FIELD OF THE INVENTION

The present invention relates to a process for preparation of Edoxaban intermediate viz. tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl) carbamate succinate of formula (1).

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Savaysa (Edoxaban tosylate monohydrate) is N-(5-chloropyridin-2-yl)-N'- [(1S,2R,4S)-4 (N,N- dimethyl carbamoyl)- 2-(5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo[5,4-c]pyridine-2- carboxamido)cyclohexyl]oxamide mono(4-methyl benzene sulfonate) monohydrate.

Savaysa is a factor X _a inhibitor, indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Savaysa is available as 15 mg, 30 mg and 60 mg oral tablets.

In the preparation of Edoxaban, compound of formula (1) having name tert-butyl ((1R,2S,5S)-2- amino-5-(dimethylcarbamoyl)cyclohexyl) carbamate succinate is a key intermediate. The present invention provides a simple and industrially advantageous process for preparing compound of formula (1) which is shown below:

The innovator in the patent US8686189B2 discloses oxalic acid salt of a cyclohexyl diamine derivative compound, which is an intermediate of Edoxaban and a method for preparing the same. This patent discloses a method for preparing an oxalic acid salt of a diamine derivative by reacting an azide with a sulfonate compound and adding oxalic acid after reduction in the presence of a metal catalyst and a hydrogen source.

Hence, there remains a need for providing efficient, safe, industrially feasible and economically viable process for manufacture of salt of cyclohexyl diamine derivative compound. Therefore, the inventors of the present invention has developed a process to manufacture the succinic acid salt of the cyclohexyl diamine derivative compound.

SUMMARY OF THE INVENTION

The problem addressed by the present invention is that of providing a better improved, efficient, economic and an industrially viable process for preparation of compound of formula (1).

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for describing the particular embodiments only, and is not intended to limit the scope of the present invention.

Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar, equivalent to those described herein can be used in the practice, or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further, the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

Accordingly, the present invention relates to an improved process for the preparation of compound of formula (1), tert-butyloxycarbonyl comprising;

(a) treating a methyl (1R,2R,4S)-2-((tert-butoxycarbonyl)amino)-4-(dimethylcarbamo yl) cyclohexane- 1 -sulfonate of formula (2) with an azide in the presence or absence of a phase-transfer catalyst to obtain a tert-butyl ((1R,2S,5S)-2-azido-5- (dimethylcarbamoyl)cyclohexyl) carbamate of formula (3);

(b) reducing the compound of formula (3); followed by adding succinic acid to obtain a compound of formula (1).

The treatment of methyl (1R,2R,4S)-2-((tert-butoxycarbonyl)amino)-4-(dimethylcarbamo yl) cyclohexane-1-sulfonate of formula (2) with an azide in the presence or absence of a phase-transfer catalyst to obtain tert-butyl ((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl) carbamate of formula (3) is in a solvent.

The azide used in step (a) is selected from alkali metal (e.g., sodium or potassium) azides; alkaline earth metal (e.g., calcium or magnesium) azides, and quaternary ammonium (e.g., tetrabutylammonium) azides. Of these, alkali metal azides are preferred, with sodium azide being particularly preferred.

The phase-transfer catalyst include quaternary ammonium salts selected from tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium sulfate, and trioctylmethylammonium chloride; quaternary phosphonium salts selected from tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, trioctyl (octadecyl) phosphonium iodide, tributyl (tetradecyl) phosphonium chloride; pyridinium compounds selected from dodecylpyridinium chloride, dodecylpyridinium bromide ; and crown ether. Of these, trioctylmethylammonium chloride, tetrabutylammonium chloride, tetrahexylammonium chloride, tetramethylammonium chloride, tetraethylammonium chloride, and dodecylpyridinium chloride are preferred, with tetrabutylammonium chloride and dodecylpyridinium chloride being particularly preferred

The solvent used in step (a) is selected from an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3- dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N- dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N- methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.

The reduction of the compound of formula (3) in step (b) is carried out in a solvent and using a reducing agent which is followed by treatment with succinic acid in a solvent.

The solvent used for reducing compound of formula (3) in step (b) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyl tetrahydrofuran, diethyl ether, 1,4- dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof. Preferably, the solvent used for reducing compound of formula (3) is alcoholic solvent. More preferably, the solvent used is methanol.

The reduction of compound of formula (3) in step (b) is carried out using reducing agent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl ₂ , FeSO ₄ , Fe powder, Raney Nickel, Pd/C, NaBH ₄ , Potassium Borohydride, SnCl ₂ .2H ₂ O, Zn dust, Sodium Borohydride with Pd/C, thiophenol/trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na ₂ S, NaBH ₄ , NaBH ₄ /BF ₃ -diethyl ether, NiCl ₂ .6H ₂ O, LiBH ₄ , LiAlH ₄ . The reduction of the compound can be carried out using reducing agent and suitably, in the presence of Lewis acid selected from AlCl ₃ , LiCl, or BF ₃ etherate; or hydrogen gas or a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate. Preferably, the reducing agent is Pd/C and hydrogen gas.

The solvent used in the preparation of succinic acid salt in step (b) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof. Preferably, the solvent used is ketone. More preferably, the solvent used is acetone.

The whole synthetic scheme of preparation of compound of formula ( 1 ) according to the present invention can be represented as below:

The term “about,” as used herein, is intended to qualify the numerical values, which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

According to the invention, the overall yield of compound of formula (1) as obtained by using the process of the present invention is at least about 84 % yield with purity of at least about 98.6 % by HPLC.

In the case of oxalic acid, the hemi-lethal dose (LD ₅₀ ) is 375 mg/kg (rat, oral), whereas the hemi- lethal dose (LD ₅₀ ) of succinic acid is 2,260 mg/kg (rat, oral) which is less toxic than oxalate.

Thus, the present invention offers below advantages over previous methods reported in the literature include: (i) easy workup procedure;

(ii) good yield and purity is achieved of the final product;

(iii) succinic acid has less LD50 value which means it is less toxic as compared to the prior art salts;

Thereby, the practicability of the reaction is greatly enhanced at both the laboratory scale and the industrial scale. The present invention results into yield of at least about 84 % with purity of at least 98.6 % by HPLC, thereby, making the process efficient, economic and industrially viable.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1

Preparation of tert-butyl ((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cvclohexyl) carbamate (3)

189.2 g of Sodium azide was charged into 530 ml of N-methyl-2-pyrrolidone (NMP) and 180.7 g of Dodecyl pyridinium chloride in a round bottomed flask at ambient temperature. It was heated at 40-45° C and maintained for 24 h. Added solution of 530 g of methyl (1R,2R,4S)-2-((tert- butoxycarbonyl)amino)-4-(dimethylcarbamoyl)cyclohexane-l-sul fonate (2) in 1060 ml of N- methyl-2-pyrrolidone at 40-45° C and maintained for 32 h at 70° C. Cooled reaction mass at RT and charged solution of 106 g sodium carbonate in 3180 ml of water. Cooled at 0-5° C and solid product separated by filtration. Dried obtained solid under vacuum at 50° C. Off white coloured 252 g dry solid product obtained.

HPLC purity -88.0 %. Yield - 55.6 %. Example 2

Preparation of tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl) carbamate succinate (1)

75 g of tert-butyl ((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl) carbamate (3) was added into 375 ml of Methanol and 3.75 g of 5% wet Palladium on carbon at ambient temperature in pressure reactor. Applied hydrogen pressure up to 5 kg per square cm at 25-35° C and maintained for 6-8 h. Filtered and remove palladium carbon followed by distilling out solvent under vacuum. Residual solvent stripped out using isopropyl alcohol and 525 ml of acetone. 28.5 g of succinic acid was charged into residue. It was heated at 45-50° C and again cooled it at 20- 25° C, when solid product was separated by filtration. It was dried under vacuum for 12 h at 50° C. Yield of white colored product was 81.0 g.

HPLC purity - 98.56 %. Yield - 83.7 %