DESC:Field of the invention

The present invention relates to a novel process for the 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-1 infection in adults and children aged 12 years and older and weighing at least 40 kg.

US8129385 B2 and WO2014100323, incorporated herein in their entirety by reference, describe various polycyclic carbamoyl pyridone derivatives and processes for their preparation. Among these polycyclic compounds, are disclosed the following tricyclic carbamoyl pyridone derivatives, of formula (A):

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein,
Ar is aryl substituted with one to three halogens;
W1 and W2 are each independently, hydrogen, C1-6 alkyl, or C1-6 haloalkyl; or
W1 and W2, together with the carbon atom to which they are attached, form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more Rx, wherein each Rx is, independently, hydrogen, halo, hydroxyl or C 1-6 alkyl, or wherein two Rx groups together with the carbon atom to which they are attached, form =0;
Y1 and Y2 are independently hydrogen, hydroxy, optionally substituted C1-8 alkyl, C1-8 haloalkyl, C1-8 alkenyl or C1-8 alkoxy, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aryloxy or optionally substituted heterocyclic group; and
D ring is optionally substituted and optionally condensed 5 to 7 membered heterocycle containing 1 to 2 hetero atom(s); wherein heteroatom is selected from N, O or S.

Preferred tricyclic carbamoyl pyridone derivatives of formula (A) include those compounds of formula (B):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
Ar is aryl substituted with one to three halogens;
W1 and W2 are each independently, hydrogen, C1-8 alkyl, or C1-8 haloalkyl; or
W1 and W2, together with the carbon atom to which they are attached, form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more Rx group;
X is -0- or –NW4 -or –CHW4;
Y is –CHW5;
W3, W4 and W5 are each independently, hydrogen or C1-8 alkyl, C6-14 aryl, C1-8 alkyl, C6-14 aryl or alkoxy; or wherein W3 and W4 or W3 and W5 taken together form a carbocyclic ring containing having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more Rx group, wherein each Rx is, independently, hydrogen, halo, hydroxyl or C1-8 alkyl, or wherein two Rx groups together with the carbon atom to which they are attached, form =0;
Z is a bond, [-CH2-]n or Y and Z taken together form [-CH2-]n; wherein n is an integer of 0 to 3.

Preferred tricyclic carbamoyl pyridone derivatives of formula (B) include those compounds of formula (I):

wherein, n is an integer of 0 to 3.

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

The fact that tricyclic series of carbamoyl pyridines are effective against viral strains is of utmost importance. At the same time it is necessary that these effective compounds are available at an economic rate and are easily manufactured. It is also necessary that these compounds are easily manufactured with no or minimal production hazards and that there exist simple and efficient methods to manufacture the same on the production floor.

H. Wang et al., Organic Letters, 2015, 17(3), 564-567 discloses the synthesis of GSK1265744, a tricyclic carbamoyl pyridone derivative having antiretroviral activity.

EP2527007B discloses certain polycyclic carbamoyl pyridine derivatives and a process for preparing such compounds.

Although a number of processes for preparing tricyclic carbamoyl pyridone derivatives have been previously disclosed and claimed, the processes disclosed in the prior art are multistep and hence cumbersome. Therefore, there exists a need to develop a simple, more economical, cost effective and efficient method of manufacturing the tricyclic carbamoyl pyridone derivatives that is suitable for industrial scale-up.

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

Objects of the invention

The object of the present invention is to provide a novel process for preparing tricyclic carbamoyl pyridone derivatives of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a novel process which proceeds via novel chemical intermediates for the synthesis of tricyclic carbamoyl pyridone derivatives of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.

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 of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof.

Yet another object of the present invention is to provide, large scale synthesis of tricyclic carbamoyl pyridone derivatives of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof having high degree of chromatographic and optical purity and low residual solvent content.

Yet another object of the present invention is to provide a process for the synthesis of tricyclic carbamoyl pyridone derivatives of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof 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 stereoisomer or pharmaceutically acceptable salt thereof,
which process comprises converting a compound of Formula (V):

into compound of Formula (I); wherein R1 and R2 in Formula (V) are same or different and are selected from a lower alkyl group, preferably a straight or branched C1-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl and wherein, n is an integer of 0 to 3.

The tricyclic carbamoyl pyridone derivatives of Formula (I) may be in the form of the R or S isomer or a mixture thereof.

In an embodiment, the conversion of a compound of Formula (V) to a compound of Formula (I) comprises cyclization of compound of Formula (V) with an acid; to form a tricyclic carbamoyl pyridinone compound of Formula (IV):
;

coupling the compound of Formula (IV) with 2,4-diflurobenzyl amine of Formula (III):

in the presence of a coupling reagent to provide compound of Formula (II)
;
followed by deprotection to obtain a tricyclic carbamoyl pyridone derivative of formula (I); wherein R2 and n are as defined above.

In another aspect, the present invention provides a compound of Formula (V):

According to yet another aspect of the present invention, there is provided a process for preparing compound of Formula (V), comprising the steps of:
coupling a compound of Formula (VI):

with a compound of Formula (VII):

wherein, R1, R2 and n are as defined above; X is leaving group preferably halide, to obtain a compound of Formula (V).

In a yet another aspect, the present invention provides a compound of Formula (VI) and a compound of Formula (VII).

In a yet another aspect, the present invention provides a process for preparing a compound of Formula (VII), comprising the steps of:
contacting a compound of formula (IX)

with haloacetaldehyde of Formula (VIII):

or haloacetaldehyde dimethyl acetal of Formula (XXIII):

optionally in the presence of an acid, to provide a compound of formula (VII); wherein n and X areas defined above and R is a lower alkyl group, preferably a straight or branched C1-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

In a yet another aspect, the present invention provides a process for preparing a compound of Formula (IX), comprising the steps of:
dehydroxylation of compound of Formula (X):

wherein n is as defined above.

In a yet another aspect, the present invention provides processes for preparing a compound of Formula (X).

The amine compounds of Formula (X), (IX), (VII) and (V) may be in the form of the R or S isomer.

The compound of Formula (I) obtained by the process of the present invention may be optionally converted to a pharmaceutically acceptable salt thereof by reaction with a suitable base.

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) or a stereoisomer or pharmaceutically acceptable salt thereof, obtainable by the process of the present invention for the manufacture of medicament, preferably an antiretroviral for the treatment of HIV-AIDS.

In another aspect, the present invention provides a use of tricyclic carbamoyl pyridone derivatives of Formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, 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) or a stereoisomer or pharmaceutically acceptable salt thereof, obtainable by a process of the present invention.

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

Further features of the present invention are defined in the dependent claims.

Detailed Description of the Invention

In an embodiment of the present invention, there is provided a process for preparing tricyclic carbamoyl pyridone derivatives of Formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, as depicted below in the general reaction Scheme 1.

Scheme 1

wherein, R1 and R2 are same or different, and are selected from a lower alkyl group, preferably a straight or branched C1-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl; X is “hal”, “halo" or "halogen" and refers to bromo, chloro, fluoro or iodo; and n is an integer of 0 to 3.

Unless otherwise stated, the term “lower alkyl” means a C1-8 alkyl group, preferably a straight or branched C1-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

R is a lower alkyl group, and X is halo as defined above.

Compound of Formula (I), (II), (IV), (V) (VII), (IX) and (X) may be in the form of the R or S isomer or a mixture thereof.

The compounds of formula (V), (VI) and (VII) are hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of Formula (I) as described herein.

In one embodiment compound (X) i. e. diol intermediate is reduced with suitable reducing agent in the presence of suitable solvent to form amino alcohol of formula (IX).

Preferably, the reducing agents are selected from but not limited to lithium aluminium hydride/THF, tributyl tin hydride/toluene and sodium tetrahydroborate/sodium periodate.

Generally, the reaction solvent must be inert. Examples of suitable solvents include, but are not limited to, alkanols, such as methanol, ethanol, propanol and isopropanol (IPA); aromatic hydrocarbons, such as benzene, toluene, the xylenes and the like; aliphatic hydrocarbons, such as pentane, hexane, octane and the like; ethers, such as diether ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran (THF), 1,4-dioxane and the like; and such miscellaneous solvents as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO). The preferred solvents are alkanols.

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 a temperature in the range from about 65 to about 70ºC.

In another embodiment compound (IX) is reacted with 2-haloacetaldehyde (VIII) in a suitable solvent to form compound (VII).

Alternatively, compound (IX) is reacted with 2-haloacetaldehyde dimethyl acetal (XXIII) in a suitable solvent to form compound (VII).

Preferably, a dehydrating agent is added to enhance the rate of the reaction. Preferred dehydrating agent includes but not limited to methane sulfonic acid and p-toluene sulfonic acid.

Preferred solvents include but not limited to hydrocarbon solvent such as toluene, xylene and halogenated hydrocarbon solvents such as methylene chloride, ethylene chloride; ethers such as THF, diethyl ether, 1,4-dioxane, and IPA.

Alternatively, reaction may be conducted in the absence of a solvent.

The reaction is carried out at temperature ranging from 20°C to the reflux temperature of the solvent used, preferably 60°C to 150°C, more preferably 100°C to 120°C.

In another embodiment compound (VII) is condensed with acid compound (VI) in the presence of suitable base to form compound (V).

Preferred base includes organic bases and inorganic bases. A suitable inorganic base according to the present invention is selected from the group consisting of alkali metal
hydroxides, alkali metal carbonates and alkali metal alkoxides. The organic base is selected form the group consisting of pyridine, diethyl amine, triethyl amine, diisopropyl ethyl amine.

The reaction is preferably carried out in the presence of a suitable solvent. Preferred solvents include but not limited to the polar and nonpolar solvents. The suitable non-polar solvent is selected from the group consisting of halogenated solvent such as chloroform, dichloromethane (MDC), 1,2-dichloroethane (EDC); polar solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP), sulfolane, diglyme, 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone and mixture thereof.

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

In another embodiment, compound (V) is cyclized, optionally in the presence of an acid, to provide a compound of formula (IV).

Examples of suitable acids 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. Preferred solvents include methylene chloride, toluene and acetonitrile.

The reaction is carried out at temperature ranging from 0°C to the reflux temperature of the solvent used, preferably 60°C to 80°C.

The cyclised compound of formula (IV) may be isolated by general purification methods known in the art or may be used directly in the next step without isolation. Preferably, the cyclised compound of formula (IV) is used without isolation.

In another embodiment the compound of formula (IV) is coupled with 2,4-diflurobenzyl amine of formula (III), in the presence of a coupling reagent and an inert organic solvent or mixture of solvents thereof to provide compound of formula (II).

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) phosphonium 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), HATU, chloroformates such as Ethyl chloroformate or isobutyl chloroformate. 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. A particularly suitable coupling reagent for use in the above process according to the present invention is ethyl chloroformate or isobutyl chloroformate.

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 (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), sulfolane, diglyme, 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, acetone, dichloromethane (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 NMP.

The coupling reaction is carried out at a temperature ranging from about 5°C to the boiling point of the reaction mass until no starting material is detectable.

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

When R is alkyl, the deprotection step is suitably carried out in the presence of a Lewis acid. Examples of suitable Lewis acids include, but are not limited to, boron trihalides such as BBr3 or BF3.Et2O, trialkyl silyl halides such as (CH3)3.Si-I or magnesium, calcium or lithium cation and a nucleophilic anion. The deprotection step is preferably carried out using magnesium or lithium cation and a nucleophilic anion. Examples of suitable magnesium cation and a nucleophilic anion include, but are not limited to, magnesium bromide, magnesium chloride, magnesium iodide and magnesium sulphide. Examples of suitable 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 step is suitably carried out in the presence of tetramethyl ammonium fluoride, tert-butyldimethylsilyl (TBDMS) ether or tert-butyldiphenylsilyl (TBDPS) ether.

When R is aryl, the deprotection step is suitably carried out in the presence of a hydrogenation catalyst such as Pd-C, Pt-C and Raney-Ni.

The reaction is carried out at a temperature in the range from about 20°C to the reflux temperature of the solvent used, and is preferably in the range from about 60°C to about 80°C.

The tricyclic carbamoyl pyridone derivatives of Formula (I) may be optionally purified in a suitable solvent or mixture of solvents.

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

In one preferred embodiment, when X is bromo, R is methyl R1 is ethyl and R2 is methyl, n is an integer of 2 and wherein compound of Formula (V) 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) according to the present invention is exemplified in Scheme 2.

Scheme 2

Compound of Formula (Ia), (IIa), (IVa), (Va) (VIIa), (IXa) and (Xa) are in the form of the R isomer.

The compounds of formula (Va), (VIa), and (VIIa) are hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of Formula (Ia) as described herein.

According to another aspect of the present invention, there is provided a process for preparing a compound of formula (Xa) as exemplified in Scheme 3.

Scheme 3

In an embodiment, solketal (XIII) can be produced by condensation reaction of glycerol (XIV) and acetone with acid catalyst such as p-toluene sulfonic acid (PTSA). Optionally, 2,2-dimethoxy propane (DMP) may be used as a water scavenger to increase rate of the reaction.

Solketal (XIII) obtained could be in the form of either the racemate or as one of the two enantiomers R and S. In the present invention, solketal (XIII) is preferably in the form of R enantiomer, which is further oxidized to aldehyde (XII) using pyridinium chlorochromate in dichloromethane or by Swern oxidation using oxalyl chloride, dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine.

The aldehyde (XII) is then reacted with ammonia in the presence of a Lewis acid to give chiral intermediate (XI). Examples of suitable Lewis acids include, but are not limited to, boron trihalides such as BBr3 or BF3.Et2O, trialkyl silyl halides such as (CH3)3.Si-I or magnesium, calcium or lithium cation and a nucleophilic anion.

The intermediate (XI) is further deprotected by acid catalyzed transacetalization in acetone or hydrolysis in wet solvents or in aqueous acid to obtain a 1,3-dicarbonyl compound of formula (Xa). Alternatively, some strong oxidation agents such as per chloric acid (HClO4) in MDC may cleave ketals. The reaction may be accelerated upon the addition of the phase-transfer catalyst such as tetra-n-butylammonium bromide (TBAB), tetra-n-butylammonium iodide (TBAI), methyltrioctylammonium chloride and the like.

Yet an alternative process for preparing a compound of Formula (Xa) according to the present invention is exemplified in Scheme 4.

Scheme 4

The compounds of formula (XVI) and (XV) are hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of Formula (I) as described herein.

In an embodiment, aldehyde (XII) is reacted with R-phenylethylamine (XVII) to give novel intermediate enamine (XVI). The reaction is preferably carried out in the presence of an inert organic solvent or mixture of solvents thereof.

The enamine (XVI) may be isolated by general purification methods known in the art or may be used in the next step without isolation. Preferably, the enamine (XVI) is used without isolation.

The enantioselective addition of methyl lithium to intermediate imine (XVI) affords the secondary amine (XV). The reaction is preferably conducted in the presence of BF3 etherate or dimethylcuprate-boron trifluoride at a temperature ranging from about
-78°C to the reflux temperature of the inert solvent used.

The amine (XV) is first debenzylated and then deprotected using a suitable deprotecting reagent to obtain a 1,3-dicarbonyl compound of formula (Xa). As is well known to the skilled person, the deprotection reagent depends on the nature of the protecting group. The deprotection may comprise hydrogenolysis of the compound of formula (XV) in the presence of a noble metal catalyst and hydrogen gas. Typically, a preferred method for deprotection of formula XV to compound of formula Xa, is catalytic reduction using catalysts such as palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel. The solvent used may be selected from alkyl acetate, lower alkylamines, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, heterocycles, dialkylethers, an acid, mixture of water and water miscible solvents, ionic liquids, halogenated solvents and mixtures thereof.

Yet an alternative process for preparing a compound of Formula (Xa) according to the present invention is exemplified in Scheme 5.

Scheme 5

The compounds of formula (XVIII) and (XV) are hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of Formula (I) as described herein.

In an embodiment, aldehyde (XII) is reacted with amino(phenyl)methanol (XIX) to give novel intermediate hydroxy imine (XVII). The reaction is preferably carried out in the presence of an inert organic solvent or mixture of solvents thereof.

The imine (XVII) undergoes reductive alkylation with methyl lithium in the presence of a reductant such as sodium cyanoborohydride (NaBH3CN), sodium borohydride (NaBH4), or sodium tri-acetoxyborohydride [NaBH(OAc)3] to obtain the secondary amine (XV).

The amine (XV) is first debenzylated and then deprotected using a suitable deprotecting reagent to obtain a 1,3-dicarbonyl compound of formula (Xa).

Yet an alternative process for preparing a compound of Formula (Xa) according to the present invention is exemplified in Scheme 6.

Scheme 6

The compounds of formula (XXI) and (XX) are hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of Formula (I) as described herein.

In an embodiment, aldehyde (XII) is reacted with S (-)-2-methyl-2-propanesulfinamide to obtain tert-butanesulfinyl ketimine (XXI). The reaction is preferably conducted under inert atmosphere at a temperature ranging from about -30°C to the reflux temperature of the inert solvent used, preferably 0°C to 60°C, more preferably 20°C to 40°C.

Examples of suitable solvents include, but are not limited to, aromatic hydrocarbons, such as benzene, toluene, the xylenes, and the like; aliphatic hydrocarbons, such as pentane, hexane, octane, and the like; chlorinated solvents, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like. The preferred solvents are chlorinated solvents.

Tert-butanesulfinyl ketimine (XXI) is then undergoes reductive alkylation with methyl magnesium bromide in the presence of a suitable inert solvent or mixture of solvents thereof to obtain novel intermediate (XX).

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 -70°C to about 40°C. In still other embodiments, the reduction is carried out at a temperature in the range of from about -60°C to about 30°C. In a particularly preferred embodiment the reaction is carried out at a temperature in the range from about -50 to about 30ºC.

A suitable inert organic solvent for use in a process according to the present invention can be selected from the group consisting of tetrahydrofuran, diethyl ether, dibutyl ether 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 Tetrahydrofuran.

The amine (XX) is then deprotected by acid in the presence of a suitable solvent, to obtain a 1,3-dicarbonyl compound of formula (Xa).

The reaction is preferably conducted at a temperature ranging from about -10°C to the reflux temperature of the inert solvent used, preferably 10°C to 50°C, more preferably 20°C to 40°C.

Examples of suitable solvents include, but are not limited to, alkanols, such as methanol, ethanol, propanol, and isopropanol; ethers, such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, 1,4-dioxane and the like; ketones such as acetone, Methyl isobutyl ketone, Ethyl isopropyl ketone and such miscellaneous solvents as N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide. The preferred solvents are alkanols and 1,4-dioxane.

In another preferred embodiment, when X is bromo, R is methyl, R1 is ethyl and R2 is methyl, n is an integer of 1 and wherein compound of Formula (V) is in the form of S isomer, the compound (I) obtained by the process of the invention includes compound of formula (Ib):

Accordingly, a process for preparing a compound of formula (Ib) according to the present invention is exemplified in Scheme 8.

Scheme 8

Compound of Formula (Ib), (IIb), (IVb), (Vb) (VIIb), (IXb) and (Xb) are in the form of the S isomer.

The compounds of formula (Vb), (VIb) and (VIIb) are hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of Formula (Ib) as described herein.

The processes of the present invention allow the synthesis of tricyclic carbamoyl pyridone derivatives of Formula (I) with a 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 a tricyclic carbamoyl pyridone derivative 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. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art.

According to another aspect of the present invention, there is provided the use of a tricyclic carbamoyl pyridone derivative 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 a tricyclic carbamoyl pyridone derivative 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 a tricyclic carbamoyl pyridone derivative 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.

Examples:-

Example 1: Preparation of solketal (XIII)

Glycerol (XIV) (100 g, 1.086 moles) along with P-toluenesulfonic acid monohydrate (1 g, 0.0052 moles) and of 2,2-dimethoxypropane (153 g, 1.47moles) were charged in 500 ml acetone. Reaction mass was stirred at 25°C for 24 hours. The reaction mass was distilled under vacuum below 50°C to afford 140 g of Solketal.

Example 2: Prepartion of compound aldehyde (XII)

The compound solketal (XIII) (109 g, 0.825 moles), sodium acetate (79 g, 0.963 moles) and Trichloroisocyannuric acid (74.4 g, 0.32 moles) were added into 500ml acetone. The reaction mass was stirred at 25-30°C for 15 minutes. A solution of Tempo (0.25 g, 0.0016 moles in 100 ml acetone) was added slowly to the reaction mass. A mild reflux was observed during addition. After complete addition, reaction mass was further stirred at 55° for 1 hour. The reaction mass was filtered through celite, the clear filtrate collected and distilled under vacuum to afford 100 g of aldehyde.

Example 3: Preparation of compound (XXI)
Aldehyde (XII), (50 g, 0.384 moles), S(-)-2-methyl-2-propanesulfinamide (XXII) (54 g, 0.443 moles) and pyridinium p-toluenesulfonate (3.6 g, 0.0143 moles) were added into 250 ml MDC. The reaction mass was stirred at 25-30°C for 10 hours. The reaction mass was quenched into 200 ml water. Organic layer was separated and distilled under vacuum below 50°C. The residue was recrystallized from heptane to afford 35 g of compound (XXI).

Example 4: Preparation of compound (XX)
A solution of enamine (XXI) (20 g, 0.0858 moles) in 75 ml Tetrahydrofuran was cooled to -50°C. A 3M solution of methylmagnesium bromide in THF (30.7 ml, 0.128 moles) was added at -50°C. Reaction mass was stirred at -50°C for 6hrs and then at room temp for 10 hours. The reaction mass was quenched in a mixture of 50 ml of saturated ammonium chloride and 50 ml MDC. Organic layer was separated and distilled under vacuum to afford 18 g of compound (XX).

Example 5: Preparation of compound (Xa)
Amine (XX) (50 g, 0.200 moles) along with 4M HCl was stirred in 100ml 1,4-dioxane at 25°C for 2 hours. The reaction mass was distilled under vacuum to afford 50 g of compound (Xa), which is used immediately for next step.

Example 6: Preparation of compound (IXa)
To a stirred solution of compound (Xa) (50 g, 0.476 moles) in 250 ml of methanol was added sodium borohydride (25 g, 0.657 moles) in small lots. After complete addition, the reaction mass was stirred at 25°C for 24 hours. The reaction mass was quenched in 40% sodium hydroxide solution and stirred at 25°C for 15-20 minutes. The insoluble were removed by filtration and the filtrate was distilled under vacuum to obtain residue. The residue was further distilled to afford compound IXa at boiling point 170°C.

Example 7: Preparation of compound VIIa

Preparation 1
To a stirred solution of bromoacetaldehyde (VIIIa) (100 g, 0.813 moles) in 500ml toluene, was added aminobutanol (IXa) (97.5 g, 1.095 moles) and methanesulfonic acid (10 ml, 0.104 moles). The reaction mass was stirred at 120°C for 2 hours. The reaction mass was distilled under vacuum to obtain residue. The residue was further purified on column using mobile phase heptane:ethyl acetate (5:1) to afford 55 g of compound VIIa.

Preparation 2

To a stirred solution of bromoacetaldehyde dimethyl acetal (XXIIIa) (203.5 g, 1.201 moles) in 500 ml toluene, was added aminobutanol (IXa) (97.5 g, 1.095 moles) and p-toluene sulfonic acid monohydrate (172.5g, 0.893 moles). The reaction mass was stirred at 120°C for 2 hours. The reaction mass was distilled under vacuum to obtain residue. The residue was further purified on column using mobile phase heptane:ethyl acetate (5:1) to afford 70 g of compound VIIa.

Example 8: Preparation of compound (Va)

To a stirred solution of compound (VIIa) (100g, 0.515 moles) and compound (VIa) (140g, 0.616 moles) in 50 ml DMF and 50ml water was added of potassium carbonate (78g, 0.565 moles) and sodium iodide (1g, 0.006 moles). The reaction mass was heated at 60°C for 3.5hrs. The reaction mass was filtered to remove insoluble. The clear filtrate was stirred in a mixture of 300 ml Ethyl acetate and 100ml water for 15 minutes. The organic layer was separated and distilled under vacuum. The solids were crystallized from isopropylalcohol, to afford 75g of compound (VA).

Example 9: Preparation of compound (IVa)

Compound (Va) (100 g, 0.293 moles) and methanesulfonic acid (10 ml, 0.154 moles) were added to 300ml acetonitrile and the reaction mass was heated at 65-70°C for 9hrs. The reaction mass distilled under vacuum and the obtained residue was stirred in 500 ml MDC and 250 ml water. The organic layer was separated and MDC was distilled completely under vacuum. The residue was stirred in 500ml methanol. The solids were isolated by filtration, dried to afford 85g of compound (IVa).

Example 10: Preparation of compound (IIa)
Compound IVa (100 g, 3.123 moles) and CDI (95 g, 0.575 moles) were stirred in 1000 mL MDC. The reaction mass was heated at 35-40° C for 1 hour. The reaction mass was then cooled to 20°C and 2,4-difluorobenzylamine (50 ml, 0.419 moles) was added slowly at 20°C. the reaction mass was further stirred at 25° C for 1 hour. The reaction mass was quenched with 500 ml water and 500 ml of 10% HCl solution. The organic layer was separated and washed with 100 ml of sodium bicarbonate solution. The organic layer was separated and distilled under vacuum to obtain residue. The residue was crystallized in 300ml Isopropylalcohol to afford 90 g of compound (IIa).

Example 11: Preparation of compound (Ia)
Compound (IIa) (100 g, 0.228 moles) along with Lithium bromide (40 g, 0.46 moles) were heated to 60° C for 4 hours. After complete conversion, the reaction mass was cooled to 25° C and quenched with 1000ml of dil. HCl. The product was extracted in 1000 ml MDC. Organic layer was separated and distilled under vacuum at 40°C. The residue was stirred in 500 ml methanol and the solids were isolated by filtration, dried to afford 90 g of compound (Ia).

Example 12: Preparation of sodium salt of compound (Ia) (n =2)
The compound (Ia) (90 g, 16.632 moles) was dissolved in methanol (10 vol) at 60-65°C. To the reaction mixture was added 2N aqueous NaOH solution (90 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 afford 8.4 g of titled compound
Efficiency: 85.90 %
,CLAIMS:1. A process for preparing tricyclic carbamoyl pyridone derivatives of Formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof, which process comprises
converting a compound of Formula (V):

into compound of Formula (I); wherein R1 and R2 in Formula (V) are same or different and are selected from a lower alkyl group, preferably a straight or branched C1-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl and wherein, n is an integer of 0 to 3.
2. The process according to claim 1, wherein the said process comprises, cyclizing compound of Formula (V) with an acid; to form a tricyclic carbamoyl pyridinone compound of Formula (IV):
;
coupling the compound of Formula (IV) with 2,4-diflurobenzyl amine of Formula (III):

in the presence of a coupling reagent to provide compound of Formula (II)
;
followed by deprotection of the compound of formula II to obtain a tricyclic carbamoyl pyridone derivative of formula (I); and optionally thereafter converting the compound of formula (Ib) to a pharmaceutically acceptable salt thereof; wherein R2 and n are as defined above.
3. The process according to claim 1 or claim 2, wherein the compound of formula I is a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof:
;

4. A compound of Formula (V):

wherein R1 and R2 in Formula (V) are same or different and are selected from a lower alkyl group, preferably a straight or branched C1-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl and wherein, n is an integer of 0 to 3.
5. Use of compound Formula (V) as claimed in claim 4, in the preparation of an antiretroviral agent.
6. Use according to claim 5, wherein the antiretroviral agent is a tricyclic carbamoyl pyridone derivative, of formula (I), or a pharmaceutically acceptable salt thereof:
7. Use according to claim 6, wherein the antiretroviral agent is a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof:
8. The process for preparing compound of Formula (V), as claimed in claim 4, comprising coupling a compound of Formula (VI):

with a compound of Formula (VII):

wherein, R1, R2 and n are as defined above; X is leaving group preferably halide, to obtain a compound of Formula (V).

9. A compound of Formula (VII)

10. The process for preparing a compound of Formula (VII), as claimed in claim 9, comprising contacting a compound of formula (IX)

with bromo acetaldehyde of Formula (VIII):

or haloacetaldehyde dimethyl acetal of Formula (XXIII):

optionally in the presence of an acid, to provide a compound of formula (VII); wherein n and X are as defined above and R is a lower alkyl group, preferably a straight or branched C1-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

11. A process for preparing a compound of Formula (IX), as claimed in claim 10, comprising the steps of:
dehydroxylation of compound of Formula (X):

wherein n is as defined above.
12. The process according to claim 11, wherein n is 1 and the compound of Formula (IX) is a compound of Formula (IXa) and the compound of Formula (X) is a compound of Formula (Xa).
13. The process for preparing a compound of Formula (Xa) as claimed in claim 12, comprising deprotecting a compound of Formula (XX),

by an acid in the presence of a suitable solvent such as alcohol, to provide a compound of formula (Xa).
14. A compound of Formula (XX)
.
15. The process for preparing a compound of Formula (XX), as claimed in claim 14, comprising reductive alkylation of Tert-butanesulfinyl ketimine (XXI)

with methyl magnesium bromide in the presence of a suitable solvent or mixture of solvents thereof to provide a compound of formula (XX).
16. A compound of Formula XXI
.
17. The process for preparing a compound of Formula (XXI), as claimed in claim 16, comprising reacting aldehyde (XII)

with S-(-)-2-methyl-2-propanesulfinamide (XXII)

to provide tert-butanesulfinyl ketimine (XXI).
18. The process for preparing compound of formula (Ia) or a pharmaceutically acceptable salt thereof: as claimed in claim 3,

which process comprises converting a compound of Formula (Va):

into compound of Formula (Ia); and optionally thereafter forming a pharmaceutically acceptable salt of the compound of formula (Ia) so formed;wherein compound of Formula (Va) is in the form of R isomer.
19. The process according to claim 18, wherein, the process comprises cyclization of compound of Formula (Va) with an acid; to form a tricyclic carbamoyl pyridinone compound of Formula (IVa)
;
coupling compound of Formula (IVa) with 2,4-diflurobenzyl amine of Formula (III):
;
in the presence of a coupling reagent to provide compound of Formula (IIa)
;
followed by deprotection to obtain a tricyclic carbamoyl pyridone derivative of formula (Ia); and optionally thereafter converting the compound of formula (Ia) to a pharmaceutically acceptable salt thereof.
20. The process according to claim 19, comprising converting a compound of formula (Ia) into sodium salt thereof.
21. A compound of Formula (Va),
.
22.The process for preparing compound of formula (Va) as claimed in 21, comprising
coupling a compound of Formula (VIa)

with a compound of Formula (VIIa)

to obtain a compound of Formula (Va).
23. A compound of Formula (VIIa),
.
24. The process for preparing a compound of Formula (VIIa), as claimed in claim 23, comprising ;contacting a compound of formula (IXa)

with bromo acetaldehyde of Formula (VIIIa)
.
Or contacting a compound of formula (IXa), with bromoacetaldehyde dimethyl acetal (XXIIIa)

optionally in the presence of an acid, to provide a compound of formula (VIIa).
25. A process for preparing a compound of Formula (IXa), comprising
dehydroxylation of compound of Formula (Xa).

26. A process for preparing a compound of formula (Ib), or a pharmaceutically acceptable salt thereof:

comprising converting a compound of formula (Vb):

to a compound of formula (Ib), and optionally thereafter, forming a pharmaceutically acceptable salt thereof.
27. The process according to claim 26, wherein, the process comprises cyclization of compound of Formula (Vb) with an acid; to form a tricyclic carbamoyl pyridinone compound of Formula (IVb)
;
coupling compound of Formula (IVb) with 2,4-diflurobenzyl amine of Formula (III):
;
in the presence of a coupling reagent to provide compound of Formula (IIb)
;
followed by deprotection to obtain a tricyclic carbamoyl pyridone derivative of formula (Ib); and optionally thereafter
converting the compound of formula (Ib) to a pharmaceutically acceptable salt thereof.
28. A process according to claim 27, comprising converting a compound of formula (Ib) into sodium salt thereof.

29. A compound of Formula (Vb)

30. The process according to any one of the preceding claims,1, 2, 3, 8, 10, 13, 15, 17, 18, 19, 22, 24, 25, 26, 27, and 28, wherein the process steps are carried out in presence or absence of a solvent.
31. The process according to claim 30, wherein the solvent is selected from the group consisting of alkanols, such as methanol, ethanol, propanol, and isopropanol; aromatic hydrocarbons, such as benzene, toluene, the xylenes, and the like; aliphatic hydrocarbons, such as pentane, hexane, octane, and the like; ethers, such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like; and polar solvents such as N,N-dimethylformamide, N,N dimethylacetamide, and dimethyl sulfoxide, N-methyl pyrrolidone (NMP), sulfolane, diglyme, acetonitrile, acetone; halogenated hydrocarbon solvents such as methylene chloride, ethylene chloride etc.
32. The process as claimed in any one of the preceding claims 2, 8, 19, 22 and 27, wherein, the coupling agent is selected from the group consisting of phenylsilane, 1,1’-carbonyldiimidazole (CDI), benzotriazol-1-yloxytris (dimethylamino) phosphonium 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), HATU, chloroformates such as Ethyl chloroformate or isobutyl chloroformate.
33. The process as claimed in any one of the preceding claims 2, 10, 13, 19, 24 and 27, wherein, the acid used for cyclization is selected from the group consisting of 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.
34. The process as claimed in any one of the preceding claims 11 or 25, wherein the dehydroxylation is carried out in presence of dehydrating agent selected from methane sulfonic acid and p- toluene sulfonic acid.
35. A pharmaceutical composition comprising a tricyclic carbamoyl pyridone derivative of formula (I) as defined in claim 1, prepared according to the process of any one of claims 1 or 2, and one or more pharmaceutically acceptable excipients.