WO2012063126A2 - Improved processes for preparing pure (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahdro-3ah-cyclopenta[d] [1,3]-dioxol-4-ol and its key starting material - Google Patents

Abstract

Provided herein is an improved, commercially viable and industrially advantageous process for the preparation of a ticagrelor intermediate, (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol, which is useful for preparing ticagrelor or a pharmaceutically acceptable salt thereof in high yield and purity. The present invention further relates to an improved process for the preparation of (lS,4R)-cis-4-acetoxy- 2-cyclopenten-l-ol, which is a key starting material in the preparation of the ticagrelor intermediate.

Description

IMPROVED PROCESSES FOR PREPARING PURE (3aR,4S,6R,6aS)-6-AMINO-2,2- DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][l,3]-DIOXOL-4-OL AND ITS KEY

STARTING MATERIAL

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to Indian provisional application Nos. 3332/CHE/2010, filed on November 9, 2010; and 1594/CHE/2011, filed on May 9, 2011 ; which are incorporated herein by reference in their entirety.

FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to improved, commercially viable and industrially advantageous processes for the preparation of a ticagrelor intermediate, (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [ 1 ,3]-dioxol-4-ol, and its key starting material, (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol.

BACKGROUND

[0002] U.S. Patent Nos. 6,251,910 and 6,525,060 disclose a variety of triazolo[4,5-d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds act as Ρ₂τ (P2Y_ADP or P2T_AC) receptor antagonists and they are indicated for use in therapy as inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, and anti-thrombotic agents. Among them, Ticagrelor, [lS-(la,2a,3 (lS*,2R^!i:),5 )]-3-[7-[2- (3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3- yl)-5-(2-hydroxyethoxy)-cyclopentane-l,2-diol, acts as an adenosine uptake inhibitor, a platelet aggregation inhibitor, a P2Y12 purinoceptor antagonist, and a coagulation inhibitor. It is indicated for the treatment of thrombosis, angina, ischemic heart diseases, and coronary artery diseases. Ticagrelor is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist and is chemically distinct from thienopyridine compounds like clopidogrel. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events. The drug has shown a statistically significant primary efficacy against the widely prescribed clopidogrel (Plavix®) in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with acute coronary syndrome (ACS). Ticagrelor is represented by the following structural formula I:

[0003] Various processes for the preparation of pharmaceutically active triazolo[4,5- d] pyrimidine cyclopentane compounds, preferably ticagrelor, their enantiomers, and their pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; 7,122,695 and 7,250,419; U.S. Patent Application Nos. 2007/0265282, 2008/0132719 and 2008/0214812; European Patent Nos. EP0996621 and EPl 135391; and PCT Publication Nos. WO2008/018823 and WO2010/030224.

[0004] In the preparation of ticagrelor, (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol, alternatively named as [3aR- (3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol, of formula II:

is a key starting material.

[0005] Various processes for syntheses of free amine or hydrochloride salt of substituted cyclopentanoloamine derivatives are apparently disclosed in U.S. Patent No. 6,525,060; PCT Publication No. WO99/05142; Synthetic communications 31(2001) 18, 2849-2854; Tetrahedron, 1997, 53, 3347; Helv. Chim. Acta, 1983, 66, 1915; Tetrahedron, 1997, 53, 3347; and Tetrahedron Lett., 2000, 41, 9537. [0006] According to U.S. Patent No. 6,525,060 (hereinafter referred to as the '060 patent), the [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-l ,3- dioxol-4-ol of formula II is prepared by a process as depicted in scheme 1.

Scheme 1 :

Osmium tetroxide

4 Days -methylmorpholine-N-oxide

[0007] According to the Ό60 patent, the hydrochloride salt of [3aR-(3aa,4a,6a,6aa)]- 6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol of formula II is prepared by reacting imidodicarbonic acid bis-(l,l-dimethylethyl)ester with (lS-cis)-4-acetoxy-2- cyclopenten-l-ol in the presence of sodium hydride and tetrakis(triphenylphosphine)palladium in tetrahydrofuran to produce a reaction mass, followed by column chromatographic purification (Si0₂, ethyl acetate: hexane 1 :9 as eluant) to produce ( 1 R-cis)-bis( 1 , 1 -dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate, which is then subjected to oxidation in the presence of osmium tetroxide (2.5% solution in t- butanol) and N-methylmorpholine-N-oxide in a solvent mixture containing tetrahydrofuran and water for 4 days to produce a reaction mass, followed by column chromatographic purification (Si0₂, ethyl acetate: hexane 1 : 1 as eluant) to produce bis(l,l-dimethylethyl)ester of [lR-(la,2p,3p,4a)]-2,3,4-trihydroxy-cyclopentenylimidodicarbonic acid. The resulting trihydroxy compound is stirred with hydrochloric acid and methanol for 18 hours to produce a reaction mixture, followed by evaporation to produce a colorless powder, which is then reacted with 2,2-dimethoxypropane and concentrated hydrochloric acid in acetone to produce [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol hydrochloride salt.

[0008] PCT Publication No. WO 2010/022121 (hereinafter referred to as the ' 121 application) describes a process for the preparation of [3aR-(3aa,4a,6a,6aa)]-6-amino- tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol. As per the process exemplified in example 1366 of the ' 121 application, (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol is reacted with potassium phthalimide in the presence of tetrakis(triphenylphosphine)palladium in dimethylformamide to produce a reaction mass, followed by quenching with water and extracting with ethyl acetate. The combined organic layer is washed with water, dried over sodium sulfate and then concentrated. The residue is purified by column chromatography (2: 1 hexanes/ethyl acetate to 1 :1 hexanes/ethyl acetate) to produce (+)-(lS,4R)-4- phthalimido-2-cyclopenten-l-ol. The resulting hydroxy compound is oxidized with osmium tertraoxide in the presence of N-methylmorpholine-N-oxide in tetrahydrofuran to produce a reaction mass, followed quenching the reaction mass with water and extracting with ethyl acetate. The combined organic layer is dried over sodium sulfate and then concentrated, followed by triturating the residue with methylene chloride to produce (1S,2R,3S,4R)-(N- phthalimidyl)cyclopentane-l,2,3-triol. The resulting triol compound is reacted with 2,2- dimethoxypropane in the presence of methanesulfonic acid in acetone to produce a reaction mass, followed by quenching the reaction mass with water and then extracting with ethyl acetate. The combined organic layers are dried over sodium sulfate and then concentrated to provide (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0-isopropylidenecyclopentane-l,2,3-triol. The resulting compound is then treated with hydrazine mono hydrate in ethanol to produce a reaction mass, followed by cooling the mass. The resulting solids are filtered and the filtrate is concentrated to produce [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H- cyclopenta-l,3-dioxol-4-ol.

[0009] U.S. Patent No.7,067,663; and PCT Publication Nos. WO2009/064249 and WO2010/030224 disclose L-tartrate, dibenzoyl-L-tartrate and oxalate salts of substituted cyclopentanoloamine derivatives.

[0010] According to the Ό60 patent, ticagrelor is prepared by the condensation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine with [3aR-(3aa,4a,6a,6aa)]-6-amino- tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol hydrochloride salt in the presence of Ν,Ν-diisopropylethylamine in tetrahydrofuran to produce [3aR-(3aa,4a,6a,6aa)]-6-[[6- chloro-5-nitro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta- 1,3-dioxo 1-4-01, followed by reduction in the presence of iron powder in acetic acid to produce [3aR-(3aa,4a,6a,6aa)]-6-[[5-amino-6-chloro-2-(propylthio)-pyrimidin-4-yl]amino]- tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol, which is then reacted with isoamyl nitrite in acetonitrile to produce [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-l,2,3- triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol. [0011] The resulting triazolo [4,5-d]-pyrimidin compound is reacted with ammonia in tetrahydrofuran to produce [3aR-(3aa,4a,6a,6aa)]-6-[7-amino-5-(propylthio)-3H- 1,2,3- triazo lo [4, 5-d] -pyrimidin-3 -yl]tetrahydro-2,2-dimethyl-4H-cyclopenta- 1 ,3 -dioxo l-4-o 1, which is then reacted with a solution of trifluoromethanesulfonyloxy-acetic acid methyl ester in tetrahydrofuran in the presence of butyllithium to produce [3aR-(3aa,4a,6a,6aa)]-6-[[7- amino-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H- cyclopenta-l,3-dioxol-4-ol]oxy]acetic acid methyl ester, followed by bromination in the presence of isoamylnitrite in bromoform to produce [3aR-(3aa,4a,6a,6aa)]-6-[[7-bromo-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta- l,3-dioxol-4-ol]oxy]acetic acid methyl ester.

[0012] The resulting bromo compound is then reacted with (lR-trans)-2-(3,4- difluorophenyl)cyclopropanamine [R-(R*,R*)]-2,3-dihydroxybutanedioate (1 : 1) salt in the presence of Ν,Ν-diisopropylethylamine in dichloromethane to produce [3aR- [3aa,4a,6a(lR*,2S^!i:),6aa]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta- l,3-dioxol-4-ol]oxy]acetic acid methyl ester, followed by reaction with diisobutylaluminium hydride (DIBAL-H) in tetrahydrofuran to produce [3aR-[3aa,4a,6a(lR*,2S^!i:),6aa]]-[[6-[7- [[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]- pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta- 1 ,3-dioxol-4-ol]oxy]-ethanol, which is then treated with trifluoro acetic acid in water to produce [lS-(la,2a,3 (lS*,2R^!i:),5 )]-3- [7-[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5- d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane- 1 ,2-diol (ticagrelor).

[0013] The processes for the preparation of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II described in the above mentioned prior art have the following disadvantages and limitations:

a) long reaction times, low yields and low purities of the products;

b) the time required for the oxidation reaction is 4 days, which is industrially not feasible;

c) the processes involve the use of excess amounts of osmium tetroxide, which is an expensive and hazardous reagent, in the oxidation reaction (from about 0.03 equivalents to about 0.12 equivalents with respect to (+)-(lS,4R)-4-phthalimido-2- cyclopenten- 1 -ol); d) the processes involve the use of expensive column chromatographic purifications; methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible; and e) the overall processes generate a large quantity of chemical waste which is difficult to treat.

[0014] Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II at lab scale and in commercial scale operations.

[0015] Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II at lab scale and in commercial scale operations.

[0016] A need remains for an improved and commercially viable process of preparing (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include reduced reaction times, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of triazolo[4,5- d]pyrimidine compounds, preferably ticagrelor, and their pharmaceutically acceptable salts in high purity and in high yield.

SUMMARY

[0017] In one aspect, provided herein is an efficient and industrially advantageous process for the preparation of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-ol, in high yield and with high chemical and enantiomeric purity. Moreover, the process disclosed herein involves reduced reaction times and reduced reagent quantities. The process avoids the tedious and cumbersome procedures of the prior processes and is convenient to operate on a commercial scale.

[0018] In another aspect, the pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][l,3]-dioxol-4-ol obtained by the process disclosed herein has a total purity, which includes both chemical and enantiomeric purity, of greater than about 90%, specifically greater than about 95%, more specifically greater than about 97%, and most specifically greater than about 99% as measured by Gas Chromatography (GC). [0019] In another aspect, the present invention also encompasses the use of pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol obtained by the process disclosed herein for preparing ticagrelor.

[0020] It has been found that the following four by-products are formed as impurities (impurity-1, impurity-2, impurity-3 and impurity-4) in the synthesis of (3aR,4S,6R,6aS)-6- amino-2,2-dimethyltetrahydro -3 aH-cyclopenta[d] [ 1 ,3 ] -dioxo l-4-o 1:

i) Impurity-1 : N-methylphthalimide, having the structural formula 1 :

ii) Impurity-2: Ν,Ν-dimethyl-phthalamide, having the structural formula 2:

iii) Impurity-3: 2,3-dihydro-phthalazine-l,4-dione, having the structural formula 3:

iv) Impurity-4: 2-benzofuran-l(3H)-one having the structural formula 4:

[0021] In another aspect, the pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][l,3]-dioxol-4-ol obtained by the process disclosed herein is substantially or essentially free of one, or more, of the impurities 1, 2, 3 and 4. [0022] In another aspect, provided also herein is an efficient and industrially advantageous process for the preparation of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol, in high yield and with high chemical and enantiomeric purity.

[0023] In yet another aspect, provided herein is a solid state form of (3aR,4S,6R,6aS)- 6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [ 1 ,3]-dioxol-4-ol.

[0024] The process for the preparation of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol disclosed herein has the following advantages over the processes described in the prior art:

i) the oxidation reaction of (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l-ol is completed within 8 to 12 hours;

ii) the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and multiple isolations;

iii) a reduced quantity of osmium tetroxide (0.002 to 0.005 equivalents with respect to the (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l-ol) is used for the oxidation reaction, thereby reducing the chemical waste produced;

iv) the process involves easy work-up methods and simple isolation processes; and v) the overall process time is shortened, the overall yield and purities are increased, there is a reduction in chemical waste, and the process avoids the use of hazardous chemicals.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of solid state form of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]- dioxol-4-ol obtained according to Example 8.

[0026] Figure 2 is a characteristic differential scanning calorimetric (DSC) thermogram of solid state form of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-ol obtained according to Example 8.

DETAILED DESCRIPTION

[0027] According to one aspect, there is provided a process for the preparation of pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II:

or an acid addition salt thereof, comprising:

a) reacting (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol of formula VI:

with phthalimide or its derivative or an alkali metal salt thereof in the presence of tetrakis(triphenylphosphine)palladium, optionally in the presence of a base, in a first solvent, to produce (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l-ol of formula V:

b) oxidizing the compound of formula V with osmium tertraoxide, wherein the osmium tetroxide is used in a ratio of less than about 0.01 equivalents with respect to the compound of formula V, in the presence of N-methylmorpholine N-oxide in a second solvent, to produce (lS,2R,3S,4R)-(N-phthalimidyl)cyclopentane-l,2,3-triol of formula IV:

c) reacting the compound of formula IV with 2,2-dimethoxypropane in the presence of an acid in a third solvent to produce (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0- isopropylidenecyclopentane-l,2,3-triol of formula III:

d) deprotecting the compound of formula III in the presence of a base in a fourth solvent to produce the (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]- dioxol-4-ol of formula II, and optionally converting the compound of formula II obtained into an acid addition salt thereof; and

e) subjecting the compound of formula II obtained in step-(d) to high vacuum distillation to produce highly pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-ol of formula II, or an acid addition salt thereof, substantially free of impurities.

[0028] As used herein, "highly pure (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol substantially free of impurities" refers to (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [ 1 ,3]-dioxol-4- ol comprising one, or more, of the impurities 1, 2, 3 and 4, each one, in an amount of less than about 0.5 area-% as measured by Gas Chromatography (GC). Specifically, the (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol, as disclosed herein, contains less than about 0.3 area-%>, more specifically less than about 0.2 area-%, still more specifically less than about 0.1 area-% of one, or more, of the impurities 1, 2, 3 and 4; and most specifically is essentially free of the impurities 1, 2, 3 and 4.

[0029] In another embodiment, the highly pure (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol obtained by the process disclosed herein has a total purity of greater than about 90%, specifically greater than about 95%, more specifically greater than about 98%, and most specifically greater than about 99% as measured by Gas Chromatography (GC).

[0030] In one embodiment, the first solvent used in step-(a) is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloro ethane, chloroform, and mixtures thereof. A most specific first solvent is tetrahydrofuran. [0031] Exemplary bases used in step-(a) include, but are not limited to, a metal hydride such as sodium hydride, a metal amide, a metal alkoxide, an alkyl lithium, a metal diisopropylamide, sodium hydroxide, sodium bicarbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, cesium hydroxide, magnesium hydroxide, calcium hydroxide, calcium oxide, triethyl amine, N,N- diisopropylethylamine, N-methylpiperidine, pyridine, N,N-dimethylaminopyridine, N- methylmorpholine and azabicyclononane.

[0032] It has been surprisingly found that the reaction in step-(a) can be conveniently and efficiently carried out in reduced reaction times in the absence of a base such as sodium hydride when the alkali metal salt of phthalimide is used as a starting material instead of phthalimide. The use of explosive reagents like sodium hydride, metal amides and alkyl lithium is not advisable, due to the handling difficulties, for scale up operations.

[0033] In one embodiment, the alkali metal salt of phthalimide used in step-(a) is sodium phthalimide or potassium phthalimide; and most specifically sodium phthalimide.

[0034] In one embodiment, the reaction in step-(a) is carried out at a temperature of- 10°C to about 60°C for about 1 hour to about 24 hours, specifically at a temperature of about 0°C to about 50°C for about 2 hours to about 20 hours, and most specifically at about 20°C to about 50°C for about 5 hours to about 15 hours.

[0035] The reaction mass containing the (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l- ol of formula V obtained in step-(a) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula IV, or the compound of formula V may be isolated and then used in the next step.

[0036] In one embodiment, the (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l-ol of formula V is isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.

[0037] The solvent used to isolate the compound of formula V is selected from the group consisting of water, an alcohol, an ether, a hydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, methanol, ethanol, isopropanol, and mixtures thereof. A most specific solvent is diisopropyl ether. [0038] Exemplary second solvents used in step-(b) include, but are not limited to, acetone, methylethyl ketone, methylisobutyl ketone, methyl tert-butyl ketone, and mixtures thereof. A most specific second solvent is acetone.

[0039] In one embodiment, the oxidation reaction in step-(b) is carried out at a temperature of about -10°C to about 40°C, specifically at a temperature of about 0°C to about 30°C, and most specifically at about 20°C to about 30°C. In another embodiment, the reaction in step-(b) is carried out for about 1 hour to about 20 hours, specifically for about 5 hours to about 15 hours, and most specifically for about 6 hours to about 12 hours.

[0040] The oxidation reaction disclosed herein involves the use of reduced amounts of osmium tetroxide, which is a very expensive and hazardous reagent, whereas the prior art processes utilize excessive amounts of osmium tetroxide for the oxidation reaction, for example, the prior art uses about 0.03 to 0.13 equivalents with respect to the (+)-(lS,4R)-4- phthalimido-2-cyclopenten-l-ol of formula V.

[0041] In one embodiment, the osmium tetroxide is used in the process disclosed herein in a ratio of about 0.002 to 0.005 equivalents, specifically about 0.0025 to 0.0035 equivalents, with respect to the (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l-ol of formula V in order to ensure a proper course of the reaction.

[0042] The reaction mass containing the (1S,2R,3S,4R)-(N- phthalimidyl)cyclopentane-l,2,3-triol of formula IV obtained in step-(b) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the compound of formula III, or the compound of formula IV may be isolated and then used in the next step.

[0043] In one embodiment, the (lS,2R,3S,4R)-(N-phthalimidyl)cyclopentane-l,2,3- triol of formula IV is isolated from a suitable solvent by the methods as described above.

[0044] The solvent used to isolate the compound of formula IV is selected from the group consisting of water, an alcohol, an ether, a hydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, methanol, ethanol, isopropanol, and mixtures thereof.

[0045] Exemplary third solvents used in step-(c) include, but are not limited to, acetone, methylethyl ketone, methylisobutyl ketone, methyl tert-butyl ketone, and mixtures thereof. A most specific third solvent is acetone. [0046] In one embodiment, the acid used in step-(c) is p-toluenesulfonic acid.

[0047] In another embodiment, the reaction in step-(c) is carried out at a temperature of about -10°C to about 50°C, specifically at a temperature of about 0°C to about 30°C, and most specifically at about 20°C to about 30°C. In another embodiment, the reaction is carried out for about 1 hour to about 10 hours, specifically for about 2 hours to about 8 hours, and most specifically for about 3 hours to about 6 hours.

[0048] The reaction mass containing the (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0- isopropylidenecyclopentane-l,2,3-triol of formula III obtained in step-(c) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the compound of formula II, or the compound of formula III may be isolated and then used in the next step.

[0049] In one embodiment, the (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0- isopropylidene cyclopentane-l,2,3-triol of formula III is isolated from a suitable solvent by the methods as described above.

[0050] The solvents and anti-solvents used to isolate the compound of formula III are selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof.

[0051] In one embodiment, the solvent used to isolate the compound of formula III is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, tert- butyl methyl acetate, ethyl formate, acetone, methylethyl ketone, methylisobutyl ketone, methyl tert-butyl ketone, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, chloroform, and mixtures thereof. A most specific solvent is ethyl acetate.

[0052] In another embodiment, the anti-solvent used to isolate the compound of formula III is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, 2-methyl- tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, and mixtures thereof. A most specific anti-solvent is n-hexane.

[0053] In one embodiment, the fourth solvent used in step-(d) is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, 2-methyl- tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Specifically, the fourth solvent is tetrahydrofuran or ethanol.

[0054] Exemplary bases used in step-(d) include, but are not limited to, sodium hydroxide, sodium bicarbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, cesium hydroxide, magnesium hydroxide, calcium hydroxide, alkyl amine, hydrazine hydrate, sodium borohydride and lithium borohydride.

[0055] Specifically, the base is selected from the group consisting of methyl amine, hydrazine hydrate and sodium borohydride.

[0056] In one embodiment, the reaction in step-(d) is carried out at a temperature of about 0°C to about 80°C, specifically at a temperature of about 10°C to about 70°C, and most specifically at about 20°C to about 65°C. In another embodiment, the reaction is carried out for about 5 hours to about 22 hours, specifically for about 6 hours to about 20 hours, and most specifically for about 10 hours to about 18 hours.

[0057] The reaction mass containing the (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II obtained in step-(d) may be subjected to usual work up methods as described above.

[0058] In one embodiment, the (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II is isolated from a suitable solvent by the methods as described above.

[0059] The solvents and anti-solvents used to isolate the compound of formula II are selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof.

[0060] In one embodiment, the solvent used to isolate the compound of formula II is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, tert- butyl methyl acetate, ethyl formate, acetone, methylethyl ketone, methylisobutyl ketone, methyl tert-butyl ketone, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, chloroform, and mixtures thereof. A most specific solvent is ethyl acetate.

[0061] In another embodiment, the anti-solvent used to isolate the compound of formula II is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, 2-methyl- tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, and mixtures thereof. A most specific anti-solvent is n-hexane.

[0062] It has been surprisingly found that purity of the (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II is significantly increased when the compound is subjected to high vacuum distillation at high temperatures.

[0063] Specifically, the vacuum distillation is performed at a pressure of about 200 mm Hg or less, more specifically at about 100 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specifically from about 5 mm Hg to about 25 mm Hg. [0064] In another embodiment, the vacuum distillation is performed at a temperature of about 85°C to about 95°C, specifically at a temperature of about 89°C to about 95°C, and most specifically at about 93°C to about 95°C.

[0065] In one embodiment, the (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II obtained by the disclosed herein is isolated as a solid state form.

[0066] According to another aspect, there is provided a solid state form of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II.

[0067] In one embodiment, the solid state form of the (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II, obtained by the process disclosed herein, is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 6.19, 12.34, 18.40, 18.82, 20.53 and 24.77 ± 0.2 degrees 2-theta substantially in accordance with Figure 1. The solid state form of the (3aR,4S,6R,6aS)-6- amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II is further characterized by a differential scanning calorimetric (DSC) thermogram having an endo therm peak at about 87.3°C substantially in accordance with Figure 2.

[0068] Acid addition salts of the compound of formula II can be prepared in high purity by using the highly pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-ol of formula II obtained by the method disclosed herein, by known methods.

[0069] The acid addition salts of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II are derived from a therapeutically acceptable acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, citric acid, glutaric acid, citraconic acid, glutaconic acid, tartaric acid, dibenzoyl-L- tartaric acid, di-p-toluoyl-L-tartaric acid, L-malic acid, malonic acid and mandelic acid.

[0070] According to another aspect, there is provided a process for the preparation of pure (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol of formula VI:

comprising:

a) reacting furfuryl alcohol with potassium dihydrogen phosphate in the presence of orthophosphoric acid in a first solvent to produce 4-hydroxy-2-cyclopentenone of formula

IX:

b) reducing the compound of formula IX with an alkali metal hydride in the presence of a trivalent rare earth metal salt or a hydrate thereof in a second solvent to produce cis-3,5- dihydroxy-l-cyclopentene of formula VIII:

c) acylating the compound of formula VIII with an acylating agent in a third solvent to produce cis-3,5-diacetoxy-l-cyclopentene of formula VII:

d) subjecting the compound of formula VII to selective hydrolysis using a recyclable immobilized enzyme in a buffer solution containing an organic or inorganic acid salt to produce highly pure (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol of formula VI, wherein the enzyme is novozyme-435 immobilized enzyme.

[0071] In one embodiment, the highly pure (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol obtained by the process disclosed herein has a total purity of greater than about 98%, specifically greater than about 99%, more specifically greater than about 99.5%, and most specifically greater than about 99.9%> as measured by Gas Chromatography (GC).

[0072] In another embodiment, the first solvent used in step-(a) is water.

[0073] In another embodiment, the reaction in step-(a) is carried out at a temperature of about 50°C to the reflux temperature of the solvent used for at least 15 hours, specifically at a temperature of about 80°C to the reflux temperature of the solvent used for about 18 hours to about 26 hours, and most specifically at the reflux temperature of the solvent used for about 20 hours to about 24 hours.

[0074] The reaction mass containing the 4-hydroxy-2-cyclopentenone of formula IX obtained in step-(a) may be subjected to a usual work up such as a washing, an extraction, a pH adjustment, an evaporation, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula VIII, or the compound of formula IX may be isolated and then used in the next step.

[0075] In one embodiment, the 4-hydroxy-2-cyclopentenone of formula IX is isolated and/or purified using a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, fractional distillation, or a combination thereof.

[0076] The solvent used to isolate the compound of formula IX is selected from the group consisting of an ether, a hydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloro ethane, chloroform, and mixtures thereof. A most specific solvent is dichloromethane.

[0077] In one embodiment, the second solvent used in step-(b) is selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, n-butanol, and mixtures thereof. A most specific second solvent is methanol.

[0078] In another embodiment, the alkali metal hydride used in step-(b) is selected from the group consisting of sodium borohydride, potassium borohydride and lithium borohydride. A most specific alkali metal hydride is sodium borohydride.

[0079] In another embodiment, the trivalent rare earth metal salt used in step-(b) is a cerium (III) halide; specifically cerium (III) chloride having a water content of about 1% to about 40% w/w; and more specifically cerium (III) chloride heptahydrate.

[0080] In another embodiment, the reduction in step-(b) is carried out at a temperature of about -100°C to about 0°C, specifically at about -100°C to -50°C, and more specifically at about -70°C to -60°C.

[0081] The reaction mass containing the cis-3,5-dihydroxy-l-cyclopentene of formula VIII: obtained in step-(b) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the compound of formula VII, or the compound of formula VIII may be isolated and then used in the next step. [0082] In one embodiment, the third solvent used in step-(c) is selected from the group consisting of tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert- butyl ether, 1,4-dioxane, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. A most specific third solvent is N,N- dimethy lformamide .

[0083] Exemplary acylating agents used in step-(c) include, but are not limited to, acetyl chloride and acetic anhydride. A most specific acylating agent is acetic anhydride.

[0084] In another embodiment, the acylation reaction in step-(c) is carried out at a temperature of about -10° to about 50°C, specifically at about 0°C to about 30°C, and more specifically at about 0°C to about 20°C.

[0085] The reaction mass containing the cis-3,5-diacetoxy-l-cyclopentene of formula VII obtained in step-(c) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the compound of formula VI, or the compound of formula VII may be isolated and then used in the next step.

[0086] In one embodiment, the cis-3,5-diacetoxy-l-cyclopentene of formula VII is isolated and/or purified using a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, fractional distillation, or a combination thereof.

[0087] The solvent used to isolate the compound of formula VII is a chlorinated hydrocarbon solvent, and more specifically dichloromethane.

[0088] It has been surprisingly and unexpectedly found that the use of the novozyme- 435 (immobilized on acrylic resin), also known as immobilized Candida antarctica Lipase B, employed in the hydrolysis reaction of step-(d); instead of other enzymes such as pancreatin, lipase, amino lipase and lipozyme; makes the process more convenient and highly selective, and avoids the emulsion formation during the work up, and thereby producing the (1S,4R)- cis-4-acetoxy-2-cyclopenten-l-ol of formula VI with higher yields and purities and thus making the process simple, convenient and cost effective. Moreover, the novozyme-435 immobilized enzyme employed herein can be recycled as many as 4 times.

[0089] In one embodiment, the inorganic acid salts employed for preparing the buffer solution in step-(d) include, but are not limited to, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and the like. A most specific inorganic acid salt is disodium hydrogen phosphate. In another embodiment, the organic acid salts employed for preparing the buffer solution in step-(d) include, but are not limited to, sodium acetate, citric acetate, and the like. These salts are employed in the hydrolysis reaction as solvents or dispersing agents. The concentration of these salts used in the buffer solutions may vary according to the type of the buffer solution. The desirable concentration of buffer solution is about 0.02M to about 2M. A most specific buffer solution is 0.5M solution of disodium hydrogen phosphate solution.

[0090] Although bi-layer reactions using organic solvents such as heptanes, diisopropyl ether etc., may also be possible, but they are not necessarily required.

[0091] The pH value of the reaction solution at the beginning of the reaction should preferably be with in the range of 7-10. In one embodiment, the pH of the reaction solution is maintained at above 7 by using inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate; and specifically sodium carbonate.

[0092] Specifically, the enzymatic reaction is carried out at a temperature of about 10°C to about 50°C. The reaction is slow at low temperatures, but there is a partial loss of enzyme activation is observed at high temperatures, therefore the temperature range of 20- 40°C is particularly preferred.

[0093] The reaction time may vary depending on the reaction temperature and the type of enzyme and the quantity of enzyme is used. In one embodiment, the reaction is carried out for about 5 hours to about 25 hours, specifically for about 10 hours to about 20 hours, and most specifically for about 12 hours to about 16 hours.

[0094] The progress of the reaction may be monitored by the methods known to those skilled in the art such as thin layer and gas chromatography.

[0095] Once the reaction in step-(d) is substantially complete, the (lS,4R)-cis-4- acetoxy-2-cyclopenten-l-ol may be isolated by the following steps: a) filtering the enzyme from the reaction mass and the recovered enzyme can be further used for next batches; b) extracting the filtrate with a suitable solvent such as a chlorinated hydrocarbon, an ester, and mixtures thereof; c) concentrating the resulting mass at a temperature of about 20°C to about 50°C under reduced pressure; and d) precipitating the (lS,4R)-cis-4-acetoxy-2-cyclopenten- l-ol by the addition of an anti-solvent at a temperature of about 0°C to about 15°C, wherein the anti-solvent is selected from the group consisting of a hydrocarbon, an ether, and mixtures thereof. Specifically, the solvent used for extraction is selected from the group consisting of dichloromethane, ethyl acetate, and mixtures thereof. Specifically, the anti- solvent is selected from the group consisting of hexane, heptane, octane, diethyl ether, diisopropyl ether, and mixtures thereof. [0096] Aptly the processes disclosed herein are adapted for the preparation of ticagrelor or a pharmaceutically acceptable salt thereof in high enantiomeric and chemical purity.

[0097] Ticagrelor and pharmaceutically acceptable acid addition salts thereof can be prepared in high purity by using the substantially pure [3aR-(3aa,4a,6a,6aa)]-6-amino- tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol of formula II obtained by the methods disclosed herein, by known methods.

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

[0098] The X-Ray powder diffraction was measured by an X-ray powder diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 40kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 1976, Corundum standard. The sample was analyzed using the following instrument parameters: measuring range= 3-45° 2-theta; step width=0.01579°; and measuring time per step=0.11 second.

Differential Scanning Calorimetry (DSC):

[0099] Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q 1000 V23.5 Build 72, Universal V4.3A TA Instruments) at a scan rate of 10°C per minute.

[0100] The following examples are given for the purpose of illustrating the present disclosure and should not be considered as limitation on the scope or spirit of the disclosure.

EXAMPLES

Example 1

Preparation of (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l-ol

Phthalimide (25.88 g) was added to a suspension of sodium hydride (60% dispersion in oil, 10.32 g) in tetrahydrofuran (250 ml) and the container was flushed with tetrahydrofuran (50 ml) at 25-30°C under a nitrogen atmosphere. The reaction mixture was heated at 40-45°C for 2 hours, followed by the addition of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol (10 g) and tetrakis(triphenylphosphine)palladium (3.6 g). The resulting mixture was stirred for 2 hours at 25-30°C under a nitrogen atmosphere, followed by the addition of excess phthalimide (10.4 g) after reaction completion. The reaction mixture was stirred for 20 hours at 25-30°C, the resulting mass was cooled to 0-5°C and then acetic acid (2 g) was added at 0-5°C. The resulting solid was filtered and washed with tetrahydrofuran (100 ml). The filtrate was distilled off under vacuum, followed by the addition of toluene (100 ml) at 25-30°C. The unwanted solid was filtered and the filtrate was washed with sodium hydroxide solution at 0- 5°C. The toluene was distilled off from the resulting filtrate under vacuum at 50°C and the residue was recrystallized in diisopropyl ether to produce 12 g of (+)-(lS,4R)-4-phthalimido- 2-cyclopenten-l-ol.

Example 2

Preparation of (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l-ol

Sodium phthalimide (297.8 g) and tetrahydrofuran (2400 ml) were placed in a reaction flask under nitrogen atmosphere and the suspension was heated at 40°C. The suspension was stirred for 2 hours at 40-45°C, followed by the addition of (lS,4R)-cis-4-acetoxy-2- cyclopenten-l-ol (100 g) and tetrakis(triphenylphosphine)palladium (16 g) at 25-30°C. The reaction mixture was stirred for 2 hours at 25-30°C, then the resulting solid was filtered and washed with tetrahydrofuran (1000 ml). The filtrate was distilled off under vacuum, followed by the addition of toluene (1000 ml) at 25-30°C. The unwanted solid was filtered and the wet cake was washed with toluene (500 ml). The resulting filtrate was washed with water (1000 ml) at 50-55°C. The toluene was distilled off from the resulting filtrate under vacuum at 50°C and the residue was recrystallized in diisopropyl ether to produce 120 g of (+)-( 1 S,4R)-4-phthalimido-2-cyclopenten- 1 -ol.

Example 3

Preparation of (lS,2R,3S,4R)-(N-Phthalimidyl)cyclopentane-l,2,3-triol

(+)-(lS,4R)-4-Phthalimido-2-cyclopenten-l-ol (200 g) was dissolved in acetone (2000 ml) at 25-30°C, followed by the addition of N-methylmorpholine-N-oxide (163.63 g) and a previously prepared solution of osmium tetroxide (0.65 g) in t-butanol (26 ml) at 20-25°C. The resulting mass was stirred for 8 hours at 20-25°C. After completion of the reaction, sodium bisulphate (100 g) was added to the reaction mass and then stirred for 30 minutes, followed by the distillation of reaction solvent. The residue was cooled to 25-30°C, followed by adjusting the pH of the mass to 1 with 50% dilute sulphuric acid. The separated product was collected by filtration and washed with water (2000 ml), followed by drying the solid to produce 180 g of (lS,2R,3S,4R)-(N-phthalimidyl)cyclopentane-l,2,3-triol (Chemical Purity by HPLC: 95%; and Optical Purity: 98%). Example 4

Preparation of (lS,2R,3S,4R)-(N-Phthalimidyl)-2,3-0-isopropylidenecyclopentane-l,2,3-triol 2,2-Dimethoxypropane (366.8 g) and p-toluenesulfonic acid (10.4 g) were added to a solution of (lS,2R,3S,4R)-(N-phthalimidyl)cyclopentane-l,2,3-triol (175 g) in acetone (1500 ml). The resulting suspension was stirred for 4 hours at 25-30°C. After completion of the reaction, acetone was distilled out under vacuum and the residue was extracted with dichloromethane (1700 ml), followed by washing the dichloromethane layer with 10% sodium bicarbonate solution (700 ml). The dichloromethane layer was concentrated under reduced pressure while maintaining the temperature at below 40°C. The concentrated mass was further dissolved in ethyl acetate (175 ml), followed by the addition of n-hexane (1700 ml) to form a precipitate. The resulting solid was washed with n-hexane (50 ml) and then dried at 50-55°C to produce 360 g of (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0- isopropylidenecyclopentane-l,2,3-triol (Chemical purity by HPLC: 95%; and Optical purity: 98.5%).

Example 5

Preparation of (3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3]- dioxol-4-ol

A solution of (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0-isopropylidenecyclopentane-l,2,3-triol (15 g) in 33% methyl amine (75 ml) was stirred at 25-30°C for 18 hours. The reaction mass was cooled to 0-5°C, the precipitated solid was filtered and then washed with ethanol (15 ml). The resulting filtrate was concentrated under reduced pressure to form a residue, followed by the addition of ethanol (30 ml). The resulting mass was cooled to 0-5°C, the solid was filtered and then washed with chilled ethanol (75 ml). The filtrate obtained was concentrated and the residue was dissolved in ethyl acetate (15 ml), followed by addition of hexane (150 ml). The resulting suspension was stirred for 1 hour at 25-30°C, the separated solid was filtered, washed with hexane (15 ml) and then dried to produce 6 g of (3aR,4S,6R,6aS)-6- amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol (Chemical purity by GC: 91.2%; and Optical purity by GC: 94%).

Example 6

Preparation of (3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3]- dioxol-4-ol A solution of (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0-isopropylidenecyclopentane-l,2,3-triol (15 g) in ethanol (75 ml) and hydrazine hydrate (10 ml) was stirred for 10 hours at 60-65°C. After completion of the reaction, the reaction mass was cooled to 0-5°C, the precipitated solid was filtered and washed with ethanol (15 ml). The filtrate was concentrated under reduced pressure to give a residue and the residue was dissolved in ethanol (30 ml). The resulting mass was cooled to 0-5°C, the separated solid was filtered and washed with chilled ethanol (7 ml). The filtrate obtained was concentrated and the residue was stirred with diisopropyl ether (20 ml), followed by filtration and drying to produce 7 g of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol (Chemical purity by GC: 97.1%; and Optical purity by GC: 98.2%).

Example 7

Preparation of (3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3]- dioxol-4-ol

Sodium borohydride (6.16 g) was added portion wise (in 3-4 portions) to a solution of (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0-isopropylidenecyclopentane-l,2,3-triol (10 g) in tetrahydrofuran (100 ml). The resulting suspension was stirred for 18 hours at 25-30°C, followed by the addition of isopropyl alcohol (100 ml) and acetic acid (35 g). The resulting mass was heated at 80-85°C for 4 hours and then cooled to 25-30°C. The reaction mass was quenched with water (50 ml), followed by extracting with dichloromethane (2 X 200 ml). The dichloromethane layer was distilled out completely and the resulting residue was dissolved in methanol (50 ml). Sodium bicarbonate (20 g) was added to the solution and then stirred for 15 minutes. The resulting mass was filtered and the filtrate was concentrated under reduced pressure while maintaining the temperature at below 50°C. The concentrated mass was further purified by column chromatographic purification (Si0₂, MDC: Methanol 1 :9 as eluent) to produce 4.1 g of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-ol (Chemical purity by GC: 92.3%; and optical purity by GC: 97.6%).

Example 8

Purification of (3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3]- dioxol-4-ol

(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol (6 g, obtained in example 5) was subjected to high vacuum distillation at 90-95°C under vacuum (5 mm Hg). The second fraction was collected at 93°C under 5 mm Hg vacuum to produce pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol (Chemical purity by GC: 99.2%; and optical purity by GC: 99.5%).

Example 9

Preparation of 4-Hydroxy-2-cyclopentenone

To a stirred solution of furfuryl alcohol (500 gm) in water (8000 ml), potassium dihydrogen phosphate (24.9 g) was added at 25-30°C. The resulting solution was stirred for 10 minutes, followed by drop wise addition of orthophosphoric acid (2 ml) at 25-30°C to adjust the pH of the mass to 4.1. The resulting mixture was heated at reflux temperature (99°C) and then stirred for 22 hours. The reaction mixture was cooled to 25-30°C, followed by filtration through a hyflo bed. The resulting clear yellow filtrate was concentrated under reduced pressure at 50-55°C and the resulting brown colored solid was suspended in dichloromethane (2 L). The suspension was then separated by filtration and the mother liquor was evaporated to dryness. The residue was degassed for 1 hour at 40°C. The crude product was purified by distillation at 110-114°C under 5 mbar vacuum over fraction distillation to produce 100 g of 4-hydroxy-2-cyclopentenone (100 gm) as a pale yellow colored liquid (Purity by GC: 98%>).

Example 10

Preparation of Cis-3,5-diacetoxy-l-cyclopentene

Cerium chloride heptahydrate (380 g) was dissolved in methanol (1700 ml) at 25-30°C and the resulting solution was cooled to -65°C, followed by the addition of 4-hydroxy-2- cyclopentenone (100 gm) at -70°C to -60°C. Sodium boro hydride (29 g) was added portion wise (in 5 portions) to the reaction mixture at -70°C to -60°C over a period of 60 minutes. The reaction mixture was stirred for 1 hour at -70°C to -60°C, followed by the addition of acetone (100 ml) at the same temperature over a period of 15 minutes to destroy the excess sodium borohydride. The temperature of the reaction mixture was raised to 25-30°C, followed by distillation of the mixture of methanol and acetone under vacuum at below 40°C and then stripping out methanol by using toluene (100 ml) at 40°C. N,N-dimethylformamide (1300 ml) was added to the resulting mass at 40°C and the resulting suspension was cooled to 25-30°C, followed by the addition of 4-dimethylamino pyridine (10 g) and triethylamine (825 g) under a nitrogen atmosphere. The suspension was cooled to 10°C under a nitrogen atmosphere, followed by drop wise addition of acetic anhydride (83 g) while maintaining the temperature at below 20°C over a period of 60 minutes. The reaction mixture was stirred for 15 hours at 25-30°C. Water (2 L) was added to the resulting mass at 25-30°C, followed by adjusting the pH to 2 by using dilute hydrochloric acid. The resulting mass was stirred for 15 minutes and then methylene dichloride (1000 ml) was added. The resulting mixture was stirred for 15 minutes, followed by separation of the water layer and then extracting with methylene dichloride (2 x 1 L). The combined organic layer was washed with water (2 x 1 L), and subsequently with 5% sodium bicarbonate (1 L) and water (2 x 1 L) at 25-30°C. The organic layer was dried over anhydrous sodium sulfate, followed by filtration and evaporation to dryness under reduced pressure to produce 160 g of crude product as a brown oil. The crude product was purified by fractional distillation column at 90°C under 5 mbar vacuum to produce 140 g of cis-3,5-diacetoxy-l-cyclopentene (Purity by GC: 96%).

Example 1 1

Preparation of (lS,4R)-cis-4-Acetoxy-2-cyclopenten-l-ol

Cis-3,5-diacetoxy-l-cyclopentene (100 g) was added to 0.5M disodium hydrogen phosphate soution of pH 7 (155 g) at 25-30°C. Novozyme-435 immobilized enzyme (0.5 g) was added to the resulting mixture and then stirred for 14 hours. The enzyme was recovered by filtration throgh a buchner funnel to use for next batches. The filtrate was extracted with methylene dichloride (5 x 1000 ml) at 25-30°C. The combined organic layer was dried over anhydrous sodium sulfate, followed by evaporation of the solvent under vacuum at below 40°C. The resulting residue was degassed for 1 hour at 40°C, followed by the addition of diisopropyl ether (300 ml) at 40°C and then stirring the suspension to get a clear solution. The solution was cooled to 0-5°C and then stirred for 30 minutes. The resulting white colored solid was filtered and then dried at 25-30°C under vacuum to produce 50 g of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol [Purity by GC: 99.9%; Chiral Purity: 99.9%; specific optical rotation: +66° (c=2.5%>, CHC1₃) (Reported Specific optical rotation: +68±2°, c = 2.3% , CHCl₃)].

Example 12

Preparation of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol (First recycle)

Cis-3,5-diacetoxy-l-cyclopentene (5 g) was added to 0.5M disodium hydrogen phosphate soution of pH 7 (7.75 g) at 25-30°C. The recovered Novozyme-435 immobilized enzyme (25 mg, recovered from the process of example 1 1) was added to the resulting mixture and then stirred of 14 hours. The enzyme was recovered by filtration through a buchner funnel to use for the next batches. The filtrate was extracted with methylene dichloride (5 x 50 ml) at 25-30°C. The combined organic layer was dried over anhydrous sodium sulfate, followed by evaporation of the solvent under vacuum at below 40°C. The residue was degassed for 1 hour at 40°C, followed by the addition of diisopropyl ether (15 ml) at 40°C and then stirring to form a clear solution. The solution was cooled to 0-5°C and then stiired for 30 minutes. The resulting white colored solid was filtered and then dried at 25-30°C under vacuum to produce 2.3 g of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol [Specific optical rotation: +65.1° (c=2.5%, CHCI3) (Reported Specific optical rotation = +68±2°, C = 2.3% , CHC1₃)].

Example 13

Preparation of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol (Second recycle)

Cis-3,5-diacetoxy-l-cyclopentene (5 g) was added to 0.5M disodium hydrogen phosphate soution of pH 7 (7.75 g) at 25-30°C. Novozyme-435 immobilized enzyme (25 mg, recovered from the process of example 12) was added to the reaction mixture and then stirred for 14 hours. The enzyme was recovered by filtration through a buchner funnel for reuse. The filtrate was extracted with methylene dichloride (5 x 50 ml) at 25-30°C. The combined organic layer was dried over anhydrous sodium sulfate, followed by evaporation of the solvent under vacuum at below 40°C. The residue was degassed for 1 hour at 40°C, followed by the addition of diisopropyl ether (15 ml) at 40°C and then stirring to get a clear solution. The solution was cooled to 0-5°C and then stiired for 30 minutes. The resulting white colored solid was filtered and then dried at 25-30°C under vacuum to produce 2.4 g of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol [Specific Optical Rotation: +67.6° (c=2.5%, CHCI3) (Reported Specific optical rotation: +68±2°, c = 2.3% , CHC1₃)].

Claims

We claim:

1. A process for the preparation of pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II:

or an acid addition salt thereof, comprising:

a) reacting (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol of formula VI:

with phthalimide or its derivative or an alkali metal salt thereof in the presence of tetrakis(triphenylphosphine)palladium, optionally in the presence of a base, in a first solvent to produce (+)-(! S,4R)-4-phthalimido-2-cyclopenten-l-ol of formula V:

b) oxidizing the compound of formula V with osmium tertraoxide, wherein the osmium tetroxide is used in a ratio of less than about 0.01 equivalents with respect to the compound of formula V, in the presence of N-methylmorpholine N-oxide in a second solvent to produce (lS,2R,3S,4R)-(N-phthalimidyl)cyclopentane-l,2,3-triol of formula IV:

c) reacting the compound of formula IV with 2,2-dimethoxypropane in the presence of an acid in a third solvent to produce (lS,2R,3S,4R)-(N-phthalimidyl)-2,3-0- isopropylidenecyclopentane-l,2,3-triol of formula III:

d) deprotecting the compound of formula III in the presence of a base in a fourth solvent to produce the (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-ol of formula II, and optionally converting the compound of formula II obtained into an acid addition salt thereof; and

e) subjecting the compound of formula II obtained in step-(d) to high vacuum distillation to produce highly pure (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-ol of formula II, or an acid addition salt thereof, substantially free of impurities.

2. The process of claim 1, wherein the first solvent used in step-(a) is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloro ethane, chloroform, and mixtures thereof; wherein the second solvent used in step-(b) is selected from the group consisting of acetone, methylethyl ketone, methylisobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; wherein the third solvent used in step-(c) is selected from the group consisting of acetone, methylethyl ketone, methylisobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; and wherein the fourth solvent used in step-(d) is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, 2- methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

3. The process of claim 2, wherein the first solvent is tetrahydrofuran; wherein the second solvent is acetone; wherein the third solvent is acetone; and wherein the fourth solvent is tetrahydrofuran or ethanol.

4. The process of claim 1, wherein the alkali metal salt of phthalimide used in step-(a) is sodium phthalimide or potassium phthalimide.

5. The process of claim 4, wherein the alkali metal salt of phthalimide is sodium phthalimide.

6. The process of claim 1, wherein the osmium tetroxide in step-(b) is used in a ratio of about 0.002 to about 0.005 equivalents with respect to the (+)-(lS,4R)-4-phthalimido-2- cyclopenten-l-ol of formula V.

7. The process of claim 6, wherein the osmium tetroxide is used in a ratio of about 0.0025 to about 0.0035 equivalents with respect to the (+)-(lS,4R)-4-phthalimido-2-cyclopenten-l- ol of formula V.

8. The process of claim 1, wherein the acid used in step-(c) is p-toluenesulfonic acid.

9. The process of claim 1, wherein the vacuum distillation in step-(e) is performed at a temperature of about 85°C to about 95°C.

10. Solid state form of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][ 1 ,3]-dioxol-4-ol.

11. The solid state form of claim 10, characterized by a powder X-ray diffraction pattern having peaks at about 6.19, 12.34, 18.40, 18.82, 20.53 and 24.77 ± 0.2 degrees 2-theta substantially in accordance with Figure 1.

12. The solid state form of claim 11, further characterized by a differential scanning calorimetric (DSC) thermogram having an endotherm peak at about 87.3°C substantially in accordance with Figure 2.

13. A process for the preparation of pure (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol of formula VI:

comprising:

a) reacting furfuryl alcohol with potassium dihydrogen phosphate in the presence of orthophosphoric acid in a first solvent to produce 4-hydroxy-2-cyclopentenone of formula IX:

b) reducing the compound of formula IX with an alkali metal hydride in the presence of a trivalent rare earth metal salt or a hydrate thereof in a second solvent to produce cis- 3,5-dihydroxy-l-cyclopentene of formula VIII:

c) acylating the compound of formula VIII with an acylating agent in a third solvent to produce cis-3,5-diacetoxy-l-cyclopentene of formula VII:

d) subjecting the compound of formula VII to selective hydrolysis using a recyclable immobilized enzyme in a buffer solution containing an organic or inorganic acid salt to produce highly pure (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol of formula VI, wherein the enzyme is immobilized Candida antarctica Lipase B.

14. The process of claim 13, wherein the first solvent used in step-(a) is water; wherein the second solvent used in step-(b) is selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, n-butanol, and mixtures thereof; wherein the third solvent used in step-(c) is selected from the group consisting of tetrahydrofuran, 2-methyl- tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, and mixtures thereof;

15. The process of claim 14, wherein the second solvent is methanol; wherein the third solvent is N,N-dimethylformamide.

16. The process of claim 13, wherein the alkali metal hydride used in step-(b) is selected from the group consisting of sodium borohydride, potassium borohydride and lithium borohydride; wherein the trivalent rare earth metal salt used in step-(b) is a cerium (III) halide; wherein the acylating agent used in step-(c) is acetyl chloride or acetic anhydride; wherein the inorganic acid salt employed for preparing the buffer solution in step-(d) is selected from the group consisting of sodium phosphate, potassium phosphate, disodium hydrogen phosphate and dipotassium hydrogen phosphate; and wherein the organic acid salt employed for preparing the buffer solution in step-(d) is sodium acetate or citric acetate.

17. The process of claim 16, wherein the alkali metal hydride is sodium borohydride; wherein the trivalent rare earth metal salt is cerium (III) chloride heptahydrate; wherein the acylating agent is acetic anhydride; and wherein the inorganic acid salt used in step-(d) is disodium hydrogen phosphate.

18. The process of claim 13, wherein the enzymatic reaction in step-(d) is carried out at a temperature of about 10°C to about 50°C.

19. The process of claim 18, wherein the enzymatic reaction is carried out at 20-40°C.

20. The process of claim 13, wherein the (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol obtained in step-(d) is isolated by the steps of: a) filtering the enzyme from the reaction mass; b) extracting the filtrate with a solvent selected from the group consisting of a chlorinated hydrocarbon, an ester, and mixtures thereof; c) concentrating the resulting mass at a temperature of about 20°C to about 50°C under reduced pressure; and d) precipitating the (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol by the addition of an anti-solvent at a temperature of about 0°C to about 15°C, wherein the anti-solvent is selected from the group consisting of a hydrocarbon, an ether, and mixtures thereof.

21. Use of the substantially pure [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl- 4H-cyclopenta-l,3-dioxol-4-ol of formula II obtained by the process of claim 1 in the process for manufacture of ticagrelor or a pharmaceutically acceptable salt thereof.