Description:FIELD OF THE INVENTION
The present application provides an improved process for the preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol which is a potential intermediate for the preparation of Ticagrelor in high yields and purity and suitable for manufacturing in commercial scale.

BACKGROUND OF THE INVENTION
Ticagrelor is a platelet aggregation inhibitor which is chemically known as (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol and whose chemical structure is the following.

Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infection with ST elevation, other coronary artery diseases and arterial thrombosis as well as other disorders related to platelet aggregation.
Several processes have been discussed in the literature for the preparation of Ticagrelor and their pharmaceutically acceptable salts, which are disclosed in US6525060, US7067663, US7250419, W02000/034283, WO2008018823 and W02010030224.
Several synthetic methods have been reported in the literature to prepare 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol compound of formula (I)

Formula (I)
WO2000034283A1discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

WO2001092263A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

WO2011017108A2 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

WO2012172426A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

WO2015067111A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

CN104610220 (B) discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.



CN106496179 (A) discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

CN111087379 (A) discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.


All the above prior art methods for the preparation of compound of formula (I) have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates. Therefore, still there is need for the development of commercially viable, cost-effective and eco-friendly process for the preparation of substantially pure 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol a Ticagrelor intermediate of compound of formula (I).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, effective and industrially feasible process for the preparation of high pure intermediate of Ticagrelor by using eco-friendly, cheaply available reagents and low boiling solvents which is cost effective and with good yields on commercial scale by avoiding repeated cumbersome and lengthy purification steps.

SUMMARY OF THE INVENTION
The improved process for the preparation of substantially pure 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol disclosed herein has the following advantages over the processes described in the prior art:
i) The prior art process disclosed reaction conditions which are not cost effective, and moreover involves tedious workup and extractions, purifications and multiple isolations;
ii) The present invention simplifies the reaction conditions and provides cost-effective process with minimum downstream activity.
iii) The present invention provides a significant amount of toluene recovery process when used a combination of minimum amount of DMF in toluene in the reaction; solvent recovery is an eco-friendly, economical, and cost-effective method of reducing waste and an option to the greenness of industrial processes;
iv) The present invention provides not only eco-friendly commercial adoptable but also provides high yield with high pure compound;
v) Using the inexpensive solvents and alkali hydroxide, alkaline metal alkoxy base characterized in that said bases reaction is cost effective;
vi) Toluene can be recovered with minimum operational loss and the recovered toluene can be reused without any further purification;
vii) The process avoids the use of expensive raw non-recoverable materials;
viii) the overall yield of the product is increased, and it is also substantially pure.
The present invention provides an improved process for the preparation of substantially pure 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1l a Ticagrelor intermediate compound of formula (I).

Formula (I)
In one aspect of the present application provides process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts, solvates and hydrates thereof;

Formula (I)
which comprises:
a) compound of formula (II) (which can be prepared by known processes from the corresponding oxazine) undergoes coupling reaction with benzyl chloroformate in presence of suitable base, catalyst and appropriate solvent gives compound of formula (III);

Formula (II) Formula (III)
b) reacting compound of formula (III) with ethyl bromoacetate in presence of appropriate base in suitable solvent or mixture of solvents gives compound of formula (IV);

Formula (IV)
c) reduced compound of formula (IV) in presence of NaBH4 in Ethanol gives compound of formula (V);

Formula (V)
d) compound of formula (V) undergoes deprotection in presence of hydrogen atmosphere with Pd-C in methanol solvent gives compound of formula (I);

Formula (I)
e) optionally purifying the compound of formula (I) in a suitable solvent.

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly indictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method, or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.
In one embodiment of the present invention is to provide a process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts, solvates and hydrates thereof;

Formula (I)
which comprises:
a)compound of formula (II) (which can be prepared by known processes from the corresponding oxazine) undergoes coupling reaction with benzyl chloroformate in presence of suitable base, catalyst and appropriate solvent gives compound of formula (III);

Formula (II) Formula (III)
b)reacting compound of formula (III) with ethyl bromoacetate in presence of appropriate base in suitable solvent or mixture of solvents gives compound of formula (IV);

Formula (IV)
c) reduced compound of formula (IV) in presence of NaBH4 in Ethanol gives compound of formula (V);

Formula (V)
d) compound of formula (V) undergoes deprotection in presence of hydrogen atmosphere with Pd-C in methanol solvent gives compound of formula (I);

Formula (I)
e) compound of formula (I) treated with L-Tartaric acid in presence of isopropyl alcohol and acetonitrile gives compound of formula (Ia);

Formula (Ia)

f) optionally purifying the compound of formula (I) in a suitable solvent.

In one embodiment of the present invention is to provide a process for the preparation of benzyl ethyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate of formula (IV) comprising steps of :

a) compound of formula (II) (which can be prepared by known processes from the corresponding oxazine) undergoes coupling reaction with benzyl chloroformate in presence of TBAB and potassium carbonate in toluene gives compound of formula (III);

Formula (II) Formula (III)
b) reacting compound of formula (III) with ethyl bromoacetate in presence of base in DMF and toluene mixture gives compound of formula (IV)

Formula (III) Formula (IV).
In another embodiment of the present invention is to provide a process for the preparation of ethyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl) amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate of formula (IV)

Formula (IV)
which comprises:
reacting compound of formula (III) with ethyl bromoacetate in presence of a base is selected form the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or more preferably sodium hydride in DMF and toluene mixture gives compound of formula (IV).
In another embodiment of the present invention, wherein the catalyst used in step (a) is selected from the group consisting of TBAB, TBAF, TBAH, TEBA more preferably TBAB.
In another embodiment of the present invention, wherein the base used in step (a) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, triethylamine, diisopropylamine more preferably potassium carbonate.
In another embodiment of the present invention, wherein the solvent used in step (a) is selected from the group comprising of toluene, xylene, benzene, acetone and more preferably toluene or mixture thereof.
In another embodiment of the present invention, wherein the base used in step (b) is selected from the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide more preferably sodium hydride.
In another embodiment of the present invention, wherein the solvent used in step (b) is selected from the group consisting of toluene, DMF, DMSO, xylene, benzene and DMA or mixture thereof, more preferably DMF and toluene mixture.

In specific embodiment of the present invention, wherein the solvent used in step (b) is DMF and toluene mixture.

In another specific embodiment of the present invention, wherein in the pharmaceutically acceptable salt of formula I is 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol. (2R,3R)-2,3-dihydroxysuccinic acid.

In another embodiment the present invention particularly describes improved process for the preparation of substantially pure 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol a Ticagrelor intermediate compound of formula (I) is illustrated in the following synthetic scheme:

Scheme 1
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt followed by optionally washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An antisolvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, xylene, chlorobenzene, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
In another embodiment the below are the abbreviations are used in the specification;
DMF- dimethylformamide; HCl-Hydrochloric acid; NaOH- Sodium Hydroxide; MTBE- Methyl tert-butyl ether, TLC- Thin layer chromatography; TBAB- Tetrabutylammonium bromide, TBAHS-tetrabutylammonium hydrogen sulphate, TBAI- tetrabutyl ammonium iodide, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography; DCM-Dichloromethane; Pd/C-Palladium Carbon, H2-Hydrogen gas, NH4Cl-Ammonium chloride, K2CO3- Potassium Carbonate Na2CO3-Sodium Carbonate; NaHCO3-Sodium bicarbonate, NaH-Sodium hydride; MeOH- Methanol; EtOAc-Ethyl acetate.
EXAMPLES
Example-1
Synthesis of benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate:
To a stirred solution of (3aR,4S,6R,6aS)-6-amino-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d](1,3)dioxol-4-ol (66 g) in acetone (200) and water (300) added TBAB (3 g) at room temperature and maintaine for 15 min. Slowly add 50% benzylchloroformate in toluene (180 g) at room temperature and maintain for 1 to 2 hrs. reaction was monitored by TLC, after completion of starting material settle the reaction mass separate the toluene layer, re-extract compound into toluene from aquoues layer. Mix the organic layers and wash with brine. Organic layer was dried over sodium sulphate and distilled under reduced pressure. Material was isolated by using toluene and dried at 40°C to 45°C to get 108 g of Benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate.
Example-2
Synthesis of ethyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate
To a stirred suspension of 60% sodium hydride (19 g) in toluene (200 mL) slowly added a solution of Benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate (100 g) in DMF and toluene mixture (250 mL) at -35°C to -30°C. After maintaining for 20 to 30 min. slowly add a solution of ethylbromoacetate (71 g) in toluene (200 mL) at 35°C to -20°C. Maintain the reaction mass below -13°C till starting material complies. Reaction mixture was monitored by TLC, after completion of starting material quenched the reaction mass with aquoues ammonium chloride solution, product was extracted into toluene. Organic layers and wash with brine. Organic layer was dried over sodium sulphate and distilled under reduced pressure. Material was isolated by using toluene and dried at 40 to 45°C to get 119g of Benzyl (3aR,4S,6R,6aS)-4-((ethoxycarbonyl)methoxy)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-6-ylcarbamate.
, Claims:1. A process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts thereof;

Formula (I)
which comprises:
a) compound of formula (II) (which can be prepared by known processes from the corresponding oxazine) undergoes coupling reaction with benzyl chloroformate in presence of suitable base, catalyst and appropriate solvent gives compound of formula (III);

Formula (II) Formula (III)
b) reacting compound of formula (III) with ethyl bromoacetate in presence of appropriate base in suitable solvent or mixture of solvents gives compound of formula (IV);

Formula (IV)
c) reduced compound of formula (IV) in presence of NaBH4 in Ethanol gives compound of formula (V);

Formula (V)
d) compound of formula (V) undergoes deprotection in presence of hydrogen atmosphere with Pd-C in methanol solvent gives compound of formula (I);

Formula (I)
e) optionally purifying the compound of formula (I) in a suitable solvent.

2. A process for the preparation of benzyl ethyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate of formula (IV) comprising steps of :

a) compound of formula (II) (which can be prepared by known processes from the corresponding oxazine) undergoes coupling reaction with benzyl chloroformate in presence of TBAB and potassium carbonate in toluene gives compound of formula (III);

Formula (II) Formula (III)
b) reacting compound of formula (III) with ethyl bromoacetate in presence of base in DMF and toluene mixture gives compound of formula (IV)

Formula (III) Formula (IV).

3. A process for the preparation of ethyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl) amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate of formula (IV)

Formula (IV)
which comprises:
reacting compound of formula (III) with ethyl bromoacetate in presence of a base is selected form the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or more preferably sodium hydride in DMF and toluene mixture gives compound of formula (IV).

4. The process as claimed in claim 1 to 3, wherein step (a) is carried out in presence of catalyst selected from the group consisting of TBAB, TBAF, TBAH, TEBA more preferably TBAB.

5. The process as claimed in claim 1 to 3, wherein step (a) is carried out in presence of base selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, triethylamine, diisopropylamine more preferably potassium carbonate.

6. The process as claimed in claim 1 to 3, wherein step (a) is carried out in presence of solvent selected from the group comprising of toluene, xylene, benzene, acetone and more preferably toluene or mixture thereof.

7. The process as claimed in claim 1 to 3, wherein step (b) is carried out in presence of base selected from the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide more preferably sodium hydride.

8. The process as claimed in claim 1 to 3, wherein step (b) is carried out in presence of a solvent is selected from the group consisting of toluene, DMF, DMSO, xylene, benzene and DMA or mixture thereof, more preferably DMF and toluene mixture.

9. The process as claimed in claim 1 to 3, wherein the solvent selected for step (b) is DMF and toluene mixture.

10. The process as claimed in claim1, where in the pharmaceutically acceptable salt is 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol. (2R,3R)-2,3-dihydroxysuccinic acid.