WO2009001374A2

WO2009001374A2 - Preparation of ethyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phenyl]-3-oxopropanoate, a key intermediate for montelukast sodium

Info

Publication number: WO2009001374A2
Application number: PCT/IN2008/000398
Authority: WO
Inventors: Ventaka Subba Raju Gottumukkala; Someswara Rao Casukhela; Satyanarayana Chava; Seeta Ramanjaneyulu Gorantla
Original assignee: Aptuit Laurus Pvt Ltd
Priority date: 2007-06-25
Filing date: 2008-06-24
Publication date: 2008-12-31
Also published as: WO2009001374A3

Abstract

A process for preparing β- ketoester of formula (III) comprises; (a)condensing alkyl 3- formylbenzoate with 7-Chloroquinaldine to give alkyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzoate; and (b) reacting alkyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzoate with an alkyl ester in presence of metal hydride/metal alkoxides to obtain a compound β- ketoester of structural formula (Ill) or (a) condensing isophthalaldehyde with 7-Chloroquinaldine to give Ethyl 3-[((7-chloro-2- quinolinyl) ethenyl)] benzaldehyde (b) reacting Ethyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzaldehyde with an α-halo ester in presence of a metal catalyst to give Ethyl 3'-[((7-chloro- 2-quinolinyl) ethenyl)phenyl] -3 -hydroxy propanoate; and (c) treating Ethyl 3'-[((7-chloro-2- quinolinyl)ethenyl)phenyl]-3-hydroxy propanoate with Collins reagent in an organic solvent to obtain a compound β- ketoester of structural formula (III).

Description

"Preparation of Ethyl 3'-[((7-chloro-2-quinolinyI)ethenyl)phenyI]-3-oxopropanoate, a key intermediate for Montelukast sodium"

Field of the invention:

The present invention provides improved methods for preparing β- ketoester derivatives which are key intermediate for producing leukotriene antagonists and their pharmaceutically acceptable salts. In one embodiment, the invention provides improved methods for preparing β- ketoester derivatives which are key intermediate for producing Montelukast.

Background of the invention:

Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. It has been found that antagonists to leukotrienes can perform valuable functions in the treatment or amelioration of certain disease states, particularly those associated with inflammation.

By way of example only, Montelukast sodium, is an important leukotriene antagonist and useful in the treatment of asthma and other related disorders.

Several synthetic routes for leukotriene antagonists such as Montelukast sodium have been developed. In relation to Montelukast sodium, the β-Keto ester (m) is an important intermediate in these processes. (WO 2006/021974 Al).

In the past, the desired β -Keto ester (πi) has been obtained through a sequence of steps consisting of the condensation of 7- chloroquinaldine and isophthalaldehyde in presence of acetic anhydride the reaction of the resulting aldehyde with methyl magnesium halide to produce a secondary alcohol, oxidation of the secondary alcohol to give an aromatic ketone and reaction of the aromatic ketone with dialkylcarbonate.

However, the synthetic strategy of the condensation of 7-chioroquinaldine with isophthalaldehyde has a number of significant disadvantages which limit the utility of the synthesis. These include: the formation of a number of by-products and a relatively low yield (US 5,869,673). Further, prior methods use expensive reagents such as methyl magnesium halides, oxalyl halides. etc., making the economically inefficient.

Our pending application AU 2006906456 discloses a process for preparing β -Keto ester of formula (in) has been obtained through a sequence of steps consisting;

a) condensing alkyl 3-formylbenzoate with 7-Chioroquinaldine to give alkyl 3- [((7- Chloro-2-quinolinyl)ethenyl)]benzoate. b) hydrolysing alkyl 3 -[((7-Chloro-2-quinolinyl)ethenylflbenzoate to give 3-[((7- Chloro-2- quinolinyl)ethenyl)]benzoate; and c) reacting 3-[((7-Chloro-2-quinolinyI)etheny]benzoic acid with a malonate to obtain a compound of structural formula (πi)

There is therefore an unfulfilled need to provide cost effective industrially feasible process for the preparation of β -Keto ester of formula (in) which can be scaled up with increased yield and purity without multi step conversions described in the prior art. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge.

Summary of the invention:

The main object of the invention is to provide a method of synthesizing a compound of formula III:

wherein R is alkyl, alkenyl, aryl or arylalkyl. In one preferred embodiment, the compound synthesized by this method has the following structural formula and the method comprises;

a. condensing alkyl 3-formylbenzoate with 7-Chloroquinaldine to give alkyl 3-[((7- chloro-2-quinolinyl) ethenyl)] benzoate; and

b. reacting alkyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzoate with an alkyl ester in presence of metal hydride/metal alkoxides to obtain a compound β- ketoester of structural formula (πi)

Scheme 1 (below) summarizes this particularly preferred embodiment.

Scheme-1

Wherin R¹ and R are individually alkyl, alkenyl, aryl or arylalkyl.

Another object of the invention is to provide an alternate, safer and scalable process for synthesizing the β -Keto ester of formula (in):

• condensing isophthalaldehyde with 7-Chloroquinaldine to give Ethyl 3-[((7-chloro-2- quinolinyl) ethenyl)] benzaldehyde;

• reacting Ethyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzaldehyde with an α-halo ester in presence of a metal catalyst to give Ethyl 3'-[((7-chloro-2-quinolinyl) ethenyl)phenyl]-3-hydroxy propanoate.

• Treating Ethyl 3'-[((7-chloro-2-quinolinyl)ethenyl)phenyl]-3-hydroxy propanoate with Collins reagent in an organic solvent to obtain a compound β- ketoester of structural formula (πi)

Scheme 2 (below) summarizes this particularly preferred embodiment.

Scheme-2

wherein R is alkyl, alkenyl, aryl or arylalkyl.

Throughout this specification, unless the context requires otherwise, the word 'comprise', and variation such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Detailed description of the invention:

It is convenient to describe the invention herein in relation to particularly preferred embodiments relating to production of β- ketoester derivative which is a key intermediate for producing Montelukast and its pharmaceutically acceptable salts. However, it is to be appreciated that other constructions and arrangements are also considered as falling within the scope of the invention. Various modifications, alterations, variations and or additions to the construction and arrangements described herein are also considered as falling within the ambit and scope of the present invention.

Accordingly the present invention provides a process for synthesizing β- ketoester (m) an intermediate of Montelukast sodium which comprises:

a) reacting benzaldehyde of formula (I) wherein R¹ is alkyl, alkenyl, aryl or alkylaryl with 7-chloroquinaldine in presence of an amine or an amine and an organic acid in a suitable organic solvent to get an ester of formula (π), b) treating the said ester of formula (π) with an ester in presence of metal hydride or metal alkoxide to get the compound β- ketoester of formula (m)

In one of the embodiments of the present invention as depicted in Scheme -1, the reaction in step (a) may be carried out in an organic solvent alone or in the presence of an organic amine or in presence of an amine and an organic acid. The organic amine used is selected from primary amine, secondary amine, tertiary amine and mixtures thereof. The oraganic acid used is selected from acetic acid, pivalic acid or benzoic acid. The organic solvent used is selected but not restricted from the groups aliphatic hydrocarbons, aromatic hydrocarbons, esters, halogenated hydrocarbons and mixture thereof, at a temperature ranging from room temperature to reflux temperature of the solvent, preferably above 80⁰C. Optionally the reaction can also be carried out in the organic amine alone, wherein the organic amine itself is used both as a base and reaction medium.

In another embodiment as depicted in Scheme -1, the reaction in step (b) may be carried out in presence of a base which is selected from hydrides and alkoxides of alkali metals and alkaline earth metals, preferable base is sodium hydride. The reaction being carried out in presence of an ester including but not restricted to methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate or mixture thereof at a temperature ranging from room temperature to boiling point of the solvent.

In accordance with the other aspect of the invention there is provided a process for synthesizing β- ketoester (HI) an intermediate of Montelukast sodium which comprises:

a) reacting isophthalaldehyde of formula (IV) with 7-chloroquinaldine in presence of an amine in a suitable organic solvent to get an aldehyde of formula (V), b) converting the said aldehyde of formula (V) to its corresponding hydroxy ester of formula (VI) c) treating the said hydroxy ester of formula (VI) with Collins reagent in an organic solvent to get the desired compound β- ketoester of formula (m).

In another embodiment as depicted in Scheme -2, the reaction in step (a) may be carried out in presence of an organic solvent in the presence of an organic amine. The organic amine used is selected from primary amine, secondary amine, tertiary amine and mixtures thereof. The organic solvent used is selected but not restricted from the groups aliphatic hydrocarbons, aromatic hydrocarbons, esters, halogenated hydrocarbons and mixture thereof, at a temperature ranging from room temperature to reflux temperature of the solvent.

In another embodiment as depicted in Scheme -2, the reaction in step (b) may be carried out in presence of α-haloester of the structural formula XCH₂COOR wherein X is chloro or bromo.

R is alkyl, alkenyl or aryl and a metal catalyst selected but not restricted to Zn, Al, In, Sn or mixtures thereof.

In another embodiment as depicted in Scheme -2, the reaction in step (c) may be carried out in presence of Collins reagent wherein the Collins reagent is being made from MnO₂, chromium salts or chromium complexes.

The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.

Example-1: Preparation of Ethyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzoate:

Method-1:

Ethyl 3-formylbenzoate (48 g, 0.269 mol) and 7-chloroquinaldine (43.5g, 0.2451mol) were suspended in toluene (240 ml), added piperidine (4.9 ml; 0.049 mol) then heated to reflux for 10 hrs by collecting water azetropically. After completion of the reaction, distilled 50% of toluene from reaction mass under vacuum at below 70⁰C. The obtained residue was cooled to 20-25⁰C and stirred for 1 hr. The reaction mass was further cooled to O⁰C for and stirred for another 2 hrs at 0-5⁰C. To the reaction mass n-hexane (48 ml) was added and the precipitated was filtered and washed with n-hexane (12 ml). The isolated product was dried at 55-60⁰C for 4 hrs (wt. 60.0 g; 74% of yield; HPLC purity > 97%).

Method-2:

Ethyl 3-formylbenzoate (10 g, 0.05 mol) and 7-chloroquinaldine (9.9g, 0.05 mol) were suspended in xylene (50 ml), added piperidine (1 ml; O.Olmol), benzoic acid (0.68g; 0.005 mol), then heated to reflux for 20 hrs. After completion of the reaction, reaction mass was diluted with water (100 ml), separated the organic layer and aq. layer was extracted with toluene (3x 50 ml). The combined organic layers were washed with water (100 ml), and distilled around 80% of toluene. To the obtained residue n-hexane was added slowly with vigorous stirring at room temperature. After 1 h stirring at room temperature, cooled to 5⁰C and continued stirring for another 1 h for complete precipitation. The precipitated product is filtered and washed with chilled n-hexane and dried at 55-60⁰C under vacuum (wt: 11.5g; 60% of yield).

ExampIe-2: Preparation of Ethyl 3'-[((7-chloro-2-quinolinyl) ethenyl) phenyl]-3-oxo propanoate:

Sodium hydride (42.6 g; 0.88 mol) was suspended in THF (200 ml) and cooled to 5⁰C. Ethylacetate (56.7 ml; 0.58 mol) was added drop wise at same temperature and continued for 30 min, then Ethyl 3-[(7-chloro-2-quinolinyl)ethenyl)] benzoate (10Og; 0.29 mol) dissolved in THF (300 ml) was added slowly at 5-10⁰C. Reaction mass temperature was raised to 25- 30⁰C, and continued for 7 hrs. Again heated to 35-40⁰C and maintained for another 3 hrs. After completion of the reaction, reaction mass was cooled to 0-5⁰C and acetic acid (70 ml) was added slowly drop wise by maintaining temperature below 5⁰C to adjust the reaction mass PH at 5-6. Distilled THF from the reaction mixture and the obtained residue was suspended in a mixture of water (500 ml) and toluene (500 ml), then filtered through celite bed and washed with toluene (50 ml). Organic layer was separated and athe aq.layer was extracted with toluene (100 ml). The combined toluene layers were washed with water (250 ml) distilled around 75-80% of solvent. To the obtained residue n-hexane was added slowly drop wise at room temperature to precipitate the compound. Continued stirring at room temperature for another lhr. The precipitated product was filtered and dried to get the product (wt; 108 g; 96% of yield).

Example-3: Preparation of 3-[((7-chIqro-2-quinoIinyl) ethenyl)] benzaldehyde:

Isophthaldehyde (8.3 g, 0.0619 mol), 7-chloroquinaldine (10.0g, 0.05629 mol) and piperidine (0.95 g; 0.01115 mol) were suspended in toluene (50 ml) then heated to reflux for 12 h by collecting water azeotropically. After completion of the reaction, reaction mass was cooled to 20-25⁰C and stirred for 1 hr. The reaction mass was further cooled to 0-5 ⁰C and stirred for another 1-2 h at 0-5 ⁰C. The precipitated product was filtered and washed with n-hexane (12 ml). The product was dried at 55-60 ⁰C for 6 h (wt: 10.0 g; 60% of yield).

Example-4: Preparation of Ethyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phenyl]-3- hydroxy propanoate:

A mixture of activated zinc (13.32g ; 0.204 mol) , toluene (20 ml) and diethylether (20 ml) were heated to 60⁰C and added a solution of 3-[((7-chloro-2-quinolinyl) ethenyl)] benzaldehyde (2Og; 0.068 mol) dissolved in mixture of toluene (20 ml) and diethylether (20 ml) slowly at the same temperature and maintained for another 30-45 min at 60° - 70⁰C. Then ethyl bromo acetate (22.75g; 0.136 mol) was added at 60-70⁰C and maintained for 3 hrs. After completion of the reaction, reaction mass was cooled to 20⁰C₅ separated the upper solvent phase and lower solid phase was dissolved in 10% aq. HCl (200 ml) and stirred for another 2 hrs at room temperature. Compound was extracted into ethylacetate, washed with 10% aq. Sodium bicarbonate solution (50 ml) followed by vacuum salt (50 ml). Separated the organic layer, dried on sodium sulphate, filtered and concentrated to give the product (wt: 12g; 46% of yield).

ExampIe-5: Preparation of Ethyl [E]-3'-[((7-chloro-2-quinolinyl) ethenyI)phenyI]-3- oxo propanoate: Ethyl-3'-[((7-chloro-2-quinolinyl) ethenyl) phenyl] -3 -hydroxypropanoate (0.5g; 0.0013 mol) was dissolved in dichloromethane (5.0 ml). To this added slowly a freshly prepared Collins reagent prepared from chromium oxide (0.39g; 0.0039 mol), pyridine (0.3 Ig; 0.0039 mol) in dichloromethane (20.0 ml). The resultant reaction mass was stirred at 20-25 ⁰C for 12 hrs. After completion of the reaction, reaction mass was diluted with water (10 ml). Organic layer was separated and washed with 10% aq. HCl (10 ml) followed by vacuum salt (10 ml). The organic layer was dried on sodium sulphate and concentrated to give the product (0.2g, 40% of yield).

Claims

We claim;

1. A process for synthesizing a compound of formula III

wherein R is alkyl, alkenyl, aryl or arylalkyl comprising the steps of: a. condensing alkyl 3-formylbenzoate with 7-Chloroquinaldine to give alkyl 3-[((7- chloro-2-quinolinyl)ethenyl)] benzoate; and

b. reacting alkyl 3-[((7-chloro-2-quinolinyl)ethenyl)] benzoate with an alkyl ester in presence of a base to obtain a compound β- ketoester of structural formula III

2. The process as claimed in claim 1, wherein the reaction in step (a) is carried out in an organic solvent alone or in the presence of an organic amine or in presence of an amine and an organic acid

3. The process as claimed in claim 1, wherein the organic amine used is selected from primary amine, secondary amine, tertiary amine and mixtures thereof

4. The process as claimed in claim 1, wherein the organic acid used is selected from acetic acid, pivalic acid or benzoic acid

5. The process as claimed in claim 1, wherein the organic solvent used is selected but not restricted from the groups aliphatic hydrocarbons, aromatic hydrocarbons, esters, halogenated hydrocarbons and mixture there of.

6. The process as claimed in claim 1, wherein the reaction in step (b) is being carried out in presence of a solvent selected from methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate and mixture thereof.

7. The process as claimed in claim I₅ wherein the reaction in step (b) is being carriedout in presence of hydrides and alkoxides of alkali metals and alkaline earth metals,

8. The process as claimed in claim 5, wherein the preferable base is sodium hydride

9. A process for synthesizing a compound of formula III

wherein R is alkyl, alkenyl, aryl or arylalkyl comprising the steps of:

a) reacting isophthalaldehyde of formula (IV) with 7-chloroquinaldine in presence of an amine in a suitable organic solvent to get an aldehyde of formula (V), b) converting the said aldehyde of formula (V) to its corresponding hydroxy ester of formula (VI) c) treating the said hydroxy ester of formula (Vl) with Collins reagent in an organic solvent to get the desired compound β- ketoester of formula (m).

10. The process as claimed in claim 9, wherein the reaction in step (a) is carried out in an organic solvent in the presence of an organic amine

11. The process as claimed in claim 10, wherein the organic solvent used is selected from the groups aliphatic hydrocarbons, aromatic hydrocarbons, esters, halogenated hydrocarbons and mixture there of

12. The process as claimed in claim 10, wherein the organic amine used is selected from primary amine, secondary amine, tertiary amine and mixtures thereof

13. The process as claimed in claim 9, wherein the reaction in step (b) is carried out in presence of α-haloester of the structural formula XCH₂COOR wherein X is chloro or bromo

R is alkyl, alkenyl or aryl and a metal catalyst selected from Zn, Al, In, Sn and mixtures thereof.

14. The process as claimed in claim 9, wherein the reaction in step (c) is carried in presence of Collins reagent wherein the Collins reagent is being made from MnO₂, chromium salts or chromium complexes.