalyst at a temperature in a range of 50-200°C under microwave radiation or without microwave for a period of 10-60 min in a solvent to afford the key intermediate (3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-3-methylpyrrolidin-2-one of formula (10) for the synthesis of sacubitril.
2. The process as claimed in claim 1, wherein said alcohol used in step (i) is selected from the group consisting of methanol or ethanol alone or in combination therefrom.
3. .The process as claimed in claim 1, wherein said base used in step (ii) is selected from the group consisting of Sodium hydride, potassium carbonate, cesium carbonate, butyl lithium, lithium diisopropyl amide, alone or in combination therefrom.
4. The process as claimed in claim 1, wherein said coupling catalyst used in step vi) is selected from the group consisting of Grignard reagent, CuI, CuCl, Cu(OTf)2, Cu(OAc)2, LiOMe, LiCl, LiI, LiOtBu, TMEDA, PPh3,DPPP, DPPE, DPPB and DPPM alone or in combination therefrom.
5. The process as claimed in claim 1, wherein said coupling catalyst used in step vi) is selected from the the group consisting of CuI, LiOMe andDPPM alone or in combination therefrom.
6. The process as claimed in claim 1, wherein said debenzylating catalyst used in step viii) is selected from the group consisting of (H2, Pd/C), (H2, Pd(OH)2/C), (H2, Pt/C), (H2, Ni), (HCOOH, Pd/C), (HCOOH, Pd(OH)2/C), Na-Liq NH3, Li-Liq NH3, Ca-Liq NH3, Li or Na in amines, Li-naphthalenide, HBr/phase transfer catalyst, aqueous ceric ammonium nitrate, and triflic acid alone or in combination therefrom.
7. The process as claimed in claim 1, wherein said debenzylating catalyst used in step viii) is triflic acid.
8. The process as claimed in claim 1, wherein said solvents used in step i) to viii) are selected from the group consisting of acetone, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, water, sulfuric acid, deuterium oxide, methyl ethyl ketone, acetonitrile, dimethyl sulfoxide, Dimethylformamide, chloroform, pentane, hexane, benzene, toluene, octane, decane, dimethyl ether, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethyl ether, 2-metetrahydrofuran, 1,4-dioxane and diethyl ether and mixtures thereof.
9. The process as claimed in claim 1, wherein the yield of the sacubitril intermediate as obtained in step viii) is in the range of 60 to 95%.