WO2006006184A2

WO2006006184A2 - A process for the manufacturing of loratadine and its intermediates

Info

Publication number: WO2006006184A2
Application number: PCT/IN2005/000235
Authority: WO
Inventors: Sanjay Suri; Tapan Kashyap; Krishan Singh Verma; Netar Singh
Original assignee: Morepen Laboratories Ltd
Current assignee: Morepen Laboratories Ltd
Priority date: 2004-07-08
Filing date: 2005-07-06
Publication date: 2006-01-19
Anticipated expiration: 2007-01-08
Also published as: WO2006006184A3

Abstract

The process comprises (i) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods, (ii) condensing in situ the phenyl acetonitrile thus obtained with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile, (iii) hydrolyzing followed by decarboxylating the said ketonitrile in situ to respective ketone in acid environment below 60° C, (iv) subjecting the ketone so obtained to reduction followed by N-oxidation, cyanation, and hydrolysis by any known methods to produce picolinic acid, (v) cyclising the said picolinic acid to tricyclic ketone by conventional methods, (vi) treating the said tricyclic ketone with organometallic compound containing Mg to produce carbinol, (viii) purifying the said carbinol with purifying agent selected from polar water miscible organic solvent followed by dehydrating with neat sulphuric acid at the temperature below 50° C, to get N-methyl product (olefin), and subjecting the said olefin to N-carbethoxylation to produce loratadine. Loratadine can also be prepared by treating cayano compound with organometallic compound containing Mg to produce a ketone by the methods known in the art followed by cyclising in presence of a mixture of sulfuric acid and a source of boric acid to get N-methyl product and converting to loratadine by N-carbethoxylation.

Description

A PROCESS FOR THE MANUFACTURING OF LORATADINE AND ITS INTERMEDIATES. FIELD OF THE INVENTION

The invention particularly relates to a process resulting into Loratadine with increased yield and higher purity. Further the process is simple to operate does not require any stringent conditions and special infrastructure. The process is reproducible, environment friendly and easy to scale up for industrial manufacture with improved quality of the title product.

BACKGROUND OF THE INVENTION Loratadine, chemically known as 8- chloro-l l-(l-ethoxycarbonyl -4- piperidylidene)-6,ll-dihydro -5 H -benzo [5,6] cyclohepta [1,2-b] pyridine is a non¬ sedating type antihistamine Hi receptor antagonist with following structure of formula I

I It possesses low central nervous system (CNS) activity indicative of non- sedation. It is also useful as antiallergant for the treatment of allergic asthma, allergic seasonal rhinitis, diabetic retinopathy and small vessel disorders associated with the diabetic mellirus. Various processes for preparing Loratadine and intermediates thereof are disclosed in U.S. Patent nos. 3,326,924; 3,717,647, 4,282,233, 4,659,716, 4,731,447, 6,608,202, 6,278,378 and journal of Medicinal Chemistry, 1972, Vol. 15, No. 7, pp 750-754. US patent 4,731,447 ('447) advocates the synthetic route for loratadine. US '447 claims advantage of reduction in number of steps from 6 to 5 and bypassing using Grignard Reagent. In accordance with column 7 lines 20 to 25, hazardous chemical such as n-butyl lithium is used under nitrogen atmosphere during reaction of respective carboxamide with benzyl halide for preparing corresponding amide. Further, according to column 8, lines 20 to 25, ring closing of respective ketone is generally carried out by treating the compound with super acid having a Hammett acidity function value of less than minus 12 to get a title compound. The super acids

used for this purpose are exemplified by HF (in liquid from) and BF3 (in gas form^

CF₃SO3H, and CH3SO3H/ BF3 etc. Further, the reaction may be carried out at a

controlled temperature to minimize side reactions. The reaction may be effected in

presence of inert co-solvent like CH2CI2. Thus, the process requires special

equipments to take care of involvement of hazardous chemicals, which may pose problems in up scaling for industrial manufacture.

According to US patent 4,659,716, ('716) the tricyclic ketone is coupled with Grignard reagent derived from 4-chloro-N-methylpiperidine to produce alcohol, which is further dehydrated under acidic environment followed by subjecting to Von Braun reaction with ethyl chloroformate to produce the desired compound. The dehydration has to be carried out under vigorous conditions such as prolonged heating at 160 to 165⁰C in presence of excess polyphosphoric acid or 85% sulphuric acid. Further, the dehydration of alcohol is sensitive reaction and may result in isomerization of N-tnethyl product (olefin) thus produced. Additionally, the Von Braun reaction produces noxious chloromethane as gaseous byproduct, which has to be eliminated before discharge to the atmosphere. Moreover, the alcohol thus produced contains inherent impurities and thus the final product obtained requires further purification in order to get a desired quality. Alternately, '716 advocates ring closing employing super acid having a Hammett acidity function value of less than minus 12 to get a title compound. This route will pose the similar problems associated with the process disclosed in '447 US patent 3,717,647 teaches condensing of nicotinic ester with phenylacetonitrile by sodium alkoxide in water miscible solvents such as ethanol at reflux temperature to produce ketonitrile. The said ketonitrile is isolated and then converted to ketone by heating with strong mineral acid such as hydrobromic or hydrosulfuric acid at reflux temperature is further hydrolyzed, decarboxylated and then reduced by well-known method like Wolff-Kishner reaction.

US 6,608,202 describes synthesis of tricyclic ketone. The patent under consideration claims to dispense with the N-tert butyl amide or anilide groups used in the alkylation step of '447,and eliminating preparation of picolinic acid. It also claims to claims to have improvement in conducting cyclising in one pot thereby improving yield and saving cost. However, the invention teaches using hazardous chemicals such as lithium diisopropyl amide (LDA).

The existing relevant prior art as stated herein above suffers from one or the other drawbacks such as using hazardous chemicals during tricyclic ketone formation or ring closing. Further, the dehydration has to be carried out under vigorous conditions. The removal of impurities accrued during dehydration requires additional steps to get a quality product. Thus the existing processes prove to be uneconomical, difficult to scale up for industrial manufacture, require skilled personnel & sophisticated infrastructure, hazardous to environment and laborious.

Thus there is an imperative need for having improved process that can obviate the problems at least to some extent though can not eliminate totally.

After continuous persistent research, we have found out that the existing processes can be improved by eliminating employing hazardous chemicals, avoiding stringent operating conditions and or incorporating one pot reactions steps to improve yield and quality of the title product. SUMMARY OF THE INVENTION:

Accordingly, the present invention aims at providing "A Process for Manufacturing

Loratadine and its Intermediates".

One of the objects of the present invention is to provide a process, which results in increased yield and higher purity. Other object of the invention is to provide a process that is simple to operate, does not require any stringent conditions and special infrastructure.

Another object of the invention is to provide a process that eliminates using hazardous chemicals and stringent operating conditions.

Yet other object of the invention is to provide a process that is environment friendly, economical, easy to scale up for industrial manufacture with improved quality of the title product and also reproducible.

STATEMENT OF INVENTION

Accordingly the present invention provides "A Process for Manufacturing

Loratadine and its Intermediates"comprising: (a) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods,

(b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile,

(c) hydrolyzing followed by decarboxylating the said ketonitrile to respective

ketone in acid environment below 60°C,

(d) subjecting the ketone obtained in step (c) above to reduction followed by N- oxidation , cyanation, and hydrolysis by any known methods to produce picolinic acid,

(e) cyclising the said picolinic acid to tricyclic ketone by conventional methods,

(f) treating the said tricyclic ketone with organometallic compound containing Mg to produce carbinol,

(g) purifying the said carbinol with purifying agent selected from polar water miscible organic solvent followed by dehydrating using neat sulphuric acid

at a temperature below 5O⁰C, to get N-methyl product (olefin),

(h) subjecting the said olefin to N- carbethoxylation to produce Ioratadine wherein step (b) & (c) are carried out in one pot.

In accordance with other aspect of this invention there is provided a process for manufacturing an intermediate ketonitrile comprising:

(a) subjecting substituted benzyl halide to cyanation in a biphasio system using water immiscible solvents by any known methods,

(b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile. In accordance with another aspect of this invention, there is provided a. process for manufacturing an intermediate ketone comprising:

(a) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods, (b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile, (c) hydrolyzing followed by decarboxylating the said ketonitrile to respective

ketone in acid environment below 60 C.

In accordance with yet another aspect of this invention there is provided a process for manufacturing an intermediate N-methyl product (olefin) comprising;

(a) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods,

(c) hydrolyzing followed by decarboxylating the said ketonitrile to respective

ketone in acid environment below 6O⁰C,

(f) treating the said tricyclic ketone with organometallic compound containing Mg to produce carbinol, (g) purifying the said carbino] with purifying agent selected from polar water miscible organic solvent followed by dehydrating with neat sulphuric acid at

a temperature below 50⁰C, to get N-methyl product (olefin),

According to yet another aspect this invention also provides a process for manufacturing of loratadine comprising:

(i) generating cyano compound of formula VIII and then treating with oraganometallic compound containing Mg to produce a ketone of formula XIII by the methods known in the art followed by cyclising in presence of a mixture of sulfuric acid and a source of boric acid to get N-methyl product of formula XU

XIII

Boric acid / H₂SO₄ or Sodium borate / H₂SO₄ or Boric anhydride / H₂SO₄

(ii) subjecting the said olefin to N- carbethoxylation to produce loratadine. DETAILED DESCRIPTION OF THE INVENTION:

The phase transfer catalyst used in cyanation of substituted benzylhalide in step (a) may be such as any conventionally used quaternary ammonium compound preferably tetrabutyl ammonium halide, Using appropriate substitution in the starting material i.e. benzylhalide one may expect respective substitution of halo ion at 7^th, 8^th, or 9^th position in the title product loratadine, Para substituted results in having substitution at 7^th, meta at 8^t1, and ortho at 9^l position, The water immiscible solvent used in the step (a) may be dichloromethane or toluene preferably toluene helps in saving water miseible solvents otherwise used in reported publications and in turn helps in increased yield. The alkali metal alkoxide may preferably be, but not limited to, sodium methoxide. The water immiscible organic solvent used insitu condensation of phenyl acetonitrile may be exemplified but not restricted to dimethyl foπnamide, dimethyl sulfoxide, tetrahydrofuran and toluene, preferably tetrahydrofuran and toluene advantageously replacing the water miseible solvents such as ethanol in condensation of nicotinic ester with phenylacetonitrile in the existing prior art. In accordance with the disclosure in column 10 lines 34 to 39 and column 6 lines 25 to 35, the condensation is effected in ethanol at reflux temperature. As aresult, the ketonitrile and impurities go in to the aqueous phase and the product is recovered from aqueous phase using organic solvent to remove impurities. By replacing ethanol with toluene to produce ketonitrile (enol nitrile in basic media) the impurities goes directly to water immiscible organic solvent leaving ketonitrile in aqueous phase thereby helps in avoiding the yield losses and saving on water miseible solvents used in hitherto known processes. Additionally, the reaction also being effected in situ without isolating the phenylacetonitrile helps in increased yield. However, phenyl acetonitrile may be used as crude after solvent recovery or as a distilled inteπnediate after high vacuum distillation. Reaction product (enol nitrile in basic media as alkali metal salt) may be centrifuged or extracted in water from reaction mass, thus avoiding solvent extraction and/ or recovery or centrifugation for product isolation, making the process simple and easily scalable. Moreover, the water immiscible solvent can be recycled and reused thereby making the process environment friendly as against the ethanol, which puts load on environment through discharge in the effluent.

Regulating temperature below 6O⁰C during addition of sulfuric acid for conversion of ketonitrile (enol nitrile in basic media) to ketone minimizes decomposition of product and thus leads to improving yield and quality of product. Conversion of tricyclic ketone to carbinol (alcohol) in step (f) may be performed in presence of tetrahydrofuran (THF) as per known methods in the prior art. The alcohol (Product of step (fj), is purified prior to its dehydration using polar water miscible solvents exemplified by lower aliphatic alcohols with up to 3 carbon atoms, aliphatic ketones such as acetone methyl isobutyl ketone, methyl-tert-butyl ketone, methyl ethyl ketone, and acetonitrile, and crystallized with base. The purified carbinol/alcohol thus produced may then be dehydrated at a temperature

less than 50 C using neat sulphuric acid. This avoids the problems associated with

dehydration under vigorous conditions as stated herein above. Further, results in a better intermediate, which in turn helps in higher yield while maintaining quality of the title product.

The cyano compound of formula VIII in step (i) of other alternative process may be generated by any known methods. The source of boric acid used in cyclization may be such as boric acid or sodium borate or boric anhydride or mixture there of, Using sodium borate/sulfuric acid, boric anhydride/sulfuric acid, boric acid/sulfuric acid in

place of HF/BF3, CF₃SO3H, CH3SO3H/BF3 is advantageous in many ways such as either elimination or dehydration; does not require special infrastructure, stringent process conditions and or skilled personnel. Further the process will be environment friendly and easy to scale up for industrial manufacture.

The invention is further illustrated with the help of schematic representation. In first aspect of the invention Loratadine is obtained following the route A Route A

Vl

VII

VIII

Loratadiπe

In second aspect of the invention Loratadine is obtained following the route B.

Route B

XlII

Boric acid / H₂SO₄

Loratadine or Sodium borate / H₂SO₄ or Boric anhydride / H₂SO₄

The invention is further illustrated by the following examples. However it should not limit the scope of invention. Further the illustrations should encompass all the deviations obvious to a person skilled in the art. Example 1 Step 1- Preparation of 3-Chlorobenzylcyanide (II) (a) 3-Chlorobenzyl chloride (10Og) is reacted with sodium cyanide (39 g) in a biphasic mixture of water (300 ml)- toluene (100 ml) in presence of tetrabutyl ammonium bromide under refluxing. Reaction mass is washed thoroughly with water to remove any sodium cyanide contents. Toluene layer can be proceeded directly for the next step or the oily product after toluene recovery or high vacuum distilled product may be used for next step.

(b) The process is followed as given in example 1 except that toluene is replaced by dichloromethane. Step 2 ; Preparation of α-Cyano-β-hydroxy-β-^-pyridyO-S-chlorostyrene sodium (IV)

3-chlorobenzyl cyanide (100 g) either as oil or distilled oil or as toluene layer from examplel, is added slowly to a mixture of sodium methoxide (58 g) and ethyl nicotinate (110 g) in toluene at 65- 7O⁰C. The reaction mixture is stirred at the same temperature for 2-4 hrs. Reaction mass is cooled to room temperature and product is extracted in water. Aqueous solution of product is proceeded as such (in-situ) for the next step,

Step 3: Preparation of 3-Pyridyl-3-chlorobenzyl ketone (V)

Aqueous solution of example 3 is cooled to 0-5⁰C and sulfuric acid (550 g) is slowly added at < 60⁰C. Reaction mass is heated to 120-125⁰C and stirring is continued for reaction completion. Reaction mass is quenched in water followed by basification and extraction in dichloromethane. Removal of solvent yielded the crude title compound which is proceeded as such for the next step.

Alternatively reaction mass after quenching in water is basified to get crystallization. Mass is centrifuged, washed with water and wet cake is used as such for next stage.

Step 4; Preparation of 3-(3-Chlorophenethyl) pyridine (VI)

(a) Crude compound V from example 4 is reacted with hydrazine hydrate (45 g) and sodium hydroxide (10.8 g) in mono ethylene glycol at 140-145⁰C. Reaction mass after cooling and dilution with water is extracted with dichloromethane. Dichloromethane layer is washed and distilled to give title compound (93 g) as oil having GC purity of 97.6%.

(b) Preparation of 3-(3-Chorophenethy) pyridine (VI)

3-Chlorobezylcyanide (5.0 kg, 33 mole ) is added slowly to a mixture of sodium methoxide (2.9 kg , 54 mole) and ethyl nicotinate (6.25 kg, 41 mole) in tetrahydrofuran (7.5 It.) at 40-48°C.The reaction mixture is stirred for 2 hrs at the same temperature .The reaction mixture is cooled to 20-25⁰C and toluene (25It) is added slowly to get crystals of α- cyano-β- hydroxy-β -(3_'pyridyl )-3- chlorostyrene as wet sodium salt. This salt as such is subjected for hydrolysis with sulfuric acid (22 kg , 220 mole) and water (10 It.) at 120-122⁰C for 4hrs. Reaction mass is cooled to 80 to 9O⁰C and poured in chilled water (100 It.) followed by basification with caustic solution at pH 7.5 to 8.0 and extracted the product in methylene chloride. Removal of solvent yielded the crude, 3- pyridyl-3-chlorobezyl ketone (V).

This crude without isolation reacted with hydrazine hydrate (2.37, 47 mole) and sodium hydroxide (0.3 kg, 9 mole) in mono ethylene glycol (18.5kg) at 140-145⁰C for 6-10 hrs to get 3-(3-chorophenethy) pyridine (VI) with an yield of 3.95 kg (54.86%) and a purity of 99.57% (GC).

Step 5: Preparation of 3- (3- Chlorophenethyl) pyridine -N -oxide (VII) Compound from example 5 or 6 (31.18 kg, 150 mole ) is heated with acetic acid (25.44kg, 410 mole) and hydrogen peroxide (40%, 40.39kg, 1190 mole) at 65 to 75⁰C for 20 to 25 hrs. The reaction mixture is basified with caustic solution (15%) to pH 8 to 9 to obtain title compound with a yield of 29.52 kg 81.9%) and purity of 97 % (HPLC). Step 6; Preparation of 2-Cyano -3- (3- chlorophenethyl) pyridine (VIII) Compound from example 7 (29.52 kg, 117 mole) is reacted with N,N-dimethyl carbamoyl (29.87 kg, 277 mole) in acetonitrile (59kg) at 35-40⁰C for 1-3 hrs followed by reaction with aqueous sodium cyanide (9. 45 kg , 190 mole in 59 It, water) at -5 to 0⁰C for 3-4 hrs. Caustic solution (5.9 kg, 0.147 mole in 89 It. water) is added to the reaction mixture and stirred for 2-3 hrs. Organic layer is separated and evaporated to get crude product followed by puzϊfϊcation in isopropyl alcohol and water (6:4) to get title compound with a yield of 22.84 kg (73.5%) with purity 99.0% (HPLC). The above crude product may further be purified in neat methanol or isopropanol. Step 7: Preparation of 3-(3-Chlorophenethyl) picolinic acid (IX) Compound from example 8 (20,84 kg, 86 mole) is heated with concentrated sulfuric acid (31.2 kg, 320 mole ) and water (17It) at 120-122⁰C for 10-12 hrs. Reaction mixture is cooled to 90⁰C and poured to cold water (166 It. ) followed by basification with sodium hydroxide solution (20%) to pH 3.2-3.5 to obtain title compound with an yield of 21.2 kg (94.4%) and purity of 99.12 % (HPLC).

Step 8: Preparation of l l-[N-Methyl-4-piperidinyl]-8-chloro-6, l l-dihydro-5H-benzo [5,6]cyclohepta[l,2 -^pyridine (XI) (a) N-Methyl piperidyl magnesium chloride prepared by addition of N^methyl -4- chloropiperidine (136 gm , 1.02 mole) to a stirred solution of magnesium metal (33.4 gm,l,374 mole ), dibromoethane (72.8 gm, 0.386 mole) and dry tetrahydrofuran (1.17L)at 20- 48°C is added slowly to a cooled (-70 to 8O⁰C) solution of 8-chloro-6, 1 1- dihydro-5H-benzo [5,6] cyclohepta [l,2-b]-l l- one, X (100gm,0.41 mole ) in dry THF (530ml). The reaction mixture is stirred for 2-3 hrs at the same temperature. The reaction mixture is quenched with 10% NH₄Cl (600ml) and extracted twice with ethyl acetate (2x 400ml). The organic phase is washed with water and dried over anhydrous sodium sulfate, filtered and solvent removed to get crude material (150 g), The crude material obtained is purified by dissolving in methanol (560ml) and crystallized with caustic solution (140 ml) at refluxing temperature. The material is filtered after cooling to 10-15⁰C and washed with water (560 ml) to obtain desired carbinol of formula XI in 73.6% yield with purity of 97.3% (ODB, HPLC) (b); The experiment is conducted as described in example 10 except that methanol is replaced by ethanol to get purified carbinol of formula XI with an yield of 70.0% and purity of 96% (ODB.HPLC) (c) The experiment is conducted as described in example 10, except that methanol is replaced by isopropanol to get purified carbinol of Formula XI with an yield of 70% and purity of 95% (ODB, HPLC).

(d) The experiment is conducted as described in example 10, except that the purification is effected as given below :

Crude product (10Og) is dissolved in acetonitrile (240 ml) at reflux temperature.

Ammonia solution (20-25%, 180ml) is slowly added and the mass is cooled to 0-5⁰C.

Purified product (65g, 69.15%) is obtained after filtration and drying having 98.35%

(HPLC, ODB). (e) The experiment is conducted as described in example 10, except that the purification is effected as given below :

Crude product (10Og) is dissolved in acetonitrile (240ml) at reflux temperature.

Triethylamine (2-10 g) is added and mass is stirred for 30 min followed by cooling to

0-5⁰C. Purified product (69g, 73.4%) is obtained after filtration and drying having assay 99.2% (HPLC, ODB),

(f) The experiment is conducted as described in example 10, except that the purification is effected as given below :

Sodium hydroxide solution (5-15%, 480 ml) was added slowly. Mass was cooled to 5- 10⁰C. Purified product (64 g, 68.1%) is obtained after filtration and drying having assay 98% (HPLC.ODB).

Step 9: Preparation of 8-chloro-6, l l-dihydro-l l-(N-methyl-4-piperidinylidene)-5H- benzo[5,6]cyclohepta[l, 2-b]pyridine (XII)

A compound of formula XI (100 gm, 0.29 mole) and concentrated sulfuric acid (368 gm, 3.93mole) is stirred at 35-45°C for 2-3 hrs. The reaction mixture is poured in chilled water and the product is extracted in toluene at pH 8-9. The toluene layer in situ proceeded for further reaction to get Loratadine of formula I Step 10; Preparation of Loratadine (I)

To the above toluene layer from example 16, containing compound XII (-93 gm, 0.29 mole) is added di isopropyl ethylamine (11.1 gm, 0.09 mole) under nitrogen atmosphere followed by slow addition of ethyl chloroformate (82 gm, 0.71 mole) at 60-

65°C and stirred for 1-2 hrs at 70-75⁰C. Reaction mixture is cooled to room temperature and water (600 ml) is added. The mixture is adjusted to pH 5.0 -5.5 with hydrochloric acid. The organic phase is washed with water and the solvent is removed to get residue as crude Loratadine .The crude Loratadine is purified in isopropyl ether followed by crystallization in acetonitrile to get 81.5 gm Loratadine of formula I (73%) with a purity of >99.4% (ODB,HPLC).

Example 2 Preparation of 8-chloro-6, ll-dihydro-l l-(N-methyl-4-piρeridinylidene)-5H-benzo [5, 6] cyclohepta [1, 2-b] pyridine (XII)

Compound XIII (100 g) prepared as per standard process given in US patent no 4,659,716 after azeotropic water removal in toluene instead of drying is heated with boric acid (115 g) in cone, sulfuric acid (415 g) for 4-8 hrs at 105-UO⁰C, Reaction mass is poured in chilled water and extracted with ethyl acetate. Solvent is removed to get the title compound as a solid in 85% yield having assay 99.5% (OAB, HPLC)

ADVANTAGES:

> Process is simple. > Process is environment friendly. > Process is high yielding while maintaining quality of the product,

> Process is easy to scale up to industrial manufacture.

> Process is reproducible.

> Process does not require any stringent conditions and special infrastructure.

Claims

We Claim:

1. A Process for Manufacturing Loratadine and its Intermediates"comprising:

(c) hydrolyzing followed by decarboxylating the said ketonitrile to respective ketone in acid environment below 6Q⁰C,

(e) cyclising the said picolinic acid to tricyclic ketone by conventional methods, (f) treating the said tricyclic ketone with organometallic compound containing

Mg to produce carbinol,

(g) purifying the said carbinol with purifying agent selected from polar water miscible organic solvent followed by dehydrating with neat sulphuric acid at a temperature below 5O⁰C, to get N-methyl product (olefin),

(h) subjecting the said olefin to N- carbethoxylation to produce loratadine wherein step (b) & (c) are carried out in one pot.

(2) A process for manufacturing an intermediate ketonitrile comprising:

(a) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods, (b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile,

(3) A process for manufacturing an intermediate ketone comprising; (a) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods,

(b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile, (c) hydrolyzing followed by decarboxylating the said ketonitrile to respective ketone in acid environment below 60 C.

(4) A process for manufacturing an intermediate N-methyl product (olefin) comprising:

(c) hydrolyzing followed by decarboxylating the said ketonitrile to respective ketone in acid environment below 60°C,

(e) cyclising the said picolinic acid to tricyclic ketone by conventional methods, (f) treating the said tricyclic ketone with organometallic compound containing Mg to produce carbinol,

(g) purifying the said carbinol with purifying agent selected from polar water miscible organic solvent followed by dehydrating with neat sulphuric acid at

a temperature below 50°C, to get N-methyl product (olefin),

(5) A process for manufacturing of loratadine comprising:

(i) generating cyano compound of formula VIII and then treating with oraganometallic compound containing Mg to produce a ketone of formula XIII by the methods known in the art followed by cyclising in presence of a mixture of sulfuric acid and a source of boric acid to get N-methyl product of formula XII

XIII

Boric acid / H₂SO₄

Loratadine or Sodium borate / H₂SO₄ or Boric anhydride / H₂SO₄

(ii) subjecting the said olefin to N- carbethoxylation to produce loratadine.

(6) A process as claimed in Claims 1 to 4 wherein the phase transfer catalyst used in cyanation of substituted benzylhalide in step (a) is quaternary ammonium compound preferably tetrabutyl ammonium halide and water immiscible solvent used in the step (a) is dichloromethane or toluene preferably toluene,

(7) A process as claimed in Claims 1 to 4 wherein the water immiscible organic solvent used in in situ condensation of phenyl acetonitrile is exemplified but not restricted to dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran and toluene, preferably tetrahydrofuran and toluene. (8) A process as claimed in Claims 1 to 4 wherein the alcohol (Product of step (f)), is purified prior to its dehydration using polar water miscible solvents exemplified by lower aliphatic alcohols with up to 3 carbon atoms, aliphatic ketones such as acetone methyl isobutyl ketone, methyl-tert-butyl ketone, methyl ethyl ketone, and acetonitrile, (9) A process as claimed in Claim 5 wherein the source of boric acid used in cyclization is boric acid or sodium borate or boric anhydride or mixture there of.