CLIAMS:N/A ,TagSPECI:
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“PROCESS FOR PREPARING POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES”

2. APPLICANT:

(a) NAME: CIPLA LTD.

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Mumbai Central, Mumbai – 400 008, Maharashtra, India.

3.PREAMBLE TO THE DESCRIPTION:

The following specification describes the invention.

Field of the invention:

The present invention relates to a novel process for synthesis of polycyclic carbamoyl pyridone derivatives, and to novel intermediates which are produced during the course of carrying out the novel process.

Background of the invention:

Polycyclic carbamoyl pyridone derivatives are known to act as human immunodeficiency virus type-1(HIV-1) integrase strand transfer inhibitors (INSTI) in combination with other antiretroviral medicinal products for the treatment of HIV-1infection in adults and children aged 12 years and older and weighing at least 40 kg.

US8129385 B2 incorporated by reference in its entirety describes various polycyclic carbamoyl pyridone derivatives and process for their preparation.

Among these polycyclic compounds, following tricyclic carbamoyl pyridone derivatives of formula (I) are included:-

wherein n is an integer of 0 to 3.

Structure–activity studies demonstrated that the tricyclic series of carbamoyl pyridines had superior potency against resistant viral strains.

The processes disclosed in the prior art are multistep and hence cumbersome. Therefore, there exists a need for a simple, more economical and efficient method of making tricyclic carbamoyl pyridone derivatives which is suitable for industrial scale-up.

The process of the present invention provides, large scale synthesis of tricyclic carbamoyl pyridone derivatives having high degree of chromatographic and optical purity and low residual solvent content.

Object of the invention:

The object of the present invention is to provide a novel process for preparing tricyclic carbamoyl pyridone derivatives of formula (I).

Yet another object of the present invention is to provide a novel process which proceeds via new chemical intermediate for the synthesis of tricyclic carbamoyl pyridone derivatives of formula (I).

Yet another object of the present invention is to provide process for the preparation of the novel intermediates useful in the synthesis of the tricyclic carbamoyl pyridone derivatives.

Yet another object of the present invention is to provide a process for the synthesis of tricyclic carbamoyl pyridone derivatives of formula (I) which is simple, economical and suitable for industrial scale-up.

Summary of the Invention:

In a first aspect, the present invention provides a process for preparing tricyclic carbamoyl pyridone derivatives of formula (I) or a salt thereof,

which comprises converting a compound of formula (V)

into compound of formula (I), wherein n is an integer of 0 to 3, preferably 1 to 3 and R in formula (V) is a protecting group selected from lower alkyl, preferably a straight or branched C1-C6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl or substituted or unsubstituted silyl or C6- C11 aryl and R1 and R2 in formula (V) are either same or different, selected from a lower alkyl group, preferably a straight or branched C1-C6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

The tricyclic carbamoyl pyridone derivatives of formula (I) may be depicted in the form of R or S isomer.

In an embodiment, the conversion comprises, contacting the compound of formula (V) with an acid to provide compound of formula (IV)

wherein R and R1 are as defined above.

The process of the present invention may further comprise the step of contacting compound of formula (IV) with an amine compound of formula (III)

optionally in the presence of an acid to provide a compound of formula (II),

wherein n and R are as defined above.

The amine compound of formula (III) and compound of formula (II) may be depicted in the form of R or S isomer.

The process of the present invention may further comprise the step of deprotecting compound of formula (II) with a deprotecting agent to from a compound of formula (I).

The compound of formula ( I ) obtained by the process of the present invention may be optionally converted to the pharmaceutically acceptable salts thereof.

In another aspect the present invention provides a compound of formula (V)

wherein R, R1 and R2 are as defined above.
According to yet another aspect of the present invention, there is provided a process for preparing compound of formula (V), comprising converting a compound of formula (VII)

to compound of formula (V), wherein R, R1 and R2 are as defined above.

In an embodiment, the conversion comprises coupling compound of formula (VII) with
2,4-diflurobenzyl amine of formula (VI)

in the presence of a coupling reagent to provide compound of formula (V).

In another aspect the present invention provides a process substantially as herein described with reference to the examples.

In another aspect the present invention provides tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by the processes substantially as herein described with reference to the examples.

In another aspect the present invention provides a use of tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by the process of the present invention for the manufacture of therapeutic agent.

In another aspect the present invention provides a use of tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by the process of the present invention, for treating HIV-AIDS.

In another aspect the present invention provides a method of treating HIV-AIDS, comprising administering the tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by a process of the present invention.

Further features are defined in the dependent claims.

Detailed Description of the Invention:

In an embodiment of the present invention, there is provided an improved synthesis of tricyclic carbamoyl pyridone derivatives of formula (I), as depicted below in the general reaction scheme 1.

Scheme 1

(Bracket indicates that the intermediate could be isolated, but is not isolated in the present invention.)

wherein n is an integer of 0 to 3, preferably 0 to 2 and R is a protecting group selected from lower alkyl, preferably a straight or branched C1-C6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl or C6- C11 aryl and R1 and R2 are same or different, selected from a lower alkyl group, preferably a straight or branched C1-C6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

Compounds of formula (I), (II) and (III) may be depicted in the form of R or S isomer.
The compound of formula (V) is one of the hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of formula (I) as described herein.

In one embodiment of the invention, compound of formula (V) is preferably converted to aldehyde compound of formula (IV) by reacting with an acid. Preferably the reaction is carried out in the presence of a catalytic amount of a strong protic acid. Examples of acid include but are not limited to hydrobromic acid, phosphoric acid, formic acid, trifluoro acetic acid, maleic acid, benzoic acid, carbonic acid and oxalic acid.
Examples of strong protic acid include but are not limited to hydrochloric acid, nitric acid, methane sulfonic acid, sulfuric acid, p-toluene sulfonic acid.

Preferably acetic acid or formic acid are used as a solvent in the combination with any of the strong protic acids as described above.

The reaction is preferably carried out in a co-solvent. The co-solvent assists in enhancing solubility of compounds having poor water solubility, thereby increasing the overall rate of the reaction. Examples of co-solvent include but are not limited to polar solvents, non polar solvents and mixture thereof.

The reaction is typically carried out at a temperature in the range of from about -70°C to about boiling point of the solvent used. Preferably, the reduction step is carried out at a temperature in the range of from about -10°C to about 80°C. In still other embodiments, it is carried out at a temperature in the range of from about 20°C to about 75°C. In a particularly preferred embodiment the reaction is carried out at 65-70ºC.

The aldehyde compound of formula (IV) may be isolated by general purification method or may be used in the next step without isolation. Preferably, aldehyde compound of formula (IV) is used in the next step without isolation.

In another embodiment of the invention, aldehyde compound of formula (IV) is reacted with an amine compound of formula (III) optionally in the presence of an acid to provide a compound of formula (II).

Examples of an acid include but are not limited to hydrobromic acid, phosphoric acid, formic acid, trifluoro acetic acid, maleic acid, benzoic acid, carbonic acid, oxalic acid hydrochloric acid, nitric acid, methane sulfonic acid, sulfuric acid and p-toluene sulfonic acid.

The reaction is preferably carried out in the presence of a solvent. The reaction solvents include but are not limited to polar solvents, non-polar solvents and mixture thereof.

The reaction is carried out at temperature ranging from 20°C to reflux temperature of the solvent used, preferably 60°C to 80°C.

In another embodiment of the invention, the compound of formula (II) is deprotected to obtain tricyclic carbamoyl pyridone derivatives of formula (I).

When R is alkyl, the deprotection is carried out in the presence of a Lewis acid. The Lewis acids include but are not limited to boron trihalides like BBr3 or BF3.Eto2, trialkyl silyl halides likes (CH3)3.Si-I or magnesium, calcium or lithium cation and a nucleophilic anion. The deprotection is preferably carried out using magnesium or lithium cation and a nucleophilic anion. Example of magnesium cation and a nucleophilic anion include but are not limited to magnesium bromide, magnesium chloride, magnesium iodide and magnesium sulphide. Example of lithium cation and a nucleophilic anion include but are not limited to lithium bromide, lithium chloride, lithium iodide and lithium sulphide. Most preferably the Lewis acid used is lithium bromide.

When R is silyl, the deprotection is carried out in in the presence of tetramethyl ammonium fluoride, tert-butyldimethylsilyl (TBDMS) ether or tert-butyldiphenylsilyl (TBDPS) ether.

When R is aryl, the deprotection is carried out in the presence of hydrogenation catalysts like Pd-C, Pt-C and Raney-Ni.

The reaction is carried out at temperature ranging from 20°C to reflux temperature of the solvent used, preferably 60°C to 80°C.

The tricyclic carbamoyl pyridone derivatives of formula (I) may be optionally purified in a suitable solvent.

The tricyclic carbamoyl pyridone derivatives of formula (I) may be converted to the pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts include but are not limited to the alkali metal salts such as sodium, potassium, calcium, lithium, magnesium; olamine and the like.

According to another aspect of the present invention, there is provided a process for preparing a compound of formula (V) as exemplified in Scheme 2.

Scheme 2

wherein R, R1 and R2 are as defined above.
In an embodiment, compound of formula (VII) is condensed with 2,4-diflurobenzyl amine of formula (VI) using a coupling reagent in the presence of an inert organic solvent to provide compound of formula (V).

A suitable coupling reagent for use in a process according to the present invention can be selected from the group comprising of phenylsilane, 1,1’-carbonyldiimidazole (CDI), benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP), 1-hydroxy benzotriazole hydrate (HOBt), PyBOP (Analog of the BOP), 1,3-dicyclohexylcarbodiimide (DCC), n-Ethyl-N’-(3-dimethylaminopropyl)carbodidimide hydrochloride (EDC HCl). These agents act in situ as activating reagents and convert the carboxylic acids to more reactive intermediates. Phenylsilane, can act as an in situ carboxylic acid activating agent, and can be effectively used as a coupling reagent to prepare carboxamides and peptides. A particularly suitable coupling reagent for use in the above process according to the present invention is CDI.

By “inert organic solvent” is meant an organic solvent, which under the reaction conditions of a process according to the present invention, does not react with either the reactants or the products. A suitable inert organic solvent for use in a process according to the present invention can be selected from the group consisting of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, sulfolane, diglyme, 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone, dichlromethane (MDC), toluene, xylene and other inert organic solvents known in the art. A particularly suitable inert organic solvent for use in the above process according to the present invention is dichlromethane.

The process is carried out at a temperature ranging from 5°C to the boiling point of the reaction mass until no starting material is detectable. Preferably, the reaction is carried out at 10-40°C, more preferably at 25-30°C.

In one preferred embodiment when R, R1 and R2 are methyl, n is an integer of 2 and wherein compound of formula (III) is in the form of R isomer, the compound obtained by the process of the invention includes compound of formula ( Ia)

Accordingly a process for preparing a compound of formula (Ia) is exemplified in Scheme 3.
Scheme 3

In another preferred embodiment when R, R1 and R2 are methyl, n is an integer of 1 and wherein compound of formula (III) is in the form of S isomer, the compound obtained by the process of the invention includes compound of formula ( Ib)

Accordingly a process for preparing a compound of formula (Ib) is exemplified in Scheme 4.
Scheme 4

According to yet another aspect of the present invention, there is provided an alternate process for preparing tricyclic carbamoyl pyridone derivatives of formula (I) as exemplified in Scheme 5 below.

Scheme 5

whererin R, R1, R2 and n are as defined above.

Compounds of formula (I) and (III) may be depicted in the form of R or S isomer.

The processes of the present invention allows synthesis of tricyclic carbamoyl pyridone derivatives of formula (I) with high degree of chromatographic and optical purity.

According to a further aspect of the present invention, there is provided tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by (or obtained by) a process according to any process of the present invention as described in the present disclosure.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising tricyclic carbamoyl pyridone derivatives of formula (I), obtainable by (or obtained by) any process of the present invention as described in the present disclosure, optionally together with one or more pharmaceutically acceptable excipients. Such excipients are well known to those skilled in the art.

According to another aspect of the present invention, there is provided the use of tricyclic carbamoyl pyridone derivatives of formula (I), obtainable by (or obtained by) any process of the present invention as described in the present disclosure, in the treatment of HIV-AIDS.

According to another aspect of the present invention, there is provided a method of treating HIV-AIDS in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of tricyclic carbamoyl pyridone derivatives of formula (I), obtainable by (or obtained by) any process of the present invention as described in the present disclosure.

In accordance with the invention as herein described, there is provided a process for preparation of tricyclic carbamoyl pyridone derivatives of formula (I) which is simple, economical and suitable for industrial scale-up.

While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

The following non-limiting Examples illustrate the processes of the present invention.

Examples:-
Example 1
Preparation of compound (V) (R, R1 and R2= methyl)
The compound (VII) (5 g, 0.015 mol), was stirred in MDC (50 ml) at 25-30ºC and CDI ( 4.37 g, 0.027 mol) was added. After the solution was stirred at 35-40ºC for 1 hour, cooled to 25-30ºC. To this compound (VI) 2,4-difluorobenzylamine ( 2.72 g, 0.019 mol) was added and the reaction mixture was further stirred for 1 hour at 25-30ºC. The reaction mixture was added to water (50 ml). To the reaction solution MDC was added, exacted and the organic layer was washed with dil HCl solution, brine solution, an aqueous saturated sodium bicarbonate solution and finally with brine solution. The solvent was distilled off under reduced pressure to obtain titled compound ( 4 g, 57 %).

Example 2
Preparation of compound (IIa) (R, R1 and R2= methyl; n =2)
The compound (V) (4 g, 0.009 mol ) was dissolved in acetonitrile (40 ml) and acetic acid ( 8ml) and methane sulfonic acid ( 2.4 ml ) were added at 25 -28°C. After the reaction mass was stirred at 65-70°C for 9 hours, solution of compound (IIIa) (R)-3 -amino-butan-1-ol (1.72 ml, 0.02 mol ) in acetonitrile (4 ml) was added and the reaction mixture was further stirred for 5 hours. After the reaction mixture was cooled to 25-30°C, the solvent was distilled off under reduced pressure at 40-45°C.To the reaction mass was added MDC (40 ml) and quenched in dil HCl solution (40 ml). The organic layer was washed with water. The solvent was distilled off under reduced pressure to obtain titled compound (3 g, 75 %).

Example 3
Preparation of compound (Ia) (n =2)
To a solution of compound (IIa) (3 g, 0.0069 mol ) in THF (30 ml) was added anhydrous LiBr ( 1.2 g, 0.01385 mol). The reaction mixture was heated to 65-70°C for 4 hours. After the reaction mixture was cooled to room temperature, quenched in dil HCl solution ( 30 ml), extracted in MDC( 30 ml). The organic layer was washed with water and the solvent was distilled off under reduced pressure. The reaction mixture was stirred in methanol ( 15 ml) for 1 hour at room temperature. The solid was isolated by filtration, washed with methanol and dried to obtain titled compound ( 2 g, 69 % ).

Example 4
Preparation of sodium salt of compound (Ia) (n =2)
The compound (Ia) ( 2 g, 0.047mol) was dissolved in methanol ( 20 ml) at 58-60°C. To the reaction mixture was added 2N aqueous NaOH solution ( 2.2 ml) and stirred further for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was isolated by filtration, washed with methanol and dried to obtain titled compound ( 1.8 g, 85 %).

Example 5
Preparation of olamine salt of compound (Ia) (n =2)
The compound (Ia) (10 g, 0.0238 mol) was dissolved in methanol ( 50 ml) at 25-28°C. The reaction mass was heated to 58-60°C. The solution of ethanolamine (1.45g, 0.0238 mol) in methanol (50 ml) was added. The reaction mass was further stirred at for 58-60°C for 1 hour. The reaction mixture was cooled to room temperature and stirred further for 1 hour. The solid was isolated by filtration, washed with methanol and dried to obtain titled compound ( 9 g, 78 %).

Example 6
Preparation of compound (IIb) (R, R1 and R2= methyl; n =1)
The compound (V) (5 g, 0.011 mol ) was dissolved in acetonitrile (50 ml) and acetic acid ( 10 ml) and methane sulfonic acid ( 3 ml ) were added at 25 -28°C. After the reaction mass was stirred at 65-70°C for 9 hours, solution of compound (IIIb) (S)-2-amino-propan-1-ol (1.8 g, 0.024 mol ) in acetonitrile ( 5 ml) was added and the reaction mixture was further stirred for 5 hours. After the reaction mixture was cooled to 25-30°C, the solvent was distilled off under reduced pressure at 40-45°C.To the reaction mass was added MDC (50 ml) and quenched in dil HCl solution (50 ml). The organic layer was washed with water. The solvent was distilled off under reduced pressure to obtain titled compound (3.3 g, 70 %).

Example 7
Preparation of compound (Ib) (n =1)
To a solution of compound (IIa) (2 g, 0.0047 mol ) in acetonitrile (80 ml) was added anhydrous MgBr2 ( 2.13 g, 0.011 mol). The reaction mixture was heated to 50-55°C for 2 hours. After the reaction mixture was cooled to room temperature, quenched in dil HCl solution (100 ml), extracted in MDC (40 ml). The organic layer was washed with water and the solvent was distilled off under reduced pressure to obtain titled compound (1.36 g, 70 %).

Example 8
Preparation of sodium salt of compound (Ib) (n =1)
The compound (Ib) ( 2 g, 0.049mol) was dissolved in methanol ( 20 ml) at 58-60°C. To the reaction mixture was added 2N aqueous NaOH solution ( 2. 5 ml) and stirred further for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was isolated by filtration, washed with methanol and dried to obtain titled compound ( 1.68 g, 79 %).

Dated this 20th day of May, 2014

Andreya Fernandes
(Regn.No.: IN/PA 1777)
Agent for the Applicant
Gopakumar Nair Associates