DESC:Technical field:
The invention relates to an improved, cost effective process for preparation of 2-(((3aR,4S,6R, 6a S)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d [1,3] dioxol-4-yl)oxy) ethanol, a key intermediate useful in the preparation of Ticagrelor or its acid addition salts or stereoisomers or derivatives thereof.

Background and prior art:
Ticagrelor is a platelet aggregation inhibitor marketed by AstraZeneca. Ticagrelor is a blood thinner and is indicated for the prevention of thrombotic events such as stroke or heart attack in people with coronary syndrome or myocardial infarction.

The process for preparation of Ticagrelor is reported in PCT Publication No. WO00034283 as per the scheme shown below:

Various processes for the preparation of ticagrelor, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282, 2007/0293513 and 2008/0214812; and European Patent Nos. EP0996621 and EP1135391; and PCT Publication Nos. WO2008/018823, WO2010/030224 and WO2012/13898.

Useful intermediates for preparation of Ticagrelor and its synthesis are disclosed in WO2011132083, WO2014086291 and WO0192263.

2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) oxy) ethanol an intermediate fragment useful in the preparation of Ticagrelor is disclosed in WO2011017108. The process for preparation is depicted below:

wherein the variables R16 to R21 represent hydrogen.
Accordingly, compound 27 is reacted with compound 28 in presence of oxidant, such as a combination of oxalyl chloride, dimethyl sulfoxide, and triethylamine, in an appropriate solvent, such as a combination of dichloromethane and dimethyl sulfoxide, at -78°C to give compound 29. Compound 29 is reacted with oxidizing agent selected from the combination of osmium tetroxide and N-methyl morpholine N-oxide, in an appropriate solvent, such as a combination of water and tetrahydrofuran, to give compound 30. Compound 30 is further reacted with 1,2-dihydroxy protecting group, such as 2,2-dimethoxypropane, in presence of p-toluene sulfonic acid, to give compound 31. Compound 31 is reduced using sodium borohydride in methanol, to give compound 32 which is further reduced with hydrogen gas and palladium on carbon in methanol to give compound 33. The amino compound 33 is protected using benzyl chloroformate in presence of potassium carbonate, in an appropriate solvent, such as a combination of water and tetrahydrofuran, to give compound Benzyl (3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyl-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-4-ylcarbamate (34).

The compound (34) was further reacted with ethyl 2-bromoacetate which was further reduced with hydrogen gas and palladium on carbon in methanol to yield Ethyl 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahvdro-3aH-cyclopentardiri,31dioxol-4-yloxy)acetate. The compound Ethyl 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahvdro-3aH-cyclopentardiri,31dioxol-4-yloxy) acetate is reacted with LiAlH4 in THF to give 2-((3aR,4S,6R,6aS)-6-amino-2.2-dimethyl-tetrahvdro-3aH-cyclopenta[dl [l,31dioxol-4-yloxy)ethanol, i.e Ticagrelor fragment as shown below.

The reagents and reaction conditions employed in the process are costly and harsh which makes the process industrially not feasible.

In view of the above, the present inventors felt a need to provide a cost effective, industrially feasible process for preparation of Ticagrelor intermediate. The process employed in the present invention is an improvement over the prior art methods and ameliorates the drawbacks of the process disclosed in WO’108 by using milder reagents and reaction conditions.

Summary of the invention
In line with the above objectives, the present invention provides an improved cost effective process for preparation of 2-(((3aR, 4S, 6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol of Formula I;

(I)

The process employed in the present invention uses mild reagents and reaction conditions to obtain compounds in good yield and purity.

In an aspect, the process for preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol of Formula I comprises the following steps:

1. Reacting mixture of (R)-tert-butyl (1-(hydroxyamino)-1-oxopropan-2-yl) carbamate and cyclopentadiene (1) in methanol with sodium periodate in water to obtain tert-butyl ((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl)carbamate (2);

2. Subjecting compound of formula (2) to oxidation in presence of KMnO4 in acetone to obtain tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptan-3-yl)-1-oxopropan-2-yl)carbamate (3);

3. Reacting compound (3) with p-toluene sulfonic acid in 2,2 dimethoxy propane to obtain tert-butyl ((R)-1-((3aR,4S,7R,7aR)-2,2-dimethyldihydro-3aH-4,7-methano [1,3] dioxolo [4,5-d][1,2]oxazin-6(4H)-yl)-1-oxopropan-2-yl)carbamate (4);

4. Reacting compound (4) with Lithium hydroxide in methanoland water mixture. to yield (3aS,4R,7S,7aS)-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3] dioxolo [4,5-d][1,2]oxazine (5);

5. Reducing the hot solution of compound (5) in diglyme with sodium borohydride to obtain (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo penta [d] [1,3]dioxol-4-ol (6 );

6. Adding benzyl chloroformate to the mixture of compound (6) and sodium carbonate dissolved in THF and water to give benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3] dioxol-4-yl)carbamate (7);

7. Reacting compound (7) with sodium hydride and methyl bromoacetate to obtain methyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyl tetra hydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate (8); and

8. Reducing the hot solution of compound (8) in diglyme with sodium borohydride to obtain compound (I).

Description of drawings
Fig 1: Schematic representation for preparation of compound (I)

Detailed description of the invention
The present invention relates to an improved process for preparation of 2-(( (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl)oxy)ethanol of Formula I;

(I)
The process employed in the present invention uses mild reagents and reaction conditions enabling to isolate the intermediates at every stage in good yield and purity.

According to the process, the first step comprises reacting (R)-tert-butyl (1-(hydroxyamino)-1-oxopropan-2-yl)carbamate (1) and cyclopentadiene in methanol at 0-5°C with the solution of Sodium Periodate in water. The reaction mixture was stirred at same temperature for about 1h. Methanol was removed under reduced pressure and extracted with ethyl acetate. The extract was dried and ethyl acetate was further removed under reduced pressure to give tert-butyl ((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl)carbamate (2) as white solid.

(2)
The step of obtaining compound (2) is an improvement over the art as the condensation reaction is effected at a temperature in the range of 0-5°C in comparison to the prior art method where a temperature of -78°C needs to be maintained. Further, the solvent used is methanol and water as against the use of corrosive and harmful solvent such as dichloromethane used in WO2011017108. .

Step (2) comprises oxidation of the double bond in compound (2) which was performed by drop wise addition of solution of KMnO4 to tert-butyl ((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl)carbamate (2) dissolved in acetone at a temperature in the range of 0-5°C. The reaction mixture was stirred for about 3hrs at 0-5°C until TLC showed completion of the reaction. Acetone was removed from the reaction mixture under reduced pressure. The reaction mass was extracted with ethyl acetate and the combined organic extracts were dried, concentrated under reduced pressure. The obtained crude product tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptan-3-yl)-1-oxopropan-2-yl) carbamate (3) as yellowish syrup was used for the next reaction without any further purification.

(3)
This step uses cheap and mild oxidizing agent i.e KMnO4.

According to step 3, the solution of tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-azabicyclo [2.2.1] heptan-3-yl)-1-oxopropan-2-yl)carbamate (3) and 2,2 dimethoxy propane in p-Toluene sulfonic acid was stirred at 25°C for about 2 hrs. After completion of the starting material as indicated by TLC, sodium bicarbonate was added. The solid was filtered off and solvent was removed under reduced pressure. The crude material was extracted with ethyl acetate and the combined extracts were dried, concentrated under reduced pressure to form solid material. To the solid mass was added isopropyl ether, stirred and filtered to give tert-butyl ((R)-1-((3aR,4S,7R,7aR)-2,2-dimethyldihydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazin-6(4H)-yl)-1-oxopropan-2-yl)carbamate (4) as a white solid.

(4)

Step 4 comprises adding Lithium hydroxide to a solution of tert-butyl ((R)-1-((3aR,4S,7R,7aR)-2,2-dimethyldihydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazin-6(4H)-yl)-1-oxopropan-2-yl)carbamate (4) in methanol: water mixture (4:1) maintained at room temperature. The reaction mixture was stirred for about 30 min at room temperature. After completion of the starting material as indicated by TLC, methanol was removed under reduced pressure. Reaction mixture was extracted with DCM and the combined organic extracts were dried and concentrated under reduced pressure. To the reaction mass was added isopropyl ether and stirred for about 15 min at RT. The solid was filtered and washed further with isopropyl ether to give (3aS,4R,7S,7aS)-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazine (5) as white solid.

(5)
Further according to step 5, sodium borohydride was added lot wise under nitrogen atmosphere to a hot solution of (3aS,4R,7S,7aS)-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2] oxazine (5) in diglyme at about 100°C. The reaction mixture was stirred at same temperature for about 2 h. After completion of the starting material as indicated by TLC, Diglyme was distilled out completely under reduced pressure. The residue obtained was cooled to room temperature, ethyl acetate was added and the mixture was stirred for about 15 min. The solid was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure to give (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (6) as yellowish solid.

(6)
Protection of the free amino group in compound (6) was carried out by reacting (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-ol (6) and sodium carbonate in THF: H2O (5: 1) with benzyl chloroformate at 0°C. The reaction mixture was stirred for about an hour at same temperature until TLC indicated completion of the reaction. This was followed by addition of water and extraction with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure. Hexane was further added to the crude product and stirred for about 15 min. The solid was filtered and washed with hexane to give benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) carbamate (7) as white fluffy solid.

(7)
According to step 7, to a cold solution of benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate (7) in DMF was added sodium hydride in the range -30°C to -5°C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 min. Methyl bromo acetate is added to the reaction mixture in the range -30°C to -5°C and further allowed to react at room temperature for about 8hrs. Ammonium chloride solution was added at 0°C to the reaction mixture followed by extraction with ethyl acetate. The combined organic layers were dried, concentrated under reduced pressure to give crude methyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) oxy)acetate (8) as yellowish syrup. This material was used for the next reaction without any further purification.

(8)

Step 8 comprises hydrogenation of compound (8) using sodium borohydride under nitrogen atmosphere. Accordingly, to the hot solution of methyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy) carbonyl) amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate (8) in diglyme at about 100°C was added sodium borohydride under nitrogen atmosphere. The reaction mixture was stirred at same temperature for about 2 h until TLC indicated completion of reaction. The solvent was then removed under reduced pressure. Residue was cooled to room temperature and added ethyl acetate, stirred for 15 min, filtered the solid and further washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by column chromatography to give 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) oxy) ethanol (I) as yellowish syrup.

The intermediate (I) obtained by the improved process of the present invention is useful for preparation of Ticagrelor or its acid addition salts or its stereoisomers or derivatives thereof.

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 included within the scope of the invention. The examples included herein are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.

Example I:
Tert-butyl((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl) carbamate (2)
To the stirred solution of (R)-tert-butyl (1-(hydroxyamino)-1-oxopropan-2-yl) carbamate 1 (50g, 245 mmol) and cyclopentadiene (80g, 1225 mmol) in methanol (500 ml) at 0 oC was added the solution of Sodium Periodate (60g, 274 mmol) in water (500 ml). The reaction mixture was stirred for 1h. Methanol was removed under reduced pressure and extracted with ethyl acetate (2x 150 ml). Dried on sodium sulfate and ethyl acetate was removed under reduced pressure to give tert-butyl ((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl)carbamate 2 (35g, 50%) as white solid.
Example II: Tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-aza bicycle [2.2.1] heptan-3-yl)-1-oxopropan-2-yl)carbamate (3)

To a solution of tert-butyl ((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl)carbamate 2 (35 g, 130 mmol) in acetone (300 ml) at 0oC was added the solution of KMnO4 (18 g, 104 mmol) in water (300 ml) drop wise. The reaction mixture was stirred for 3h at 0oC. After completion of the starting material as indicated by TLC, acetone was removed under reduced pressure. The reaction mass was extracted with ethyl acetate (3x 150 ml). The combined organic extracts was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptan-3-yl)-1-oxopropan-2-yl)carbamate 3 (30 g, 80 %) as yellowish syrup was used for the next reaction without any further purification.

Example III: Tert-butyl ((R)-1-((3aR,4S,7R,7aR)-2,2-dimethyldihydro-3aH-4,7-methano [1,3] dioxolo [4,5-d][1,2]oxazin-6(4H)-yl)-1-oxopropan-2-yl)carbamate (4)

The solution of tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptan-3-yl)-1-oxopropan-2-yl)carbamate 3 (30g, 99 mmol) and p-Toluene sulfonic acid (3g, 19.8 mmol) in 2,2 dimethoxy propane (500 ml) was stirred at 25oC for 2h. After completion of the starting material as indicated by TLC, sodium bicarbonate (5g) was added. Filtered off the solid and solvent was removed under reduced pressure. Crude material was extracted with ethyl acetate (2 x 100 ml). The combined extracts was dried on sodium sulfate and concentrated under reduced pressure to form solid material. 60 ml of isopropyl ether was added, stirred for 15 min and filtered to give tert-butyl((R)-1-((3aR,4S,7R,7aR)-2,2-dimethyldihydro-3aH-4,7-methano [1,3] dioxolo [4,5-d][1,2]oxazin-6(4H)-yl)-1-oxopropan-2-yl)carbamate 4 (30 g, 91 %) as white solid.

Example IV: (3aS,4R,7S,7aS)-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3] dioxolo[4,5-d][1,2]oxazine (5)

To a solution of tert-butyl ((R)-1-((3aR,4S,7R,7aR)-2,2-dimethyldihydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazin-6(4H)-yl)-1-oxopropan-2-yl)carbamate 4 (30 g, 87.7 mmol) in methanol: water (4:1, 300 ml) at room temperature was added Lithium hydroxide (9 g, 219 mmol). The reaction mixture was stirred for 30 min at room temperature. After completion of the starting material as indicated by TLC, methanol was removed under reduced pressure. Reaction mixture was extracted with DCM (3x 100 ml). The combined organic extracts was dried on sodium sulfate and concentrated under reduced pressure. 30 ml of isopropyl ether was added and stirred for 15 min at RT. Filtered the solid and washed with isopropyl ether (1x10 ml) to give (3aS,4R,7S,7aS)-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazine 5 (14.5g, 96.7%) as white solid.

Example V: (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-ol (6)

To a hot solution of (3aS,4R,7S,7aS)-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazine 5 (13 g, 76 mmol) in diglyme (50 ml) at 100 oC was added sodium borohydride (5.6 g, 190 mmol) lot wise under nitrogen atmosphere. The reaction mixture was stirred at same temperature for 2 h. After completion of the starting material as indicated by TLC, diglyme was distilled completely under reduced pressure. Residue was cooled to room temperature; ethyl acetate (300 ml) was added and stirred for 15 min. The solid was filtered and washed with ethyl acetate (50 ml). Filtrate was concentrated under reduced pressure to give (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol 6 (12g, 91%) as yellowish solid.

Example VI: Benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclo penta [d][1,3]dioxol-4-yl)carbamate (7)

To the mixture of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (6) (12 g, 69 mmol) and sodium carbonate (14 g, 138 mmol) in THF: H2O (5: 1, 300 ml) was added benzyl chloroformate (13 g, 72.8 mmol) at 0oC. The reaction mixture was stirred for 1 h at 0 oC. After completion of the starting material as indicated by TLC was added 50 ml of water and extracted with ethyl acetate (3x 200 ml). The combined organic layers was dried on sodium sulfate and concentrated under reduced pressure. Hexane (20 ml) was added to the crude product and stirred for 15 min. The solid was filtered and washed with hexane (5 ml) to give benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate (7) (12 g, 56 %) as white fluffy solid.

Example VIII: Methyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate (8)

To a cold solution of benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate (7) (12 g, 39 mmol) in DMF (200 ml) was added sodium hydride (3 g, 46.8 mmol) at -5oC under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 min. Methyl bromo acetate (8 g, 58.6 mmol) was added at -5 oC to the reaction mixture and allowed to react at room temperature for 8 h. Ammonium chloride solution (500 ml) was added at 0oC to the reaction mixture and extracted with ethyl acetate (3x 200 ml). The combined organic layers was dried on sodium sulfate and concentrated under reduced pressure to give crude methyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate 8 (8g) as yellowish syrup. This material was used for the next reaction without any further purification.

Example IX: 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo penta [d] [1,3] dioxol-4-yl)oxy)ethanol (Formula I)

To a hot solution of methyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)acetate 9 (8g, 21 mmol) in diglyme ( 50 ml) at 100oC was added sodium borohydride (3.19 g, 84.4 mmol) under nitrogen atmosphere. The reaction mixture was stirred at same temperature for 2 h. After completion of the starting material as indicated by TLC, solvent was removed under reduced pressure. Residue was cooled to room temperature, added ethyl acetate (50 ml), stirred for 15 min, filtered the solid and washed with 30 ml of ethyl acetate. Filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2) using Ethyl acetate : Hexane (7:3) as mobile phase to give 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) oxy) ethanol (I) (3.2g, 72%) as yellowish syrup.
Industrial Advantages:
The present invention provides cost effective and industrially feasible process for preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) oxy) ethanol (I), useful intermediate for synthesis of ticagrelor.
• The reagents used are cheaper and in process step (a) relating to preparation of tert-butyl ((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl)carbamate (2), even though the reagent sodium periodate used is expensive it is compensated by milder reaction conditions 0-5°C instead of -78°C.
• Step (b) relating to oxidation of intermediate (2) to tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptan-3-yl)-1-oxo propan-2-yl)carbamate (3) the present invention uses a mild and cheap oxidizing agent such as KMnO4.
• Similarly, in reduction process step (e) for preparation of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (6 ), the present invention avoids the use of expensive, poisonous metals such as Pd and employs the use of milder and safe reducing agent such as sodium borohydride.
• It is possible to isolate the intermediates at every step in good yield and purity which allows their use directly for the next step.
,CLAIMS:We claim;

1. An improved and cost effective process for preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol of Formula I

(I)
characterized by;
a. Reacting a mixture of (R)-tert-butyl (1-(hydroxyamino)-1-oxopropan-2-yl) carbamate and cyclopentadiene (1) in methanol with sodium periodate in water to obtain tert-butyl ((R)-1-((1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl)-1-oxopropan-2-yl)carbamate (2);
b. Subjecting compound of formula (2) to oxidation in presence of KMnO4 in acetone to obtain tert-butyl ((R)-1-((1S,4R,5R,6R)-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptan-3-yl)-1-oxopropan-2-yl)carbamate (3);
c. Protecting hydroxyl groups of compound (3) with 2,2 dimethoxy propane in presence of p-toluene sulfonic acid to obtain tert-butyl ((R)-1-((3aR,4S,7R,7aR)-2,2-dimethyldihydro-3aH-4,7-methano [1,3] dioxolo [4,5-d][1,2]oxazin-6(4H)-yl)-1-oxopropan-2-yl)carbamate (4);
d. Reacting compound (4) with Lithium hydroxide in methanol and water mixture to yield (3aS,4R,7S,7aS)-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazine (5);
e. Reducing the hot solution of compound (5) in diglyme with sodium borohydride to obtain (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (6 );
f. Adding benzyl chloroformate to the mixture of compound (6) and sodium carbonate dissolved in a mixture of THF and water to give benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3] dioxol-4-yl)carbamate (7);
g. Reacting compound (7) with sodium hydride and methyl bromoacetate to obtain methyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2-dimethyltetra hydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl)oxy)acetate (8); and
h. Reducing the hot solution of compound (8) in diglyme with sodium borohydride to obtain intermediate (I).

2. The process according to claim 1, wherein the temperature of step (a) is in the range of 0-5°C.

3. The process according to claim 1, wherein the temperature of step (b) is in the range of 0-5°C.

4. The process according to claim 1, wherein the ratio of methanol: water mixture of step (d) is 4:1.

5. The process according to claim 1, wherein the reaction temperature of step (d) is room temperature.

6. The process according to claim 1, wherein the reaction temperature of step (g) is in the range of -30°C to room temperature (RT).

7. The process according to claim 1, wherein the compound of formula (I) is useful for preparation of Ticagrelor or its acid addition salts or stereoisomers or derivatives thereof.