DESC:Field of the invention:
The present invention relates to novel polymorphs and salts of polycyclic carbamoyl pyridone derivatives and processes for their preparation.

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 WO2006/1 16764, incorporated herein in their entirety by reference, describe various polycyclic carbamoyl pyridone derivatives and processes for their preparation. Among these polycyclic compounds, is disclosed the following tricyclic carbamoyl pyridone derivative, of formula (A):

Formula A
or a stereoisomer or pharmaceutically acceptable salt thereof. Compound of formula (A) is chemically termed as (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

Structure–activity studies have demonstrated that thee 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.

As the crystal modification of an active substance is important to the reproducible active substance content of a preparation, there is a need to clarify as far as possible any existing polymorphism of an active substance present in crystalline form. If there are different polymorphic modifications of an active substance care must be taken to ensure that the crystalline modification of the substance does not change in the pharmaceutical preparation later produced from it. Otherwise, this could have a harmful effect on the reproducible potency of the drug. Against this background, active substances characterized by only slight polymorphism are preferred.

Generally, a crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. Crystalline forms may also exhibit improved solubility, hygroscopicity, bulk properties, and/or flowability. The solid state form of a compound can also affect its behavior on compaction and its storage stability.

The discovery of a new crystalline form of a pharmaceutically useful compound provides an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Another criterion which may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of manufacturing process is the solubility of the active substance. If for example pharmaceutical solutions are prepared (eg for infusions) it is essential that the active substance should be sufficiently soluble in physiologically acceptable solvents. It is also very important for drugs which are to be taken orally that the active substance should be sufficiently soluble. It is clearly advantageous when this repertoire is enlarged by the discovery of new crystalline forms of a useful compound.
There is a need in the art to provide a pharmaceutically active substance which not only is characterized by high pharmacological potency but also satisfies the above-mentioned physicochemical requirements as far as possible.

Objects of the invention:
The object of the present invention is to provide novel crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

Another object of the present invention is to provide process for the preparation of crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

Another object of the present invention is to provide a novel salts of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, namely potassium salt.

Yet another object of the present invention is to provide novel crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt.

Yet another object of the present invention is to provide process for the preparation of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt.

Yet another object of the present invention is to provide novel crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt.

Another object of the present invention is to provide process for the preparation of crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt.

Yet another object of the present invention is to provide pharmaceutical composition comprising novel crystal forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

Yet another object of the present invention is to provide a pharmaceutical composition comprising novel forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt.

Yet another object of the present invention is to provide a pharmaceutical composition comprising novel crystal forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt.

Summary of the Invention:
The present invention provides novel polymorphic forms of (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

In one embodiment , the present invention provides crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, hereinafter referred to as Form C-I and Form C-II.

In another embodiment the present invention provides novel pharmaceutical salt namely (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt .

The potassium salt according to the invention is characterized by good crystallinity and further observed to exhibit different crystal modifications. These crystalline potassium salts herein after referred to as Form K-I, Form K-II and Form K-III.

In another embodiment, the present invention provides crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt, hereinafter referred to as Form N-I and Form N-II.

The crystalline nature of the forms according to the present invention is characterized by X-ray powder diffraction. Accordingly, the invention also provides methods for preparing these novel salts and forms.

The invention also provides pharmaceutical compositions comprising any of these forms optionally in association with pharmaceutical carriers/excipients.

The invention also provides methods of treatment of diseases or symptoms wherein (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide or salt thereof is useful. In particular, these new methods are for similar therapeutic indications to those described in the above identified patents and applications and are incorporated herein by reference.

Further aspects, features and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS:
FIG. 1 represents a powder X-ray diffraction pattern of Form C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

FIG. 2 represents a powder X-ray diffraction pattern of Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

FIG. 3 represents a powder X-ray diffraction pattern of Form K-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt.

FIG. 4 represents a powder X-ray diffraction pattern of Form K-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt.

FIG. 5 represents a powder X-ray diffraction pattern of Form N-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt.

FIG. 6 represents a powder X-ray diffraction pattern of Form N-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt.

FIG. 7 represents a powder X-ray diffraction pattern of Form K-III of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt.

Detailed Description Of The Invention:
Pursuing experimental work for improving the manufacturing and treating the starting drug substance by crystallization in varying physico-chemical conditions (such as crystallization solvent, temperature, concentration, filtration methods ... ), the Inventors have now identified novel polymorphic forms and salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

The present invention is based on a surprising discovery that (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide can exist in different crystalline forms and salts, and these forms and salts can be prepared readily from environmentally friendly solvent systems using appropriate methods.

The new crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide have been characterized respectively by powder X-ray diffraction spectroscopy which produces a fingerprint that is unique to the crystalline form and is able to distinguish it from all other crystalline and amorphous forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.
As polymorphic forms are reliably characterized by peak positions in the X-ray diffractogram, the polymorphs of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 2? values are accurate to within ± 0.2 degrees. All the powder diffraction patterns were measured on a MiniFlex 2 advanced X-ray powder diffractometer with a copper-K-a radiation source.

Thus, in one aspect, the present invention provides the crystalline (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide which is herein and in the claims designated as Form C-I, which is substantially non-hygroscopic and has good flow characteristics.

In one embodiment, the crystalline Form C-I is characterized by an X-ray powder diffraction pattern comprising the following 2? values measured using CuKa, radiation.

In an embodiment, the crystalline Form C-I has an XRD pattern with characteristics peaks at 5.497, 12.905, 15.419, 16.663, 17.944, 18.610, 22.474, 23.894, and 26.111± 0.2 °2?.

In an embodiment, the crystalline Form C-I has an XRPD pattern with those peaks at °2? values ± 0.2 °2? as depicted in Table 1.

Table 1: Table of values for the XRPD pattern depicted in Figure 1
Peak value (°2?) Relative Intensity [%]
5.497 100.00
12.905 7.29
15.419 2.53
16.663 2.41
17.944 4.23
18.610 2.48
22.474 2.18
23.894 2.73
26.111 3.05

Those skilled in the art would recognize that Form C-I may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention there is provided a process for the preparation of the crystalline Form C-I. The process comprise: dissolving (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a polar solvent , non-polar solvent or an admixture thereof , and isolating any resulting precipitated solid therefrom.

Suitable polar solvents include, but are not limited to the C1- C4 alcohols e.g.methanol, ethanol, isopropanol, n-buatnol and the like and mixtures thereof; ketone such as acetone; organic solvents, such as nitriles, e.g., acetonitrile and the like DMF; DMSO; NMP; THF and the like and mixtures thereof. Suitable non polar solvents include, but are not limited to, aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents and the like and mixtures thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. Preferably, the solvent used is selected from an admixture of polar and non polar solvent in a ratio of 1:10 to 10:1. In one embodiment, the temperature during the dissolution step is about 40°C to about boiling point of the solvent used. More preferably, the temperature during the dissolution step is about 40°C to about 90°C. In one embodiment, the isolating includes precipitating the Form C-I by cooling, solvent removal, adding a non-solvent, or a combination of these methods.

The (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide used for the above process, as well as for the following processes, may be in any polymorphic form such as crystalline or amorphous or in a mixture of any polymorphic forms such as hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof.

The (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, used for the above process, as well as for the following processes, describe in this application can be obtained by any method known to a skilled artisan.

The crystalline Form C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide obtained according to the present invention is substantially free from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide. "Substantially free" from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide shall be understood to mean that the polymorph C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide contains less than 10%, preferably less than 5%, of any other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and less than 1% of other impurities or solvates.

According to yet another aspect, the present invention provides the crystalline (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, which is herein and in the claims designated as Form C-II which is substantially non-hygroscopic and has good flow characteristics.

In one embodiment, the crystalline Form C-II is characterized by an X-ray powder diffraction pattern comprising the following 2? values measured using CuKa, radiation:

In an embodiment, the crystalline Form C-II has an XRD pattern with characteristics peaks at 24.075 and 24.561 ± 0.2 °2?.

The crystalline Form C-II may have an XRD pattern with characteristics peaks at 24.075 and 24.561 ± 0.2°2?. The XRD pattern may have further peaks at 17.058 and 27.598 ± 0.2°2?. The XRD pattern may have still further peaks at 5.295, 12.150, 14.283, 16.286, 17.670, 20.184, and 24.917 ± 0.2°2?.

In an embodiment, the crystalline Form C-II has an XRPD pattern with those peaks at °2? values ± 0.2 °2? as depicted in Table 2.

Table 2: Table of values for the XRPD pattern depicted in Figure 2
Peak value (°2?) Relative Intensity [%]
5.295 17.81
12.150 27.24
14.283 16.63
16.286 18.36
17.058 54.45
17.670 20.78
20.184 10.66
24.075 100.00
24.561 75.65
24.917 16.67
27.598 44.76

Those skilled in the art would recognize that Form C-II may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention there is provided a process for the preparation of the crystalline Form C-II. The process comprise: stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a polar solvent/s , non polar solvent/s or an admixture thereof , and isolating any resulting precipitated solid.

Suitable polar solvents include, but are not limited to the C1- C4 alcohols e.g., methanol, ethanol, isopropanol, n-buatnol and the like and mixtures thereof; ketone such as acetone; organic solvents, such as nitriles, e.g., acetonitrile and the like DMF; DMSO; NMP; THF and the like and mixtures thereof. Suitable non polar solvents include, but are not limited to, aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents and the like and mixtures thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. Preferably, the solvent used is selected from an admixture of polar and non-polar solvent in a ratio of 1:10 to 10:1. In one embodiment, the temperature during the dissolution step is about 40°C to about boiling point of the solvent used. More preferably, the temperature during the dissolution step is about 40°C to about 90°C. In one embodiment, the isolating includes precipitating the Form C-II by cooling, solvent removal, adding a non-solvent, or a combination of these methods.

The crystalline Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide obtained according to the present invention is substantially free from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide. "Substantially free" from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide shall be understood to mean that the polymorph C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide contains less than 10%, preferably less than 5%, of any other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and less than 1% of other impurities or solvates.

According to yet another aspect of the present invention, there is provided novel pharmaceutical salt namely potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.

The combination of physical properties of the novel potassium salt of the present invention with respect to the degree of crystallinity, particle diameter, density, hygroscopicity, water content and content of other solvents are favorable and permit the manufacture of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt in a form which possesses the desired properties.

In another aspect, the present invention provides processes for preparation of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt , which comprises the step of mixing (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 1 hour to about 5 hours, isolating the precipitated potassium salt.

In one embodiment mixing includes dissolving, slurrying or suspending the (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in the solvent.

Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like and mixtures thereof. The source of potassium can be added either as a solution in water or it may be added as a solid to the solution of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable organic solvent. The sequence of addition of water and/or potassium source is not particularly critical. Additionally, the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide solution or a (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide solution may be added to the potassium source.

Suitable solvents include, but are not limited to, aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; ketones; nitriles; alcohols and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. Useful ketones include acetone, iso butyl ketone, methyl isobutyl ketone, and the like and mixtures thereof. Useful organic solvents are selected such as nitriles, e.g., acetonitrile and the like; C1 -C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like and mixtures thereof.

In one embodiment, the isolating includes obtaining the potassium salt from a mixture formed after addition of source of potassium. In one embodiment, the isolating includes precipitating the potassium salt by cooling, solvent removal, adding a non-solvent, or a combination of these methods.

Alternatively, the (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt, may be prepared by a process comprising; converting any salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide into the free base and subsequently converting free base into the (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt using a source of potassium.

In an embodiment potassium salt obtained may be in any polymorphic form or in a mixture of any polymorphic forms such as amorphous, crystalline, hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof.

In an embodiment, the potassium salt obtained according to the invention is characterized by good crystallinity and low amorphisation during grinding and compression. In addition it is not hygroscopic and is readily soluble in physiologically acceptable solvents.

The crystalline potassium salt herein and in the claims designated as Form K-I which is substantially non-hygroscopic and has good flow characteristics.

In one embodiment, the crystalline Form K-I is characterized by an X-ray powder diffraction pattern comprising the following 2? values measured using CuKa, radiation:

In an embodiment, the crystalline Form K-I has an XRD pattern with characteristics peaks at 6.877 and 17.846, ± 0.2 °2?.

The crystalline Form K-I may have an XRD pattern with characteristics peaks at 6.877 and 17.846 ± 0.2 °2?. The XRD pattern may have further peaks at 11.341, 18.599, 20.436, 23.02, 23.792, 24.194, 26.55 and 30.23 ± 0.2 °2?. The XRD pattern may have still further peaks at 5.496, 12.268, 13.847, 16.433, 17.294, 24.671, and 27.78 ± 0.2 °2?.

In an embodiment, the crystalline Form K-I has an XRPD pattern with those peaks at °2? values ± 0.2 °2? as depicted in Table 3.

Table 3: Table of values for the XRPD pattern depicted in Figure 3
Peak value (°2?) Relative Intensity [%]
5.496 21.77
6.877 100.00
11.341 51.94
12.268 11.90
13.847 14.17
16.433 23.13
17.294 20.12
17.846 74.77
18.599 46.66
20.436 33.39
23.02 57.55
23.792 38.86
24.194 40.21
24.671 22.30
26.55 45.91
27.78 11.39
30.23 44.82

Those skilled in the art would recognize that Form K-I may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for
preparing crystalline Form K-I of 3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt, the process comprising; mixing 3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , in a suitable first solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 1 hour to about 5 hours, isolating the precipitated Form K-I of potassium salt.

In one embodiment mixing includes dissolving, slurrying or suspending the (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in the solvent.

Suitable first solvent/s include, but are not limited to, polar solvents and non- polar solvents. Polar solvents include nitriles, e.g., acetonitrile and the like; C1 _4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketiones , e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the solvent is preferably a C1 -C4 alcohols, with methanol being preferred.

Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate, potassium chloride and the like and mixtures thereof, with potassium hydroxide being preferred.

The source of potassium can be added either as a solution in a suitable second solvent or it may be added as a solid to the mixture of (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable first solvent. The sequence of addition of potassium source is not particularly critical. Additionally, the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture or a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture may be added to the potassium source.

Suitable second solvent/s includes, but are not limited to, polar solvents and non- polar solvents. Polar solvents include nitriles, e.g., acetonitrile and the like; C1 _4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketiones , e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the second solvent is preferably a C1 -C4 alcohols, with methanol being preferred.

In a preferred embodiment, the process of preparation of Form K-I comprises stirring (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in methanol at about 30°C to about 65°C, adding a solution of potassium hydroxide in methanol to the suspension at about 30°C to about 65°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form K-I from the suspension.

The crystalline Form K-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt, obtained according to the present invention is substantially free from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide. "Substantially free" from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide shall be understood to mean that the polymorph K-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide contain less than 10%, preferably less than 5%, of any other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and less than 1% of other impurities or solvates.

According to yet another aspect, the present invention provides the crystalline (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt which is herein and in the claims designated as Form K-II which is substantially non-hygroscopic and has good flow characteristics.

In one embodiment, the crystalline Form K-II is characterized by an X-ray powder diffraction pattern comprising the following 2? values measured using CuKa, radiation:

In an embodiment, the crystalline Form K-II has an XRD pattern with characteristics peaks at 6.573 and 18.876 ± 0.2 °2?.

The crystalline Form K-II may have an XRD pattern with characteristics peaks at, 6.573 and 18.876 ± 0.2 °2?. The XRD pattern may have further peaks at 22.804 ± 0.2 °2?. The XRD pattern may have still further peaks at 7.083, 11.401, 15.411, 24.923 and 26.612 ± 0.2 °2?.

In an embodiment, the crystalline Form K-II has an XRPD pattern with those peaks at °2? values ± 0.2 °2? as depicted in Table 4.

Table 4: Table of values for the XRPD pattern depicted in Figure 4
Peak value (°2?) Relative Intensity [%]
6.573 100.00
7.083 11.65
11.401 15.09
15.411 18.35
18.876 68.00
22.804 52.94
24.923 25.82
26.612 26.03

Those skilled in the art would recognize that Form K-II may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for
preparing crystalline Form K-II of 3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt, the process comprising; mixing 3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , in a suitable first solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 1 hour to about 5 hours, isolating the precipitated Form K-II of potassium salt.

In one embodiment mixing includes dissolving, slurrying or suspending the (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in the solvent.

Suitable first solvent/s include, but are not limited to, polar solvents and non-polar solvents. Polar solvents include nitriles, e.g., acetonitrile and the like; C1-C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the solvent is preferably a C1- C4 alcohols, with t-butanol being preferred.

Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like and mixtures thereof, with potassium t-butoxide being preferred.

The source of potassium can be added either as a solution in a suitable second solvent or it may be added as a solid to the mixture of (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable first solvent. The sequence of addition of potassium source is not particularly critical. Additionally, the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture or a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture may be added to the potassium source.

Suitable second solvent/s includes, but are not limited to, polar solvents and non- polar solvents. Polar solvents include nitriles, e.g., acetonitrile and the like; C1-C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the second solvent is preferably a C1C4 alcohols, with t-butanol being preferred.

In a preferred embodiment, the process of preparation of Form K-II comprises stirring (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in t-butanol at about 30°C; adding a solution of potassium hydroxide to the suspension at about 30°C; heating the suspension at about 80°C to about 85°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form K-II from the suspension.

The crystalline Form K-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt, obtained according to the present invention is substantially free from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide. "Substantially free" from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide shall be understood to mean that the polymorph K-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide contains less than 10%, preferably less than 5%, of any other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and less than 1% of other impurities or solvates.

According to yet another aspect, the present invention provides the crystalline (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, sodium salt which is herein and in the claims designated as Form N-I, which is substantially non-hygroscopic and has good flow characteristics.

In one embodiment, the crystalline Form N-I is characterized by an X-ray powder diffraction pattern comprising the following 2? values measured using CuKa, radiation:

In an embodiment, the crystalline Form N-I has an XRD pattern with characteristics peaks at 20.157, and 23.596 ± 0.2 °2?.

The crystalline Form N-I may have an XRD pattern with characteristics peaks at, 20.157, and 23.596 ± 0.2°2?. The XRD pattern may have further peaks at 6.637, 18.280, 18.669, and 22.582 ± 0.2°2?. The XRD pattern may have still further peaks at 14.341, 14.991, 15.855, 17.458, 21.381, 26.051, 27.098, 28.426, and 29.166± 0.2°2?.

In an embodiment, the crystalline Form N-I has an XRPD pattern with those peaks at °2? values ± 0.2 °2? as depicted in Table 5.

Table 5: Table of values for the XRPD pattern depicted in Figure 5
Peak value (°2?) Relative Intensity [%]
6.637 56.67
14.341 11.33
14.991 12.00
15.855 11.73
17.458 15.92
18.280 36.11
18.669 48.03
20.157 63.75
21.381 12.45
22.582 43.59
23.596 100.00
26.051 12.58
27.098 22.67
28.426 22.24
29.166 18.83

Those skilled in the art would recognize that Form N-I may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention there is provided a process for the preparation of the crystalline Form N-I. The process comprise: stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, in a first polar solvent or mixture of polar solvents for a period of time ranging from about 30 minutes to about 5 hours at a temperature ranging from about 25°C to boiling point of the solvent used, adding a source of sodium, stirring for at least 1 hour to about 5 hours and isolating the precipitated Form N-I of sodium salt.

Suitable first polar solvent/s include, but are not limited organic solvents, such as water; C1- C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; nitriles, e.g., acetonitrile and the like; ketones, e.g., acetone, methyl isobutyl ketone, iso butyl ketone, and the like and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the first solvent is preferably a C1-C4 alcohols, with ethanol being preferred.

Suitable sources of sodium include sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium carbonate and the like and mixtures thereof, with sodium hydroxide being preferred.

The source of sodium can be added either as a solution in a suitable second solvent/s or it may be added as a solid to the mixture of (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable first solvent. The sequence of addition of sodium source is not particularly critical. Additionally, the sodium salt formation can be carried out in any known manner, for example, the sodium source can be added into a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture or a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture may be added to the sodium source.

Suitable second solvent/s include, but are not limited to, polar solvents and non-polar solvents. Polar solvents include water; nitriles, e.g., acetonitrile and the like; C1-C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the second solvent is preferably a mixture of water and C1- C4 alcohols, with ethanol being preferred.

In a preferred embodiment, the process of preparation of Form N-I comprises stirring (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in ethanol at about 30°C; heating the suspension at about 60°C to about 65°C; adding an aqueous sodium hydroxide solution in ethanol to the suspension at about 60°C to about 65°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form N-I from the suspension.
In an alternative embodiment, the process of preparation of Form N-I comprises stirring (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in t-butanol at about 30°C; adding sodium t-butoxide to the suspension at about 30°C; heating the suspension at about 30°C to about 85°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form N-I from the suspension.

The crystalline Form N-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt, obtained according to the present invention is substantially free from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide. "Substantially free" from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide shall be understood to mean that the polymorph N-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide contains less than 10%, preferably less than 5%, of any other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and less than 1% of other impurities or solvates.

According to yet another aspect, the present invention provides the crystalline (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt which is herein and in the claims designated as Form N-II which is substantially non-hygroscopic and has good flow characteristics.

In one embodiment, the crystalline Form N-II is characterized by an X-ray powder diffraction pattern comprising the following 2? values measured using CuKa, radiation:

The crystalline Form N-II may have an XRD pattern with characteristics peaks at 5.191, 9.264, 13.686, 15.185, 15.513 and 21 .317 ± 0.2 °2?. The XRD pattern may have further peaks at 10.777, 12.585, 12.876, 15.936, 18.693, 23.635, 24.282, 25.84, 26.57, 27.931 and 29.24 ± 0.2 °2?.

In an embodiment, the crystalline Form N-II has an XRPD pattern with those peaks at °2? values ± 0.2 °2? as depicted in Table 6.

Table 6: Table of values for the XRPD pattern depicted in Figure 6
Peak value (°2?) Relative Intensity [%]
5.191 100.00
9.264 10.08
10.777 3.21
12.585 7.33
12.876 6.58
13.686 10.30
15.185 16.32
15. 513 17.00
15.936 5.32
18.693 6.57
21 .317 10.57
23.635 6.43
24.282 6.90
25.84 2.14
26.57 2.41
27.931 5.29
29.24 2.01

Those skilled in the art would recognize that Form N-II may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention there is provided a process for the preparation of the crystalline Form N-II. The process comprise: stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, in a first polar solvent or mixture of polar solvents for a period of time ranging from about 30 minutes to about 5 hours at a temperature ranging from about 25°C to boiling point of the solvent used, adding a source of sodium, stirring for at least 1 hour to about 5 hours and isolating the precipitated Form N-II of sodium salt.

Suitable first polar solvent/s include, but are not limited organic solvents, such as water; C1- C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; nitriles, e.g., acetonitrile and the like; ketones, e.g., acetone, methyl isobutyl ketone, iso butyl ketone, and the like and mixtures thereof. In a preferred embodiment, the first solvent is preferably a mixture of water and a C1 -C4 alcohols, with ethanol being preferred.

Suitable sources of sodium include sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium carbonate and the like and mixtures thereof, with sodium hydroxide being preferred.

The source of sodium can be added either as a solution in a suitable second solvent/s or it may be added as a solid to the mixture of (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable first solvent. The sequence of addition of sodium source is not particularly critical. Additionally, the sodium salt formation can be carried out in any known manner, for example, the sodium source can be added into a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture or a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture may be added to the sodium source.

Suitable second solvent/s include, but are not limited to, polar solvents. Polar solvents include water; nitriles, e.g., acetonitrile and the like; C1 -C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketiones , e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. In a preferred embodiment, the second solvent is preferably water.

In a preferred embodiment, the process of preparation of Form N-II comprises stirring (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a mixture of water and ethanol in the ratio of 1:10 to 10:1, more preferably in the ratio of 1:4, at about 30°C; heating the suspension at about 70°C to about 85°C; adding an aqueous sodium hydroxide solution to the suspension at about 70°C to about 85°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form N-II from the suspension.

The crystalline Form N-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium salt obtained according to the present invention is substantially free from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide. "Substantially free" from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide shall be understood to mean that the polymorph N-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide contains less than 10%, preferably less than 5%, of any other crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide (including hydrates and solvates) and/or amorphous forms and less than 1% of other impurities or solvates.

According to yet another aspect, the present invention provides the crystalline (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt which is herein and in the claims designated as Form K-III which is substantially non-hygroscopic and has good flow characteristics.

In one embodiment, the crystalline Form K-III is characterized by an X-ray powder diffraction pattern comprising the following 2? values measured using CuKa, radiation:

In an embodiment, the crystalline Form K-III has an XRD pattern with characteristics peaks at 6.698, 17.627, 18.383, 22.808 and 25.897 ± 0.2°2?.

The crystalline Form K-III may have an XRD pattern with characteristics peaks at, 6.698, 17.627, 18.383, 22.208 and 25.897 ± 0.2°2?. The XRD pattern may have further peaks at 11.13, 20.402, 23.707,24.112, 31.102 ± 0.2°2?. The XRD pattern may have still further peaks at 12.107, 13.608, 17.070, 22.344, 24.588, 26.914 and 27.663 ± 0.2°2?.

In an embodiment, the crystalline Form K-III has an XRPD pattern with those peaks at °2? values ± 0.2 °2? as depicted in Table 7.

Table 7: Table of values for the XRPD pattern depicted in Figure 7
Peak value (°2?) Relative Intensity [%]
6.698 100.00
11.13 38.50
12.107 10.12
13.608 14.99
17.070 21.24
17.627 69.79
18.383 50.17
20.402 44.29
22.344 20.45
22.808 86.94
23.707 44.17
24.112 43.74
24.588 16.75
25.897 52.62
26.914 17.49
27.663 12.90
31.102 37.00

Those skilled in the art would recognize that Form K-III may be further characterized by other methods including, but not limited to DSC, IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for
preparing crystalline Form K-III of 3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt, the process comprising; mixing 3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , in a suitable first solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 10 minutes to about 2 hours, isolating the precipitated Form K-III of potassium salt.

In one embodiment ‘mixing’ includes dissolving, slurrying or suspending the (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in the solvent.

Suitable first solvent/s includes, but are not limited to, polar solvents and non- polar solvents. Polar solvents include nitriles, e.g., acetonitrile and the like; C1 to C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the solvent is preferably a C1 to C4 alcohols solvent, with methanol being preferred.

Suitable sources of potassium include potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like and mixtures thereof, with potassium hydroxide being preferred.

The source of potassium can be added either as a solution in a suitable second solvent or it may be added as a solid to the mixture of (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable first solvent. The sequence of addition of potassium source is not particularly critical. Additionally, the potassium salt formation can be carried out in any known manner, for example, the potassium source can be added into a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture or a (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide mixture may be added to the potassium source.

Suitable second solvent/s include, but are not limited to, polar solvents and non- polar solvents. Polar solvents include nitriles, e.g., acetonitrile and the like; C1 to C4 alcohols, e.g., methanol, ethanol, n-butanol, n-propanol, and the like; ketones, e.g. acetone, iso butyl ketone, methyl isobutyl ketone, and the like, DMF, DMSO, THF and mixtures thereof. Non polar solvents include aromatic solvents such as alkyl, aryl, halo substituted benzenes; chlorinated solvents; and the like and mixture thereof. Useful aromatic solvents include toluene, xylene, chlorobenzene, bromobenzene and the like and mixtures thereof. Useful chlorinated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, perchloroethylene and the like and mixtures thereof. In a preferred embodiment, the second solvent is preferably a C1 to C4 alcohols, with methanol being preferred.

In a preferred embodiment, the process of preparation of Form K-III comprises stirring (3S,11aR)-N-[(2,4-difluorophenyl) methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in methanol at about 30°C; heating the suspension at about 60°C to about 65°C; adding a solution of potassium hydroxide to the suspension at about 65°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days, preferably 30 minutes to about 2 hours, more preferably 60 minutes; and isolating the crystalline solid Form K-III from the suspension.

The crystalline Form K-III of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium salt, thus obtained according to the present invention is substantially free from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide. "Substantially free" from other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide shall be understood to mean that the polymorph K-III of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide contains less than 10%, preferably less than 5%, of any other forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and less than 1% of other impurities or solvates.

Certain operational steps are well known in the art and, unless otherwise indicated, any known method for performing these functions may be used in the processes of this invention.

The process of invention may be used as a method for purifying any form or salts of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, as well as for the preparation of the new polymorphic forms and salts.

According to yet another aspect of the present invention, there is provided use of the crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide as described above, in the preparation of a medicament useful in treating or preventing viral infection, for example, an HIV infection, in a human comprising administering to the human a therapeutically effective amount of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide selected from the group consisting of any one or combination of the crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and/or crystalline forms of potassium salt or sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide described herein above.

In another aspect, the present invention provides solid pharmaceutical compositions, comprising, as an active ingredient, any one or combination of the crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and/or crystalline forms of potassium salt or sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide described herein, optionally together with one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art for preparation of variety of pharmaceutical dosage forms.

Furthermore, the compounds in accordance with the present invention may be administered to a patient in need thereof in any type of galenical form such as tablets, capsules or in a liquid formulation.

Suitably, the pharmaceutical composition is in the form of a tablet suitable for oral delivery.

In another aspect, the present invention provides a method of treating or preventing viral infection, for example, an HIV infection, in a human comprising administering to the human a therapeutically effective amount of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide selected from the group consisting of any one or combination of the crystalline forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide and/or crystalline forms of potassium salt or sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide described herein above.

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 (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide
Compound (3S,11aR)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (70 g, 0.1670 moles) was stirred in 700 ml of THF at 25±5°C. Added lithium bromide (34.80 g, 0.4009 moles). The reaction mass was heated to 62-65°C and stirred further for 12-15 hours. After completion of the reaction, reaction mass was cooled to 25±5°C. To the reaction mass, acetone was added (350 ml), followed by water (70 ml) and stirred for 30 minutes. The reaction mass was filtered on hyflo. The clear filtrate was quenched in 5 % acetic acid solution (2.1 lit) and stirred for 2-3 hours. The solid was isolated by filtration and dried to yield 62.0 g of titled compound.

Example 2: Preparation of Form C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 1 g, 0.002469 moles ) stirred in a mixture of MDC ( 40 ml) and methanol ( 40 ml) at room temperature. The suspension was heated under stirring to 40-45°C to get clear solution. The solvent was distilled under reduced pressure at 40-45°C. The solid was isolated and dried under vacuum at 50°C –55°C for 4-5 hours to yield 0.9 g of titled compound.

The XRD of the final product is set forth in FIG. 1, which was recorded and identified as polymorph Form C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide

Example 3: Preparation of Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 62 g, 0.1530 moles ) stirred in a mixture of DMF ( 434 ml) and methanol ( 434 ml) at room temperature. The suspension was heated under stirring to 70-75°C and stirred further for about 1 hour. The reaction mass was cooled to 25±5°C and stirred further for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C –55°C for 12-15 hours to yield 56.0 g of titled compound.

The XRD of the final product is set forth in FIG. 2 which was recorded and identified as polymorph Form C-II of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide

Example 4: Preparation of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , potassium salt
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 5 g, 0.01234 moles ) was taken up in methanol (100 ml) and treated with 1 N potassium hydroxide in methanol (12.5 ml, 0.01234 moles). The resulting suspension was stirred at room temperature for 30 min. Ether was added and the solids were collected to provide the potassium salt of the title compound as a white powder (5 g, Efficiency :- 91%).

Example 5: Preparation of Form K-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , potassium salt
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 5 g, 0.01234 moles ) stirred in methanol ( 75 ml) at room temperature. The suspension was heated under stirring to 60-65°C and treated with 2N potassium hydroxide in methanol (5.5 ml). The resulting suspension was stirred at 60-65°C for 30 minutes, cooled to room temperature and further stirred for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C –55°C for 12-15 hours to yield= 5.1 g of titled compound.

The XRD of the final product is set forth in FIG. 3 which was recorded and identified as polymorph Form K-I of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, potassium salt.

Example 6: Preparation of Form K-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , potassium salt
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 1 g, 0.002469 moles ) stirred in t-butanol (20 ml) at room temperature and treated with potassium t- butoxide ( 0.3 g,0.002678moles). The suspension was heated under stirring to 80-85°C, stirred for 30 minutes, cooled to room temperature and further stirred for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C –55°C for 12-15 hours to yield 0.92 g of titled compound.

The XRD of the final product is set forth in FIG. 4 which was recorded and identified as polymorph Form K-II of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, potassium salt.

Example 7: Preparation of Form N-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, sodium salt
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 1 g, 0.002469 moles ) stirred in t-butanol (20 ml) at room temperature and treated with sodium t- butoxide ( 0. 25 g, 0.00259moles). The suspension was heated under stirring to 80-85°C, stirred for 30 minutes, cooled to room temperature and further stirred for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C –55°C for 12-15 hours to yield 0. 88 g of titled compound.

The XRD of the final product is set forth in FIG. 5 which was recorded and identified as polymorph Form N-I of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, sodium salt.

Example 8: Preparation of Form N-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, sodium salt

Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 1 g, 0.002469 moles ) stirred in ethanol (10 ml) at room temperature. The suspension was heated under stirring to 60-65°C and treated with 8% sodium hydroxide solution (2 ml). The resulting suspension was heated under stirring to 60-65°C, for 30 minutes, cooled to room temperature and further stirred for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C –55°C for 12-15 hours to yield 1 g of titled compound.

The XRD of the final product is set forth in FIG. 5 which was recorded and identified as polymorph Form N-I of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, sodium salt.

Example 9: Preparation of Form N-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , sodium salt
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide (5 g, 0.01234 moles ) stirred in a mixture of ethanol (800 ml) and water ( 200 ml) at room temperature. The suspension was heated under stirring to 70-75°C and treated with 1N sodium hydroxide solution (12.5 ml). The resulting suspension was heated under stirring to 70-75°C, for 30 minutes, cooled to room temperature and further stirred for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C –55°C for 12-15 hours to yield 5.0 g of titled compound.

The XRD of the final product is set forth in FIG. 6 and was recorded and identified as polymorph Form N-II of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, sodium salt.

Example 10: Preparation of Form K-III of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide , potassium salt
Compound (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide ( 5 g, 0.01234 moles ) stirred in methanol ( 50 ml) at room temperature. The suspension was heated under stirring to 60-65°C and treated with 2N potassium hydroxide in methanol ( 5.5 ml). The resulting suspension was stirred at 60-65°C for 10 minutes, cooled to room temperature and further stirred for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C –55°C for 12-15 hours to yield= 5.1 g of titled compound.

The XRD of the final product is set forth in FIG. 7 and was recorded and identified as polymorph Form K-III of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, potassium salt.
,CLAIMS:1. Form C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide,characterized by having an XRD pattern comprising peaks at 5.49, 12.90, 15.41, 16.66, 17.94, 18.61, 22.47, 23.89, and 26.11± 0.2 °2?, .
2. The Form C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 1, characterized by having an XRD pattern as shown in Figure 1.
3. Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, characterized by having an XRD pattern comprising peaks at 24.07 and 24.56 ± 0.2 °2?.
4. The Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 3, characterized by having an XRD pattern comprising further peaks at 17.05 and 27.59 ± 0.2°2?.
5. The Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 4, characterized by having an XRD pattern comprising further peaks at 5.29, 12.15, 14.28, 16.28, 17.67, 20.18, and 24.91 ± 0.2°2?.
6. The Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 3 to 5, characterized by having an XRD pattern as shown in Figure 2.
7. Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide.
8. Crystalline Form K-I of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, characterized by having an XRD pattern comprising peaks at 6.877 and 17.846 ± 0.2 °2?.
9. The Crystalline Form K-I of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 8, characterized by having an XRD pattern comprising further peaks at 11.341, 18.599, 20.436, 23.02, 23.792, 24.194, 26.55 and 30.23 ± 0.2 °2?.
10. Crystalline Form K-I of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 9, characterized by having an XRD pattern comprising further peaks at 5.496, 12.268, 13.847, 16.433, 17.294, 24.671, and 27.78 ± 0.2 °2?.
11. Crystalline Form K-I of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 8 to 10, characterized by having an XRD pattern as shown in Figure 3.
12. Crystalline Form K-II of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, characterized by having an XRD pattern comprising peaks at 6.573 and 18.876 ± 0.2 °2?.
13. The crystalline Form K-II of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 12, characterized by having an XRD pattern comprising further peaks at 22.804 ± 0.2 °2?.
14. The crystalline Form K-II of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 13, characterized by having an XRD pattern comprising further peaks at 7.083, 11.401, 15.411, 24.923 and 26.612± 0.2 °2?.
15. The crystalline Form K-II of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 12 to 14, characterized by having an XRD pattern as shown in Figure 4.
16. Crystalline Form K-III of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide, characterized by having an XRD pattern comprising peaks at 6.698, 17.627, 18.383, 22.808 and 25.897 ± 0.2 °2?.
17. The crystalline Form K-III of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 16, characterized by having an XRD pattern comprising further peaks at 11.13, 20.402, 23.707,24.112, 31.102± 0.2 °2?.
18. The crystalline Form K-III of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 17, characterized by having an XRD pattern comprising further peaks at 12.107, 13.608, 17.070, 22.344, 24.588, 26.914 and 27.663 ± 0.2 °2?.
19. The crystalline Form K-III of Potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 16 to 18, characterized by having an XRD pattern as shown in Figure 7.
20. Crystalline Form N-I of sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide characterized by having an XRD pattern comprising peaks at 20.157, and 23.596 ± 0.2 °2?.
21. The crystalline Form N-I of Sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 20, characterized by having an XRD pattern comprising further peaks at 6.637, 18.280, 18.669, and 22.582 ± 0.2 °2?.
22. The crystalline Form N-I of Sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 21, characterized by having an XRD pattern comprising further peaks at 14.341, 14.991, 15.855, 17.458, 21.381, 26.051, 27.098, 28.426, and 29.166 ± 0.2 °2?.
23. The crystalline Form N-I of Sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 20 to 22, characterized by having an XRD pattern as shown in Figure 5.
24. Crystalline Form N-II of sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide characterized by having an XRD pattern comprising peaks at 5.191, 9.264, 13.686, 15.185, 15.513 and 21 .317± 0.2 °2?.
25. The crystalline Form N-II of Sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 24, characterized by having an XRD pattern comprising further peaks at 10.777, 12.585, 12.876, 15.936, 18.693, 23.635, 24.282, 25.84, 26.57, 27.931 and 29.24 ± 0.2 °2?.
26. The crystalline Form N-II of Sodium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 24 and 25, characterized by having an XRD pattern as shown in Figure 6.
27. A process for preparing crystalline Form C-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 1 and 2, the process comprising dissolving (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a mixture of methanol and MDC at a temperature ranging from about 40-45°C, concentrating under vacuum to dryness, isolating the precipitated Form C-I and drying under vacuum at about 50-55°C for at least 4 hours.
28. A process for preparing crystalline Form C-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to any one of claims 3 to 6, the process comprising; dissolving (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a mixture of methanol and DMF at a temperature ranging from about 70-75°C; cooling the reaction mass at a temperature ranging from about 25-30°C, isolating the precipitated Form C-II and drying under vacuum at about 50-55°C for at least 12 hours.
29. A process for preparing potassium salt of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide according to claim 7, the process comprising; dissolving (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in a suitable solvent at 30°C to the boiling point of the solvent used, adding a source of potassium, stirring for at least 1 hour to about 5 hours and isolating the precipitated potassium salt.
30. The process according to claim 29, wherein a source of potassium is selected from the group comprising of potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like.
31. A process for preparing crystalline Form K-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium according to any one of claims 8 to 11, the process comprising; stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in methanol to 60-65°C , treating with potassium hydroxide, cooling the reaction mass at a temperature ranging from about 25-30°C, stirring the suspension for a period of 30 minutes to about 60 minutes; isolating the precipitated Form K-I and drying under vacuum at about 50-55°C for at least 12 hours.
32. A process for preparing crystalline Form K-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium according to any one of claims 12 to 15, the process comprising; stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in t-butanol, treating with potassium t- butoxide, heating to 80-85°C, stirring for 30 minutes, cooling the reaction mass at a temperature ranging from about 25-30°C, isolating the precipitated Form K-II and drying under vacuum at about 50-55°C for at least 12 hours.
33. A process for preparing crystalline Form K-III of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide potassium according to any one of claims 16 to 19, the process comprising; stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in methanol to 60-65°C , treating with potassium hydroxide, cooling the reaction mass at a temperature ranging from about 25-30°C, stirring the suspension for a period of 10 minutes; isolating the precipitated Form K-III and drying under vacuum at about 50-55°C for at least 12 hours.
34. A process for preparing crystalline Form N-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium according to any one of claims 20 to 23, the process comprising; stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in ethanol at about 30°C; heating the suspension at about 60°C to about 65°C; treating with sodium hydroxide solution; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days; and isolating the crystalline solid Form N-I from the suspension.
35. A process for preparing crystalline Form N-I of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium according to any one of claims 20 to 23, the process comprising; stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in t-butano;l adding sodium t-butoxide to the suspension at about 30°C; heating the suspension at about 80°C to about 85°C; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days; and isolating the crystalline solid Form N-I from the suspension.
36. A process for preparing crystalline Form N-II of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide sodium according to any one of claims 24 to 26, the process comprising; stirring (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide in mixture of ethanol and water; heating the suspension to 70-75°C; treating with 1N sodium hydroxide solution ; stirring the suspension for a period of 10 minutes to about 60 minutes; cooling the suspension to temperature ranging from about 20°C to about 30°C; stirring for a period of time ranging from about 30 minutes to about 2 days; and isolating the crystalline solid Form N-II from the suspension.
37. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the forms of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a-hexahydro[1, 3]oxazolo[3, 2-a]pyrido[1, 2-d]pyrazine-8-carboxamide as defined in any of claims 1 to 2 to 3 to 6, 7, 8 to11, 12 to 15, 16 to 19, 20 to 23 and 24 to 26 optionally in combination with one or more pharmaceutical acceptable excipients.