FIELD OF THE INVENTION

The present invention relates to chiral amine and a process for preparation thereof. The present invention also relates to a one pot route process for the synthesis of chiral amino group compounds by the reduction of nitro olefins using chiral ligand. The present invention particularly relates to a series of compounds containing chiral amino group that is used for the synthesis of Sitagliptin. More particularly, the present invention relates to the use of said compounds for the synthesis of potent antidiabetic drug Sitagliptin (a DPP-IV inhibitor).

BACK GROUND OF THE INVENTION & DESCRIPTION OF PRIOR ART

Chiral amines have proven to be powerful pharmacophores for defining new pharmaceutical drugs. Chiral primary amines are currently the reliable building blocks that chemists often turn to during the synthetic planning of an alkaloid, while medicinal chemists require them because they hold greater diversification potential verses secondary or tertiary chiral amine building blocks development of drug candidates. Historically, the cinchona alkaloids were the first chiral amines to be used in asymmetric catalysis. Chiral amines represent a powerful and useful means of accomplishing chemical transformations. Their diverse range of activity allows them to function as acids/bases, nucleophiles, and chiral promoters. From natural products such as the alkaloids and simple amino acids to more complex compounds such as peptides and heterocyclic amines, these catalysts are offering promising results in numerous areas of organic synthesis. Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released in response to a meal. By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes, thus tending to prevent an exceed and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents. In modern organo-catalysis, the use of chiral secondary amines has proven to be an extremely powerful approach, and dominated the field of amino catalysis early on. Recent impressive advances in secondary amine-catalyzed enantioselective reactions demonstrate the extraordinary usefulness and versatility of secondary amines in asymmetric synthesis, establishing them as privileged catalysts in modern organocatalysis. The complementarily of secondary amine catalysis is expected to move asymmetric oganocatalysis to a new height. Enantiomerically pure amines play an important role in stereoselective organic synthesis. They are used as resolving agents, chiral auxiliaries and as building blocks in pharmaceuticals and other important bioactive molecules. They are frequently used as synthons for the preparation of various pharmaceutically active substances and agrochemicals, or as resolving agents for chiral acids. a-Amino acids such as L-proline constitute a special class of chiral amines and are composing the main part of the chiral pool. The use of these compounds in enantioselective synthesis of pharmaceuticals, agrochemicals and several interesting natural products has been complied. β-Amino Acids are components of many bioactive natural and synthetic products, such as the antitumor agents Taxol and cryptophycin, the msecticidal and antifungal agent jasplakinolide and arninopeptidase inhibitor bestatin. Synthetic β-Amino acids are also precursors of bioactive β-lactams. Reference may be made to following prior arts for the utilization of β-Amino Acids: a) Wam,M.C.;Taylor,H.L,;Wall,M.E

71,93,2325.

b) Shih.C. ;Gossett,L.S.;Gruber,J.M. ;Grossman,C.S. ;Andis,S.L.;Sehultz,R.M. ;

Worzalla. J.F. ; Corbett,T.H.;Metz,J.T. Bio OrgMed. Chem.Lett.1999,6,69. c) Crews, P. ; Manes, L.V. ; Boehler, M. Tetrahedron Lett.1986, 27, 2797.

d) Roers,R.; Verdi e, G. L Tetrahedron Lett. 2001, 42, 3563.

e) Benaglia, M.:Cinqiuni,M.: Cozzi, F. Eur. J. Org. Chem.WQO, 1.

Reference may be made to following prior arts for the synthesis of β-Amino Acids: a) Phenylalanine Aminomutase-Catalyzed Addition of Ammonia to Substituted Cinnamic Acids: A Route to Enantiopure a- and β-Amino Acids, Journal of Organic Chemistry, 74(23), 9152-9157; 2009

b) Preparation of l H-benzimidazole derivative end-capped with amino acid or peptides as hepatitis c vims inhibitors,Romme, Jeffery lee, PCT Int.AppL, 2012018325, 09, Feb 2012.

c) Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia: Mansukhlal C. Wani, Harold Lawrence Taylor, Monroe E. Wall, Philip Coggon, Andrew T. McPhail, J. Am. Chem. Soc , 1971, 93 (9), pp 2325-2327

d) Recent advances in the stereoselective synthesis of b-amino acids Mei Liu and Mukund P. Sibi*, Tetrahedron 58, 2002, 7991-8035.

e) Enantioselective synthesis of β-aminoacid: Abele,S.; seebachJJ.i¾r.J Org. chem.2 , 1

In the above prior art it has been observed that most of the synthetic methods needs high pressure, critical reactions condition, difficult product separation. Moreover synthesis of β- Amino Acids from β-nitroacrylate is not known. Again β-nitroacrylate could be synthesized very easily from nitroalkane and ethyl glyoxalate which is a simple and efficient process involving three steps only

To develop a novel route to sitagliptin 1, it is desirable to synthesize the chiral ?-amino acid part of the molecule first. Based on the past and present experience on handling nitro aliphatic compounds, it is desirable to use nitro chemistry for the synthesis of the desired target.

OBJECTIVES OF THE INVENTION

Accordingly, the main object of the present invention is to provide a one pot route process for the synthesis of chiral amino group compounds by the reduction of nitro olefins using chiral ligand.

Another object of the present invention relates to series of compounds containing chiral amino group that is used for the synthesis of Sitagliptin

Still another object of the present invention is to use the said compounds for the synthesis of potent antidiabetic drug Sitagliptin (a DPP-IV inhibitor). Yet another object of the present invention is to provide a process for the preparation of (3R)-3-amino-l-[3 rifluoromethyl)-5,6-dihydro-[l,2,4]-triazolo-[4,3-(x]-pyrazi ne-7(8H)- yl]-4-(2,4,5-trifluorophenyl)-butane-l-one and intermediates thereof.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the synthesis of chiral amines by the reduction of nitro olefins using chiral ligand wherein the said process comprises of following steps :- a) mixing under stirring anhydrous copper (II) fluoride, Josiphos catalyst in toluene for about 60-90 minutes followed by addition of PMHS, phenyl silane, water, and a nitro olefin having formula I with vigorous stirring, (formula I),

wherein:

R= COOMe, COOEt, or COO¾u,

stirring the solution obtained in step a) for a time period in the range of 10-12 h, adding phenyl silane and continuing stirring for a time period in the range of 3-4 h; c) adding TBAF solution prepared in THF to the solution obtained in step b), stirring for a time period in the range of about 1-2 hour; d) adding water to the solution obtained in step c), extracting and drying with ether and Na ₂ S0 ₄ and purifying the residue to obtain chiral amines having formula II and chiral nitro compounds having formula III, (formula II)

NO,

o

(formula III);

e) reducing the nitro compounds (formula III) to the amines (formula II) by adding the mixture of chiral nitro (formula III) and a compound selected from ethyl acetate or ethanol to a resin- 10% Pd/C in a pyrex glass bottle, placing the bottle in a parr apparatus followed by flushing with argon, hydrogen under a pressure in the range of 40 to 45 psi for a time period of 3 to 4h at a temperature in the range of 25 to 27 °C, purifying the product to obtain chiral amine (formula II); and

f) adding HC1 dropwise to the solution of compound (formula II) obtained in step e) at a temperature of 25 to 27 °C and heating the mixture at reflux for a time period of 6 to 7 h followed by cooling to obtain compound having formula (IV) _{formula (IV).}

According to one embodiment of the present invention, the ratio of the Josiphos catalyst and CuF ₂ used in step a) is 1: 1.

The present invention also provides a chiral amines prepared by the aforesaid process.

According to another embodiment of the present invention, the percent yield of the chiral amine obtained is in the range of 85 to 88%. According to one embodiment of the present invention, the representative compounds prepared by the aforesaid process comprises of:- a) 3- -Amino-4- b) 3- -Amino-4- c) 3- -Amino-4- d) 3- -Amino-4- e) 3- -Amino-4- f) 3- -Amino-4- g) 3- -Amino-4- h) 3- -Amino-6- i) 3- -Amino-4-

J) 3- -Amino-4- k) 3- -Amino-4-

1) 3- -amino-oc

The present invention also provides a process of preparing compound of formula I, by comprising dissolving compound of formula (V) in a solvents selected from DCM, DMF, toluene, ethyl acetate and a basic alumina followed by stirring at a temperature in the range of 25 to 27 °C for a time period in the range of 1 to 2 hours, purifying the product to obtain compound of the formula I, formula V,

wherein:

R= COOMe, COOEt, or COO¾u,

Ri

In one of the embodiment, the present invention provides a process for preparation of sitagliptin using chiral amine wherein the process steps comprising: - a) dissolving compound (6) in solvents selected from DCM, DMF, toluene and ethyl acetate and in a basic alumina followed by stirring at a temperature in the range of 25 to 27 °C for a time period in the range of 1 to 2 hours, purifying the product to obtain compound (7a), b) mixing under stirring anhydrous copper (II) fluoride, Josiphos catalyst in toluene for 60 minutes followed by addition of PMHS, phenyl silane, water, nitro olefin with vigorous stirring,

c) stirring the solution obtained in step b) for a time period of 12 h, adding phenyl silane and continuing stirring for a time period of 4 h, d) adding TBAF solution prepared in THF to the solution obtained in step c), stirring for a time period of about 1 hour,

e) adding water to the solution obtained in step d), extracting and drying with ether and Na ₂ S0 ₄ and purifying the residue with flash chromatography to obtain chiral amines (8a),

f) adding HC1 dropwise to the solution of compound (8a) obtained in step f) at a temperature of 25 to 27 °C and heating the mixture at reflux for a time period of 6 to 7 h followed by cooling to obtain compound (10), g) reacting 3-Trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- ajpyrazine, acid with compound (10) in the presence of solvents selected from ethanol, NMM and HOBt followed by cooling the contents and adding EDC, h) stirring the reaction mixture obtained in step g) at a temperature of 25 to 27 °C for a time period of 3 to 4 hr followed by addition of water, and i) isolating the product obtained in step h) via extractive workup with methanol (3 x 15 mL) and concentrated in vacuo followed by purification using chromatographic methods to obtain Sitagliptin.

In yet one embodiment of the present invention, chiral amine used is obtained from vinyl nitro compounds using Josiphos catalyst to obtain sitagliptin.

In yet another embodiment of the present invention, one pot asymmetric reduction of both olefin and nitro group of p-nitro-a,P-unsaturated ester to obtain Sitagliptin.

BRIEF DESCRIPTION OF DRAWINGS & FIGURES

Scheme 1: Synthesis of chiral amino ester part of Sitagliptin. Reagents and conditions: (a) CH ₃ NO ₂ , NaOH, MeOH, rt; (b) NaBH ₄ , CHC1 ₃ , Silica gel, z-PrOH, rt; (c) Ethyl gly oxalate, DBU, rt; (d) Ac ₂ 0, I ₂ , rt; (e) Basic alumina, DCM, rt; (f) Josiphos catalyst, phenylsilane, PMHS, CuF ₂ , rt; (g) H ₂ , Pd-C, ethyl acetate, rt.

Scheme 2: Synthesis of different analogues chiral amino ester part of Sitagliptin. Reagents and conditions: (a) Josiphos catalyst, phenyl silane, PMHS, CuF ₂ , rt; (b) H ₂ , Pd-C, ethyl acetate, rt.

Figure 1: Structures of Compounds synthesized.

Scheme 3: Synthesis of different analogues chiral amino ester part of Sitagliptin.

Scheme 4: Synthesis of Sitagliptin

Reagents and conditions: (a) 2M HCl, reflux; (b) 3-Trifluoromethyl-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazine (A), EDC, Cat. HOBt, NMM, ethanol, rt.

ABBREVIATION USED

DBU l,8-diazabicyclo[5,4,0]undec-7-ene

i-prOH isopropanol

Ac ₂ 0 acetic anhydride

PMHS Polymethylhydrosiloxane

EDC 1, 2-dichloroethane HOBt Hydroxybenzotriazole

NMM N-Methylmorpholine

MeOH methanol

TBAF Tetra-n-butylammonium fluoride

DCM dichloromethane

DETAILED DESCRIPTION OF THE INVENTION

The problem which the present invention proposes to solve is to obtain a novel route for the synthesis of chiral amine from vinyl nitro compound and its application for the synthesis of novel DPP IV inhibitor Sitagliptin.

Most of the chiral amines correspond to interesting core structures for the synthesis of biologically active compounds. Chiral amines (1°, 2° & 3°) are important target molecules owing to their extensive use and importance as potent pharmacophores. Compounds containing chiral amine moiety is more active and plays a prominent role in biological activity. In addition it is a highly efficient route in bond formations among diverse building blocks for chemical synthesis. The incretion mimetic and their related agents, the dipeptidyl peptidase-4 (DPP-IV) inhibitors, are becoming important and potential agents in the treatment of type 2 diabetes i.e. the most common form of diabetes. Accordingly, this process is applied to develop a novel route to Sitagliptin, the only DPP-IV inhibitors marketed in India will be an excellent discovery to the diabetologist's armamentarium. The structural complexity and intriguing biological activities of this natural product continue to attract the attention of chemists and biologists. The structural characteristic of this natural product is the densely functionalized 3-amino-l-(3-trifluoromethyl-5,6-dihydro-8H[l,2,4]- triazolo-[4,3-a]-pyrazin-7-yl-3-amino-butan-l-one core arranged with a heavily substituted 2,4,5-trifluoro-phenyl ring which makes it a synthetically challenging molecule.

Accordingly, the present invention provides a process for the synthesis of chiral amines by the reduction of nitro olefins using chiral ligand wherein the said process comprises of following steps :- a) dissolving compound (6) in solvents selected from DCM, 20mL and basic alumina followed by stirring at a temperature in the range of to 25 to 27 C for a time period in the range of 1 to 2 hours, purifying the product with flash chromatography to obtain compound (7),

b) mixing and stirring anhydrous copper (II) fluoride, Josiphos catalyst in toluene for about 60 minutes followed by addition of PMHS, phenyl silane, water, nitro olefin with vigorous stirring,

c) stirring the solution obtained in step b) for a time period of 12 h, adding phenyl silane and continuing stirring for a time period of 4 h,

d) adding TBAF solution prepared in THF to the solution obtained in step c), stirring for a time period of 1 hours,

e) adding water to the solution obtained in step d), extracting and drying with ether and Na ₂ S0 ₄ and purifying the residue with flash chromatography to obtain chiral amines (8) and chiral nitro compounds (9),

f) reduction of nitroalkanes 9a to amines 8a by adding the mixture of chiral nitro (9) and ethyl acetate to the resin-10% Pd/C in a pyrex glass bottle, placing the bottle in a parr apparatus followed by flushing with argon, hydrogen under a pressure in the range of 40 to 45psi for a time period of 3 to 4h at a temperature in the range of 25 to 27 °C, purifying the product so obtained with chromatographic procedure to obtain chiral amine (8),

g) adding HC1 (other acids) dropwise to the solution of compound (8) obtained in step f) at a temperature of 25 to 27°C and heating the mixture at reflux for a time period of 6 to 7 h followed by cooling to obtain compound (10).

In an embodiment of the present invention a series of compound with general formula R-X-Rl wherein X represents the reduced chiral amine part, Rl represents different substituted benzaldehyde and R represents the ethyl ester part as obtained by the process.

In another embodiment of the present invention a process using Josiphos catalyst to synthesize chiral amine from vinyl nitro compounds to obtain sitagliptin.

In another embodiment of the present invention a process wherein one pot asymmetric reduction of both olefin and nitro groups of p-nitro-a,P-unsaturated ester to obtain Sitagliptin. In yet another embodiment of the present invention a process wherein the percent yield of the chiral amine obtained is in the range of 85 to 88% In yet another embodiment of the present invention a process wherein the ratio of the Josiphos catalyst and CuF2 used in step b) is 1 : 1.

In yet another embodiment of the present invention wherein the solvent used is selected from the group consisting of DCM, DMF, Toluene, ethyl acetate. In yet another embodiment of the present invention a process of preparation of sitagliptin using compound 8 wherein the process steps comprising in the following steps :- a) adding 3-Trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]p yrazine to the compound 10 in the presence of solvents selected from ethanol, NMM and HOBt followed by cooling the contents and adding EDC,

b) stirring the reaction mixture obtained in step a) at a temperature of to 25 to 27 °C for a time period of 3 to 4h followed by addition of water, c) isolating the product obtained in step b) via extractive workup with methanol (3 x 15 mL) and then drying over anhydrous sodium sulphate and concentrated in vacuo followed by purification using flash column chromatography to obtain sitagliptin.

In an embodiment of the invention wherein chiral amine used is obtained from vinyl nitro compounds using Josiphos catalyst to obtain sitagliptin.

In another embodiment of the invention wherein one pot asymmetric reduction of both olefin and nitro group of p-nitro-a,P-unsaturated ester to obtain Sitagliptin.

A reliable procedure for synthesis of chiral amine unit 8a has been developed, and eventually led to the total synthesis of DPP IV inhibitor Sitagliptin. Required chiral amine 8a for the synthesis of DPP IV inhibitor Sitagliptin has been obtained from 2,4,5- trifluorobenzaldehyde in six steps using this developed novel synthetic route. The synthetic approach utilizes Josiphos catalyst (i.e. chiral reduction) in order to synthesize DPP IV inhibitor Sitagliptin. Asymmetric reduction of ?-nitro-<x, ?-unsaturated ester has been performed to install the chiral center of Sitagliptin. Scheme 3 has been performed to complete the synthesis of ?-amino acid part of novel dipeptidyl peptidase-4 inhibitor Sitagliptin. A series of (with different substrate Rl) different chiral amines was synthesized by using the Josiphos catalyst (Scheme 2).

Different vinyl nitro esters are derived using some known reaction methods using some commercially existing aromatic and aliphatic aldehydes. The present invention provides the full account of the enantioselective total synthesis of Sitagliptin, which features some important reactions for the rapid assembly of the molecular framework of these DPP IV inhibitor. The present invention disclosed the investigation with the development of an efficient synthesis of chiral amine skeleton 8a (Scheme 1). The present invention provides (1) the application of a nitro aldol addition reaction for the preparation of ?-nitrostyrene from substituted aromatic and aliphatic aldehydes by performed the reaction using sodium hydroxide as base in methanol, (2) reduction of conjugated double bond with sodium borohydride and silica gel in CHC1 ₃ and iso-propanol mixture (5: 1) afforded intermediate nitroethane, (3) the compound was subjected to Henry's nitro aldol reaction with ethyl glyoxaldehyde using l,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as base to give 2- nitroalcohol, (4) then, the nitro aldol product was treated with acetic anhydride in presence of molecular iodine as catalyst to give the acetate derivative, (5) elimination of acetic acid from nitro acetate derivative using basic alumina in dichloromethane solvent afforded the nitro acrylate and (6) the final one pot asymmetric reduction of vinyl nitro ester using Josiphos catalyst results optically pure ?-amino acid part of Sitagliptin followed by standard peptide coupling generated Sitagliptin 1. In the asymmetric reduction of vinyl nitro ester using Josiphos catalyst we got small amount of the partially reduced nitro compound 9a, finally the nitro group was reduced by hydrogenation to the corresponding chiral amine 8a. The compound 7a is also an important intermediate from which /J-nitro ester can be synthesized. Enzymatic de-esterification of this /J-nitro ester to give the exact ?-nitro acid in optically pure form will be explored.

The next embodiment of the present invention is to synthesize Sitagliptin 1, the only DPP-IV inhibitor, which is even more demanding (Scheme 4). Ester hydrolysis and peptide coupling completed the synthesis of Sitagliptin. The subject of the present invention is products corresponding to the general formula Ri-X-R, wherein the functional moiety X represents chiral amine part, R represents ester part (EtCOO) and finally Ri represents different substituted aliphatic and aromatic aldehydes.

General Formula

R ₁ : Different Commercially avilable substituted

aliphatic and aromatic aldehyde

R: -COOEt

1H NMR and 13C NMR spectra were recorded using a Bruker DPX-300 NMR machine. IR spectra were recorded on a Perkin-Elmer 1640 FT-IR spectrometer. Elemental analysis data were measured on a Perkin-Elmer (Model no. AE 2400) C, H, N analyzer. Optical rotations were measured using a Perkin-Elmer 343 polarimeter. Mass spectra were recorded on WATERS Micro-mass ZQ 4000 (ESI Probe) spectrometer. Flash chromatography (Combifiash) was performed with Merck silica gel (230-400 mesh), column chromatography was performed with Merck silica gel (100-200 mesh) and preparative TLC was carried out on plates prepared with Merck Silica gel G. Moisture sensitive reactions were conducted under a dry nitrogen atmosphere. THF was distilled from benzophenone ketyl prior to use. All solvents were distilled at their boiling point and other commercially available reagents were used as received, unless otherwise stated. Glassware was oven dried at 120 °C over night. All the reagents were used as purchased from commercial suppliers without further purification. All analytical data were recorded at Analytical Chemistry Division (CSIR- NEIST, Jorhat-6, Assam, India).

Ethyl acetate

The commercially available 2,4,5-trifluorobenzaldehyde (2) was treated with nitromethane in presence of NaOH and MeOH to get nitro alkene 3 which was again subjected to reduction by NaBH ₄ /Silica gel to give the compound 4 in 63.8% overall yield. Then, Henry reaction of 4 with ethyl glyoxaldehyde in presence of DBU afforded the nitro aldol product 5 which was converted to the β-nitro acrylate derivative 7a via the formation of the acetate derivative 6 by general acetylation method. Finally, the asymmetric reduction of β- nitroacrylate 7a using Josiphos, CuF ₂ gave chiral amine 8a (88%) and chiral nitro alkane 9a (12%). Hydrogenation of 9a using Pd/C-H2 also gave the compound 8a in 67.71 % yield.

The following examples are given by way of illustrations and should not construe the scope of the invention.

Example 1

The compound 2 is commercially available in the market and purchased from Sigma, Aldrich. Synthesis of jff-nitrostyrene compound [1, 2, 4-trifluoro-5-(2-nitro-vinyl)-benzene] (3):

To a mixture of 2, 4, 5-trifluorophenyl benzaldehyde (5 g, 31.25 mmol) and nitromethane (3.62 g, 59.37 mmol) in methanol (50 mL) a ice cooled aqueous solution of sodium hydroxide (30 mL) was added till a bulky white precipitate appears. After standing for 30 min, 40 ml of ice cooled water was added to reaction mixture followed by drop wise addition of 4 M HC1 (50 mL). A pale yellow crystalline precipitate separates as soon as the alkaline solution mixes with the acid. The solid settles to the bottom of the vessel when the stirrer is stopped. Decant most of the cloudy liquid layer, filter the residue by suction and wash with water until it becomes free from chlorides. Purification was done by column chromatography (eluent: 15% ethyl acetate in hexane) to afford 3 (5.89 g, 29.06 mmol, 93%) as Yellowish gum. The spectral analysis for the compound is:

R _f = 0.46 (Hexane/EtOAc 9: 1); ¾ NMR (300 MHz, CDC1 ₃ ) δ 7.98 (d, J = 13.83 Hz, 1H, CH=CHN0 ₂ ), 7.68 (d, J = 13.8 Hz, 1H, CH=CHN0 ₂ ), 7.43-7.32 (m, 1H, Aromatic), 7.13-7.04 (m, 1H, Aromatic) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 159.2, 149.9, 145.2, 138.9, 132.7, 120.2, 116.8, 108.9 ppm. IR (CHC1 ₃ ) v 2924, 1542 cm ^"1 . ESIMS: m/z (%) 203 [M ⁴ . Analysis calculated for C ₈ H ₄ F ₃ N0 ₂ C 47.31, H 1.98, N 6.9. Found C 47.29, H 1.29, N 6.1.

Example 2

Synthesis of 3-(2,4,5-trifluorophenyl)-nitroethane (4):

β-nitrostyrene (3) (5 g, 24.63 mmol) was dissolved in iPrOH (1 g) and CHC1 ₃ (20 mL) with silica gel (1 g) and to this system sodium borohydride (1.86 g, 49.26 mmol, 2 equv) was added over ½ h at 27 °C. Dilute HCL (25 mL) was added to decompose the excess NaBH ₄ The reaction mixture was stirred at 27 °C, and the advancement of the reaction was observed by TLC (1:9, Ethyl acetate/Hexane). When the reaction was completed, the reaction mixture was filtered. The filtrate is extracted with DCM and washed with 1% HC1 acid (25 mL). The organic phase was dried with anhydrous Na ₂ S0 ₄ , the solvent was evaporated under reduced pressure and the residue was purified by column chromatography. The column was packed in hexane and run in 10% ethyl acetate in hexane solvent system to afford 4 (4.54 g, 22.16 mmol, 90%) as Yellowish gum. The spectral analysis of the compound is Compound 4:

Rf = 0.42 (Hexane/EtOAc 9: 1); 1H NMR (300 MHz, CDC13) 5 4.64 (t, J = 13.83 Hz, 2H, CH2CH2N02), 3.32 (t, J = 13.8 Hz, 2H, CH2CH2N02), 7.11-7.03 (m, 1H, Aromatic), 6.98-6.91 (m, 1H, Aromatic) ppm; 13C NMR (75 MHz, CDC13) δ 159.4, 147.9, 144.5, 138.9, 126.7, 118.9, 74.1, 26.6 ppm; IR (CHC13) v 2954, 1522 cm-1 ESIMS: m/z (%) 205 [M+]. Analysis calculated for C8H6F3N02 C 46.84, H 2.95, N 6.83. Found C 46.29, H 2.79, N 6.79.

Example 3

Synthesis of 2-nitroalcohol (5) (2-Hydroxy-3-nitro-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester):

To the solution of nitroalkane (4) (4.5 g, 21.95 mmol) and ethyl gyloxalate (8.96 g, 87.8 mmol, 4 eqv) in DCM (30 mL), DBU (1.67 g, 10.97 mmol) was added and stirred at 27 °C. After completion of the reaction ether was added to the reaction mixture and the ether layer was washed with 2% HCL then with water and brine solution. The ether layer was dried over anhydrous Na ₂ S0 ₄ , concentrated the filtrate under reduced pressure and the crude combination was purified by column chromatography (5% Ethyl acetate in Hexane) to afford 5 (5.93 g, 19.31 mmol, 88%) as Yellowish gum. The spectral analysis of the compound is:

R _f = 0.42 (Hexane/EtOAc 9: 1); ¾ NMR (300 MHz, CDC1 ₃ ) δ ΊΛ Ι-Ί 9 (m, 1H, aromatic), 7.38-7.36 (m, 1H, aromatic), 5.03 (m, 2H, CHN0 ₂ ), 4.42 (d, J = 3.18 Hz, 1H, CHOH), 4.30 (q, 2H, OCH ₂ CH ₃ ), 4.01 (d, J = 3.25 Hz, 2H, CH ₂ CHN0 ₂ ), 2.05 (s, 1H, OH), 1.35 (t, J = 3.84 Hz, 3H, OCH ₂ CH ₃ ) ppm; ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 170.6, 119.7, 106.2, 105.8, 87.5, 70.9, 63.4, 28.8, 14.01 ppm. IR (CHC1 ₃ ) v 2954, 1740, 1559 cm ^"1 ; ESIMS: m/z (%) 330.2 [M + Na] ⁺ ; Analysis calculated for Ci ₂ H ₁₂ F ₃ N0 ₅ C 46.91, H 3.94, N 4.56. Found C 46.75, H 3.79, N 4.39.

Example 4

Synthesis of acetate derivative (6) 2-Acetoxy-3-nitro-4-(2, 4, 5-trifluoro-phenyl)-butyric acid ethyl ester:

To a solution of nitroalcohol (5.9 g, 19.2 mmol) (5) added acetic anhydride (2.35 g, 23.04 mmol, 1.2 eqv.) and molecular iodine (0.487 g, 1.92 mmol 0.1 eqv) at 27 °C. The mixture was stirred continuously at 27 °C. The completion of the reaction is monitored by TLC (1 :9 ethyl acetate/hexane). The mixture was diluted with DCM (25 mL) and saturated aqueous sodium thiosulphate (15 mL) and the combined organic phase was washed with sodium bicarbonate (3 x 20 mL) and brine (3 x 20 mL). The organic phase was dried over MgS0 ₄ , filtered, and concentrated. The residue was purified via silica gel chromatography (petroleum ether to 5% Ethyl acetate/petroleum ether) to give the acetate derivative 6 (5.96 g, 17.08 mmol, 89%) as Yellowish gum. The spectral analysis of the compound is:

R _f = 0.76 (Hexane/EtOAc 9: 1); ¾ NMR (300 MHz, CDC1 ₃ ) 7.05-6.90 (m, 2H, aromatic), 5.19 (m, 2H, CHN0 ₂ ), 4.82 (d, J = 3.18 Hz, 1H, CHOH), 4.30 (q, 2H, OCH ₂ CH ₃ ), 3.37 (d, J = 3.25 Hz, 2H, CH ₂ CHN0 ₂ ), 2.20 (s, 3H, COCH ₃ ), 1.35 (t, J= 3.84 Hz, 3H, OCH ₂ CH ₃ ) ppm; ^1J C NMR (75 MHz, CDC1 ₃ ) δ 172.6, 171.5, 159.1, 146.2, 142.5, 130.2, 119.1, 105.8, 87.1, 79.9, 61.4, 20.8, 18.4, 14.8 ppm; IR (CHC1 ₃ ) v 2954, 1758, 1561 cm ^"1 ; ESIMS: m/z (%) 349 [M ⁺ ]; Analysis calculated for Ci ₄ H ₁₄ F ₃ N0 ₆ C 48.14, H 4.04, N 4.01. Found C 48.01, H 4.00, N 3.91.

Example 5

Synthesis of nitro acrylate (7a) [3-Nitro-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester ] :

A solution of the compound (6) (5 g, 14.31 mmol) was dissolved in DCM (25 mL) and added basic alumina (13.51 g) to the same. The solution was stirred for 2 h at 27 °C and finally filtered and washed with DCM and dried over anhydrous MgS0 ₄ and concentrated under reduced pressure. The crude residue was purified by flash chromatography (elution with 5% ethyl acetate in petroleum ether). Concentration of the appropriate fractions afforded the desired compound 7a (3.92 g, 13.59 mmol, 95%) as Yellowish gum. The spectral analysis of the compound is as follows :-

R _f = 0.56 (Hexane/EtOAc 9: 1); ¾ NMR (300 MHz, CDC1 ₃ ) 5132-122 (m, 2H, aromatic), 6.38 (s, 1H, CH), 4.43 (s, 2H, CH ₂ CN0 ₂ ), 4.37 (q, 2H, OCH ₂ CH ₃ ), 1.38 (s, 3H, CH ₂ CH ₃ ) ppm; ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 170.6, 162.5, 150.1, 146.2, 122.5, 121.4, 119.1, 105.1, 60.2, 59.9, 24.8, 14.6 ppm; IR (CHC1 ₃ ) l727, 1633, 1544 cm ^"1

ESIMS: m/z (%) 312 [M + Na] ⁺ Analysis calculated for Ci ₂ H ₁₀ F ₃ NO ₆ C 49.84, H 3.49, N 4.84. Found C 49.71, H 3.31, N 4.80.

Example 6

Synthesis of the different chiral secondary amines 8a and chiral nitro compounds 9a: E _t

7a Chiral /?-aminoester 8a Chiral ^-nitroester 9a H ₂ / Pd-C

Ethyl acetate

Treatment of the vinyl nitro compounds 7a with Josiphos catalyst in toluene furnished the desired chiral secondary amines 8a and chiral secondary nitro compounds 9a: In a round bottom flask, anhydrous copper (II) fluoride (0.040 g, 0.394 mmol, 0.029 eqv) & (R)- (S) Josiphos (0.277 g, 0.433 mmol, 0.0319 eqv) were dissolved in toluene (15 mL). After stirring for 60 min PMHS (227.3 μΐ _^ , 0.788 mmol, 0.058 eqv) was added followed by phenyl silane (0.152 g, 1.40 mmol, 0.1037 eqv) & water (0.141 g, 7.88 mmol, 0.58 eqv). After stirring for 5 min the nitro olefin (3.92 g, 13.59 mmol) was added with vigorous stirring. After stirring for 12 h, Phenyl silane (1.47 g, 13.59 mmol, 1 eqv) was added and stirring continued for 4 h. TBAF solution (14.2 g, 54.36 mmol, 1.0 M in THF, 4 eqv) was added and stirring continued for 1 h. Water (20 mL) was added and the mixture extracted with ether (2 ^χ 30 mL). After drying over anhydrous Na ₂ S0 ₄ the organic part was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (50% ethyl acetate/petroleum ether to 75% ethyl acetate/petroleum ether) to give various chiral amines 8a (3.12g, 11.95 mmol, 88%), 8b (1.53g, 6.48 mmol, 86%), 8c (1.5 g, 4.79 mmol, 82%), 8d (1.49 g, 5.95 mmol, 83%), 8e (1.51 g, 7.31 mmol, 86%), 8f (1.56 g, 6.27 mmol, 87%), 8g (1.48 g, 6.73 mmol, 84%), 8h (1.51 g, 6.45 mmol, 85%), 8i (1.60 g, 5.59 mmol, 88%), 8j (1.52 g, 5.34 mmol, 84%), 8k (1.57 g, 6.52 mmol, 88%) and 81 (1.42 g, 7.61 mmol, 82%) and chiral nitro compounds 9a (0.474 g, 1.63 mmol, 12%), 9b (0.241 g, 0.904 mmol, 12%), 9c (0.281 g, 0.819 mmol, 14%), 9d (0.221 g, 0.789 mmol, 1 1%), 9e (0.201 g, 0.85 mmol, 10%), 9f (0.221 g, 0.793 mmol, 11%), 9g (0.261 g, 1.04 mmol, 13%), 9h (0.302 g, 1.13 mmol, 15%), 9i (0.180 g, 0.572 mmol, 9%), 9j (0.321 g, 1.01 mmol, 16%), 9k (0.201 g, 0.741 mmol, 10%) and 91 (0.241 g, 1.1 1 mmol, 12%) as white gummy liquid respectively.

Reduction of nitro group (3-Nitro-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester) (9a) to amine of chiral nitroalkane (3-Amino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester) (8a) compounds by hydrogenation:

Nitroalkane (9) (0.039 g, 0.133 mmol) was dissolved in the ethyl acetate (5 mL) and the solution was added to the resin-10% Pd/C (0.009 g, x mmol) in a 500 mL pyrex glass bottle. After that, the bottle was placed in a parr apparatus and after flushing with argon and hydrogen, hydrogenation was started under pressure (50 psi) for 5 h in 27 °C, without stirring. After completion of the reaction, the resin was filtered off and washed with ethyl acetate (3 x 10 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica (50% ethyl acetate/petroleum ether to 75% ethyl acetate/petroleum ether) to give various chiral amines 8a (0.378 g, 1.45 mmol, 89%), 8b (0.150 g, 0.632 mmol, 70%), 8c (0.184 g, 0.589 mmol, 72%), 8d (0.134 g, 0.536 mmol, 68%), 8e (0.121 g, 0.580 mmol, 69%), 8f (0.160 g, 0.642 mmol, 81%), 8g (0.174 g, 0.790 mmol, 76%), 8h (0.204 g, 0.870 mmol, 77%), 8i (0.130 g, 0.457 mmol, 80%), 8j (0.268 g, 0.848 mmol, 84%), 8k (0.155 g, 0.644 mmol, 87%) and 81 (0.164 g, 0.876 mmol, 79%).

The spectral analyses of series of compound (8a) and (9a) are as follows:- (R) 3-Amino-4-(2,4,5-trifluoro-phenyl)-butyricacidethylester(8a) ,

(R) 3-nitro-4(2,4,5-trifluorophenyl)butyricacidethylester(9a).

Compound 9a (3-Nitro-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester)

Yellowish gummy.

R _f = 0.68 (Hexane/EtOAc 9: l).[a] _D ²⁵ (c 0.92, CHC1 ₃ ) = +2.86.

¾ NMR (300 MHz, CDC1 ₃ ) 7.31-7.22 (m, 2H, aromatic), 6.93-6.84 (m, 1H, CHH ⁷ ), 6.57-6.51 (m, 1H, CHH ⁷ ), 6.35-6.27 (m, 1H, CH), 4.22 (q, J= 7.14 Hz, 2H, CH ₂ ), 3.27 (d, J = 7.05 Hz, 2H, CH ₂ ), 1.31 (t, J = 7.14 Hz, 3H, CH ₃ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 171.0, 134.1, 127.8, 125.4, 123.9, 121.2, 105.3, 60.9, 38.5, 28.2, 14.1 ppm.IR (CHC1 ₃ ) v2985, 1736, 1518 cm ^"1 ESIMS: m/z (%) 291.2 [M ⁺ ]. Analysis calculated for Ci ₂ H ₁₂ F ₃ N0 ₄ C 49.49, H 4.15, N 4.81. Found C 49.31, H 4.10, N 4.80.

Compound 8a (3-Amino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester ) Yellowish gummy. R _f = 0.12 (Hexane/EtOAc 9: 1). [α] _Ό ²⁵ (c 0.75, CHC1 ₃ ) = -2.1. ¾ NMR (300 MHz, CDC1 ₃ ) £7.82-7.22 (m, 2H, aromatic), 5.29 (bs, 1H, CH), 2.93-2.88 (m, 2H, CH ₂ ), 2.03 (brs, 2H, NH ₂ ), 1.61 (m, 2H, CH ₂ ), 1.40-1.25 (m, 2H, CH ₂ ), 0.97 (t, J= 7.26 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) δ 172.0, 152.1, 151.0, 150.4, 118.2, 105.3, 60.2, 50.1, 48.3, 33.4, 14.6 ppm. IR (CHC1 ₃ ) v2963, 1714 cm ^"1 ESIMS: m/z (%) 261.2 [M ⁺ ].

Analysis calculated for d ₂ H ₁₄ F ₃ N0 ₂ C 55.17, H 5.40, N 5.36. Found C 55.12, H 5.38, N 5.31. Compound 8b (3-Amino-4-(4-methoxy-phenyl)-butyric acid ethyl ester)

Colourless gummy. R _f = 0.22 (Hexane/EtOAc 9: 1). [α] _Ό ²⁵ (c 0.92, CHC13) = +1.32.

¾ NMR (300 MHz, CDC1 ₃ ) £7.34-7.26 (m, 4H, aromatic), 4.32 (q, J= 6.99 Hz, 2H, CH ₂ ), 4.01 (s, 3H, OCH ₃ ), 3.82 (m, 1H, CH), 2.77 (d, J = 6.95 Hz, 2H, CH ₂ ), 2.48 (d, J = 6.87 Hz, 2H, CH' ₂ ), 2.04 (bs, 2H, NH ₂ ), 1.30 (t, J= 7.22 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) δ 173.0, 160.2, 133.9, 129.3, 114.8, 60.8, 56.9, 48.2, 46.4, 46.5, 14.8 ppm. IR (CHC1 ₃ ) v2967, 1732 cm ^"1

ESIMS: m/z (%) 260 [M + Na] ⁺ Analysis calculated for Ci ₃ H ₁₉ N0 ₃ C 65.80, H 8.07, N 5.90. Found C 65.10, H 7.92, N 5.21.

Compound 9b (4-(4-methoxy-phenyl)-3-nitro-butyric acid ethyl ester) Colourless gummy. R _f = 0.57 (Hexane/EtOAc 9: l). [a] _D ²⁵ (c 0.92, CHC1 ₃ ) = +4.1 1.

¾ NMR (300 MHz, CDC1 ₃ ) £ 7.29-7.20 (m, 4H, aromatic), 4.92 (m, 1H, CH), 4.25 (q, J = 7.15 Hz, 2H, CH ₂ ), 3.90 (s, 3H, OCH ₃ ), 3.42 (d, J = 7.01 Hz, 2H, CH ₂ ), 3.01 (d, J = 6.21 Hz, 2H, CH' ₂ ), 1.48 (t, J = 7.15 Hz, CH ₃ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 160.4, 132.2, 129.4, 114.7, 88.9, 60.8, 58.2, 40.6, 40.2, 14.8 ppm. IR (CHC1 ₃ ) v2957, 1756, 1520 cm ^"1

ESIMS: m/z (%) 267.2 [M ⁺ ].

Analysis calculated for Ci ₃ H ₁₇ N0 ₅ C 58.42, H 6.41, N 5.24. Found C 58.02, H 6.40, N 5.02. Compound 8c [3-Amino-4-(4-benzyloxy-phenyl)-butyric acid ethyl ester]

Colourless gummy. R _f = 0.17 (Hexane/EtOAc 9: 1). [α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +3.12.

¾ NMR (300 MHz, CDC1 ₃ ) 7.52-7.41 (m, 5H, aromatic), 7.26-7.20 (m, 4H, aromatic), 5.62 (s, 2H, CH ₂ ), 4.26 (q, J = 7.10 Hz, 2H, CH ₂ ), 3.69 (m, 1H, CH), 3.29 (d, J = 6.54 Hz, 2H, CH ₂ ), 3.02 (d, J= 6.58 Hz, 2H, CH ⁷ ₂ ), 2.4 (brs, 2H, NH ₂ ), 1.41 (t, J = 7.16 Hz, 3H, CH ₃ ) ppm.

1 ³ C NMR (75 MHz, CDC1 ₃ ) £ 172.0, 160.2, 150.1, 131.8, 130.2, 128.7, 128.2, 117.4, 80.9, 60.4, 50.2, 48.4, 44.8, 14.4 ppm. IR (CHC1 ₃ ) v2957, 1734 cm ^"1 ESIMS: m/z (%) 336.3 [M + Na] ⁺ Analysis calculated for d ₉ H ₂₃ N0 ₃ C 72.82, H 7.40, N 4.47. Found C 72.75, H 7.29, N 4.02. Compound 9c [4-(4-Benzyloxy-phenyl)-3-nitro-butyric acid ethyl ester

Colourless gummy. R _f = 0.55 (Hexane/EtOAc 9: 1). [α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +1.05.

¾ NMR (300 MHz, CDC1 ₃ ) £ 7.29-7.24 (m, 5H, aromatic), 7.23-7.21 (m, 4H, aromatic), 5.89 (s, 2H, CH ₂ ), 4.89 (m, 1H, CH), 4.29 (q, J = 7.25 Hz, 2H, CH ₂ ), 3.49 (d, J = 7.04 Hz, 2H, CH ₂ ), 3.03 (d, J = 6.23 Hz, 2H, CH ₂ ), 1.41 (t, J = 7.20 Hz, 3H, CH ₃ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 172.9, 150.4, 144.9, 132.3, 129.4, 128.7, 127.6, 127.4, 1 14.2, 1 14. 1, 85.6, 80.1, 60.4, 40.2, 40.1, 14.6 ppm. IR (CHC1 ₃ ) v2957, 1736, 1530 cm ^"1 ESIMS: m/z (%) 366.3 [M + Na] ⁺

Analysis calculated for d ₉ H ₂₁ N0 ₅ C 66.46, H 6.16, N 4.08. Found C 66.41, H 6.10, N 4.02. Compound 8d [3-Amino-4-(4-dimethylamino-phenyl)-butyric acid ethyl ester] Colourless gummy. R _f = 0.15 (Hexane/EtOAc 9: 1). [α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +2.43.

¾ NMR (300 MHz, CDC1 ₃ ) £ 7.29-7.21 (m, 4H, aromatic), 4.39 (q, J = 7.41 Hz, 2H, CH ₂ ), 3.92 (m, 1H, CH), 2.89 (s, 6H, 2CH ₃ ), 2.88 (d, J = 7.1 1 Hz, 2H, CH ₂ ), 2.86 (d, J = 6.99 Hz, 2H, CH' ₂ ), 2.1 (brs, 2H, NH ₂ ), 1.42 (t, J = 7.13 Hz, 3H, CH ₃ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 172.0, 148.4, 129.3, 128.6, 1 13.2, 113.1, 60.4, 52.1, 50.1, 48.2, 43.0, 14.6 ppm.

IR (CHC1 ₃ ) v2957, 1736 cm ^"1 ESIMS: m/z (%) 250 [M ⁴ .

Analysis calculated for d ₄ H ₂₂ N ₂ 0 ₂ C 67.17, H 8.86, N 11.19. Found C 67.10, H 8.81, N 11.10. Compound 9d (3-Nitro-4-phenyl-butyric acid ethyl ester dimethyl amine)

Colourless gummy. ¾ = 0.64 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +3.11.

¾ NMR (300 MHz, CDC1 ₃ ) £ 7.28-7.23 (m, 4H, aromatic), 5.21 (m, 1H, CH), 4.83 (q, J = 6.81

Hz, 2H, CH ₂ ), 3.49 (d, J = 6.22 Hz, 2H, CH ₂ ), 3.01 (d, J = 6.35 Hz, 2H, CH' ₂ ), 2.93 (s, 6H, 2CH ₃ ), 1.43 (t, J = 7.24 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 150.4, 128.6, 128.4, 128.2, 113.2, 113.1, 86.4, 60.8, 44.5,

38.6, 38.2, 14.2 ppm.

IR (CHC1 ₃ ) v2932, 1730, 1532 cm ^"1

ESIMS: m/z (%) 280 [M ⁺ ].

Analysis calculated for Ci ₄ H ₂ oN ₂ 0 ₄ C 59.99, H 7.19, N 9.99. Found C 59.89, H 7.10, N 9.82.

Compound 8e (3-Amino-4-phenyl butyric acid ethyl ester)

Colourless gummy.

R _f = 0.12 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +4.77.

¾ NMR (300 MHz, CDC1 ₃ ) 7.28-7.21 (m, 5H, aromatic), 4.82 (q, J = 7.22 Hz, 2H, CH ₂ ), 3.89

(m, 2H, NH ₂ ), 3.01 (d, J = 7.06 Hz, 2H, CH ₂ ), 2.92 (d, J = 7.06 Hz, 2H, CH ⁷ ₂ ), 2.0 (brs, 2H,

NH ₂ ), 1.42 (t, J = 7.26 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 138.9, 128.6, 128.2, 128.1, 124.2, 62.4, 52.1, 48.3, 48.1, 14.9 ppm.

IR (CHC1 ₃ ) v2940, 1728 cm- 1

ESIMS: m/z (%) 230.2 [M + Na] ⁺ .

Analysis calculated for C ₁₂ H ₁₇ N0 ₂ C 69.54, H 8.27, N 6.76. Found C 69.50, H 8.15, N 6.49. Compound 9e (3-Nitro-4-phenyl butyric acid ethyl ester)

Colourless gummy.

R _f = 0.65 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +8.12.

¾ NMR (300 MHz, CDC1 ₃ ) £ 7.30-7.25 (m, 5H, aromatic), 5.21 (m, 1H, CH), 4.81 (q, J = 7.1 1 Hz, 2H, CH ₂ ), 3.45 (d, J = 6.98 Hz, 2H, CH ₂ ), 3.01 (d, J = 6.52 Hz, 2H, CH ⁷ ₂ ), 1.47 (t, J = 6.99 Hz, 3H, CH ₃ ) ppm.

1 ³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 138.4, 128.8, 128.6, 128.3, 128.1, 121.2, 89.4, 62.1, 40. 1, 38.6, 14.0 ppm.

IR (CHC1 ₃ ) 2929, 1741, 1545 cm- 1

ESIMS: m/z (%) 260 [M + Na] ⁺ . Analysis calculated for Ci ₂ H ₁₅ N0 ₄ C 60.75, H 6.37, N 5.90. Found C 60.65, H 6.30, N 5.82. Compound 8f (3-Amino-4-(3,4,5-trimethyl-phenyl)-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.15 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +4.05.

¾ NMR (300 MHz, CDC1 ₃ ) £7.25-7.23 (m, 2H, aromatic), 4.56 (q, J= 6.98 Hz, 2H, CH ₂ ), 3.97 (m, 1H, CH), 2.91 (d, J = 6.58 Hz, 2H, CH ₂ ), 2.81 (d, J = 6.48 Hz, 2H, CH ⁷ ₂ ), 2.36 (s, 9H, 3CH ₃ ), 2.01 (brs, 2H, NH ₂ ), 1.46 (t, J= 7.28 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) 172.0, 140.2, 140.1, 140.0, 138.9, 127.2, 127.1, 66.2, 52.1, 49.6, 49.2, 46.8, 4.6, 9.2 ppm.

IR (CHC1 ₃ ) v2956, 1745 cm ^"1

ESIMS: m/z (%) 249.3 [M ⁺ ].

Analysis calculated for Ci ₅ H ₂₃ N0 ₂ C 72.25, H 9.30, N 5.62. Found C 72.21, H 9.26, N 5.60. Compound 9f (3-Nitro-4-(3,4,5-trimethyl-phenyl)-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.67 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +2.36.

¾ NMR (300 MHz, CDC1 ₃ ) £7.26-7.23 (m, 2H, aromatic), 5.1 (m, 1H, CH), 4.6 (q, J = 7.25

Hz, 2H, CH ₂ ), 3.62 (d, J = 7.36 Hz, 2H, CH ₂ ), 3.01 (d, J = 6.98 Hz, 2H, CH ⁷ ₂ ), 2.81 (s, 9H, 3CH ₃ ), 1.46 (t, J= 7.14 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 138.9, 138.6, 138.2, 126.4, 126.1, 89.7, 62.6, 40.3, 40.1,

16.2, 14.6, 10.1 ppm.

IR (CHC1 ₃ ) v2957, 1736, 1545 cm ^"1

ESIMS: m/z (%) 279.3 [M ⁺ ].

Analysis calculated for d ₅ H ₂₁ N0 ₄ C 64.50, H 7.58, N 5.01. Found C 64.42, H 7.50, N 4.98.

Compound 8g (3-Amino-4-p-totyl-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.17 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +1.52.

¾ NMR (300 MHz, CDC1 ₃ ) £7.26-7.24 (m, 4H, aromatic), 4.82 (q, J= 7.25 Hz, 2H, CH ₂ ), 3.96

(m, 1H, CH), 3.02 (d, J = 7.09 Hz, 2H, CH ₂ ), 2.92 (d, J = 7.08 Hz, 2H, CH ⁷ ₂ ), 2.31 (s, 3H, CH ₃ ),

1.42 (t, J= 7.18 Hz, 3H, CH ₃ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 172.0, 140.1, 139.4, 138.2, 128.3, 128.1, 128.0, 62.4, 52.1, 45.8, 44.2, 21.2, 14.2 ππμ.

IP (ΧΗΧλ ₃ ) 2944, 1740 cm ^"1

ESIMS: m/z (%) 221 [M ⁺ ].

Analysis calculated for Ci ₃ H ₁₉ N0 ₂ C 70.56, H 8.65, N 6.33. Found C 70.48, H 8.55, N 6.31. Compound 9g (3-Nitro-4-p-totyl-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.77 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHCI ₃ ) = +11.33.

¾ NMR (300 MHz, CDC1 ₃ ) 7.28-7.21 (m, 4H, aromatic), 5.21 (m, 1H, CH), 4.89 (q, J = 7.55 Hz, 2H, CH ₂ ), 3.61 (d, J= 7.05 Hz, 2H, CH ₂ ), 3.01 (d, J= 7.05 Hz, 2H, CH ⁷ ₂ ), 2.48 (s, 3H, CH ₃ ), 1.42 (t, J= 7.14 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.1, 138.2, 138.1, 128.4, 128.3, 128.1, 128.0, 89.4, 62.1, 41.2, 41.0, 22.4, 14.2 ppm.

IR (CHCI ₃ ) v2928, 1739, 1560 cm ^"1

ESIMS: m/z (%) 274.2 [M + Na] ⁺ .

Analysis calculated for Ci ₃ H ₁₇ N0 ₄ C 62.14, H 6.82, N 5.57. Found C 62.10, H 6.79, N 5.50. Compound 8h (3-Amino-6-phenyl-hexanoic acid ethyl ester)

Colourless gummy.

R _f = 0.17 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHCI ₃ ) = +5.47.

¾ NMR (300 MHz, CDC1 ₃ ) £7.24-7.21 (m, 5H, aromatic), 4.82 (q, J= 7.10 Hz, 2H, CH ₂ ), 3.64 (m, 1H, CH), 3.01 (t, J = 6.93 Hz, 2H, CH ₂ ), 2.92 (d, J = 6.83 Hz, 2H, CH ₂ ), 2.01 (brs, 2H, NH ₂ ), 1.82 (m, 2H, CH ₂ ), 1.65 (m, 2H, CH2), 1.40 (t, J = 7.14 Hz, 3H, CH3) ppm.

1 ³ C NMR (75 MHz, CDC1 ₃ ) δ 172.1, 140.4, 129.2, 129.1, 128.4, 128.3, 62.1, 48.2, 46.2, 38.5, 38.1, 28.0, 14.6 ppm.

IR (CHC1 ₃ ) 2932, 1731 cm ^"1

ESIMS: m/z (%) 235 [M ⁺ ].

Analysis calculated for d ₄ H ₂₁ N0 ₂ C 71.46, H 8.99, N 5.95. Found C 71.40, H 8.89, N 5.90. Compound 9h (3-Nitro-6-phenyl-hexanoic acid ethyl ester)

Colourless gummy.

R _f = 0.69 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHCI ₃ ) = +6.58. ¾ NMR (300 MHz, CDC1 ₃ ) £ 7.24-7.22 (m, 5H, aromatic), 4.81 (m, 1H, CH), 4.26 (q, J = 6.89 Hz, 2H, CH ₂ ), 3.01 (d, J = 7.02 Hz, 2H, CH ₂ ), 2.96 (d, J = 7.55 Hz, 2H, CH ₂ ), 1.97 (m, 2H, CH ₂ ), 1.82 (m, 2H, CH ₂ ), 1.42 (t, J= 6.99 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.0, 140.9, 129.4, 129.3, 128.6, 127.2, 82.0, 62.1, 38.4, 38.3, 30.7, 28.2, 14.8 ppm.

IR (CHC1 ₃ ) v2960, 1750, 1538 cm ^"1

ESIMS: m/z (%) 265.3 [M ⁺ ].

Analysis calculated for Ci ₄ H ₁₉ N0 ₄ C 63.38, H 7.22, N 5.28. Found C 63.30, H 7.20, N 5.20. Compound 8i (3-Amino-4-(3-bromo-phenyl-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.11 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHCI ₃ ) = +6.19.

¾ NMR (300 MHz, CDC1 ₃ ) 7.29-7.21 (m, 4H, aromatic), 4.35 (q, J= 1.11 Hz, 2H, CH ₂ ), 3.92 (m, 1H, CH), 3.01 (d, J = 6.85 Hz, 2H, CH ₂ ), 2.97 (d, J = 6.35 Hz, CH ⁷ ₂ ), 2.02 (brs, 2H, NH ₂ ), 1.42 (t, J= 7.11 Hz, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 144.9, 137.1, 129.2, 129.1,62.1, 50.1, 48.4, 48.2, 14.2 ppm. IR (CHC1 ₃ ) v2953, 1751 cm ^"1

ESIMS: m/z (%) 286.1 [M ⁺ ].

Analysis calculated for Ci ₂ H ₁₆ BrN0 ₂ C 50.37, H 5.64, N 4.89. Found C 50.31, H 5.61, N 4.80. Compound 9i (3-Nitro-4-(3-bromo-phenyl-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.69 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHCI ₃ ) = +4.54.

¾ NMR (300 MHz, CDC1 ₃ ) £ 7.29-7.06 (m, 4H, aromatic), 5.21 (m, 1H, CH), 4.26 (q, J = 6.59 Hz, 2H, CH ₂ ), 3.92 (d, J = 6.11 Hz, 2H, CH ₂ ), 3.01 (d, J = 5.97 Hz, 2H, CH ⁷ ₂ ), 1.46 (t, J = 7.01 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.0, 145.9, 133.2, 133.1, 128.2, 128.0, 122.1, 89.1, 61.5, 38.4, 38.0, 14.2 ppm.

IR (CHC1 ₃ ) v2935, 1741, 1562 cm ^"1

ESIMS: m/z (%) 339 [M + Na] ⁺ .

Analysis calculated for Ci ₂ H ₁₄ BrN0 ₄ C 45.59, H 4.46, N 4.43. Found C 45.51, H 4.42, N 4.40. Compound 8j (3-Amino-4-(4-bromo-phenyl-butyric acid ethyl ester)

Colourless gummy. R _f = 0.12 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +2.21.

¾ NMR (300 MHz, CDC1 ₃ ) £7.27-7.20 (m, 4H, aromatic), 4.86 (q, J= 7.15 Hz, 2H, CH ₂ ), 3.97 (m, 1H, CH), 3.02 (d, J = 7.02 Hz, 2H, CH ₂ ), 2.94 (d, J = 7.01 Hz, 2H, CH' ₂ ), 2.04 (brs, 2H, NH ₂ ), 1.46 (t, J= 1.15 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.1, 142.1, 140.1, 138.2, 120.4, 62.1, 51.2, 50.0, 48.2, 14.9 ppm.

IR (CHC1 ₃ ) 2941, 1746 cm ^"1

ESIMS: m/z (%) 309 [M + Na] ⁺ .

Analysis calculated for Ci ₂ H ₁₆ BrN0 ₂ C 50.37, H 5.64, N 4.89. Found C 50.32, H 5.61, N 4.80. Compound 9j (3-Nitro-4-(4-bromo-phenyl-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.72 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHCI ₃ ) = +1.89.

¾ NMR (300 MHz, CDC1 ₃ ) 7.41-7.27 (m , 4H, aromatic), 5.61 (m, 1H, CH), 4.81 (q, J = 7.61 Hz, 2H, CH ₂ ), 3.92 (d, J = 7.54 Hz, 2H, CH ₂ ), 3.01 (d, J = 7.15 Hz, 2H, CH ⁷ ₂ ), 1.46 (t, J = 7.15 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.0, 138.4, 138.2, 129.4, 128.6, 128.2, 90.2, 64.2, 42.1, 40.0, 14.8 ppm.

IR (CHCI ₃ ) v2929, 1741, 1530 cm ^"1

ESIMS: m/z (%) 316 [M ⁺ ].

Analysis calculated for C ₁₃ H ₁₄ BrN0 ₄ C 45.59, H 4.46, N 4.43. Found C 45.50, H 4.40, N 4.40. Compound 8k (3-Amino-4-(4-chloro-phenyl)-butyric acid ethyl ester)

Colourless gummy.

R _f = 0.14 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHCI ₃ ) = +5.22.

¾ NMR (300 MHz, CDC1 ₃ ) £7.28-7.22 (m, 4H, aromatic), 4.82 (q, J = 6.98 Hz, 2H, CH ₂ ), 3.96 (m, 1H, CH), 3.01 (d, J = 6.85 Hz, 2H, CH ₂ ), 2.98 (d, J = 5.48 Hz, 2H, CH ⁷ ₂ ), 2.04 (brs, 2H, NH ₂ ), 1.38 (t, J= 7.44 Hz, 3H, CH ₃ ) ppm.

1 ³ C NMR (75 MHz, CDC1 ₃ ) £ 172.1, 148.2, 131.2, 129.6, 129.2, 129.0, 62.1, 50.1, 48.6, 46.4, 14.8 ppm.

IR (CHC1 ₃ ) v2931, 1739 cm ^"1

ESIMS: m/z (%) 241 [M ⁺ ]. Analysis calculated for Ci ₂ H ₁₆ ClN0 ₂ C 59.63, H 6.67, N 5.79. Found C 59.61, H 6.65, N 5.72. Compound 9k (3-Nitro-4-(4-chloro-phenyl)-butyric acid ethyl ester)

Colourless gummy. R _f = 0.69 (Hexane/EtOAc 9: 1). [α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +3.34.

¾ NMR (300 MHz, CDC1 ₃ ) 7.28-7.22 (m, 4H, aromatic), 5.26 (m, 1H, CH), 4.81 (q, J = 7.85 Hz, 2H, CH ₂ ), 3.96 (d, J = 6.58 Hz, 2H, CH ₂ ), 3.01 (d, J = 6.24 Hz, 2H, CH ⁷ ₂ ), 1.46 (t, J = 7.15

Hz, 3H, CH ₃ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.1, 140.1, 139.6, 139.4, 129.4, 129.7,

129.1, 87.4, 62.1, 42.1, 40.7, 14.6 ppm. IR (CHC1 ₃ ) v2928, 1743, 1548 cm ^"1

ESIMS: m/z (%) 271.6 [M ⁺ ]. Analysis calculated for Ci ₂ H ₁₄ ClN0 ₄ C 53.05, H 5.19, N 5.16.

Found C 53.01, H 5.10, N 5.12.

Compound 81 (3-amino-octanoic acid ethyl ester)

Colourless gummy.R _f = 0.16 (Hexane/EtOAc 9: l).[a] _D ²⁵ (c 0.92, CHC13) = +1.68.

¾ NMR (300 MHz, CDC1 ₃ ) £ 4.82 (q, J = 7.11 Hz, 2H, CH ₂ ), 3.92 (m, 1H, CH), 3.01 (d, J =

6.59 Hz, 2H, CH ₂ ), 2.01 (brs, 2H, NH ₂ ), 1.82-1.29 (m, 11H, aliphatic), 0.92 (t, J = 7.54 Hz, 3H,

CH ₃ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 62.1, 49.6, 47.4, 42.1, 38.2, 33.4, 28.4, 22.3, 18.2, 14.6 ppm.IR (CHC1 ₃ ) v2939, 1756 cm ^"1 ESIMS: m/z (%) 187 [M ⁺ ]. Analysis calculated for

CioH ₂₁ N0 ₂ C 64.13, H 11.30, N 7.48. Found C 64.10, H 11.26, N 7.41.

Compound 91 (3-amino-octanoic acid ethyl ester)

Colourless gummy.

R _f = 0.72 (Hexane/EtOAc 9: 1).

[α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = +3.12.

¾ NMR (300 MHz, CDC1 ₃ ) £ 4.89 (m, 1H, CH), 4.23 (q, J = 7.54 Hz, 2H, CH ₂ ), 3.01 (d, J =

6.98 Hz, 2H, CH ₂ ), 2.01-1.30 (m, 11H, aliphatic), 0.92 (t, J= 4.52 Hz, 3H, CH ₃ ) ppm.

¹³ C NMR (75 MHz, CDC1 ₃ ) £ 172.4, 84.2, 62.1, 38.2, 32.3, 30.4, 28.3, 24.2, 18.0, 14.6 ppm.

IR (CHC1 ₃ ) v2951, 1750, 1539 cm ^"1

ESIMS: m/z (%) 217.2 [M ⁺ ].

Analysis calculated for Ci ₀ H ₁₉ NO ₄ C 55.28, H 8.81, N 6.45. Found C 55.19, H 8.71, N 6.38.

Example 7 a b

Sitagliptin 1 Synthesis of Sitagliptin 1

Reagents and conditions: (a) 2M HCl, reflux; (b) 3-Trifluoromethyl-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3-a]pyrazine (A), EDC, Cat. HOBt, NMM, ethanol, rt.

The Chiral nitro amine 8a was hydrolyzed with 2M HCl to get compound 10 followed by addition of A, EDC, cat.HoBt, NMM, ethanol we get Sitagliptin 1

Synthesis of Compound (10) [3-Amino-4-(2,4,5-trifluorophenyl)-butyric acid] (>5-amino acid part of Sitagliptin):

2.0 M aq HCl (15 mL) was added dropwise to 8a (3 g, 11.48 mmol) at 27°C and the resultant mixture was heated at reflux for 6 h. The reaction mixture was then allowed to cool to 27°C and concentrated in vacuo to give 10 as a colourless oil (2.46 g, 10.56 mmol, 92%). The spectral analysis of the compound is as follows :-

R _f = 0.11 (Ethyl acetate); [α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = -6.54. ¾ NMR (300 MHz, CDC1 ₃ ) 7.30- 7.29 (m, 1H, Aromatic), 7.11-7.08 (m, 1H, Aromatic), 4.12-4.10 (m, 1H, CH), 2.98-2.96 (m, 1H, CHH ⁷ ), 2.88-2.84 (m, 1H, CHH ⁷ ), 2.79-2.76 (m, 1H, CfflTCOOH), 2.58-2.53 (m, 1H, CHH'COOH), 2.03 (brs, 2H, NH ₂ ) ppm ¹³ C NMR (75 MHz, CDC1 ₃ ) £ 177.4, 159.8, 152.6, 146.8, 123.2, 122.8, 120.4, 118.5, 105.6, 49.2, 45.6, 34.2 ppm

IR (CHC1 ₃ ) 2935, 1720 cm ^"1 ESIMS: m/z (%) 233 [M ⁺ ]. Analysis calculated for CioH ₁₀ F ₃ N0 ₂ C 51.51, H 4.32, N 6.01. Found C 51.50, H 4.28, N 5.96.

Example 8

Synthesis of compound Sitagliptin 1 :

To a 100 mL three-neck round bottom flask equipped with mechanical stirrer was added the amine A [3-Trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine] (1.97 g, 10.29 mmol), ethanol (10 mL), NMM (2.28 g, 22.63 mmol), carboxylic acid 10, (2.4 g, 10.29 mmol), and HOBt (0.208 g, 1.54 mmol). The contents were then cooled to 10 °C, and EDC (1.91 g, 12.34 mmol) was added. The reaction was stirred at 25 °C for 3 h followed by the addition of water (20 mL). Product was isolated via extractive workup with methanol (3 x 15 mL) then dried over anhydrous sodium sulphate and concentrated in vacuo. Purification via flash column chromatography (eluent CH ₂ Cl ₂ /MeOH, 10: 1) gave 1 as colourless oil (3.60 g, 8.84 mmol, 86%). The Spectral Analysis of all compounds: ¾ = 0.13 (Ethyl acetate); [α] _Ό ²⁵ (c 0.92, CHC1 ₃ ) = -22.4. ¾ NMR (300 MHz, CDC1 ₃ ) «57.11- 7.09 (m, 1H, Aromatic), 6.99-6.92 (m, 1H, Aromatic), 5.10-4.99 (m, 2H, CH ₂ ), 4.31-4.28 (m, 4H, NCH ₂ CH ₂ N), 3.60 (brs, 1H, CH), 2.83-2.80 (m, 1H, CHH ⁷ ), 2.70-2.65 (m, 1H, CHH ⁷ ), 2.60- 2.50 (m, 2H, CH ₂ ), 2.03 (brs, 2H, NH ₂ ) ppm. ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 171.2, 170.8, 151.2, 149.6, 156.8, 148.3, 146.8, 142.7, 122.1, 118.8, 118.3, 105.7, 48.9, 43.5, 42.4, 39.9, 37.9, 36.2 ppm. IR (CHClj) 3372, 1645 cm ^"1 ; ESIMS: m/z (%) 430 [M + Na] ⁺ ; Analysis calculated for Ci ₆ H ₁₅ F ₆ N ₅ O C 47.18, H 3.71, N 17.19. Found C 47.01, H 3.62, N 17.10.

ADVANTAGES OF THE PRESENT INVENTION in the present invention it has been observed that the:-

1. Synthesis of β-amino acids from β-nitroacrylate does not need high pressure, critical reactions condition.

2. Product separation was also easy.

3. Moreover synthesis of β-amino acids from β-nitroacrylate is not known. Again β- nitroacrylate could be synthesized very easily from nitroalkane and ethyl glyoxalate which is a simple and efficient process involving three steps only.