The following specification describes the nature of the application:

Preparation of (3aR 4S 6R 6aS)-6-amino-2 2-dimethyltetrahydro-3aH-cyclopenta[d][1 3]dioxol-4-ol and its derivatives

INTRODUCTION
The present application concerns an improved process for the preparation of cyclopentyl derivatives which are useful intermediates in the preparation of pharmaceutically active agents and in particular the compound [1S-(1? 2? 3?(1S* 2R*) 5?)]-3-[7-[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 (ticagrelor).
Ticagrelor and similar such compounds  are disclosed in WO 00/34283 and WO 99/05143 as pharmaceutically active P2T (which is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used as  inter alia  as inhibitors of platelet activation  aggregation  or degranulation. The compound of Formula I is useful in the preparation of ticagrelor or analogues thereof. The present application provides a novel process for the preparation of a compound of Formula I or its salts:

Formula I

Processes for the preparation of the compound of Formula I or its precursor compounds are described in Patent Application Publications WO 01/92263 A1  WO 2005/095377 A1 and WO 2009/064249 A1.
These publications involve use of multi-step synthesis and/or use of low temperature to minimize the side-reactions  use of chiral acid for resolution of key starting material. The reported methods either results in low yields or do not directly result in desired purities of the intermediate compound of Formula I.
Thus there remains a need to prepare compounds of Formula I of high purity and in good yield while overcoming the drawbacks presented by the processes described in the art.

SUMMARY
The present application provides a process for preparation of compound of Formula I comprising:
Cis-hydroxylation of compound of Formula IV with a suitable reagent to afford compound of Formula III

Formula IV Formula III
Protection of cis-diol of Formula III to afford compound of Formula II

Formula II
Reduction of compound of Formula II with a suitable reducing agent to afford compound of Formula I

DETAILED DESCRIPTION
The present application provides a process comprising:
a) cis-hydroxylation of compound of Formula IV with a suitable reagent to afford compound of Formula III

Formula IV Formula III

b) Protection of cis-diol of Formula III to afford compound of Formula II

Formula II
c) Reduction of compound of Formula II with a suitable reducing agent to afford compound of Formula I
The compound of Formula IV can be prepared by reaction of compound of Formula V with alkyl bromoacetate as per the process disclosed in US6251910. Further compound of Formula V can be prepared by methods known in the art.
Step a) involves cis-hydroxylation of compound of Formula IV with a suitable hydroxylating agent under suitable reaction conditions. There is no particular restriction on the nature of the hydroxylating agent used  and any hydroxylating agent such as sodium permanganate  osmium tetraoxide  4-methyl morpholine-4-oxide and like  that are commonly used in reactions of this type may equally be used here.
The step a) is carried out in presence of a suitable solvent that is inert to the reaction conditions employed. Solvents that can be employed in step a) include  but are not limited to: alcohols  such as  for example  methanol  ethanol  2-propanol  ethylene glycol; diglyme  ethers  such as  for example  diisopropyl ether  methyl tert-butyl ether  diethyl ether  1 4-dioxane  tetrahydrofuran (THF)  or methyl THF; esters  such as  for example  ethyl acetate  isopropyl acetate  or t-butyl acetate; ketones  such as acetone or methyl isobutyl ketone; halogenated hydrocarbons  such as dichloromethane  dichloroethane  chloroform  or the like; nitriles  such as acetonitrile; polar aprotic solvents  such as N N-dimethylformamide  N N-dimethylacetamide  N-methyl pyrrolidone  dimethylsulfoxide  or the like; water; or any mixtures of two or more thereof.
Step a) is done in presence of a suitable base. The suitable base employed include but not limited to inorganic bases like sodium bicarbonate  sodium carbonate  sodium hydroxide and like or organic base like triethyl amine  morpholine etc.
Addition of hydroxylating agent is preferably done at low temperature such as -10 to 0oC.
Step b) involves protection of cis-diol of Formula III with 2 2-dimethoxy propane in presence of a suitable catalyst to afford the compound of Formula II.
Suitable catalyst employed in said step includes but not limited to organic acids like p-toluene sulfonic acid  methanesulfonic acid and like.
Suitable solvent which is inert to the reaction conditions can be selected from the list mentioned above for step a).
Step c) involves reduction of compound of Formula II with a suitable reducing agent to afford compound of Formula I.
The said step involves reduction of both the functional groups viz.  azide and ester groups. This can be materialized by employing a single reducing agent for reducing both functional groups in one reaction or by sequential addition of functional group specific reducing agent. Preferably  the reducing agent employed in said step reduces both functional groups.
Suitable reducing agents employed in said step includes but not limited to sodium borohydride  lithium aluminium hydride  vitride  sodium cyanoborohydride  palladium-carbon  RANEY nickel  and platinium oxide  or any other suitable reagent. In a preferred embodiment  reducing agent is Lithium aluminium hydride.
Suitable solvent which is inert to the reaction conditions can be selected from the list mentioned above for step a).
Optionally compound of Formula I can be treated with a suitable acid to afford its acid addition salts.
The present application further provides novel intermediates of Formula II and III. The said compounds in racemic as well as optically active forms  in all the physical forms are included within the scope of application.
In another aspect of the present application provides a process comprising;
a) conversion of compound of Formula V to compound of Formula VI under suitable reaction conditions

Formula V Formula VI
b) cis-hydroxylation of compound of Formula VI with a suitable reagent to afford compound of Formula VII

Formula VII
c) Protection of cis-diol of Formula VII to afford compound of Formula VIII

Formula VIII
d) Removal of phthalimide group from Formula VIII to afford compound of Formula IX

Formula IX
e) Protection of compound of Formula IX with a suitable protecting group to afford compound of Formula X.

Formula X
Step a) involves reaction of compound of formula V with suitable source of phthalimide like potassium phthalimide in presence of triphenyl phosphine and tetrakis (triphenyl phosphine) palladium to afford compound of Formula VI.
Conditions for steps b) and c) are similar to that described for aforementioned aspect of the application to result compounds of Formula VII and VIII  respectively.
Step d) involves removal of phthalimide group using a suitable deprotection method known in the art. For example  said step involves treatment of compound of Formula VIII with a suitable amine such as methyl amine  hydrazine hydrate and like to afford compound of Formula IX. The said reaction can optionally be carried out in a suitable inert solvent.
Step e) involves protection of amino functionality of compound of Formula IX to afford compound of Formula X 
Some suitable protecting groups are disclosed in T. W. Greene et al.  Protective Groups in Organic Synthesis  3rd Ed.  John Wiley & Sons  Inc.  1999  and other groups are described in the literature.
The chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants  though certain reactions may benefit from using an excess of one or more of the reactants. Additionally  many of the reactions disclosed throughout the specification  may be carried out at room temperature  but particular reactions may require the use of higher or lower temperatures  depending on reaction kinetics  yields  or the like. Furthermore  many of the chemical transformations may employ one or more compatible solvents  which may influence the reaction rate and yield. Depending on the nature of the reactants  the one or more solvents may be polar protic solvents  polar aprotic solvents  non-polar solvents  or some combination.
The compounds obtained by the chemical transformations of the present application  can be used for the following 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  or by transforming them into a salt or by washing with an organic solvent or with an aqueous solution  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 anti-solvent 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 from 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  or 2-propanol; ethers  such as  for example  diisopropyl ether  methyl tert-butyl ether  diethyl ether  1 4-dioxane  tetrahydrofuran (THF)  or methyl THF; esters  such as  for example  ethyl acetate  isopropyl acetate  or t-butyl acetate; ketones  such as acetone or methyl isobutyl ketone; halogenated hydrocarbons  such as dichloromethane  dichloroethane  chloroform  or the like; hydrocarbons  such as toluene  xylene  or cyclohexane; nitriles  such as acetonitrile or the like; water; or any mixtures of two or more thereof. In one embodiment  slurrying process with water is employed.
The compounds at various stages of the process may be isolated using conventional techniques known in the art. For example  useful techniques include  but are not limited to  decantation  centrifugation  gravity filtration  suction filtration  concentrating  cooling  stirring  shaking  combining a solution with an anti-solvent  adding seed crystals  evaporation  flash evaporation  simple evaporation  rotational drying  spray drying  thin-film drying  freeze-drying  or the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and  if desired  the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely  or almost completely  at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including  but not limited to  tray drying  spray drying  fluidized bed drying  or thin film drying under atmospheric or a reduced pressure.
The isolated solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer  vacuum oven  air oven  fluidized bed dryer  spin flash dryer  flash dryer  or the like  at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C  less than about 60°C  less than about 40°C  or any other suitable temperatures  in the presence or absence of an inert atmosphere such as nitrogen  argon  neon  or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product  such as  for example  from about 1 hour to about 15 hours  or longer.
DEFINITIONS
The following definitions are used in connection with the present application  unless the context indicates otherwise. All percentages and ratios used herein are by weight of the total composition  unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25°C and atmospheric pressure unless otherwise designated. All ranges recited herein include the endpoints  including those that recite a range "between" two values. As used herein  a "room” or “ambient” temperature includes temperature from about 15°C to about 35°C  from about 20°C to about 30°C  or about 25°C.
As used herein  "comprising" means the elements recited  or their equivalents in structure or function  plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. Terms such as "about " "generally " "substantially " or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify  as those terms are understood by those of skill in the art. This includes  at very least  the degree of expected experimental error  technique error  or instrument error for a given technique used to measure a value.
The term  “high purity”  means at least about 97%  at least about 98%  at least about 99%  at least about 99.5%  or at least about 99.9%  by weight as determined using high performance liquid chromatography (HPLC). Correspondingly  the total level of impurities may be less than about 3%  2%  1%  0.5%  or 0.1%  by weight  as determined using HPLC.
An “alcohol” is an organic liquid containing a carbon bound to a hydroxyl group  including  but not limited to  methanol  ethanol  2-nitroethanol  2-fluoroethanol  2 2 2-trifluoroethanol  hexafluoroisopropyl alcohol  ethylene glycol  1-propanol  2-propanol (isopropyl alcohol)  2-methoxyethanol  1-butanol  2-butanol  i-butyl alcohol  t-butyl alcohol  2-ethoxyethanol  diethylene glycol  1-  2-  or 3-pentanol  neo-pentyl alcohol  t-pentyl alcohol  diethylene glycol monomethyl ether  diethylene glycol monoethyl ether  cyclohexanol  benzyl alcohol  phenol  glycerol  C1-6 alcohols  or the like.
An “ether” is an organic liquid containing an oxygen atom –O- bonded to two other carbon atoms  including  but not limited to  diethyl ether  diisopropyl ether  methyl t-butyl ether  glyme  diglyme  tetrahydrofuran  1 4-dioxane  dibutyl ether  dimethylfuran  2-methoxyethanol  2-ethoxyethanol  anisole  C2-6 ethers  or the like.
A “halogenated hydrocarbon” is an organic liquid containing a carbon bound to a halogen  including  but not limited to  dichloromethane  1 2-dichloroethane  trichloroethylene  perchloroethylene  1 1 1-trichloroethane  1 1 2-trichloroethane  chloroform  carbon tetrachloride  or the like.
A “ketone” is an organic liquid containing a carbonyl group -(C=O)- bonded to two other carbon atoms  including  but not limited to  acetone  ethyl methyl ketone  diethyl ketone  methyl isobutyl ketone  C3-6 ketones  or the like.
A “hydrocarbon” is a liquid compound formed from carbon and hydrogen atoms  and may be linear  branched  cyclic  saturated  unsaturated  non-aromatic  or aromatic. Examples include  but are not limited to  n-pentane  isopentane  neopentane  n-hexane  isohexane  3-methylpentane  2 3-dimethylbutane  neohexane  n-heptane  isoheptane  3-methylhexane  neoheptane  2 3-dimethylpentane  2 4-dimethylpentane  3 3-dimethylpentane  3-ethylpentane  2 2 3-trimethylbutane  n-octane  isooctane  3-methylheptane  neooctane  cyclohexane  methylcyclohexane  cycloheptane  C5-C8 aliphatic hydrocarbons  petroleum ethers  benzene  toluene  ethylbenzene  m-xylene  o-xylene  p-xylene  indane  naphthalene  tetralin  trimethylbenzene  chlorobenzene  fluorobenzene  trifluorotoluene  anisole  C6-C10 aromatic hydrocarbons  or the like.
A “nitrile” is an organic liquid containing a cyano -(C=N) bonded to another carbon atom  including  but not limited to  acetonitrile  propionitrile  C2-6 nitriles  or the like.
A “polar aprotic solvent” has a dielectric constant greater than 15 and includes: amide-based organic solvents  such as hexamethyl phosphoramide (HMPA) or hexamethyl phosphorus triamide (HMPT)  N-methyl pyrrolidone; nitro-based organic solvents  such as nitromethane  nitroethane  nitropropane  or nitrobenzene; ester-based organic solvents  such as ?-butyrolactone  ethylene carbonate  propylene carbonate  butylene carbonate  dimethyl carbonate  or propiolactone; pyridine-based organic solvents  such as pyridine or picoline; or sulfone-based solvents  such as dimethylsulfone  diethylsulfone  diisopropylsulfone  2-methylsulfolane  3-methylsulfolane  2 4-dimethylsulfolane  3 4-dimethylsulfolane  3-sulfolene  or sulfolane.
Any organic solvents may be used alone  or two or more of these or in combination with water in desired ratios could be employed.
Acid addition salts are typically pharmaceutically acceptable  non-toxic addition salts with “suitable acids”  including but not limited to: inorganic acids such as hydrohalic acids (for example  hydrofluoric  hydrochloric  hydrobromic  or hydroiodic acids) or other inorganic acids (for example  nitric  perchloric  sulfuric  or phosphoric acids); or organic acids  such as organic carboxylic acids (for example  xinafoic  oxalic  propionic  butyric  glycolic  lactic  mandelic  citric  acetic  benzoic  2- or 4-methoxybenzoic  2- or 4-hydroxybenzoic  2- or 4-chlorobenzoic  salicylic  succinic  malic  hydroxysuccinic  tartaric  fumaric  maleic  hydroxymaleic  oleic  or glutaric acids)  organic sulfonic acids (for example  methanesulfonic  trifluoromethanesulfonic  ethanesulfonic  2-hydroxyethanesulphonic  benzenesulfonic  toluene-p-sulfonic  naphthalene-2-sulphonic  or camphorsulfonic acids)  or amino acids (for example  ornithinic  glutamic  or aspartic acids).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples  which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES
EXAMPLE 1: PREPARATION OF 4-HYDROXYCYCLOPENT-2-ENONE.
Furfuryl alcohol (150 g)  distilled water (3 L) was charged in a round bottom flask and mixture is degassed with nitrogen for 60-90 minutes at room temperature. To the mixture  potassium dihydrogen phosphate (0.91 g) was added and mixture was stirred for 15-20 minutes  pH of the mixture was adjusted to about 4.1 by addition of diluted 10% phosphoric acid (1.5 mL) and stirred for another 10-20 minutes. The reaction mixture was maintained under reflux for about 40 hours and the completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature followed by extraction with dichloromethane (4x300 mL) and stirring for 15-30 minutes. The organic layers were separated and washed with water (13.5 mL). The aqueous layers were combined and subjected to complete distillation under vacuum at 60-65oC. Then sequentially three lots of isopropyl alcohol (3x150 mL) was added and completely removed under vacuum at 60-65oC and then the residue was dissolved in dichloromethane (300 mL)  filtered and bed was washed with dichloromethane (75 mL). The filtrate was subjected to complete distillation at 40-45oC under vacuum to afford the title compound having about 91% purity.

EXAMPLE 2: PREPARATION OF (1R  3S)-rel-4-CYCLOPENTENE-1 3-DIOL
4-hydroxycyclopent-2-enone (100 g) and methanol (950 mL)  tetrahydrofuran (950 mL) were charged in a clean and dry round bottom flask and stirred for 10 minutes at room temperature. To the mixture  cerium chloride heptahydrate (66.78 g) was added and the reaction mass was stirred at 25-35oC for 30 minutes under nitrogen atmosphere. The reaction mixture was cooled to -35 to -25oC and a pre-prepared solution of sodium borohydride [sodium hydroxide (2.44 g) was added to pre-cooled water (20 mL) and stirred to make clear solution followed by addition of sodium borohydride (19.26 g)  methanol (50 mL) and tetrahydrofuran (50 mL)  mixture was stirred at 25-35oC to result in colorless solution] was drop-wise added under nitrogen atmosphere over a period of 2 hours. The reaction mass was stirred at -35 to -25oC for 1-2 hours under nitrogen atmosphere and completion of the reaction was monitored by TLC. After completion of reaction  the temperature is raised to -20 to 0oC followed by drop-wise addition of acetic acid (60 mL). Again the temperature of the mixture was raised to 30 to 35oC and it was stirred for 1-2 hours. The mixture was filtered and wet cake was washed with methanol (100 mL). The filtrate was subjected to distillation under vacuum at 55oC up to 5-6 volumes. To the reduced volume  ethyl acetate (1 L) was added  stirred for 1-2 hours and then filtered through silica bed and washed with ethyl acetate (500 mL). The ethyl acetate was concentrated under vacuum up to 5 volumes and then passed through microfilter paper  bed was washed with ethyl acetate (100 mL). The ethyl acetate was completely concentrated at 55-60oC under vacuum followed by sequential addition and evaporation of toluene (3x200 mL) to chase acetic acid from the crude compound to afford title compound in about 86% yield.

EXAMPLE 3: PREPARATION OF (1R 3S)-rel-4-CYCLOPENTENE-1 3-DIOL DIACETATE.
(1R 3S)-rel-4-cyclopentene-1 3-diol (100 g) and ethyl acetate (1000 mL) were charged into a round bottom flask  filtered through silica bed and bed was washed with ethyl acetate (500 mL). The combined filtrate was charged into another round bottomed flask and to it sequentially sodium acetate (172.11 g)  dimethyl aminopyridine (6.09 g)  acetic anhydride (245.9 mL)  were added under nitrogen atmosphere. The temperature of the reaction mixture was raised to 35-40oC and stirred for about 2-3 hours  completion of the reaction was monitored by TLC. The reaction mixture was cooled to 25-35oC and was subjected to washing with saturated sodium bicarbonate (100 g in 1000 mL water). Aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layer was washed with saturated sodium bicarbonate (100 g in 1000 mL water) and then organic layer was subjected to complete distillation under vacuum at 55oC to afford the crude compound. The crude compound was distilled under vacuum at about 120-140oC to afford the title compound in 82% yield.

EXAMPLE 4: PREPARATION OF (1R 3S)-rel-4-CYCLOPENTENE-1 3-DIOL DIACETATE.
(1R 3S)-rel-4-cyclopentene-1 3-diol (100 g)  dichloromethane (1000 mL) were charged into a round bottom flask  filtered through silica bed and bed was washed with dichloromethane (500 mL). The combined filtrate was charged into another round bottomed flask and to it sequentially triethyl amine (291.7 mL)  dimethyl aminopyridine (6.09 g)  acetic anhydride (245.9 mL)  were added under nitrogen atmosphere. The temperature of the reaction mixture was raised to 35-40oC and stirred for about 2-3 hours and completion of the reaction was monitored by TLC. The reaction mixture was cooled to 25-35oC and was subjected to washing with saturated sodium bicarbonate (1000 mL). Aqueous layer was extracted with dichloromethane (500 mL). The combined organic layer was washed with saturated sodium bicarbonate (1000 mL) and then organic layer was subjected to complete distillation under vacuum at 55oC to afford the crude compound. The crude compound was distilled under vacuum at about 120-140oC to afford the title compound in about 80% yield.

EXAMPLE 5: PREPARATION OF (1R 3S)-(+)-1-ACETOXY-3-HYDROXY-4-CYCLOPENTENE
(1R 3S)-rel-4-cyclopentene-1 3-diol diacetate (85 g)  methyl tert-butyl ether (85 mL) were charged into a round bottomed flask followed by addition of phosphate buffer (0.1 M  765 mL). The reaction mixture was cooled to 15-20oC and Novozyme-435 (2.125 g) was added and reaction mass was maintained for 18 hours at same temperature  completion of the reaction was monitored by TLC. The reaction mixture was filtered through hyflow supercel bed and enzyme was washed with MTBE (85 mL). The filtrate was diluted with heptane (850 mL) and organic layer was separated. Aqueous layer was washed with heptane (2x425 mL) and then with MTBE (170 mL). Then aqueous layer was saturated with sodium chloride (340 g) and pH was adjusted to 7.0 with 50% sodium hydroxide (34 mL)  excess of sodium chloride was filtered followed by addition of MTBE (425 mL) to the filtrate. The mixture was stirred and organic layer was separated. Aqueous layer was extracted with MTBE (2x 425 mL). Combined MTBE extracts were dried over sodium sulfate and completely concentrated under vacuum below 45oC to afford the crude compound. The crude compound was dissolved in diisopropyl ether (37 mL) at 40oC and mixture was kept at 2-8 oC for 10-12 hours and then stirred for 15-30 minutes at 2-8oC. The solid was filtered and washed with hexane (2x125 mL)  dried under vacuum for 1-2 hours at 20 oC to afford the title compound having 99.11% purity.

EXAMPLE 6: PREPARATION OF (1R 3S)-(+)-1-ACETOXY-3-HYDROXY-4-CYCLOPENTENE (Formula V). (1R 3S)-rel-4-cyclopentene-1 3-diol diacetate (72 g)  methyl tert-butyl ether (72 mL) were charged into a round bottomed flask followed by addition of phosphate buffer (0.1 M  648 mL). The reaction mixture was cooled to 15-20oC and Novozyme-435 (1.8g) was added and reaction mass was maintained for 3 hours at same temperature  completion of the reaction was monitored by TLC. The reaction mixture was filtered through and enzyme was washed with MTBE (72 mL). The filtrate was diluted with hexane (720 mL) and layers were separated. Aqueous layer was washed with hexane (2x360 mL). Further  aqueous layer was saturated with sodium chloride (250 g)  followed by addition of MTBE (146 mL) and pH was adjusted to 7.0 with 50% sodium hydroxide (60 mL)  excess of sodium chloride was filtered. The filtrate was diluted with MTBE (360 mL). The mixture was stirred and organic layer was separated. Aqueous layer was extracted with MTBE (2x360 mL). All the organic layers were combined and dried over sodium sulfate (20 g) and concentrated under vacuum below 45oC to afford the title compound in about 71% yield.

EXAMPLE 7: PREPARATION OF (1S 4R)-4-AZIDO-2-CYCLOPENTEN-1-OL
Triphenyl phosphine (11.06 mg)  tetrakis(triphenylphosphine)palladium (40.66 mg) and sodium azide (54.9 mg) were charged in a round bottomed flask and stirred for 10 minutes under nitrogen atmosphere. Then  (1R 3S)-(+)-1-acetoxy-3-hydroxy-4-cyclopentene (100 mg) was dissolved in THF (3.54 mL) and slowly added to the above reaction mixture over a period of 10 minutes under nitrogen atmosphere. Reaction mixture was stirred for 4-5 hours at room temperature and completion of the reaction was monitored by TLC. The reaction mixture was filtered through celite and filtrate was concentrated under vacuum at below 45 oC. The resultant mixture was dissolved in ethyl acetate (25 mL) and washed with water (2 x 7mL) followed by separation of organic layer. The combined organic layer was dried with sodium sulphate (0.5 g) and concentrated under vacuum at below 45oC to afford the title compound in about 40% yield.

EXAMPLE 8: PREPARATION OF (1S 4R)-4-AZIDO-2-CYCLOPENTEN-1-OL
Triphenyl phosphine (0.81 g)  tetrakis(triphenylphosphine)palladium (2.87 g) and sodium azide (4.85 g) were charged in a round bottomed flask and stirred for 10 minutes under nitrogen atmosphere. Then  (1R 3S)-(+)-1-acetoxy-3-hydroxy-4-cyclopentene (8.85 g) was dissolved in THF (313.2 mL) and slowly added to the above reaction mixture over a period of 10 minutes under nitrogen atmosphere. Reaction mixture was stirred for 4-5 hours at room temperature and completion of the reaction was monitored by TLC. The reaction mixture was filtered and filtrate was concentrated under vacuum at below 45 oC. The resultant mixture was dissolved in ethyl acetate (200 mL) and washed with water (2 x 50mL). Aqueous layer was further extracted with ethyl acetate (50 mL). The organic layers were combined and dried with sodium sulphate (3 g) and concentrated under vacuum at below 45oC to afford the title compound in about 63% yield.

EXAMPLE 9: PREPARATION OF TERT-BUTYLETHYL 2-((1S 4R)-4-AZIDOCYCLOPENT-2-ENYLOXY)ACETATE (FORMULA IV)
(1S 4R)-4-azido-2-cyclopenten-1-ol (100 mg) and THF (4 mL) was charged in a round bottomed flask under nitrogen atmosphere. The mixture was cooled to 0 to 5 oC and subsequently potassium tert-butoxide (178.9 mg) was added  mixture was stirred under nitrogen atmosphere. Then potassium iodide (39.55 mg) was charged followed by drop-wise addition of tert-butyl bromoacetate (187 mg) at 0 to 5 oC under nitrogen atmosphere. The temperature of the mixture was raised to room temperature and stirred at same for about 2hours  completion of the reaction was monitored by TLC. The solvent was distilled out completely under vacuum at below 45oC followed by addition of ethyl acetate (25 mL). The ethyl acetate layer was subjected to washings with water (2x10 mL). The organic layer was separated followed by distillation of solvent under vacuum at below 45oC. The crude material obtained was purified by preparative thin layer chromatography to afford the title compound.

EXAMPLE 10: PREPARATION OF TERT-BUTYL 2-((1S 4R)-4-AZIDOCYCLOPENT-2-ENYLOXY)ACETATE (FORMULA IV)
(1S 4R)-4-azido-2-cyclopenten-1-ol (3.8 g) and THF (60 mL) was charged in a round bottomed flask under nitrogen atmosphere. The mixture was cooled to 0 to 5oC and subsequently potassium tert-butoxide (2.58 g) was added  mixture was stirred under nitrogen atmosphere. Then tert-butyl bromoacetate (4.50 g) was added  mixture was stirred for 5 minutes followed by addition of potassium iodide (1.03 g) at 0 to 5oC under nitrogen atmosphere. The temperature of the mixture was raised to room temperature and stirred at same for about 2 hours  completion of the reaction was monitored by TLC. The solvent was distilled out completely under vacuum at below 45oC followed by addition of ethyl acetate (100 mL). The ethyl acetate layer was subjected to washings with water (2x50 mL). The organic layer was separated and dried with sodium sulfate (10 g)  filtered  washed with ethyl acetate (50 mL) followed by distillation of solvent under vacuum at below 45oC. The crude material obtained was purified by column chromatography to afford the title compound.

EXAMPLE 11: PREPARATION OF TERT-BUTYL 2-((1S 4R)-4-AZIDO-2 3-DIHYDROXYCYCLOPENTYLOXY)ACETATE (FORMULA III)
Tert-butyl 2-((1S 4R)-4-azidocyclopent-2-enyloxy)acetate (6.1 g) and acetone (90 mL) was charged in round bottom flask and mixture was cooled to -15 to -10oC. To the mixture at the same temperature  sodium bicarbonate (6.42 g) and ethylene glycol (6.39 g) were added followed by slow addition of sodium permanganate (40%  9.5 g) over a period of 10 minutes and mixture was stirred for another 15 minutes  completion of the reaction was monitored by TLC. The reaction mixture was quenched by addition of precooled sodium bisulfate solution (60 mL) and the mixture was filtered  bed was washed with acetone (15 mL). The filtrate was subjected to complete distillation under vacuum at below 45oC. To the obtained mass  ethyl acetate (300 mL) was added and washed with water (2x50 mL). The organic layer was subjected to distillation under vacuum at below 45oC to afford the title compound.

EXAMPLE 12: PREPARATION OF TERT-BUTYL 2-((4S 6R)-6-AZIDO-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-YLOXY) ACETATE (FORMULA II)
Tert-butyl 2-((1S 4R)-4-azido-2 3-dihydroxycyclopentyloxy)acetate (1.5 g) and 2 2-dimethoxy propane (30 mL) was charged in a round bottom flask. To the mixture  p-toluenesulfonic acid (95.8 mg) was added at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and completion of the reaction was monitored by TLC. The reaction mixture was quenched by addition of 10% sodium bicarbonate solution (1g in 10 mL water) was added and organic layer was separated. To the organic layer  ethyl acetate (150 mL) was added and washed with water (25 mL). The ethyl acetate layer was dried and solvent was completely distilled under vacuum at below 45oC to afford the title compound.

EXAMPLE 13: PREPARATION OF TERT-BUTYL 2-((4S 6R)-6-AZIDO-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-YLOXY) ACETATE (FORMULA II)
tert-butyl 2-((1S 4R)-4-azido-2 3-dihydroxycyclopentyloxy)acetate (6 g) and 2 2-dimethoxy propane (120 mL) was charged in round bottom flask. To the mixture  p-toluene sulfonic acid (380 mg) was added at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and completion of the reaction was monitored by TLC. The reaction mixture was quenched by addition of 10% sodium bicarbonate solution (1g in 10 mL water). To the mixture  ethyl acetate (250 mL) was added and washed with water (50 mL). The layers were separated and ethyl acetate layer was completely distilled under vacuum at below 45oC to afford the title compound.

EXAMPLE 14: PREPARATION OF 2-((3aR 4S 6R 6aS)-6-AMINO-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[D][1 3]DIOXOL-4-YLOXY) ETHANOL (FORMULA I)
tert-butyl 2-((4S 6R)-6-azido-2 2-dimethyltetrahydro-3aH-cyclopenta[d][1 3]dioxol-4-yloxy) acetate (1.4 g) and THF (8 mL) was charged in a round bottom flask and reaction mixture was cooled to 0oC under nitrogen atmosphere. To the cooled mixture  lithium aluminium hydride (0.33 g) was added and stirred for about 2 hours under nitrogen atmosphere  completion of the reaction was monitored by TLC. The reaction mixture was allowed to attain to room temperature followed by addition of ammonium chloride solution (10 mL). Then the mixture was diluted with ethyl acetate (10 mL)  layers were separated and aqueous layer was again extracted with ethyl acetate (10 mL). The organic layers are combined and washed with water (2 x 5mL) followed by complete distillation of solvent from organic layer under vacuum. The obtained mass was diluted with ethyl acetate (5 mL). To this mixture  a solution of oxalic acid (0.5 g) in acetone (5 mL) was slowly added and stirred for overnight. The solid was isolated by filtration and suck dried to afford the title compound.

EXAMPLE 15: PREPARATION OF 2-((1R 4S)-4-HYDROXYCYCLOPENT-2-ENYL)ISOINDOLINE-1 3-DIONE (FORMULA VI)
Triphenyl phosphine (0.258 g)  tetrakis(triphenylphosphine)palladium (0.812 g)  potassium pthalimide (1.30 g) and dimethyl sulfoxide (6.85 mL) were charged in a round bottomed flask and stirred for 10 minutes under nitrogen atmosphere. Then  a solution of (1R 3S)-(+)-1-acetoxy-3-hydroxy-4-cyclopentene (1.0 g) in THF (34.2 mL) was slowly added to the above reaction mixture over a period of 25 minutes under nitrogen atmosphere. Reaction mixture was stirred for 12-14 hours at room temperature under inert atmosphere and completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum at below 45oC and the obtained mass was taken in dichloromethane (30 mL) and filtered  the solid was washed with dichloromethane (15 mL). The combined filtrate was washed with sodium chloride solution (2x10 mL). The organic layer was concentrated under vacuum below 45oC to afford the crude material. The crude material was purified by column chromatography using ethyl acetate and hexane as eluent. The fractions containing the desired compound were concentrated under vacuum to afford the title compound in about 59% yield.

EXAMPLE 16: PREPARATION OF 2-((1R 4S)-4-HYDROXYCYCLOPENT-2-ENYL)ISOINDOLINE-1 3-DIONE (FORMULA VI)
Triphenyl phosphine (10.07 g)  tetrakis(triphenylphosphine)palladium (31.70 g)  potassium pthalimide (50.81 g) and dimethyl sulfoxide (267.15 mL) were charged in a round bottomed flask and stirred for 10 minutes under nitrogen atmosphere. Then  a solution of (1R 3S)-(+)-1-acetoxy-3-hydroxy-4-cyclopentene (39 g) in THF (1133 mL) was slowly added to the above reaction mixture over a period of 40 minutes under nitrogen atmosphere. Reaction mixture was stirred for 12-14 hours at room temperature and completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum at below 45oC and the obtained mass was taken in dichloromethane (1170 mL) and filtered  the solid was washed with dichloromethane (585 mL). The combined filtrate was washed with water (2x390 mL) and sodium chloride solution (2x390 mL). The organic layer was concentrated under vacuum below 45oC to afford the crude material. The crude material was purified by column chromatography using dichloromethane and hexane as eluent. The fractions containing desired compound were concentrated under vacuum to afford the title compound in about 84% yield.

EXAMPLE 17: PREPARATION OF 2-((1R 2S 3R 4S)-2 3 4-TRIHYDROXYCYCLOPENTYL)ISOINDOLINE-1 3-DIONE (FORMULA VII)
2-((1R 4S)-4-hydroxycyclopent-2-enyl)isoindoline-1 3-dione (0.94 g) and acetone (15 mL) were charged in round bottom flask and mixture was stirred for 10 minutes. To the mixture  sodium bicarbonate (1.03 g) and ethylene glycol (1.619 g) were added and mixture was cooled to -5 to 15oC. To the cooled mixture  sodium permanganate (40% aqueous solution  0.611 g) was drop-wise added while maintaining the temperature below -10oC. Then the mixture was maintained for 30 hours at the same temperature  completion of the reaction was monitored by TLC. To the mixture  aqueous sodium bisulfate solution (25%  5 mL) was added and the mixture was stirred for 1 hour at room temperature. The reaction mass was filtered through celite bed  bed was washed with acetone (5 mL). The combined filtrate was subjected to complete distillation under vacuum at below 40oC. To the obtained mass  ethyl acetate (12 mL) was added and washed with water (2 mL). The aqueous layer was extracted with ethyl acetate (6 mL)  then combined organic layer was subjected to distillation under vacuum at below 45oC to afford the title compound.

EXAMPLE 18: PREPARATION OF 2-((1R 2S 3R 4S)-2 3 4-TRIHYDROXYCYCLOPENTYL)ISOINDOLINE-1 3-DIONE (FORMULA VII)
2-((1R 4S)-4-hydroxycyclopent-2-enyl)isoindoline-1 3-dione (15.50 g) and acetone (155 mL) were charged in round bottom flask and mixture was stirred for 10 minutes. To the mixture under inert atmosphere  solution of osmium tetra oxide (0.086 g)  50% aqueous solution of N-methyl morpholine N-oxide (11.88g) are added and reaction mass was maintained at room temperature for 10-12 hours  completion of the reaction was monitored by TLC. The reaction mixture was filtered and bed was washed with acetone (2x75 mL). The combined filtrate was completely concentrated under vacuum below 45oC to afford the crude mass. The crude mass was diluted with dichloromethane (310 mL) and solid obtained was isolated by filtration. The wet material was dried under vacuum below 45oC for 2-3 hours to afford the title compound in about 70% yield.

EXAMPLE 19: PREPARATION OF 2-((3aS 4R 6S 6aR)-6-HYDROXY-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-YL)ISOINDOLINE-1 3-DIONE (FORMULA VIII)
2-((1R 2S 3R 4S)-2 3 4-trihydroxycyclopentyl)isoindoline-1 3-dione (54 g)  acetone (540 mL) and 2 2-dimethoxy propane (213 mL) were charged in a round bottom flask and stirred for 30 minutes at room temperature under nitrogen atmosphere. To the mixture p-toluene sulfonic acid was added and mixture was further was maintained for about 3 hours at room temperature  completion of the reaction was monitored by TLC. To the mixture 10% sodium bicarbonate solution (60 mL) was added and aqueous layer was separated. Then aqueous layer was extracted with ethyl acetate (540 mL  100 mL). Combined organic layer was dried over sodium sulfate and solvent was completely distilled under vacuum at below 45oC to afford the title compound in 88% yield.

EXAMPLE 20: PREPARATION OF 2-((3aS 4R 6S 6aR)-6-HYDROXY-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-YL) ISOINDOLINE-1 3-DIONE (FORMULA VIII)
2-((1R 2S 3R 4S)-2 3 4-trihydroxycyclopentyl)isoindoline-1 3-dione (12 g) and 2 2-dimethoxy propane (120 mL) were charged in a round bottom flask and stirred for 15 minutes at room temperature under nitrogen atmosphere. To the mixture  p-toluene sulfonic acid (0.199 g) was added and mixture was further maintained for 30 minutes. The temperature of the reaction mass was raised to 50oC and maintained for 2 hours at 50oC  completion of the reaction was monitored by TLC. Then the reaction mixture was cooled to room temperature followed by addition of 10% aqueous sodium bicarbonate solution (60 mL). Aqueous layer was extracted with ethyl acetate (2x72 mL). Organic layers were combined and washed with 10% sodium bicarbonate solution (60 mL) followed by sodium chloride solution (2x36 mL). The organic layer was subjected to distillation under vacuum below 40oC to afford the crude compound. The crude compound was purified by column chromatography to afford the title compound.

EXAMPLE 21: PREPARATION OF (3aR 4S 6R 6aS)-6-AMINO-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-OL (FORMULA IX)
2-((3aS 4R 6S 6aR)-6-hydroxy-2 2-dimethyltetrahydro-3ah-cyclopenta[d][1 3]dioxol-4-yl)isoindoline-1 3-dione (0.1 g) and ethanol (1 mL) were charged in a round bottom flask and stirred for 10 minutes. Then methyl amine solution (40%  0.255 mL) was drop-wise added at 0-5oC and mixture was allowed to stir at room temperature for 12-14 hours  at which point completion of the reaction was monitored by TLC. The solvent from the reaction mixture was distilled under vacuum below 45oC followed by addition of ethanol (0.3 mL) and its distillation. The crude mass obtained was diluted with ethyl acetate (1.2 mL). The solid obtained was isolated by filtration  washed with ethyl acetate (0.3 mL). The combined filtrate was washed with 1M sodium hydroxide solution (0.5 mL). Layers were separated and aqueous layer was extracted with ethyl acetate (0.2 mL). Combined organic layer was concentrated under vacuum below 45oC to afford the title compound.

EXAMPLE 22: PREPARATION OF (3aR 4S 6R 6aS)-6-AMINO-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-OL (FORMULA IX)
2-((3aS 4R 6S 6aR)-6-hydroxy-2 2-dimethyltetrahydro-3ah-cyclopenta[d][1 3]dioxol-4-yl)isoindoline-1 3-dione (5.8 g) and ethanol (58 mL) were charged in a round bottom flask and stirred for 10 minutes. Then methyl amine solution (40%  14.82 mL) was drop-wise added at 0-5oC and mixture was allowed to stir at room temperature for 12-14 hours  at which point completion of the reaction was monitored by TLC. The solvent from the reaction mixture was distilled under vacuum below 45oC followed by addition of ethanol (17.4 mL) and its distillation. The crude mass obtained was diluted with ethyl acetate (69.6 mL). The solid obtained was isolated by filtration  washed with ethyl acetate (23.2 mL). The combined filtrate was washed with 1M sodium hydroxide solution (11.6 mL). Layers were separated and aqueous layer was extracted with ethyl acetate (17.4 mL). Combined organic layer was concentrated under vacuum below 45oC to afford the title compound.

EXAMPLE 23: PREPARATION OF BENZYL (3aS  6aR)-6-HYDROXY-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-YLCARBAMATE (FORMULA X)
(3aR 4S 6R 6aS)-6-amino-2 2-dimethyltetrahydro-3aH-cyclopenta[d][1 3]dioxol-4-ol (2.9 g)  methyl iso-butyl ketone (450 mL) were charged in a round bottom flask under nitrogen atmosphere. To the mixture  anhydrous potassium carbonate (27.78 mL) was added and mixture was cooled to 0 to 5oC. Then slowly Cbz-chloride (50%  62.87 mL) was added to the mixture under inert atmosphere and temperature of the mixture was raised to room temperature. The reaction mixture was maintained at the same temperature for about 6 hours and completion of the reaction was monitored by TLC. The reaction was quenched by addition of water (50 mL)  layers were separated. The solvent from organic layer was completely distilled under vacuum at below 45oC followed by addition of ethyl acetate (500 mL). The ethyl acetate layer was subjected to washings with water (2x100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). Organic layers were combined  dried over sodium sulfate  filtered and then distilled completely under vacuum to afford the crude compound. The crude compound was purified by column chromatography using ethyl acetate and hexane as eluent. The fractions containing desired compound were pooled and distilled under vacuum at below 45oC. To the obtained compound  methyl tert-butyl ether (90 mL) was added and mixture was stirred for about 1 hour. The obtained solid was filtered and washed with MTBE (15 mL) to afford the title compound.

EXAMPLE 24: PREPARATION OF BENZYL (3aS  6aR)-6-HYDROXY-2 2-DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 3]DIOXOL-4-YLCARBAMATE (FORMULA X)
(3aR 4S 6R 6aS)-6-amino-2 2-dimethyltetrahydro-3aH-cyclopenta[d][1 3]dioxol-4-ol (3.2 g)  dichloromethane (48 mL) were charged in a round bottom flask under nitrogen atmosphere. The mixture was cooled to 0 to 5oC followed by addition of anhydrous potassium carbonate (3.06 g). Then slowly Cbz-chloride (50% toluene  3.15 g) was added and the mixture was maintained at the same temperature for 5-6 hours under inert atmosphere and completion of the reaction was monitored by TLC. The reaction was quenched by addition of water (128 mL)  layers were separated. The aqueous layer was extracted with dichloromethane (16 mL). The organic layers were combined  dried over sodium sulfate  filtered and then distilled completely under vacuum to afford the crude compound. The crude compound was purified by column chromatography using methanol and dichloromethane as eluent. The fractions containing desired compound were pooled and distilled under vacuum at below 45oC to afford the title compound.