Title of Invention

A PROCESS FOR SYNTHESIZING LORATADINE

Abstract

ABSTRACT 1232/CHENP/2004 A process for synthesizing loratadine The present invention relates to a process and new oxazolinic intermediates for the preparation of 4-(8-chloro-5,6dihydro-l lH-Benzo-[5,6]-cichtohepta-[l,2-b]-pyridin-ll-ylidene)-l-piperidinecarboxylic acid ethyl ester (loratadine) is described. The process starts from 2-(4,4-dimethyl-4,5-dihydrooxazoi-2-yl)-2yl)-3-methyl-pyridine, a new intermediate to obtain loratadine. 2-(4,4-dimethyl-4,5-dihydrooxazoi-2-yl)-3-methyl-pyridine is condensed with 3-chloro-benzyI-chloride and the resultant product is treated with Grignard reagent of 4-chloro-N-methyl-piperidine. [3-(2-(3-chloro-phenyl)-ethyl-pyridin-2-yl]-t-(methyt-piperidin-4-yl)-methanone is obtained for subsequent hydrolysis. Starting from this last compound it is possible to obtain loratadine with known methods.

Full Text

The present invention relates to a process for preparing loratadine, a medicinal product with antihistamine activity. Loratadme is ethyl 4-(8-chloro-5,6-dihydro-l 1H-ben2»[5,qcyclohep^l^b]pyridin-U-yUdenB)-l^iperidinecarbOTyl^ (Jhe Merck Index, 1201 ed., 5608, p. 953). More specifically, the invention relates to a process for synthesizing loratadine from a novel intermediate, 2-(4,4-dimethyl-4,5-dihydrooxazol-2-Yl)-3-methylpyridine. Loratadine was described for the first time in Schcring patent US 4 282 233. hi the said patent, the synthesis of loratadine is described starting with 8-chloro-ll-(l-metfaylpiperid-4-ylidene)^,n4ihydro-5H-benzo[5,6]cvcloheptaj;i^-b]pyridine a), which reacts with ethyl chloroformate in benzene. Scheme 1 illustrates the reaction. Schering patent US 4.731.447 describes the synthesis of compound a) from compound b), the latter compound being obtained from 3-mcthyl-2-cyanopvridme in four steps. Compound b) gives compound a) by cychzation with a superacid having a Hammett acidity constant lower than -12. Patent US 4.731.447 in turn describes the synthesis of compound c) from 3-[2 However, given meir chemical corrosiveness, superacids are problematic to use industrially. The synthesis of a) from compound c) is described in Schering patent US 4.659.716. a) is obtained by reacting compound c) with the Qrignard reagent of 4-chloro-N-methylpiperidine, to give 8-cMoro-n Surprisingly, a process that represents one of the aspects of the present invention has now been found, this process making it possible to synthesize loratadine from 2-3-nwthylpvridine of formula L Compound m, along with compound VI which may be present, is then converted under hydrolyric conditions into the intermediate b) and finally from the said intermediate into loratadine by known methods. Scheme 2 compares the process that is the object of the present invention with the processes described by Sobering, indicated by the abbreviations Z, SI and S2, respectively. A second aspect of the present invention is represented by the novel compounds of formulae I, D and m and their use for the preparation of loratadine. A third aspect is represented by a process for obtaining the intermediate b) from compound I, which, by treatment with lithium diisopropylamide (LDA) at 0°C and then with 3-chlorobenzyl chloride, gives compound U. Subsequent treatment of compound II with the Grignard reagent of 4-chloro-N-methyIpiperidiiic produces compound IH, which, on hydrolysis, gives the intermediate b). A fourth aspect of the invention is represented by an alternative method, relative to processes SI and S2 of scheme 2, for obtaining the intermediate c) from compound D, which is hydrolysed to give 3-[2^3^h]orophenyl)ethyl]-pyridhic-2-carboxylio acid of formula IV. The acid function of compound IV is converted into the corresponding acid chloride and then coupled via a Friedel-Crafts reaction to give the intermediate c). A fifth aspect of the present invention is a process for synthesizing loratadine by preparation of compound n to give c) according to the process described above, followed by conversion ofc)mtolorataxhOTaccorinngtoJaownteclmi(jues. A preferred embodiment of the invention consists in using 2-(4l4-dhnerhyl-4,S~ dihydrooxaOTl-2-yl)-3-me%h^dme of formula I as starting compound. Obviously, the use of oxazoEne analogues such as the 4-methyl-, 4,4-diethyl- or 4-ethyfoxazoline, bearing the same substituent in position 2, fall within the spirit of the present invention. The choice of the 4,4-dimeQiylQj[8zoline {compound I) is based solely on criteria of process economics. The route that has been found to be the most advantageous for obtaining compound I is that described in the article by Fryzuk M. D., Jafarpour L. and Rettig S. J., Tetrahedron; Asymmetry, 1998, 9, 3191. The experimental conditions for obtaining 2-(4,4-dimethy]-4,S-dthydrooxa2ol-2-yl)-3-metJiylpyridme were drawn from this article. The latter compound is obtained by reaction between 2-cyano-3-methylpyridine and l.l-dimethylaaninoethanol, using anhydrous ZnCl) as catalyst at 140°C for 15 hours, in the absence of solvent. Compound I thus obtained was reacted with 3-chlorobenzyl chloride or an analogue thereof (gee scheme 3) in the presence of a strong base, preferably lithium diisopropylanride (IDA). The reaction was performed in an inert solvent (THF, toluene, diethyl ether or hexane); tetrahydrofiiran (THF) and a temperature range of between -1S°C and 25°C and preferably between -5°C and +5°C are particularly preferred, giving 3-[2-(3-chIorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridinc of formula n. Addition of the Grignard reagent to compound H takes place selectively and therefore, as is seen in scheme 2, an additional step is avoided, which is, however, necessary by the Scheringprocess SI. Finally, compound HI may be converted into b) by hydrolysis, and loratadine is obtained from this product according to known techniques. The following experimental examples are now given for Hie purposes of illustrating the invention more clearly, without, however, limiting it Example 1 Compound V may in turn be converted into die oxazoline by treatment with mesyl chloride and triethylamine in CHjClj at -S°C. Compound I may also be distilled at 105-112°C and at 1.5 mmHg to give an oxazoline litre >97%. Yield 98.5% Compound I: 'H-NMR (200 MHz, CDCIj) 6 (ppm): 8.52 (dd, J-4.3 and 1.8 Hz, 1 H); 7.57 (dd, J = 7.9 and 1.8 Hz, 1 H); 7.25 (dd, J = 7.9 and 4.3 Hz, 1H); 4.14 (a, 2 H); 2.59 (a, 3 H); 1.42 (s, 6 H). 521.7 ml of anhydrous THF and 521.7 ml of 2M LDA solution (1.04 mol) are placed in a 3-litre jacketed reactor equipped with a mechanical stirrer and thermometer, and maintained under a nitrogen atmosphere, the internal temperature is brought to -5°C and & solution consisting of 158.8 g of oxazoline (0.835 mol) and 834.7 ml of anhydrous THF is men added slowly, keeping the temperature at about 0°C. After adding a few drops of solution, a strong blue-violet colour is obtained. The total addition time is about one hour. 154.6 g (0.96 mol) of 3-chlorobenzyl chloride are then added over about 1,5 hours, while still maintaining the temperature at 0°C. At the end of the reaction, 521.7 g of water are added while bringing the temperature to 20-25°C. The two phases are then separated and the organic phase is evaporated to give an oil. The crude product thus obtained is taken up in toluene and filtered through Tonsil. The filtrate is concentrated to give 268.1 g of an oil win an HPLC titre of 79%. 91.8% conversion, yield - 80.2% 'H-NMR (200 MHz, CDC1,) 5 (ppm): 8.58 (dd, 1 H); 7.31-7.10 (m, 5 H); 4.17 (s, 2 H); 3 37-3.28 (m, 2 H); 2.95-2.86 (m, 2 H); 1.47 (a, 6 H) "C-NMR (50 MHz, CDC1,) 6 (ppm): 160.78 (s); 147.75 (d); 146.07 (s); 144.10 (s); 139.22 10 g of magnesium filings (0.41 mol) and 163 g of anhydrous THF are placed in a 400 ml reactor equipped with a mechanical stirrer, a bubble condenser, a thermometer and a 100 ml dropping funnel, under a nitrogen atmosphere. The system is brought to 60°C and about 1 ml of Vitride® (70% w/w solution of sodium dihydrobis(2-methoxyethoxy)aliiminate in toluene) and about 5% of the solution of 4-cbJoro-N-methylpiperidine (S7.7 g, 0.41 mol) in 163 g of anhydrous THF are added. After a few minutes, a gentle exothermicity is noted. The remainder of the solution is men added slowly. Once the addition is complete, the reaction mixture is maintained at 60°C overnight The Grignard suspension, which is easily stirrable, is used without further modification in the subsequent coupling stage. Coupling 116 g of crude 3-[2 (0.32 mol) and 368.6 g of anhydrous THF are placed in a 1-litre reactor equipped with a mechanical stirrer, a thermometer and a 500 ml dropping funnel, under a nitrogen atmosphere. The solution is cooled to -20°C. Addition of the Grignard reagent prepared in the preceding stage is then started, while keeping the temperature at about -20°C, Next, the cooling is stopped and the system is allowed to return to room temperature. The reaction progress is followed by HPLC. After leaving overnight at room temperature, the HPLC monitoring shows about 2.9% (by area) of unreacted 3-[2-(3-chlorophenyl)emyl]-2- dimethyl-4,5-dihydrooxazol-2-yl)pyridinc. The mixture is diluted with toluene (200 ml) and 270 g of acetic acid (aqueous 10% wAv solution) are added slowly, The resulting mixture is stirred for about 30 minutes and then left to stood for a further 30 minutes. The phases are separated. The organic phase gives 146 g of a crude product, in the form of a dark oil, consisting of a mixture of compound HI and a small amount of compound VI. The mixture of the two products is used in the subsequent reaction without further purification. 5 g of compound IV with a titre of 70% arc placed in a 250 ml reactor, 70 g of SOClj are added dropwise at room temperature and me mixture is brought to 55-60°C and left to react for three hours. The disappearance of the acid is monitored by TLC and the excess SQCl* is then distilled off to give 6 g of a dark residue. This residue is dissolved in about 10 ml of dichloroethane, the reaction mixture is cooled to 0°C and 5.3 g of AlClj are men added poitionwise. The resulting mixture is then left overnight at between -5°C and 0°C. At the end of the reaction, the mixture is acidified with IN HC1, while keeping the temperature between 10-15eC, the phases are separated, a second acidic extraction is carried out with SO ml of water and the aqueous phases are combined and basified with NaOH to pH 12, and then re-extracted with toluene. After evaporating off ate solvent, a solid is obtained, which, when crystallized from diisopropyl ether, gives 2 g of a pale yellow solid with an NMR thre >99%, 62% yield. WE CLAIM : 1. A process for synthesizing loratadine, which consists in i) reacting 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I with 3-chlorobenzyl chloride, in the presence of a strong base, to give 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) pyridine of formula II ii) reacting compound II with the Grignard reagent of 4-chloro-N-methylpiperidine, in an inert solvent, to give[3-[2-(3-chlorophenyl) ethyl]-2- [4, 4-dimethyl-2-(l-methyl-piperidin-4-yl)-oxazolidin-2-yl] pyridine of formula III ii) hydrolysing compound III to give the intermediate of formula b) which is converted by known methods into loratadine. 2. The process as claimed in claim 1, in which the strong base is preferably lithium diisopropylamide. 3. The process as claimed in claim 1, in which the inert solvent is preferably tetrahydrofuran. 4. A process for synthesizing the intermediate (b), which consists in i) reacting 2- (4, 4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I with 3-chlorobenzyl chloride, in the presence of a strong base, to give 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) pyridine of formula II ii) reacting compound II with the Grignard reagent of 4-chloro-N-methylpiperidine, in an inert solvent, to give[3- [2- (3-chlorophenyl) ethyl]-2- [4,4-dimethyl-2-(l-methyi-piperidin-4-yl)-oxazolidin-2-yl] pyridine of formula III iii) hydroiysing compound III to give the intermediate of formula (b) 5. The process as claimed in Claim 4, in which the solvent is preferably tetrahydrofuran, while the strong base is preferably lithium diisopropylamide. 6. The process as claimed in Claim 4, in which the hydrolysis is preferably performed in acidic medium. ii) hydrolysing the oxazoline group of the compound of formula II to give 3- [2- (3-chlorophenyl)ethyI]-2-pyridinecarboxylic acid of formula IV iii) converting the compound of formula IV into the corresponding acid chloride and subsequently condensation to give compound (c) via a Friedel-Crafts reaction. 8. The process as claimed in Claim 7, in which the solvent is preferably tetrahydrofuran, while the strong base is preferably lithium diisopropylamide. 9. The process as claimed in Claim 7, in which the hydrolysis is preferably performed in acidic medium. 10. Compound chosen from i) 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I ii) 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) pyridine of formula II iii) 3-[2-(3-chlorophenyI)ethyl]-2-[4,4-dimethyl-2-(l-methyl-4-piperidyl)-2-oxazolidinyl] pyridine of formula III

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