This invention relates to A Process For The Production Of Loratadine.

BACKGROUND OF THE INVENTION

This invention relates to an improved process for the production of Loratadine. The present invention particularly relates to a process that results in the production of Loratadine with high yield and high purity. The present invention also relates to a process for the manufacture of intermediates with high yield and purity useful in the production of Loratadine.
Loratadine, 8-chloro- 11 -(1 -ethoxycarbonyl-4-piperidylidene)-6, 11 -dihydro-5H-benzo [5,6]cyclohepta[1,2-b]pyridene, is a non-sedating type antihistamine H1 receptor antagonist with following structure (I)
(Structure Removed)
It possesses low central nervous system (CNS) activity indicative of non-sedation. It is also found useful as anti-allergy agent for the treatment of allergic asthma, allergic seasonal rhinitis, diabetic retinopathy, and other small vessel disorders associated with the diabetes mellitus.

The presence of chlorine atom at the 8th position makes the chemistry of loratadine uniquely problematical and reductive preparations are ineffective because of the

emoval of chlorine at the 8th position.
Various processes for preparing intermediate to loratadine are disclosed in US Patent Nos. 3,326,924 & 3,717,647 and Journal of Medicinal Chemistry, 1972, vol. 15, No. 7, pp75O to754. US Patent No. 3,326,924 teaches preparation of various aza-dibenzo[a,d] cycloheptene derivatives which involve production of a tricyclic aromatic ketone which is reacted with a Grignard reagent such as N-methyl-4-piperidyl magnesium halide (or zinc halide) preferably chloride. Dehydration gives N-methyl product. The process is, however, hindered by the amount up to 30% of 1,6-addition product which is generated in the Grignard reaction causing problems in yield and purification.
US Patent No. 4,282,233 describes the process for the preparation of loratadine from the product of the above reaction by demethylation or carbethoxylation. The low yield of intermediate compound and the purity levels of the intermediate compound affect the yield and purity of loratadine produced using these intermediates. Several alternative processes are summarized below:
As indicated above US Patent No. 4,282,233 and ES Patent No. 503,803 teach the process for loratadine using intermediate obtained through multi-step cumbersome process, using Grignard reagent, disclosed in US Patent No. 3,326,924.
US Patent Nos. 4,659,716; 4,731,447 and 4,873,335 advocate synthetic route for loratadine. The process requires use of hazardous organometallic reagents such as LDA or butyl lithium and super acids like BF3 gas and liquid HF.
Cid et al have reported (tetrahedron, 1988, vol. 44, 6197-6200) cross coupling reactions between tricyclic ketone and a cyclic ketone using low valent titanium. However, the low valent titanium has to be generated using lithium metal that is hazardous on

industrial scale and is required to be used in high volumes to prevent the reaction stopping at the diol stage.
ES Patent No.2,040,177, advocates the use of trimethyl phosphite which makes the Process inconvenient from industrial viewpoint.
ES Patent Nos. 2,009,465 and 2,009,466 suggest the interchange in the order of last two reactions of the process disclosed in US Patent NO. 4,282,233.

Es Patent 2,080,700 and Canadian Patent No.2,134,128 teach the use of palladiumcatalysed condensation of an olefin an intermediate prepared through multi-step and complex reaction disclosed in ES Patent No. 2,080,699.

Both Canadian Patent Nos. 1,272,480 & 1,160,230 and EU Patent No. 396 083 suggest using strong acid conditions for condensation and dehydration reactions where a Hammet acidity function of less than —12 is required.
US Patent No. 6,084,100 advises reductive cross coupling of tricyclic ketone and N-substituted piperidone, in presence of low valent titanium generated by zinc, at a temperature in the range of 10 and —20 0C preferably between 0 and —50C. The subsequent reaction is carried out at room temperature and above resulting in low yield of about 40%.
US Patent No. 6,093,827 advocates preparation of carbinol by reacting a dibenzosuberone with an aliphatic ketone in presence of low valent titanium generated in-situ by zinc. The process results in crude carbinol due to contamination with deoxygenated tricycle. Thus the reaction causes problems in yield and quality of the carbinol and subsequently the yield and quality of final product loratadine.

According to the previous knowledge, there exists a need for improved process for the production of loratadine which is use less hazardous material, ii) avoid use of unstable reagents, iii) provide improved yield, quality & selectivity, particularly on industrial scale production and iv) eliminate stringent reaction conditions in order to make it industrially feasible.
SUMMARY OF THE INVENTION:

Accordingly the main object of the present invention is to provide a process that obviates the drawbacks of the existing processes.

Another object of the present invention is to provide a process that gives enhanced yield and quality of the desired product- loratadine.

Still another object of the present invention is to provide a process that is industrially feasible.
Yet another object of the present invention is to provide a process, which results in the production of an intermediate compound in high yield & purity so as to attribute high yield & improved quality to the desired end product.
Still yet another object of the present invention is to provide a process that results in to a product meeting ICH guidelines.
The present invention also provides a process, which avoids use of hazardous reagents and stringent reaction conditions and yet produces a product with improved quality & yield.

STATEMENT OF THE INVENTION:
Accordingly, the present invention provides a process for the production of loratadine, chemically known as 8-chloro- 11 -(1 -ethoxycarbonyl-4-piperidylidene)-6, 11 -dihydro5

5H-benzo [5,6]cyclohepta[1,2-b]pyridene, which comprises reacting a tricyclic aromatic ketone with an organometallic compound containing Mg in presence of organic solvent then hydrolyzing and isolating loratadine by conventional methods wherein the reaction between cyclic ketone and the said organometallic compound is effected at a glacial temperature.

In one of the embodiment of the present invention, the tricyclic aromatic ketone used may be such as dibenzocycloheptene, particularly dibenzosuberone.

The said cyclic ketone may be of formula II and has chemical name 8-chloro-6,1 1-dihydro-5H-benzo [5 ,6]cyclohepta[ 1 ,2-b]pyridine- 11-one
(Formula Removed)
In another embodiment of the present invention is that the cyclic ketone of formula II may be prepared according to US Patent No. 3,326,924 or to ES Patent No. 554 898.

In yet another embodiment of the present invention is that the organometallic compound containing Mg may be N-methyl-piperidyl magnesium salt of formula III where in, z represents halogen. Particularly z may be chloro. N-methyl-piperidyl magnesium chloride may be prepared by any standard method known in the art by reacting Nmethyl-4-chloropiperidine with magnesium metal and dibromoethane in dry tetrahydrofuran.

(Formula Removed)

Still another embodiment of the present invention is that the Organic solvent used may be an inert solvent preferably ethereal solvent, more preferably tetrahydrofuran. Still yet another embodiment of the present invention is that the reaction between the compound of formula II and of formula III may be effected at a temperature in the range of 00 to —950C. The reaction may be carried out at a temperature between —80 and
—95 0C. Preferably the reaction is conducted at —85 to —950C.
A process of this invention also deals with the preparation of an intermediate carbinol of formula IV with increased yield and purity, which is further dehydrated and either demethylated or carboethosylated to give loratadine.
(Formula Removed)
DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention is characterized by reacting tricyclic aromatic ketone of formula II with N-methyl-piperidyl magnesium chloride at a temperature in the range of —80 to-95 0C to get a carbinol of formula IV. It was noticed that the yield and purity of the carbinol is increased when produced by condensation at a low

temperature as defined above. The process has an advantage that magnesium is comparatively cheap and safe to use on industrial scale. The invention provides an economical process for the preparation of carbinol. The carbinol thus obtained is dehydrated by any known methods to N-methyl product (olefin)
(Formula Removed)
The N-methyl product is further either demethylated or carbethxylated to get loratadine with enhanced purity & high yield. Though the addition of reagents is carried out at a temperature <300C in US Pat. No. 6,093,827, the reaction was conducted at reflux temperature for the production of intermediate compound. This results in the production of crude product with around 89% yield. When further converted to loratadine it gives 68% yields and > 98% pure. The process as described in US Pat. No. 6,084, 100 also teaches addition of reagents at a temperature in the range of o to —50C.

However, the mixture was allowed to react for about 3hours before heating to around 400C. The yield of loratadine was reported as 40% and the purity was not indicated. The Canadian Pat. No. 2134128 reports 60% yield of intermediate and 51% that of loratadine. But the process uses hazardous reagents such as phosphine and NaH. The document is silent in regard to purity.
The other patents also claim purity & yield to the tune of not exceeding 80%. The process in accordance with the present invention substantiates purity and yield of loratadine >99% & 82% to 90%respectively from the N-mithyl product of Formula V. The invention is further illustrated in a non-limiting fashion by the following examples.

EXAMPLE 1

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, 1.374 mole), dibromoethane (72.8 gm, 0.386 mole) and dry terahydrofuran (THF) (1.17 L) at 20 to 480C, is added slowly to a cooled (-85 to —950C) solution of 8-chloro-6,1 1 -dihydro-5H-benzo[5,6]cyclohepta[ 1 ,2-b]-1 1-one (100 gm, 0.41 mole) in dry THF (530m1). The reaction mixture is stirred for 2-3 hours at the same temperature. The reaction mixture is quenched with 10% NH4Cl (600m1)and extracted twice with ethyl acetate (2x400 ml).The organic phase is washed with water and dried over anhydrous sodium sulfate, filtered and solvent removed. The crude material obtained (141 gni) is purified by acetonitrile to obtain desired carbinol compound (101 gm) in 71.8 % yield with a purity of 94.35% (0DB, HPLC).

EXAMPLE 2

The experiment is conducted as described in the Example 1,except the reaction temperature was maintained at —15 to —350C in stead of —85 to —950C. The yield of isolated 11 -(N-methyl-4-piperidinyl)- 11 -hydroxy-8-chloro-6, 11 -dihydr-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (carbinol) was 100 gm with a purity of 87.71% (ODB,HPLC) giving a yield of 71.1%.

EXAMPLE 3

The reaction was carried out at a temperature of —25 to —450C following the steps as described in Example 1. The yield of isolated I 1-(N-inethyl-4-piperidinyl)-1 1-hydroxy-8-chloro-6, 11 -dihydro-SH-benzo [5,6] cyclohepta[ 1 ,2-b]pyridine (carbinol) was 103 gin with a purity of 87.99% (ODB,HPLC) giving a yield of 73.2 %.

EXAMPLE 4

The reaction was performed at a temperature of —35 to —550C following the steps as described in Example 1. The yield of isolated 11 -(N-inethyl-4-piperidinyl)- 11 -hydroxy8-chloro-6, 1 1-dihydr-5H-benzo[5 ,6]cyclohepta[ 1 ,2-b]pyridine (carbinol) was 104 gm with a purity of 92.6% (ODB,HPLC) giving a yield of 73.9%.

EXAMPLE 5

The reaction was carried out following steps given in Example 1. However, the temperature was maintained at —55 to —650C instead of —85 to —950C. The yield of isolated 11 -(N-methyl-4-piperidinyl)- 11 -hydroxy- 8-chloro-6, 11 -dihydr-5H-benzo [5,6] cyclohepta[1,2-b]pyridine (carbinol) was 100 gm with a purity of 9 1.07% (ODB,HPLC) giving a yield of 71.1%.

EXAMPLE 6

Preparation of 8-chloro-6, 11 -dihydro- 11 -(N-methyl-4-piperidinylidene)-5H-benzo[5 ,6] cyclohepta[1,2-b] pyridine of formula V.
A mixture of 11 -(N-inethyl-4-piperidinyl)- 11 -hydroxy-8-chloro-6, 11 -dihydro-5H-
benzo(5,6) cyclohepta (1,2-b) pyridine (carbinol) of formula IV (1.0 kg, 0.0029 mole) and concentrated sulphuric acid (3.68 kg, 0.0375 mole) is stirred at 35 to 450C for 2 to 3 hrs. the reaction mixture is poured in chilled water and the product (olefin) is extracted in ethyl acetate at 8-9 pH. The organic phase is dried over anhydrous sodium sulphate and solvent is removed. The residue is crystallized in hexane to give 0.8 kg of olefin of formula V (80%) with a purity of >98% (0DB, HPLC).

EXAMPLE 7

Preparation of Loratadine
To a mixture of 8-chloro-6, 11 -dihydro- 11 -(N-methyl-4-piperidinylidene)-SH-benzo (5,6)cyclohepta (1,2-b) pyridine (olefin) of formula V (1.0 kg, 0.0031 mole) and diisopropylethylamine (0.074 kg, 0.00057 mole) in Toluene (6 Lt) under nitrogen atmosphere, ethylchloroformate (0.775 kg, 0.0071 mole) is added slowly at 60 to 650C and stirred for 1 to 2 hrs. at 70-750C. Reaction mixture cooled to room temperature and water (5.0 Lt) is added. The mixture is adjusted to 5.0 - 5.5 pH with hydrochloric acid. The organic phase is washed with water and the solvent is removed. The residue is purified in isopropyl ether followed by crystallization in acetonitrile to get 0.9 kg loratadine (90%) with a purity of >99% (0DB, HPLC).
Table 1 is hereby incorporated to illustrate the effect of reaction temperature on the yield, and Table 2 shows the effect of reaction temperature on the purity of the compound of formula IV. Table 3 indicates the yield and quality of compound of formula 1-loratadine obtained from N-methyl product of formula V.

TABLE 1

Comparative Data to illustrate Effect of Temperature for Preparation of ii(N-methyl-4-piperidinyl)- 11 -hydroxy-8-chloro-6, 11 -dihydr-5H-benzo [5 ,6jcyclohepta [1,2-bipyridine a compound of Formula IV.
(Table Removed)

RP*--Relative Purity
0DB — On dry basis

TABLE 2

YIELD and QUALITY of COMMERCIAL BATCHES of 11-(N-methyl-4-piperidinyl)-

11 -hydroxy-8-chloro-6, 11 -dihydr-SH-benzo [5,6] cyclo- hepta[ I ,2-b]pyridine a

compound of Formula IV.

(Table Removed)
Note--Temperature of process reaction was maintained between —85 & —950C

TABLE 3

YIELD AND QUALITY OF LORATADINE OF FORMULA I OBTAINED FROM

THE COMPOUND OF FORMULA V

(Table Removed)

ADVANTAGES

(1) Process uses relatively mild conditions easy to be carried out industrially.
(2) Process avoids use of hazardous and unstable reagents.
(3) Process does not require use of expensive and special equipment.
(4) Process results in the production of an intermediate compound with high yield and purity.
(5) Process is high yielding.
(6) The product obtained has improved purity & meets ICH standards.

We Claim:

1. A process for the production of loratadine chemically known as 8-chloro-1 1-(1-ethoxycarbonyl-4-piperidylidene)-6, 11 -dihydro-5H-benzo[5 ,6]cyclohepta[ 1,2-bipyridene which comprises reacting a tn-cyclic aromatic ketone with an organometallic compound containing Mg in presence of organic solvent then hydrolyzing and isolating loratadine by conventional methods wherein the reaction between cyclic ketone and the said organometallic compound is effected at a glacial temperature.
2. A process as claimed in claim 1 wherein the the-cyclic aromatic ketone such as dibenzocycloheptene, particularly dibenzosuberone is used.
3. A process as claimed in claim 1 wherein the said tn-cyclic ketone is chemically known as 8-chloro-6, 11 -dihydro-5H-benzo[5 ,6] cyclohepta[ 1 ,2-b]pyridine- 11-one & has structural formula II
(Formula Removed)
4. A process as claimed in claim 1 wherein the cyclic ketone of formula II is prepared according to US Patent No. 3,326,924 or to ES Patent No. 554 898.
5. A process as claimed in claim 1 wherein the organometallic compound containing Mg is N-methyl-piperidyl magnesium salt of formula III where in, z represents halogen particularly chloro.
(Formula Removed)

6. A process as claimed in claim 1 wherein N-methyl-piperidyl magnesium chloride is prepared by any standard method known in the art such as by reacting N-methyl-4-chloropiperidine with magnesium metal and dibromoethane in dry tetrahydrofuran.

7. A process as claimed in claim 1 wherein the organic solvent used is an inert solvent preferably ethereal solvent, more preferably tetrahydrofuran.

8. A process as claimed in claim 1 wherein the reaction between the compound of formula II and of formula III may be effected at a temperature in the range of 00 to —950C.
9. A process as claimed in claim 1 & 8 wherein the reaction may be carried out at a temperature between —80 and —95 0C. Preferably the reaction is conducted at —85 to —950C.
10. A process for the production of loratadine substantially as herein described with reference to the examples.