Title of Invention

A PROCESS FOR PREPARING BENZOCYCLOHETAPYRIDIN-11-ONES

Abstract

A process for the preparation of benzolycloheptapyridin-11-ones of the general formula III wherein R1, R2, R3, R4, R5, R6 and R7 are independently selected from one or more of the following groups: hydrogen, halogen, C1-C6 alkyl, CI - C6 alkoxy, which comprises a) reacting a compound of general formula (1), wherein R1, R2, R3, R4, R5, R6 and R7are as defined above; and wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above, with anhydrous HF/BF3 at a temperature in the range of-100°C to -20°C, to produce a compound of formula (IT), b) hydrolysing said compound of formula 11 to obtain said compound of the general formula III.

Full Text

The PATENT ACT, 1970 (39 of 1970) Complete Specification A PROCESS FOR PREPARING BENZOCYCLOHETAPYRIDIN-11-ONES CADILA HEALTHCARE LIMITED, Zydus Tower, Satellite Cross Road, Ahmedabad, 380 015, Gujarat India. The following specification describes the nature of the invention and the manner in which it is to be performed: Field of the invention: The present invention relates to a process for the preparation of benzocyclohetapyridin-11-ones compounds. Background of the invention: The present invention provides a new process for preparing benzocyclohepta pyridine-11-ones. Benzocyclohepta pyridine-11-ones compounds are well known in the art and there are several teachings in the prior art for the preparation of this compound. Benzocyclohepta pyridine-11-ones typically have the formula (III): The substituents R1, R2, R3, R4, R5, R6 and R7 are independently selected from the groups consisting of hydrogen, halogen, alkoxy. As used herein, the term "alkyl" means straight or branched hydrocarbon chains of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, optionally substituted by one or more substituents selected from alkoxy, halo, or CF3. "Alkoxy'1 means a group having the formula -O-alkyl. "Halo" refers to fluorine, chlorine or bromine. These compounds are useful as intermediates in the preparation of antihistamines and as inhibitors of farnesyl protein transferase (FPT) especially loratadine and azatadine. US 3326924, 4659716, 5998620, 6372909; WO 0005215, 0030589, 0179175; CN 1151987; J. Med. Chem. 34, 461-463 (1961); Bioorg. Med. Chem Lett 3, 1073-1078 (1993), which are herein incorporated by references describe various processes for the preparation of compounds having formula III. Similarly WO-0030589 also describes cyclization of compound (I) by CF3SO3H to compound III. US 3326924 describes the preparation of compounds having the formula III as shown in the scheme I. 2 SCHEME: 1 Main disadvantage of the process as disclosed therein is the formation of undesired isomeric product IV in substantial amount (Scheme - 2). In an alternative method amide derivative of the acid is cyclised by or HF / BF3. The process suffers the disadvantage of difficult operation and low yield. Carboxylic acid derivatives (Scheme 11, X = OH) is cyclised by polyphosphoric acid at 200°C. The process disclosed therein results in poor yield of the desired products of formula (III) with a lot of polymeric material formation, making the process unsuitable on commercial scale. CN 1151987 discloses the preparation of III by cyclization of 3-[2-(3,8-dihalo-phenyl) ethyl-2-pyridine by BuNLi or i-Pr2NLi at - 100°C to 20°C The starting material used therein is difficult to prepare, moreover use of expensive and hazardous lithium compounds restricts the scope of the process for commercial use. US 4659716 describes the use of HF / BF3 for cyclization of (l-methyl-4-piperazinyl)-[3-[2-(3- chlorophenyl)ethyl]-2-pyridyl]methanone for preparation of corresponding benzocycloheptapyridinylidene piperidine derivative. The same methodology is employed for cyclization of compounds of formula I to get the desired compound of formula III (Scheme - 1). Summary of the invention: The present invention discloses herein a new process for the preparation of benzocycloheptapyridin-ll-ones having formula (III) by intramolecular cyclization of compounds 3 having the formula (I) with anhydrous hydrofluoric acid and boron trifluoride, hydrolyzing the resulting corresponding imino compound having formula (Tl) to the corresponding tricyclic ketone as shown in the scheme - 2. SCHEME: 2 4 Accordingly, the present invention provides a process for the preparation of benzolycloheptapyridin-11-ones of the general formula III wherein R1, Rz, R\ R4, R5, R6 and R7 are independently selected from one or more of the following groups: hydrogen, halogen, C1-C6 alkyl, C l - C6 alkoxy, which comprises a) reacting a compound of general formula (I), wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above, with anhydrous HF/BF3 at a temperature in the range of-100°C to -20°C, to produce a compound of formula (II), (ii) wherein R1, R2, R3, R4, R5, R6and R7are as defined above; and b) hydrolysing said compound of formula II to obtain said compound of the general formula III. Preferably, said compound of formula I is reacted with said anhydrous HF/BF3 at a temperature in the range of-60 to -75°C. Preferably, said hydrolysis is carried out by dumping the reaction product of said compound of formula II and said anhydrous HF/BF3 in ice-water, stirring the reaction mass for 20 - 80 hours at -50 °C to 70 °C to hydrolyse the compound of formula III. In a preferred embodiment, said compound of formula III is isolated by collecting the salt of said compound of formula III with tetrafluoroboric acid, stirring the salt with water and adjusting the pH in the range of 6 to 10 with alkali to liberate said compound of formula III, extracting said compound of Formula III with solvent extraction and distillation and recovering said compound of formula 111 in pure form by centrifugation and drying ,i In a preferred embodiment, said anhydrous HF is employed in an amount of 10 to 60 moles, preferably, 20 to 30 moles with respect to the compound I used. In an embodiment of the invention, said BF3 is used in a molar ratio of 1 to 10 moles to that of compound I. In another preferred embodiment, said BF3 gas is passed in for a period ranging from 20 to 60 hours, more preferably, from 45 to 55 hours. Preferably, during hydrolysis the temperature is maintained in the range of 20 to 40°C. Detailed description of the invention: The present invention seeks to provide an alternative method for the preparation of compounds having formula 111 from compounds having formula 1 comprising following steps: (1). intramolecular cyclization of compounds having the formula (I) with anhydrous hydrofluoric acid and boron trifluoride, and (2) hydrolyzing the resulting corresponding imino compound having formula (II) to the corresponding tricyclic ketone In a preferred embodiment of the invention, compounds having formula I are dissolved in 10 -60 moles preferably 20 -30 moles of hydrofluoric acid at -20° to -100°, preferably at -60 to -75°C. To this 1-10 moles, more preferably 4-5 moles of boron trifluoride is slowly passed at this temperature for 45 to 55 hours showing complete conversion of compound I to compound II (Scheme- 1). The reaction mass is dumped into ice-water. This is stirred for 20 to 50 hours, preferably 25 to 35 hours at -50 °C to 70°C, preferably at 25 to 35°C to compounds having formula - III (Scheme-1). The solid thus obtained is tetrafluoroboric acid salt of compound of formula - 111 which is treated with base such as hydroxide or carbonates salts of lithium, sodium, potassium or ammonia. Potassium carbonate is the most preferred base, thereby liberating compound of formula (III), which is extracted in non-polar solvent, which is selected from aromatic hydrocarbon such as benzene, toluene, xylene and alkyl halides such as methylene chloride, chloroform, ethylene dichloride, trichloroethane. Toluene is the most preferred solvent for extraction. The solvent is removed by distillation at reduced pressure and the residue thus obtained is stirred with aliphatic hydrocarbon solvent, the solid is centrifuged and dried to get the pure compound having the formula III. 6 The invention is illustrated by the following representative example Example-I 8-Chloro-5, 6-dihydro-[5,6]cycIohepta[l,2-b]-pyridin-l 1-one (V): A solution of 30 kgs of (3-[2-(3-chlorophenyl)ethyl]-2-cyanopyridine) in 60 kg of anhydrous hydrofluoric acid is slowly passed through 40 kg of boron trifluoride at -60 °C to -75 C in about 45 to 55 hours. The reaction mass is then dumped over ice-water and stirred for 25 to 35 hoursat25°C to35°C. The solids are then filtered, washed with water, and then suspended in 500 L water; a solution of 12 kg of potassium carbonate in 120 L water is added to bring pH of aqueous solution more than 7.0, title compound (V) is extracted in toluene (460 L), toluene layer containing compound (V) is subjected to distillation to remove toluene to give a residue which is stirred with 144 L of hexane and the solution is cooled to 5° C to 10 °C. The product obtained by centriftigation is dried at 60°C -70°C to give 23 kg the title compound (V) with a yield of 76.4%. 7 We claim: 1) A process for the preparation of benzolycloheptapyridin-11-ones of the general formula III wherein R1, R2, R3, R4, R5, R6 and R7 are independently selected from one or more of the following groups: hydrogen, halogen, C1-C6 alkyl, CI - C6 alkoxy, which comprises a) reacting a compound of general formula (1), wherein R1, R2, R3, R4, R5, R6 and R7are as defined above; and 8 wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above, with anhydrous HF/BF3 at a temperature in the range of-100°C to -20°C, to produce a compound of formula (IT), b) hydrolysing said compound of formula 11 to obtain said compound of the general formula III. 2. A process as claimed in claim 1 wherein said compound of formula I is reacted with said anhydrous HF/BF3 at a temperature in the range of -60 to -75°C. 3. A process as claimed in claim 1 or 2, wherein said hydrolysis is carried out by dumping the reaction product of said compound of formula II and said anhydrous HF/BF3 in ice-water, stirring the reaction mass for 20 - 80 hours at -50 °C to 70 °C to hydrolyse the compound of formula III. 4. A process as claimed in any preceding claim wherein said compound of formula III is isolated by collecting the salt of said compound of formula III with tetrafluoroboric acid, stirring the salt with water and adjusting the pH in the range of 6 to 10 with alkali to liberate said compound of formula 111, extracting said compound of Formula III with solvent extraction and distillation and recovering said compound of formula III in pure form by centrifugation and drying. 5. A process as claimed in any preceding claim wherein alkyl comprises straight or branched chain having 1 to 6 carbon atoms. 6. A process as claimed in any preceding claim wherein said halo is selected from fluorine, chlorine or bromine radicals 7. A process as claimed in any preceding claim wherein said anhydrous HF is employed in an amount of 10 to 60 moles with respect to the compound I used. 8. A process as claimed in claim 7 wherein anhydrous HF is used in a molar ratio of 20 to 30 mole with respect to the compound of formula I. 9. A process as claimed in any preceding claim wherein BF3 is used in a molar ratio of 1 to 10 moles to that of compound 1. 10. A process as claimed in claim 9 wherein said molar ratio is preferably 4 to 5 moles. 11. A process as claimed in any preceding claim wherein said BF3 gas is passed in for a period ranging from 20 to 60 hours. 12. A process as claimed in claim 11 wherein BF3 gas is preferably passed in for a period ranging from 45 to 55 hours. 13. A process as claimed in claim 3 wherein said temperature is maintained within the range of 25°C to35°C. 9 14. A process as claimed in claim 3 wherein the reaction mass is stirred preferably for period ranging from 25 to 35 hours. 15. A process as claimed in any one of claims 3 to 14 wherein during hydrolysis the temperature is maintained in the range of 20 to 40°C. 16. A process as claimed in claim 4 wherein the pH adjusted is preferably in the range of 7 to 8. 17. A process as claimed in any one of claims claim 4 to 16, wherein said alkali is selected from hydroxide or carbonate salt of lithium, sodium, potassium or ammonia. 18. 19. A process as claimed in claim 18 wherein the solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, alkylhalides such as methylene chloride, chloroform, ethylene dichloride, trichloroethane. 20. A process as claimed in any one of claims claim 4 to 19 wherein after distillation the residue is crystallized by stirring with hexane, heptane or cyclohexane. 22. A process as claimed in any one of claims 4 to 20 wherein the product collected 10 by centrifugation is dried at a temperature in the range of 60 - 70 °C.

Documents:

1154-mum-2002-cancelled pages(30-10-2003).pdf

1154-mum-2002-claims.doc

1154-mum-2002-claims.pdf

1154-mum-2002-correspondence(ipo).pdf

1154-mum-2002-correspondence.pdf

1154-mum-2002-description(granted).doc

1154-mum-2002-description(granted).pdf

1154-mum-2002-form 1.pdf

1154-mum-2002-form 19.pdf

1154-mum-2002-form 2(granted).pdf

1154-mum-2002-form 2(title page).pdf

1154-mum-2002-form 3-30-oct-2003.pdf

1154-mum-2002-form 3.pdf

1154-mum-2002-form-2(granted).doc

1154-mum-2002-international (search report).pdf

1154-mum-2002-pct document.pdf

1154-mum-2002-petition 138.pdf

1154-mum-2002-power of attorney.pdf

1154-mum-2002-us patent.pdf