FIELD OF THE INVENTION:

The present invention relates to economical, industrially viable process for the preparation of N-Boc-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (6) via novel intermediates;4-bromo-l,2,3,6-tetrahydropyridine(13) and its N-protected derivatives (12) and (14) and salt (15) which are used as key intermediates and building blocks for the synthesis of several biologically active compounds.

BACKGROUND OF THE INVENTION:

Several biological active compounds have been reported in the literature where the molecular framework partially contains or requires the introduction of the structural motifs that can be prepared by using the compounds that are represented in formula 11, 12, 13, 14 and 6. Such molecules/agents appear to have the potential for the prevention and/or treatment of disorders related to abnormal protein kinase activities and hyper-proliferative disorders such as cancer; histamine H4 receptor-associated conditions; inflammatory diseases; pruritus; pain; diseases associated with angiogenesis inhibitors of focal adhesion; rejection reactions due to transplantation, graft versus host diseases, autoimmune diseases; allergic diseases; neurodegenerative diseases; Hepatitis C virus (HCV); a reperfusion injury, diabetes mellitus, a diabetic complication; an ischemic condition; renal failure; a vascular disease, a cardiovascular disease; an ocular or ophthalmologic disease; nephropathy, contrast induced nephropathy; erectile dysfunction or urinary incontinence; smooth muscle myosin and/or non-muscle myosin.

Synthesis of N-Boc-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (6) is known in the art.
Paul Eastwood in Tetrahedron Letters 41(19), 2000, 3705-3708 discloses a simple preparation of cyclic vinyl boronates derived from the vinyl triflates of N-protected tetrahydropyridines as shown in below scheme. Further Suzuki coupling of the boronates with aryl bromides, iodides and triflates proceeds in good yield to give 4-aryl tetrahydropyridines.

Further the known process for the preparation of N-Boc-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (6) is represented herein below in scheme 1,wherein the N-benzyl piperidone (1) is converted into its acid salt (2) followed by protecting the compound (2) with BOC in presence of base and suitable solvent to yield Boc-protected oxo-piperidine (3); Scheme:!
Further the Boc-protected oxo-piperidine 3 (tert-butyl 4-oxopiperidine-l-carboxylate) using reagents that are known in the art such as lithium hexamethyldisilzide (LHMD or lithium di-isopropyl amide (LDA) gives the lithium enolate (4), which is then treated with a triflating agent selected from trifluoroacetic anhydride, trimethylsilyl trifluoromethanesulfonate, N-phenyl triflimide, preferably N-phenyl triflimide to obtain the enol triflate (5) which is subsequently subjected to the Suzuki reaction conditions wherein the compound (5) is heated to a temperature ranging between 65°C to 110°C with bispinacolato borane along with a base preferably potassium acetate using l,l'-Bis-diphenylphosphino ferrocene (dppf) as the ligand in a suitable solvents such as dioxane or tetrhydrofuran (THF).

United States Patent Publication 20110086836 discloses preparation of substituted phenylpiperidine derivatives as melanocortin-4 receptor modulators, wherein substituted 2-bromo-phenol and 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are reacted in a Suzuki coupling in the presence of a base and a catalyst such as dichloro (l,l'-bis(diphenyl-phosphino)-ferrocene)palladium(II) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to give the Boc-protected A moiety as an intermediate compound.
United States Patent Publication 20110319434 discloses synthesis of bicyclic heterocyclic derivatives from N-Boc-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, wherein these compounds are used for treating or preventing treating an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a cognitive disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose etc.

Until now the synthesis of the compound of formula 6 is done using reagents such as trifluoromethanesulfonic (or triflic) anhydride, N,N-bis(trifluorornethylsulfonyl)aniline or related aryl triflimides which are highly air sensitive and expensive. It is therefore necessary to provide an alternate protocol for the synthesis of compounds as shown in formula 6 which does not require the use of the above mentioned unstable reagents.

In view of the above explanation, it is the object of the present invention to develop an economical, industrially viable synthetic procedure for the construction of above mentioned compounds/ intermediates, 11,12,13,14, 15 and 6 which are used as key intermediates and building blocks for the synthesis of several biologically active compounds and substances of commercial value.

SUMMARY OF THE INVENTION:

In accordance with the above objective, the present invention provides economical, industrially viable process for the preparation of compound (6), via novel intermediates (12), (13), (14), (15) starting from acid salt of 4-halo pyridine.

The process include the following steps:

i. treating acid salt of 4-halo pyridine (9), with alkylating/arylating agent in suitable solvent to give N-substituted pyridinium salt, preferably N-benzyl pyridinium salt or an N-methyl/alkyl pyridinium salt (10);

ii. reducing compound (10) to obtain intermediate compound (11);

iii. reacting compound (11) with alkyl or aryl chloroformate in organic solvent to obtain carbamate intermediate (12);

iv. converting compound (12) to the secondary amine (13) or ammonium salt (15) using organic or inorganic acid;

v. protecting compound (13) with BOC in presence of base and suitable solvent to
yield BOC protected compound (14) and;

vi. cross-coupling BOC protected compound (14) with bispinacolato borane or any
related tetra substituted bis-borane in the presence of palladium or transition metal
salts or complexes with a suitable ligand to obtain compound of formula (6).

In an aspect of the invention, there is provided novel intermediates having general Formula-I or its quaternary ammonium salt (wherein the counter ion in the quaternary ammonium salt is the conjugate base of an organic acid such as any carboxylic acid or sulfonic acid or conjugate base of an in-organic acid or Bronsted such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid).

Formula-I

wherein X is selected from CI, Br, F, I;

Y is any nitrogen protecting group such as, methyl, benzyl, substituted benzyl, naphthayl, or selected from -H, alkyl, sulfonyl, -CONR2, COOR2, wherein R2 is substituted or unsubstituted (C1-C10) alkyl, aryl, alkylaryl, trialkyllsilane, oxazoline, -CF3, -FMoc, Troc, Teoc, Alloc,

In an aspect, there is provided novel intermediate (12) having formula;

wherein X is selected from CI, Br, F, I;

R2 is selected from substituted or unsubstituted (C1-C10 ) alkyl, aryl, alkylaryl, trialkylsilane, oxazoline, -CF3, -FMoc, Troc, Teoc, Alloc.

In another aspect, there is provided novel intermediate (13) having formula;

wherein, X is described hereinabove.

In another aspect, the novel intermediate compound 14, having Formula,

wherein, X is described hereinabove .

In another aspect, the novel intermediate compound 15 having Formula,
wherein, X is described hereinabove ; Z (counter ion) which is the conjugate base of an organic acid such as any carboxylic or sulfonic acid or conjugate base of an in-organic acid or Bronsted acid such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid.

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 and briefly described as follows.

The present invention relates to economical, industrially viable process for the preparation of N-Boc-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (6) via novel intermediates (12), (13), (14), (15) starting from acid salt of 4-halo pyridine (9); which are used as key intermediates and building blocks for the synthesis of several biologically active compounds.

The process includes the following steps: i. treating acid salt of 4-halo pyridine (9), with alkylating/arylating agent in suitable solvent to give N-substituted pyridinium salt, preferably N-benzyl pyridinium salt or a N-methyl/alkyl pyridinium salt (10); ii. reducing compound (10) to obtain intermediate compound (11); iii. reacting compound (11) with alkyl or aryl chloroformate in organic solvent to obtain carbamate intermediate (12); iv. converting compound (12) to the secondary amine (13) or ammonium salt (15) using organic or inorganic acid; v. protecting compound (13) with BOC in presence of base and suitable solvent to yield BOC protected compound (14) and; vi. cross-coupling BOC protected compound (14) with bispinacolato borane or any related tetra substituted bis-borane in the presence of palladium or transition metal salts or complexes with a suitable ligand to obtain compound of formula (6).

The compound of formula 8 is made by treating 4-amino pyridine 7 dissolved in a solution of hydrobromic acid with bromine at a temperature ranging between 0 to 10°C. The resulting mixture is treated with an aqueous solution of sodium nitrite at an ambient temperature ranging between 0 to 5°C then brought to an ambient temperature and finally heated to a temperature around 50°C. The obtained product is taken into a suitable solvent, preferably dichloromethane into which a stream of hydrogen chloride gas is bubbled. The resulting hydrochloride salt as shown in formula 9 derived from 4-halopyridine can also be made by treating the 4-halopyridine base with a suitable aqueous, alcoholic or organic solution of hydrochloric acid. In the context of this application, all salts that can be obtained by treating 4-halopyridine with any inorganic or organic acid known in the art can be used for the subsequent transformation as shown in the Scheme 2. Scheme 2:

wherein X is selected from CI, Br, F, I;

R1 is selected from substituted or unsubstituted (C1-C10) alkyl group; or any benzyl or
substituted benzylic group, R2 is selected from is substituted or unsubstituted (C1-C10) alkyl, aryl, alkylaryl, trialkyllsilane, oxazoline, -CF3, -FMoc, Troc, Teoc, Alloc, and Z is conjugate base of an organic acid such as any carboxylic acid or sulfonic acid, or conjugate base of an in-organic acid or Bronsted acid such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid.

Accordingly, the acid salt of 4-halo pyridine 9 is treated with any alkylating /arylating/acylating agent, such as aryl halide, preferably substituted or unsubstituted benzyl halide or an alkyl halide, preferably methyl halide in a suitable solvent at elevated temperature gives N-benzyl pyridinium salt or the N-methyl/alkyl pyridinium salt 10 with a counter ion derived from the kind of leaving group that was initially a part of the alkylating/arylating /acylating reagent. Further the pyridinium salt 10 is treated with a suitable reducing agent selected from metal hydrides such as sodium borohydride, borane or an aluminium hydride to obtain compound (11). Since these reactions are exothermic, care is taken to perform the reaction at low temperatures (in the range of -30°C to 10°C). When using borohydride salts it is preferred to use a protic solvent or a mixture of any organic solvent with water or a suitable alcohol.The intermediate compound (11) is treated with an alkyl or aryl chloroformate in a suitable solvent at ambient temperature resulting in intermediate carbamate compound (12), which is further in-situ converted to the secondary amine (13) or ammonium salt (15) by the reaction with an organic or in organic acid.

Alternatively, the secondary amine (13) is further treated with a suitable reagent know in the art for protecting a nitrogen atom preferably tert-Butyl carbamates to obtain Boc-protected compound (14). Accordingly compound (14) is prepared by treating the secondary amine (13) which is formed in-situ under suitable conditions from compound (12), by an exchange protocol or by the subsequent isolation and treatment of the amine (13) with protecting agent such reaction involves the use of any in-organic or organic base in a suitable solvent at ambient conditions. Further the cross-coupling of N-protected compound (14) with bispinacolato borane or any related tetra substituted bis-borane in the presence of a metal salt or complex with a suitable ligand and an organic or in-organic base in a suitable solvent at elevated temperatures (in the range of 20°C-150°C) affords intermediate compound of formula (6).

In one embodiment, the starting material i.e. acid salt of 4-halo pyridine (9) is 4-chloro pyridine hydrochloride that subsequently yields the compound (6).

In another embodiment, the starting material i.e. acid salt of 4-halo pyridine (9) is 4-bromopyridine hydrochloride that subsequently yields the compound (6).

Alternatively , the intermediate compound (6)can be made using conditions well known in the art such as as the Barbier type of reactions which involve the insertion of a metal such as magnesium, zinc, aluminum and tin into a carbon-halide bond to give an organo-metallic species, wherein the insertion of Mg is carried out by . Grignard reaction and when zinc is used the transformation is referred to as the Reformatsky reaction. The other method for metallation involves the treatment of the organo-halide with an alkyl lithium reagent such as butyl lithium to obtain the organo lithium species similar to compound (4) as depicted in Scheme 1. These organo-metallic intermediates can be treated with a trialkyl boronate ester followed by pinacol or by the use of a pinacol substituted mono alkyl boronate reagent, to get the intermediate compound (6).

In accordance with the instant process, the protecting agents are selected from 9-Fluorenylmethyl carbamate; t-ButyI carbamate; di-tert-butyl dicarbonate; Benzyl carbamate; Acetamide; Trifluoroacetamide, Benzylamine, Tritylamine, p-Toluenesulfonamide, Allyloxycarbonyl chloride, 2,2,2-Trichlorethoxycarbonyl chloride, Trialkylsilyl chloride etc.
Further the alkyl or aryl chloroformate is selected from 1-Chloroethyl chloroformate, Ethyl chloroformate, Benzyl chloroformate, 4-Nitrobenzyl chloroformate etc; whereas the alkylating agent is selected from substituted or unsubstituted (C1-C10) alkyl halide; arylating agent is selected from substituted or unsubstituted benzyl-halide; acylating agent is selected from-COCl,-carboxyl group or carbomoyl.

The cross-coupling reaction can be carried out in the presence of a transition metal salt, wherein the metal ion is selected from Cu, Ni, Co, Rh, Pd, Ru and their salt is selected from anion such as fluoronium, chloronium, bromonium, iodonium, acetate etc. The metal of choice for such cross coupling reactions is palladium.

Further the cross-coupling reactions can be performed in presence of a metal (preferably palladium) salt or complex with suitable ligands, wherein mono or bis-phosphine ligand is selected from l,l'-Bis-diphenylphosphino ferrocene (dppf),l,l'-bis(di tert-butylphosphino) ferrocene (dtbpf),l,l'-bis-(diisopropylphosphino) ferrocene (dippf) and l,l'-bis-(di-tert-butylphosphino) ferrocene (dtbpf); preferably (l,l'-Bis-diphenylphosphino) ferrocene (dppf) including mono or bis phosphines that do not have the ferrocene moiety. Such phosphines can be used in their free state or in the form or fluoroborate phophonate salts.

In the instant process the organic solvent is selected from polar protic solvent such as methanol, ethanol, water, isopropanol,n-butanol or aprotic solvent such as ethyl acetate, acetone, dichloromethane (DCM), Tetrahydrofuran(THF), Acetonitrile, or non-polar solvents such as hexane, benzene, toluene, l,4-dioxane,ether or mixtures thereof.
Further the organic base is selected from tri-substitued amine bases such as triethylamine, di-isopropylethyl amine, tributylamine, dimethylaniline, pyridine etc and inorganic base selected from metal carbonates, bicarbonates,acetate, hydroxides, ammonia, preferably sodium or potassium carbonate or acetate.

In an embodiment, there is provided novel intermediates having general Formula-I or its quaternary ammonium salt (wherein the counter ion in the quaternary ammonium salt is the conjugate base of an organic acid such as any carboxylic acid or sulfonic acid or conjugate base of an in-organic acid or Bronsted acid such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid).

Formula-I

wherein X is selected from CI, Br, F, I;

Y is any nitrogen protecting group such as methyl, benzyl, substituted benzyl, naphthayl, or selected from -H, alkyl, sulfonyl, -CONR2, COOR2 , wherein R2 is substituted or unsubstituted (C1-C10) alkyl, aryl, alkylaryl, trialkyllsilane, oxazoline, -CF3, -FMoc, Troc, Teoc, Alloc,

The novel compounds/ intermediates, 12, 13, 14, and 15 are used as key intermediates and building blocks for the synthesis of several biologically active compounds and substances of commercial value.
Accordingly disclosed herein is the novel intermediate compound (12) prepared by reacting compound (11) with alkyl or aryl chloroformate in organic solvent.

wherein X is selected from Cl, Br, F, or I;

R2 is selected from is substituted or unsubstituted (C1-C10) alkyl, aryl, alkylaryl,
trialkylsilane, oxazoline, -CF3, -FMoc, -Troc, -Teoc, -Alloc.

In another embodiment, the novel intermediate compound (13) is obtained by reacting compound (12) with an inorganic or organic acid in suitable organic solvent.
wherein, X is described hereinabove.

The novel intermediate compound (14) is prepared by reacting compound (13) with BOC in presence of base and suitable solvent.

wherein, X is described hereinabove.

Further, the novel intermediate compound (15) is prepared by reacting compound (12) with excess amount of an inorganic or organic acid in suitable organic solvent.

wherein, X is described hereinabove,

Z is conjugate base of an organic acid such as any carboxylic acid or sulfonic acid, or conjugate base of an in-organic acid or Bronsted such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid.
In yet another embodiment, the compound of Formula 11, when X is Chloride and Rl is benzyl, methyl or alkyl i,e.(l-benzyl-4-Chloro-l,2,3,6-tetrahydropyridine or l-alkyl-4-Chloro-l,2,3,6-tetrahydropyridine ) can be obtained from compound of Formula 1 (1-benzyl 4-piperidone or 1-alkyl 4-piperidone) using chlorinating agent such as phosphorous oxychloride and phosphorous pentachloride at suitable temperature.

The invention will now be illustrated with help of examples. The aforementioned embodiments and below mentioned examples are for illustrative purpose and are not meant to limit the scope of the invention. Various modifications of aforementioned embodiments and below mentioned examples are readily apparent to a person skilled in the art. All such modifications may be construed to fall within the scope and limit of this invention as defined by the appended claims.

Examples:

1. Preparation of 4-bromopyridine hydrochloride; Compound 09 Procedure:

600 ml of HBr was charged into the 10L 3N RB flask and cooled to 0°C. 100 g of 4-amino pyridine, 07, was added portion wise for 10 min followed by the addition of 495 g (160 ml) of bromine for 30 min at 0°C. 190 g of sodium nitrite in 1 litre water was added to this reaction mixture for 30 min at 0-5°C, stirred the mixture for 30 min at the same temperature and for an additional 30 min at ambient, temperature before it was cooled to 0°C. Reaction mixture was decolorized with 1 Litre of saturated solution of sodium sulphite. After complete decolorization the reaction mixture was brought to ambient temperature and then heated to 50°C for 30 min. Progress of the reaction was monitored by TLC. On completion of the reaction, the contents were basified to a pH-9 with sodium carbonate solution and then product was extracted with DCM. HC1 gas was passed into organic layer at 0°C as the 4-bromo pyridine is not stable in its free form. To yield the required hydrochloride salt, Compound 09 as off-white solid.

2. Preparation of l-Benzyl-4-bromopyridinium bromide (or l-AlkyI-4- bromopyridinium halide) Compound 10 Procedure:

50 g of Compound 09 was taken in 500 ml of acetonitrile and charged into a 1L 3N RB flask. 59.5 g of Benzyl bromide was added to reaction mixture and was allowed to reflux overnight. Progress of the reaction was monitored by TLC. On completion of the reaction, the contents were cooled to 10°C, filtered and dried to yield the required product, compound 10, as a yellow solid. The mother liquors were concentrated to yield a semi¬solid. To this 50 ml of hexane was added, stirred for 10 min, filtered and dried to yield compound 10 as a yellow colored solid.

N-Alkyl-4-bromo pyridinium bromide and N-methyI-4-bromo pyridinium bromide salts are prepared using the same procedure as described above using an alkyl halide in place of benzyl bromide. Further these products are converted to the final required product 6 using the same transformations described below for the 1 -benzyl-4-bromo option.

3. Preparation of l-benzyl-4-bromo-l, 2,3, 6-tetrahydropyridine; Compound 11 a Procedure:

30 g of Compound 10 in 300 ml of methanol was charged into a 1L 3N RB flask at ambient temperature under nitrogen atmosphere and cooled to -15°C. 3.56 g of NaBH4 was added portion wise to reaction mixture at -15°C and stirred for 1 h at same temperature. Progress of the reaction was monitored by TLC. On completion of the reaction, the reaction mixture was warmed to 0°C, quenched with 300 ml of ice water and extracted with DCM. Organic layer was dried over sodium sulfate and concentrated to give the crude product which was filtered through a pad of basic alumina to yield the required Compound 11 a as a light green liquid.

4. Preparation of Tert-butyl 4-bromo-5,6-dihydropyridine-l(2H)-carboxylate;
Compound 14 a Procedure:

13 g of Compound 11a in 30 ml of DCM was charged into a 250 ml 3N RB flask at ambient temperature. 7.3 g of 1 -Chloroethyl chloroformate was added slowly for about 10 min at ambient temperature and stirred for 1 h at same temperature. Progress of the reaction was monitored by TLC. On completion of the reaction, 130 ml of methanol was added to reaction mixture at ambient temperature and allowed to reflux for 2 h. Progress of the reaction was monitored by TLC (10% ethyl acetate/hexane). On completion of the reaction, the reaction contents were concentrated and the residue obtained was diluted with 130 ml of DCM to this was added 5.73 g of TEA at 10°C.Then 11.3 g of Boc anhydride was added to the reaction mixture and stirred overnight at ambient temperature. Then reaction mixture was washed with water and dried over sodium sulfate. Organic layer was filtered concentrated to give the crude which was purified by column chromatography to yield the required compound 14a as a pale yellow semi solid.

5. Preparation of Tert-butyl 5,6-dihydro-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-
yl)pyridine-l(2H)-carboxylate; Compound 06 Procedure:

44 ml of 1, 4-Dioxane was charged into a 100ml 3N RB flask at ambient temperature, nitrogen gas was flushed for 10 min. 2.5 g of Compound 14 a was added at ambient temperature and then again nitrogen gas was flushed for 10 min. 2.66 g of Bispinacolato diborane was added to reaction mixture and nitrogen gas was flushed for 10 min. 2.8 g of Potassium acetate was added to reaction mixture and nitrogen gas was flushed for 10 min. 116 mg of PdCl2(dppf)CH2Cl2 was added and nitrogen gas was flushed for 10 min. Finally, 78 mg of Dppf was added to the reaction mixture and nitrogen gas was flushed for 10 min. The whole reaction mixture was heated to 70-80°C overnight. Progress of the reaction was monitored by TLC . On completion of the reaction, reaction contents were concentrated and purified by column chromatography to yield the required compound 06 as a white solid.

6. Preparation of Benzyl 4-bromo-5, 6-dihydropyridine-l(2H)-carboxylate; Compound 12 a
Procedure:

1.5 g of l-benzyl-4-bromo-l,2,3,6-tetrahydropyridine, Compound 11, in 7.5 ml of benzyl chloroformate was charged into a 50 ml 2N RB flask at ambient temperature and stirred for 12 hrs. Progress of the reaction was monitored by TLC. On completion of the reaction, the contents were passed through a silica gel column to yield the required product, Compound 12a, as a pale yellow liquid.

7. Preparation of 4-Bromo-l, 2, 3, 6 tetrahydropyridine; Compound 13 Procedure:

1 g of Compound 12 a in 1:1 ratio of 5 ml of 1,4 Dioxane, 5ml of 6N aq. HC1 was charged into the 50ml 3N RB flask at ambient temperature and allowed to reflux for 6 hrs. Progress of the reaction was monitored by TLC. On completion of the reaction, the mixture temperature was brought to ambient temperature, washed with 2 x 10 ml of hexane and basified with aq. Na2CO3 and extracted with ethyl acetate. Combined organic

We claim,

1. A process for the preparation of N-Boc-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (6) via novel intermediates (12), (13), (14), (15), which are used as key intermediates and building blocks for the synthesis of biologically active compounds,

wherein the said process comprises;

i. treating acid salt of 4-halo pyridine (9), with alkylating/arylating agent in suitable
solvent to give N-substituted pyridinium salt, preferably N-benzyl pyridinium salt
or N-methyl/alkyl pyridinium salt (10);

wherein, X is selected from CI, Br, F, or I, R1 is selected from substituted or unsubstituted (C1-C10) alkyl group; or any benzyl or substituted benzylic group; ii. reducing compound (10) to obtain intermediate compound (11);

wherein, X is selected from CI, Br, F, or I; R1 is described hereinabove, iii. reacting compound (11) with alkyl or aryl chloroformate in organic solvent to obtain carbamate intermediate (12), wherein, X is described hereinabove; R2 is substituted or unsubstituted (C1-C10) alkyl, aryl, alkylaryl, trialkylsilane, oxazoline, -CF3, -FMoc, -Troc, -Teoc, -Alloc.

converting compound (12) to the secondary amine (13) or ammonium salt (15) using organic or inorganic acid,

wherein, X is described hereinabove; Z is selected from conjugate base of an organic acid such as any carboxylic acid or sulfonic acid, or conjugate base of an in-organic acid or Bronsted acid such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid.
protecting compound (13) with BOC in presence of base and suitable solvent to yield BOC protected compound (14) and;

wherein, X is described hereinabove;
cross-coupling BOC protected compound (14) with bispinacolato borane or tetra substituted bis-borane in the presence of palladium or transition metal salts or complexes with a suitable ligand to obtain compound of formula (6).

2. The process according to claim 1, wherein the acid salt of 4-halo pyridine (9) is selected from the group consisting of 4-brotno pyridine hydrochloride or 4-chloro pyridine hydrochloride.

3. The process according to claim 1, wherein alkylating/arylating agent is selected from selected from the group consisting of (C1-C10) alkyl halide, benzyl-halide or substituted benzyl halide.

4. The process according to claim 1, wherein the protecting agents are selected from the group consisting of 9-Fluorenylmethyl carbamate; t-Butyl carbamate; di-tert-butyl dicarbonate; Benzyl carbamate; Acetamide; Trifiuoroacetamide, Benzylamine, Tritylamine, p-Toluenesulfonamide, Allyloxycarbonyl chloride, 2,2,2-Trichlorethoxycarbonyl chloride, Trialkylsilyl chloride.

5. The process according to claim 1, wherein the alkyl or aryl chloroformate is selected from the group consisting of 1-Chloroethyl chloroformate, Ethyl chloroformate, Benzyl chloroformate, 4-Nitrophenyl chloroformate.

6. The process according to claim 1, wherein the organic solvent is selected from the group consisting of polar protic solvent such as methanol, ethanol, water, isopropanol, n-butanol or aprotic solvent such as ethyl acetate, acetone, dichloromethane (DCM), Tetrahydrofuran(THF), Acetonitrile, or non-polar solvents such as hexane, benzene, toluene, l,4-dioxane,ether or mixtures thereof.

7. The process according to claim 1, wherein the organic base is selected from the group consisting of tri-substitued amine bases such as triethylamine, di-isopropylethyl amine, tributylamine, dimethylaniline, pyridine and inorganic base selected from metal carbonates,bicarbonates,acetate,hydroxides, ammonia, preferably sodium or potassium carbonate or acetate.

8. The compound of Formula-I; or its quaternary ammonium salt (wherein the counter ion is the conjugate base of an organic acid such as any carboxylic acid or sulfonic acid or conjugate base of an in-organic acid or Bronsted acid such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid), represented as;

Formula-I

wherein X is selected from CI, Br, F, I and Y is any nitrogen protecting group such as methyl, benzyl, substituted benzyl, naphthayl, or selected from -H, alkyl, sulfonyl, -CONR2, COOR2, wherein R2 is substituted or unsubstituted (C1-C10) alkyl, aryl, alkylaryl, trialkyllsilane, oxazoline, -CF3, -FMoc, Troc, Teoc, Alloc.

9. The compound of Formula (12) according to claim 8, prepared by reacting compound (11) with alkyl or aryl chloroformate selected from the group consisting of 1-Chloroethyl chloroformate, Ethyl chloroformate, Benzyl chloroformate, 4-Nitrophenyl chloroformate in organic solvent.
wherein, X is selected from CI, Br, F or I ;

R2 is selected from substituted or unsubstituted (C1-C10) alkyl, aryl, alkylaryl,
trimethylsilane, oxazoline, -CF3, -FMoc, Troc, Teoc, Alloc.

10. The compound of Formula (13), according to claim 8, obtained by reacting compound (12) with an organic acid such as any carboxylic acid or sulfonic acid or conjugate base of an in-organic acid or Bronsted acid such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid in suitable organic solvent.
wherein, X is selected from CI, Br, F or I.

11. The compound of Formula (14), according to claim 8, prepared by reacting compound (13) with BOC in presence of base and suitable solvent.

wherein, X is selected from CI, Br, F or I.

12. The compound of Formula (15), according to claim 8, prepared by reacting compound (12) with excess amount of an inorganic or organic acid in suitable organic solvent. wherein, X selected from CI, Br, F or I,

Z is conjugate base of an organic acid such as any carboxylic acid or sulfonic acid or conjugate base of an in-organic acid or Bronsted acid such as Hydrochloric acid, Nitric acid, Phosphoric acid, Sulphuric acid, Boric acid, Hydrofluoric acid, Hydrobromic acid, Perchloric acid.

13. The compounds according to claims 9 to 12, wherein the organic solvent is selected from polar protic solvent such as methanol, ethanol, water, isopropanol, n-butanol or aprotic solvent such as ethyl acetate, acetone, dichloromethane (DCM), Tetrahydrofuran (THF), Acetonitrile, or non-polar solvents such as hexane, benzene, toluene, 1,4-dioxane,ether or mixtures thereof.

14. The compounds according to claims 9 to 12, wherein the organic base is selected from tri-substitued amine bases such as triethylamine, di-isopropylethyl amine, tributylamine, dimethylaniline, pyridine and inorganic base selected from metal carbonates,bicarbonates,acetate,hydroxides, ammonia, preferably sodium or potassium carbonate or acetate.