WO2015162630A1 - Novel processes for preparing triazolo [4,5-d]- pyrimidines, including ticagrelor, vianew intermediates and new route of synthesis. - Google Patents

Novel processes for preparing triazolo [4,5-d]- pyrimidines, including ticagrelor, vianew intermediates and new route of synthesis. Download PDF

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WO2015162630A1
WO2015162630A1 PCT/IN2015/000181 IN2015000181W WO2015162630A1 WO 2015162630 A1 WO2015162630 A1 WO 2015162630A1 IN 2015000181 W IN2015000181 W IN 2015000181W WO 2015162630 A1 WO2015162630 A1 WO 2015162630A1
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formula
compound
compound according
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ticagrelor
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WO2015162630A4 (en
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Punitkumar Rameshbhai RASADIA
Narendrakumar RAMANI.Vaibhav
Bipin Pandey
Vijay Nagjibhai BHADANI
Dipakkumar Dhanjibhai VACHHANI
Anamik Kantilal SHAH
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Anlon Chemical Research Organization
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The present invention relates to novel processes for preparing triazolo [4,5-d] pyrimidines, including Ticagrelor, via new intermediates and new routes of synthesis. The synthesis begins with readily available and inexpensive starting material such as 5-nitro-2,4,6-trichloropyrimidine and leads to series of novel intermediates, which are commercially viable and industrially advantageous (solid intermediates, high yields and convenient experimental condition) for the preparation of highly pure Ticagrelor.

Description

NOVEL PROCESSES FOR PREPARING TRIAZOLO [4,5-d]- PYRIMIDINES, INCLUDING TICAGRELOR, VIA NEW INTERMEDIATES AND NEW ROUTE OF SYNTHESIS

CROSS REFERENCES

This patent application claims the benefits of Indian provisional applications 1457/MUM/2014 filed on 25th April 2014 and 3849/MUM/2014 filed on 2nd December 2014, the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to 'ti e field of organic synthesis and describes novel and improved processes for preparing triazolo [4,5-d] pyrimidines, including Ticagrelor, via new intermediates and new route of synthesis. The present disclosure particularly relates to series of novel intermediates, which are commercially viable and industrially advantageous for the preparation of highly pure Ticagrelor.

BACKGROUND OF THE INVENTION

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 and their use. Ticagrelor,(l S,2S,3R,5S)-3-[7-[{(l R,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-l ,2,3-triazolo [4,5-d] pyrimidine-3-yl]-5-(2-hydroxyethoxy)-l ,2-cyclopentanediol \ , has the following chemical structure. Ticagrelor is currently marketed by Astra Zeneca under the trade name BRILINTA and BRILIQUE. Its CAS Number is 274693-27-5. Ticagrelor is a reversibly binding oral P2Y|2 ADP receptor antagonist. Ticagrelor is indicated for the treatment or prevention of thrombotic events e.g. stroke, heart attack, acute coronary syndrome or myocardial infarction with ST elevation, other coronary artery diseases and arterial thrombosis plus other disorders related to platelet aggregation (WO 00/34283).

- ] - WO 99/05143 discloses a series of triazolo [4,5-d]pyrimidine compounds, including Ticagrelor 1. WO 01/92262 and WO 2013/079589 disclose various crystalline and amorphous forms of Ticagrelor 1. IP. Com Journal 201 1 , 1 1 (7A),3 and IP.com Journal 201 1 ,U(6B),26 disclose new crystalline forms and amorphous forms of Ticagrelor. The co-crystal of Ticagrelor 1, with acetyl salicylic acid are reported in WO 2012/164286 (US2014/0148403), where as WO 2014/000719 reports co-crystals with 3-hydroxy-2-naphthoic acid and solvate with 1 ,4-dioxane. Recently WO 2014/006091 has disclosed adducts with divalent metal salts as CaCl and MgCl2. Crystalline form of Ticagrelor are reported in WO 2014/166337, whereas WO 2015/014089 reports preparation and use of Ticagrelor monohydrate. WO 2015/037016 reports formation of amorphous Ticagrelor via its ferulate salt.

Figure imgf000003_0001

Most of synthetic strategies reported for Ticagrelor 1 use mainly three fragments such as, substituted 2-propylthiopyrimidines (Scheme-1); (lR,2S)-2-(3,4- difluorophenyl)cyclopropyl amines or its salts (Scheme-2) and (3aR, 4S, 6R, 6aS)-6-amino-2,2-dimethyl tetrahydro-3aH-cyclopenta[d][l ,3]-dioxol-4-ol It) and their analogues H and 12 (Scheme-3). The notation PGs indicates protecting group. Scheme-1

Figure imgf000003_0002
Scheme-2 its salts

l

Figure imgf000004_0001

Scheme-3

Figure imgf000004_0002
Scheme-4 (WO 2012/138981 and US 2012/032497)

Figure imgf000004_0003

16

17

EP1299390 by Astra Zeneca describes the synthesis and use of 4,6-dichloro-2- (propylsulfanyl)-5-pyrimidin amine 3 and 4,6-dichloro-5-[(E)-2-(4- methylphenyl)diazenyl]-2-(propylsulfanyl) pyrimidine 6 for manufacture of Ticagrelor (Scheme- 1). An improved process for 4,6-dichloro-5-nitro-2- (propylthio) pyrimidine 4 is reported in WO201 1/101740, where as WO2012/138981 by Teva discloses the use of formylated amines 5, to get solid intermediates at later stages of synthesis. Similarly WO2014/023681 discloses the use of diazo-intermediate 6 for the preparation of amino 3 (Scheme- 1) and their consequent application for the synthesis of Ticagrelor 1.

Indian Patent Application 3779/MUM/2013, discloses the synthesis of highly pure (lR,2S)-2-(3,4-difluorophenyl)cycloproply amine 7 (Scheme-2) without its urea analogue as impurity. Various chiral auxiliary based asymmetric cyclopropanation and subsequent synthetic transformations are reported in WOO 1/92200, WO01/92263, WOl 1/017108 and Bio.Org. Med. Chem. Lett. 2007, 17, 6013- 6018. Asymmetric chiral catalytic reduction by CBS-catalyst, followed by enantio-and stereospecific rearrangements and subsequent Hoffman rearrangement to get 7 has been reported in WO08/018822 and WO08/018823. Another alternative involving asymmetric chiral catalytic reduction by CBS catalyst and use of nitro-group as amine precursor has been disclosed in WOl 1/132083. Similarly WO12/001531 and WO2013/144295 describe the chiral synthesis of 7 and its salts. Recently WO2012/085665 has disclosed the use of various amino protecting groups including benzyl 8 and t-BOC 9 to get novel intermediates in the synthesis of Ticagrelor.

The third fragment of aminocyclopentanetriol e.g., (3aR,4S,6R,6aS)-6-amino-2,2- dimethyl-tetrahydro-3aH-cyclopenta[d][l ,3]-dioxol-4-ol 10, its substituted analogue 11 and protected ethylene glycol side chain 12 are reported in WO99/05142, 'Synthetic Communications 2001,31,2849-2854; Tetrahedron 1997, 53, 3347; Helv. Chim. Acta 1983, 66, 1915; Tetrahedron 1997, 53, 3347; Tetrahedron Lett. 2000, 41 , 9537; J.Org. Chem. 1990, 55,3853; J.Org. Chem., 2005, 70, 6884.

EP2666771 describes an efficient process for the synthesis of 10 and unprotected diol of 11, as key intermediates for Ticagrelor.

U.S. Patent Nos. 7,067,663, WO2009/064249 and WO2010/030224 disclose L- tartrate, dibenzoyl-L-tartrate and oxalate salts of substituted cyclopentanoloamine derivatives, and their use in coupling to pyrimidines with improved yields.

Scheme 5 (WO2012/085665)

Figure imgf000006_0001

Recently, Teva has disclosed several novel intermediates e.g. protection of diol with cyclic ketones 13, or separately individually protected diols 14 and their coupling with formylated amines to get solid intermediates 15 and several advanced level synthetic intermediates of 16 and 17, (Sheme-4) in WO2012/138981 and US 2012/032497, for efficient manufacture of Ticagrelor.

Similarly WO2012/085665 describes another set of novel intermediates e.g. N- benzylated 18 and its functionalized analogue 19, which subsequently led to advanced level N-Boc 20 and N-Benzyl 21 (Scheme-5) intermediates, which are claimed to be useful for the synthesis of Ticagrelor 1. Selective oxygen-selective alkylation of an advanced intermediate containing amino alcohol is reported in a recent patent WO 2014/154908. Similarly WO 2015/037016 describes coupling of amines of aminols to activated pyrimidines in aqueous medium in the presence of an inorganic base e.g. potassium phosphate.

Each of the process patents cited above, during last 3-5 years, describe some or other negative aspects of the disclosed processes e.g. liquid/oily advanced level intermediates or formation of 25-30% side products and consequent separation problems or low conversions or commercially unavailable reagents e.g. methyl-2- (trifluoromethyl sulfonyloxy) acetate or racemization and/or dehydration possibilities during acidic work-up etc. (Please go through section [0005] to [0006] in WO2012/138981 for these comments), or the drawbacks of existing processes of tedious and cumbersome procedures as lengthy and multiple synthetic steps, tedious work-up procedures, multiple crystallizations or isolation steps, column chromatographic purifications, use of hazardous and explosive materials etc. (once again please go through section [0007] in WO2012/085665 for additional negative aspects of existing processes, etc). The inventors of this application agree with several of these negative aspects of current existing synthetic processes (prior art). Additionally, just to mention few stringent experimental conditions in prior art e.g. maintaining oxygen concentration below 2% in reaction mixture (claim 1 (b) in US2012/0101274) or use of very special catalysts employing Platinum (2%) and Vanadium (1%) on carbon with 8 bar pressure (example 3 in US2012/0101274) or involving a unit operation of sealing a reactor containing ethanolic solutions and heating it to 120-125°C for 35hrs (example 4, step-1 in US 7,381 ,828 and example 14 in WO2012/138981 ), require special reactors and difficult unit operations, which are not suitable for commercial manufacturing and applications.

Therefore, there is a need in the prior art for innovative design of route of synthesis of Ticagrelor, which starts with readily available and inexpensive starting materials and provides operationally simple, solid and novel intermediates with high yield and purity.

SUMMARY OF THE INVENTION

The present invention provides novel and improved processes for preparing triazolo [4,5-d]pyrimidines, including Ticagrelor, via new intermediates and new route of synthesis. Designing a new route of synthesis starting from readily commercially available and inexpensive starting material e.g. 5-nitro-2,4,6- trichloropyrimidine, naturally leads to formation of series of novel intermediates, which are commercially viable and industrially advantageous for the preparation of highly pure Ticagrelor 1. In one embodiment, the number "of steps in the process are less and involve shorter reaction times.

In another embodiment, the process does not involve extremely low temperatures (cryogenics) or high pressure. In another aspect, the process avoids the use of hazardous and explosive chemicals as sodium hydride, diazomethane.

In yet another embodiment, the processes avoid the use of tedious and cumbersome procedures like column chromatography and multiple isolation and/or purifications. According to yet another embodiment, the reactions are clean (from one spot in TLC to another spot in TLC) and high yielding, which ultimately results in increased overall yields. In yet another embodiment, the process starts from readily available and inexpensive starting material. Additionally, the processes involve easy work-up methods and simple isolation procedures, which results in reduction of chemical waste.

In one of the most important aspect, the coupling of protected aminocyclopentane triol does not require to be in its salts form e.g. L-tartarate, dibenzoyl-L-tartarate and oxalate salts, as required in U.S. Patent Nos. 7,067,663, WO2009/064249 and WO2010/030224. The preferred aspects of the embodiments disclose novel broad generic and useful compounds e.g. 24, 25, 26, 27, 29 and 30, as described in scheme 6. The meaning of X and R1, R2 are discussed in "Detailed Description of Invention" section. More specifically, the most preferred aspect of the embodiment discloses 6 novel and useful compounds 32, 33, 34, 35, 29 and 36 (scheme 7). In another embodiments, the present invention describes a series of novel compounds e.g. 38, 39, 40, 41, 43 and 44 (in scheme 8), 45, 46, 47, 48, 49, 50, 51 (in scheme 9), 52, 53, 54, 55 (in scheme 10) and 58, 59, 60, 61, 62, 63, and 64 (in scheme 1 1). The invention also describes various processes, reagents, reaction conditions in steps 'a', 'b', 'c', 'd', 'e', 'f , 'g', 'h' and to prepare above novel compounds. According to certain specific embodiments, all these novel compounds are useful intermediates for the manufacturing of Ticagrelor. The reactions involve convenient experimental conditions, are easily scalable, high yielding and operationally simple, as most of the intermediates are solid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses improved processes for the preparation of Triazolo[4,5-d]-pyrimidines, including Ticagrelor 1, via novel intermediates and new route of synthesis. The term "acyl" means a radical of the general formula -C(0)-R, wherein -R is hydrogen or hydrocarbyl. When R is alkyl, the acyl group may be, for example, acetyl (-C(0)CH3), propionyl (-C(O)Et), benzoyl (-C(0)C6H5), formyl (-C(O)H) and the like.

The term "alkoxy/aryloxycarbonyl" means a radical of general formula -OC(O)- R, wherein R is a hydrocarbyl group, such as a C|.6 alkyl or C6.jo aryl or a C7.12 aryl alkyl group. For example, carbo ethoxy is (-C02Et), carbomethoxy is (- C02Me) and benzyloxycarbonyl is (-C02CH2Bn).

The term "alkyl", by itself or as a part of another substituent means, unless otherwise stated, a straight, branched or cyclic chai hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e., C( -6 means one to six carbons) and includes straight, branched chain or cyclic groups. Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, neopentyl, hexyl, cyclohexyl and cyclopropyl methyl etc. The term "cycloalkyl" refers to ring-containing "alkyl" radicals. Examples include cyclohexyl, cyclopentyl, cyclopropyl methyl and norbornyl.

The terms "halo" or "halogen" by themselves or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine or iodine atom, preferably chlorine, bromine and iodine. The term "hydrocarbyl" refers to any moiety comprising only hydrogen and carbon atoms. Preferred hydrocarbyl groups are (Ci-Ci2) hydrocarbyl, such as (C7) hydrocarbyl is benzyl.

The term "protecting groups" for O-H, 1 ,2-diols and N-H discussed in schemes and texts, are groups which can be added and removed using known reaction conditions and reagents, which are fully described in "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts, 4th Edition, John Wiley, 201 1. Several of the N-H protecting group are also good "leaving groups" e.g. formyl, acetyl, mesylates & tosylates etc.

The term 'deketalization', which is deprotection of ketal to diol, can also be found in above book.

The term 'leaving group' are mostly electron withdrawing groups e.g. chloro, bromo, iodo, fluoro, tosylates (p-toluyl sulfonyl), besylates (benzene sulfonyl), brosylates (p-bromobenzene sulfonyl) and nosylates (p-nitrobenzene sulfonyl), etc. and the like, which are attached to aliphatic/aromatic or heterocyclic nucleus.

The term 'antisolvent' is used to describe those solvents in which the compound is either least soluble or insoluble.

According to one aspect, there is provided a process for preparing a triazolo [4,5- djpyrimidine compound of formula 22.

Figure imgf000010_0001

22

Or pharmaceutically acceptable salts thereof, where in R1, R2, R3, R4, R5 are each independently selected from hydrogen and a "halogen" atom, where in halogen atom is F, CI, Br or I; R6 is C1-6 "alkyl" and "X" is O, N and S. In one embodiment, the group 'R6' is selected from methyl, ethyl, n-propyl, isopropyl, n- butyl and sec-butyl. More specifically R6 is n-propyl.

In another embodiment, 'X' in 22 can be any hetero atom as S, O, N. More specifically 'X' is S. More specifically R3, R4 are F and R6 is propyl, which is Ticagrelor l.

In one embodiment, the present invention provides following novel compounds, broadly depicted as generic structures, discussed in scheme 6. The meaning of X and R1, R2 is described in subsequent text.

Figure imgf000011_0001

The process comprises:

Step 'a' involves coupling a compound of formula 11 {Scheme 6)

Figure imgf000011_0002

11

With a compound of formula 23 {Scheme 6)

Figure imgf000012_0001

23

Where X is independently electron withdrawing group type leaving group such as chloro, bromo, iodo, mesylate, tosylate, besylate, brosylate, nosylate and the like and their permutation, combination there of. Where R ,R is both oxygen (such as N02 in 31 in scheme 7), where R is -H and R2 is electron withdrawing group type amine protecting groups such as formyl, acetyl, mesyl, tosyl, besyl, nosyl, etc. to produce a compound according to formula 24 (Scheme 6)

Figure imgf000012_0002

24 and converting the compound of formula 24 to a compound of formula 1_ (Ticagrelor).

Step 'b' comprises reducing the compound of formula 24 (-NR , R =NG2) or hydrolyzing (-NR* ,R2, RI =H, R2 as mentioned above) or deprotecting -NHR2 to produce a compound of formula 25.

Figure imgf000012_0003
Step 'c' is about diazotizing the compound of formula 25 to produce a triazolopyrimidine compound of formula 26

Figure imgf000013_0001

26

Step 'd' involves reacting the formula 26 compound with (lR,2S)-2-(3,4- difluorophenyl)cyclopropyl amine 7, to produce a compound of formula 27

Figure imgf000013_0002

27

Step 'e' discloses reacting the compound of formula 27: with propyl thio- nucleophiles/reagents (alkali or alkali earth metal salts of 1 -propanethiol) or thiourea and trapping the intermediate with propyl -X (X is chloro, bromo, iodo, mesylate, tosylate etc) to produce a compound of formula 28

Figure imgf000013_0003

28

Finally, step 'f involves hydrolyzing (deketalization) the compound of formula 28 to produce Ticagrelor. Alternatively, the -X in 27 can be substituted with -SH to produce 29, discussed in the step 'g' of detailed discussion section of scheme 7.

Selective deketalization of 27, in turn, can lead to preparation of 30, which can utilized to produce Ticagrelor 1, as discussed in step 'e' of scheme 7. In a certain specific embodiments, the present invention provides novel compounds of formula 32, 33, 34, 35, 29 and 36, discussed in scheme 7.

Most specifically the process comprises:

Step 'a', which is reacting 5-nitro-2,4,6-tri"halo"pyrimidine compound, specifically trichloro compound of formula 31.

Figure imgf000014_0001

31

With (3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyl- tetrahydro-3aH- cyclopenta[d]-[l ,3]dioxol-4-amine

Figure imgf000014_0002

11

Scheme-6

Figure imgf000015_0001

Alternatively

Figure imgf000015_0002
Scheme- 7

Figure imgf000016_0001

Alternativel

Figure imgf000016_0002

In the presence of a 'first base' in a 'first solvent' to produce a 5-nitro mono- aminated pyrimidine of formula 32 or its acid addition salt there of.

Figure imgf000017_0001

Step 'b' comprises reduction of 5-nitro-mono-aminated pyrimidine 32 to 5-amino- mono-aminated pyrimidine of formula 33 with a "reducing agent" in a 'second solvent' .

Figure imgf000017_0002

Step V involves diazotization of 5-amino-mono-aminated pyrimidine 33 to dichloro triazolo [4,5-d] pyrimidine 34, with a "suitable diazotization reagent" and "acids" in a 'third solvent' to give compound of formula 34

Figure imgf000017_0003
Step 'd' involves regioselective coupling of dichloro triazolo [4,5-d] pyrimidine 34 with highly pure (lR,2S)-2-(3,4-difluorophenyl)cyclopropyl amine 7 or its salts, in the presence of a 'second base' and 'fourth solvent' to give the advanced level mono-chloro triazolo[4,5-d] pyrimidine intermediate of formula 35

Figure imgf000018_0001

35

Step 'e' describes strategic substitution of 'propylthio' to mono-chloro of 35 with ' suitable reagent' in 'fifth solvent' to give the penultimate intermediate ketal protected Ticagrelor of formula 28

Figure imgf000018_0002

Step 'f ' involves deketalization of protected Ticagrelor 28 in the presence of water and suitable acid in 'sixth solvent' to ive Ticagrelor 1

Figure imgf000018_0003

Step 'g' describes additionally the formation of a novel and useful 5- thioltriazolo[4,5-d]pyrimidine intermediate 29 from mono-chloro 35, with 'suitable reagents' and in the presence of 'seventh solvent'

Figure imgf000019_0001

Alternatively 35 is selectively deketalized, under mild conditions to give 36.

The steps a, b, c, d, e and f described in above synthetic sequence are summarized in Scheme-7. The reagents, solvents and reaction conditions mentioned in scheme-7 are only representative in nature. The detailed discussion about these steps is provided in next section.

In one embodiment, the compounds of formula 32, 33, 34, 35, 29 and 36 are novel and constitute an important aspect of disclosure. All these novel compounds are useful for manufacture of Ticagrelor L Although for a person skilled in the art and in the light of disclosures already made in preceding sections for various steps of step 'a', 'b', V, 'd', 'e', 'f and 'g' for schemes 6 and 7, the details of chemical steps involved in schemes 8,9,10 and 11 should be clear, but still a brief description about steps 'a', 'b\ 'c', 'd', 'e\ 'f , 'g', 'h' and 'i' is necessary, for clarity and for complete disclosure of specification. Thus step 'a' in schemes 8, 9, 10 and 1 1 , involves coupling of trichloronitropyrimidine 31 to aminols (37 in scheme 8, 10 in scheme 9, 10 in scheme 10 and 57 in scheme 1 1), in the presence of 'first base' and 'first solvent' to give coupled product e.g. 38 (scheme 8), 45 (scheme 9), 45 (scheme 10) and 58 (scheme 1 1) respectively. Step 'b' comprises reduction of 5-nitro-mono-aminated dichloro pyrimidine 38 (scheme 8), 45 (scheme 9 and 10), and 58 (scheme 1 1) with a "reducing agent" in a "second solvent" to corresponding amines eg 39, 48 and 60 respectively. Same step 'b' can also be utilized for the reduction of nitro in alternatively obtained 46 (scheme 9), 52 (scheme 10) and 59 (scheme 1 1 ) to provide corresponding amines e.g. 47, 53 and 62 respectively.

Step 'c' involves diazotization of 5-amino-mono-aminated dichloro pyrimidine e.g. 39 (scheme 8), 48 (scheme 9 and 10) and 60 (scheme 1 1) to dichlorotriazolo [4,5-c/]pyrimidines 40, 50 and 61 respectively. Similarly, step 'c' can as well be used for diazotization of 47 (scheme 9) 53 (scheme 10) and 62 (scheme 1 1 ) to triazolo [4,5-fiT)pyrimidines 49, 54 and 63 respectively.

Step 'd' comprises regioselective coupling of dichlorotriazolo[4,5-d]pyrimidines 40 (scheme 8) or 50 (scheme 9) or 54 (scheme 10) or 61 (scheme 1 1 ) with a highly pure (1R, 2S)-2-(3,4-difluorophenyl)cyclopropyl amine 7 or its salts, in the presence of a "second base" and "forth solvent" to give the advanced level mono- chloro triazolo[4,5-d]pyrimidines 41, 49, 51 and 63 respectively. Alternatively, the reagents, solvents and reaction conditions of above mentioned step 'd' can as well be utilized for conversion of 45 to 46 (scheme 9) and 58 to 59 (scheme 1 1 ). Step 'e' involves the strategic step of introduction of 'propylthio' group to the mono-chlorotriazolo pyrimidines 41 (schemes 8 and 1 1), 35 (schemes 7 and 9) and 51 (scheme 10) with a "suitable reagent" in "fifth solvent" to another advanced level intermediate 42 (scheme 8), 28 (scheme 9, 7), 55 (scheme 10) and 42 (scheme 1 1). Similarly, these conditions can be utilized for conversion of 44 to 1 (scheme 8).

Step 'f describes deketalization (deprotection) of diols 42 (scheme 8), 28 (schemes 9 and 10) and 42 (scheme 1 1) in the presence of water and suitable acid in "sixth solvent" to give Ticagrelor 1. Alternatively, same/similar deprotection reaction conditions of step 'f can be utilized for conversion of 41 to 44 (scheme 8).

Another alternative route involves step 'g' where the mono-chloropyrimidines 41 (scheme 8) if first converted to mono-thiols 43, with suitable reagent in 'seventh solvent' and subsequently the thiol is propylated with activated propyls e.g. propyl chloride or propyl bromide or propyl mesylate or propyl tosylate, followed by deketalization (similar to step 'f ) to give Ticagrelor 1 (scheme 8).

Step 'h' involves the attachment of -CH2-CO-OR.' (R1 = methyl, ethyl etc) to free -OH in 49 (scheme 9) or 50 (scheme 10) or 63 (scheme 1 1), in the presence of 'third base' and 'eighth solvent' to give 51, 54 or 64 respectively.

Selective reduction of ester in 51 to 35 (schemes 7 and 9), 55 to 28 (schemes 9 and 10) and 64 to 41 (scheme 1 1) constitutes the details of step 'i'.

In a certain specific embodiments, schemes 8,9, 10 and 1 1 describe several novel compounds e.g. 38, 39, 40, 41, 43, 44 (in scheme 8), 45, 46, 47, 48, 49, 50, 51 (scheme 9), 52, 53, 54, 55 (in scheme 10) and 58, 59, 60, 61, 62, 63 and 64 (in scheme 1 1). All these novel compounds are useful intermediates for manufacture of Ticagrelor 1.

Scheme-8

Figure imgf000021_0001

Figure imgf000021_0002
Alternatively

Figure imgf000022_0001

Scheme-9

(Route of Synthesis for Novel Compounds)

Figure imgf000023_0001
Scheme- 10

(Route of Synthesis for other Novel Compounds)

Figure imgf000024_0001

Figure imgf000025_0001

-24- Detailed Descriptions about Steps, Solvents, Reaction conditions and Reagents:

The following descriptions and details provided for steps 'a', 'b', 'c', 'd', 'e', 'f and 'g' and solvents ('first solvent', 'second solvent', 'third solvent', 'fourth solvent', 'fifth solvent' and 'sixth solvent' etc.) and reagents/reaction conditions are true for reactions described in scheme 6 and 7 also.

Step V:

As disclosed in Schemes-8,9,10 and 1 1 , step 'a' describes coupling of cyclopentane aminols 37 or 10 or 56 or 57 to 31 in 'first solvent'. Exemplary 'first solvent' used in step 'a' include, but are not limited to are C|-C6 alcohols such as methanol, ethanol, propanol, isopropyl alcohol, isobutanol, t-butanol or glycol based solvents as ethylene glycol and propylene glycol, PEG (polyethylene glycol). One can also use ethers such as t-butyl methyl ether, THF (tetrahydrofuran), methyl-THF, DME. Polar and aprotic solvents such as DMF, NMP (N-methyl pyrrohdinone) and acetonitrile. If necessary, mixture of above solvents with/without varying amounts of water can also be used for efficient coupling in step 'a'. The choice of suitable solvent is dependent on the solubility of substrates and their stability.

The coupling reaction in step 'a' is carried out in the presence of 'first base', which can be both organic and inorganic bases. Suitable organic bases are triethyl amine, diisopropyl ethyl amine or pyridine, where as inorganic bases can be sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium carbonate, potassium carbonate and the like.

The molar ratio of pyrimidine 31 to aminols can be 1 to 1 or 1 to 1.2 - Step 'b':

The 'suitable reducing agents' in step 'b' include, but are not limited to, are noble metal catalysts such as palladium or platinum or their complexes/compounds, raney-nickel, ferrous sulfate heptahydrate in aqueous ammonia and the like, and the metals such as iron, zinc, cobalt, nickel and mixture thereof. The reduction may be carried out in the presence or absence of hydrogen gas.

In one embodiment, the reduction is carried out by using other reducing agents such as ferric chloride-hydrazine hydrate, sodium dithionate, tin chloride hydrate, tin chloride hydrate-hydrochloric acid, tin-hydrochloric acid, zinc-ammonium formate, zinc-formic acid, zinc-acetic acid, zinc-hydrochloric acid, zinc- hydrazinium monoformate, magnesium-ammonium formate, zinc-dust- ammonium chloride and mixture there of. A more specific reducing agent is Fe/Ac0H-H2O (iron and acetic acid). In another embodiment, the reduction in step 'b' is carried out by a catalytic hydrogen transfer process. Specifically, the c'atalytic transfer hydrogenation employs various reagents e.g. 1 ,4-cyclohexadiene, cyclohexene, ammonium formate, formic acid, sodium formate, hydrazine, 1 ,3-cyclohexadiene, trialkyl ammonium formate and mixture there of. Catalytic transfer hydrogenation reagents are well known and a selection can be made from these reagents.

In one embodiment, the reduction is carried out at a temperature of about 5° to 80°C, for at least 30 min., specifically at a temperature of about 10°C to about 50°C for about 1 hour to about 10 hours, and most specifically at about 20°C to about 40°C for about 2 hours to about 3 hours. If necessary, slower addition of the metal catalysts or the reagents is employed to minimize the impurity formation.

The reaction mass containing 5-amino-mono-aminated pyrimidine 25 (scheme 6), 33 (scheme 7), 39 (scheme 8) or 48 (schemes 9 and 10) or 60 (scheme 1 1) is isolated by usual work-up and can be purified :by formation of acid-salts. Alternatively it can be used directly in the next "step to produce the triazolo compounds.

The solvent used to isolate the 5-amino-mono-aminated pyrimidines mentioned above are selected from the group consisting of water, aliphatic ethers, a hydrocarbon solvent, aliphatic alcohols and mixtures there of. Specifically, the solvent is selected from the group consisting of water, diisopropyl ether, n- heptane, n-pantane, n-hexane, dichloromethane, ethyl acetate. A most specific solvent is dichloromethane or ethyl acetate.

Step V:

Exemplary 'suitable diazotization reagents' used in step 'c' include, but are not limited to, are metal nitrite and an alkyl nitrite and mixture thereof.

In one embodiment, the nitrite reagent is selected from the group consisting of sodium nitrite, potassium nitrite, lithium nitrite, butyl nitrite, isoamyl nitrite and mixture thereof.

Exemplary acids used in step 'c' include, but are not limited to, mineral acids and organic acids, In one embodiment, the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, butanoic acid, pivalic acid, pentanoic acid, hexanoic acid, methane sulfonic acid, p-toluene sulfonic acid and mixture thereof.

In another embodiment, the reaction in step 'c' is carried out at temperature of about -15°C to about 50°C, for at least 30 minutes, specifically at a temperature of about - 10°C to about 30°C for about 1 hour to about 10 hours and most specifically at about 0°C to about 25°C for about 2 hours to 4 hours.

If necessary, slower addition of the; acid is employed to minimize the impurity formation. Specifically, the acid addition time can vary anywhere between 1 hour 30 minutes to about 16 hours and more specifically about 2 hours to about 5 hours. Work-up involves quenching of excess nitrite with sodium bi-sulfite (NaHS03/Water).

The reaction mass containing dichloro-triazolo[4,5-d] pyrimidine 26 (scheme 6), 34 (scheme 7), 40 (scheme 8) or 50 (schemes 9 and 10)or 61 (scheme 1 1 ) in step 'c' may be subjected to usual work-up and purification protocol, followed by isolating and/or recovering from a suitable solvents, e.g. water, an alcohol, a ketone, an ester, an aliphatic ether, a hydrocarbon solvent, a chlorinated hydrocarbon and mixture there of. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, acetone, isopropanol, ethyl acetate, n-butyl-acetate, dichloromethane, diisopropyl ether, methyl tert-butyl ether, toluene, heptane, n-hexane, cyclohexane and mixture there of.

The reaction mass obtained from step 'c' may be used directly in the next step 'd' to couple with chiral cyclopropyl amine 7 or dichloro-triazolo[4,5-d]pyrimidines, mentioned above, may be isolated, purified and then used in the next step.

Step 'd': .

The regioselective coupling of dichlorotriazolo[4,5-d]pyrimidines, disclosed above, with highly pure (lR,2S)-2-(3,4-difluorophenyl)cyclopropyl amine 7 or its salts in step 'd' gives mono-chloro triazolo[4,5-d]pyrimidines 27 (scheme 6), 35 (scheme 7), 41 (scheme 8)or 49 (scheme 9)or 51 (scheme 10)or 63 (scheme 1 1). Recently filed Indian patent application 3779/MUM/2013 (3rd Dec.2013) discloses the synthesis of highly pure 7, without its urea analogue, as impurity. The urea analogue of 7 is claimed as a product patent and suitable methods of analysis are disclosed for monitoring and control of quality of 7. The 'second base' used in step 'd' can be both organic and inorganic bases. Suitable organic bases are triethyl amine, diisopropyl ethyl amine or pyridine, where as inorganic bases can be sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium phosphate, potassium carbonate and the like.

Exemplary 'fourth solvent' used in step 'd' include but are not limited to, are Ci- C6 alcohols such as methanol, ethanol, propanol, isopropyl alchohol, isobutanol, t- butanol or glycol based solvents as ethylene glycol and propylene glycol PEG (polyethylene glycol). One can also use ethers such as t-butyl methyl ether, THF (tetrahydrofuran), methyl-THF, DME. Polar and aprotic solvents such as DMF, NMP (N-methyl pyrrolidinone) and acetonitrile. If necessary, mixture of above solvents with/without varying amounts of water can also be used for efficient coupling in step 'd'. The use of antisolvents e.g. Toluene, Xylenes, Hexane, Petroleum ether, cyclohexane, cycloheptane and other C6 to Ci0 hydrocarbyl is useful to get solid. The choice of suitable solvent is dependant on the solubility of substrates and their stability. Step V:

The strategic step 'e' in this invention involves the introduction (substitution) of 'propylthio' to mono-chloro compound of formula 27 (scheme 6), 35 (scheme 7), 41 in schemes 8 and 1 1 , 35 in scheme 9, 51 in scheme 10 with 'suitable reagents' in 'fifth solvent'. The 'suitable reagents' in step 'e' include, but are not limited to, are alkali and alkali earth metal salts of 1 -propanethiol such as CH3CH2CH2SNa, CH3CH2CH2S-K, CH3CH2CH2S-Li, (CH3CH2CH2S)2Ca, CH3CH2CH2S-Ca, (CH3CH2CH2S)Mg and the like. Alternatively, such salts can be prepared in-situ as well, as per prior arts. The 'suitable reagents' in step 'e' can as well constitute neat heating with 1-propanethiol in the presence of suitable inorganic bases such as sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodamide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like. Alternatively, organic bases such as triethyl amine, diisopropylethylamine, pyridine and the like can also be used.

Another 'suitable reagent' in step 'e' involves use of thiourea, heating in a polar and/or alcoholic solvents and trapping the 'in-situ' intermediate with either propyl chloride, or propyl bromide, or propyl mesylate or propyl tosylate or any other good leaving group attached to propyl. The 'fifth solvent' in step 'e' should be such that the substrate is soluble and is stable. Exemplary 'fifth solvents' include, but not limited to, are methanol, ethanol, THF, 2-methyl THF, N-methyl pyrrolidinone, DME, 1 ,4-Dioxane, methyl tert-butyl ether and diisopropyl ether, DMF, DMSO and the like. The work-up and. use of toluene and/or other anti-solvents mentioned, similar to step 'd', leads to isolation of solid intermediates.

Step T:

The last step 'f in the synthesis of Ticagrelor 1 involves deketalization of protected Ticagrelor 28 (schemes 6, 7, 9 and 10), 42 (schemes 8 and 1 1) in the presence of water and suitable acid in 'sixth solvent'. The 'suitable acids' include, but not limited to, are both organic and mineral acids. In one embodiment, the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, butanoic acid, pivalic acid, pentanoic acid, hexanoic acid, methane sulfonic acid, p-toluene sulfonic acid and mixture thereof.

The 'sixth solvent' in step 'f include, but not limited to, are methanol, ethanol, propanol, butanol, THF, 1,4-Dioxane, DMF, 2-methyl-THF, toluene and aqueous mineral acids as biphasic systems, with varying percentage of water. Purification : of Ticagrelor 1 was achieved, optionally either by recrystallization in a suitable solvent or by purification by dissolving in a suitable solvent and addition of antisolvent.

Step 'g':

Additionally, this invention discloses a novel and useful compound such as 5-thiol triazolo[4,5-d]pyrimidine 29 from mono-chloro 27 (scheme 6), 35 (schemes 7). The "suitable reagents" in step 'g' include, but not limited to, are H2S bubbling in a solution of 35, H2S bubbling in a solution of 35 containing water and as inorganic base as sodium hydroxide, potassium hydroxide and the like, reacting a solution of 35 with KSH, NaSH.xH20 or Na2S in H20 or potassium ethyl thioxanthate in ethanol and subsequent hydrolysis. Thiourea can also be used as a source of sulfur and subsequent acidic work-up as discussed in step 'g', can lead to the desired thiol compound of 29.

Step 'h':

The attachment of -CH2-COOR1 to free alcohols 49 to 51 in scheme 9, 50 to 54 in scheme 10, 63 to 64 in scheme 1 1 is carried out in step 'h', with a suitable reagent in the presence of 'third base' and 'eighth' solvent. The suitable reagent is L-CH2-COOR', where R1 is Ci to C4 alkyl (preferably ethyl) and L- is a leaving group, especially halogens (preferably bromide). The 'third base' can be potassium tert-butoxide, sodium hydroxide or a Ci-C alkyl lithium species. The 'eighth solvent' used in step 'h' can be a polar solvent such as tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane and the like. The reaction can be carried out even at lower temperatures, depending on the reactivity, stability and selectivity of functional groups.

Step : The chemoselective reduction of ester -CH2-CO-OR' in step 'i' is accomplished using a suitable reducing agent. Suitable reducing agents are those which can selectively reduce ester functionality, for example, hydride based reducing agents such as sodium borohydride, BF3:Et20, lithium borohydride, Lithium triethyl borohydride, L-selectride, sodium borohydride in the presence of Lewis acids e.g. A1C13, BF3:Et20, Cone. H2SO4 etc., diborane and its complexes. The 'ninth solvent' used in such reductions are preferable aprotic solvents e.g. Tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, DME, methyl tert-butyl ether, diisopropyl ether and the like.

For a person skilled in the art, it is possible to alter sequence of steps and get same intermediates as shown in scheme 10. Thus, one can get suitably functionalized protected aminol 56 from protected cyclopentane aminol 10, employing obvious functional group transformations of protecting amine of 10 either with tert- Butoxycarbonyl (BOC) or Benzyloxy carbamate (Cbz), followed by attaching - CH2-CO-OR1 to -OH (Where R1 is alkyl, preferably ethyl) under basic conditions (similar to chemistry discussed in step 'h') and finally deprotecting BOC/Cbz with standard procedures, to get 56. However, as the nature of chemical transformations of step 'a' (coupling of amine to trichloro nitropyrimidine 31), step 'b' (reduction of nitro to amine), step 'c' (diazotization of triazole formation), step 'd' (coupling of cyclopropylamine 7), step 'h' (attachment of CH2-COOR1 to free -OH), step 'i' (reduction of ester), step 'e' (attachment of propylthio CH3CH2CH2S" group) and finally step 'f (deprotection of ketal), by and large, remain same even in Scheme- 10, as discussed in previous Schemes 6,7,8 and 9, such minor modification of altering synthetic steps can be regarded as obvious, for a person skilled in the art. Several such minor modifications and/or alternations with differing permutation and combinations are possible for the synthesis of same intermediates disclosed in Scheme-6,7,8, 9, 10 and 1 1. Similarly one can change protecting groups of 1 ,2-diol from acetone based in 10 (Scheme- 10) to cyclopentanone (n=l) based 57 or, cyclohexanone based (n=2) 57. (scheme 1 1) and get a series of novel intermediates of 58, 59, 60, 61, 62, 63, and 64 with n=l or n=2 by simple manipulations of 1 ,2-diol protecting group; (Scheme- 1 1). Similarly change of R in 51, 52, 53, 54, 55 and 64 by various alkyls, discussed in preceding text, can provide various other novel compounds. All such minor alternations, modifications with their various permutation and combination thereof, are included in the scope of this invention.

Following examples present the key aspects of invention. These examples are non-optimized processes and are only illustrative in nature and do not limit the scope and spirit of invention. It will be apparent for those skilled in the art that many obvious modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES:

Example-1: Synthesis of 2-(((3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin- 4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4- yl)oxy)ethanol 32

Figure imgf000033_0001

To a cooled and stirring solution of 4.5gm of 2,4,6-trichloro-5-nitropyrimidine 31 in 40ml of THF and sodium carbonate, another solution of 4.3gm of 2- (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]dioxol-4-yl)oxyl)ethanol 11 in 25ml THF was added slowly, drop wise. The reaction mixture was slowly brought to room temperature and stirred for 3-4 hrs. The progress of reaction was monitored by TLC. The work-up involved removal of THF under reduced pressure, water addition to the residue and extracting in ethyl acetate. Concentration of ethyl acetate layer and usual purification gave 4.8gm of oily liquid 32 (59%), which gave a satisfactory mass of 408 in MS. Some of the selective and characteristic peak in Ή NMR were 8.5δ (1H, d for N-H), 4.75 (1H, m), 4.6 (d, 1H), 4.47 (d, 1Ή), 4.07 (m, 1 H), 3.75 - 3.9 (m, 4H), 2.28 (m, 1H), 1.85 (m, 1H), 1.4 (s, 3H), 1.2 (s, 3H).

Example-2: Synthesis of 2-(((3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin- 4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4- .

yl)oxy)ethanol 32

Figure imgf000034_0001

Dissolve 0.02 mole (4.53 gm) 2,4,6-Trichloro-5-Nitropyrimidine 31 in 40 ml THF cool it to 10°C under stirring. Dissolve 0.02 mole 2-(((3aR,4S,6R,6aS)-6-amino- 2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol Π (4.34 gm) in 25 ml THF. Charge the solution of Π drop wise in reaction mass. Stir for 3-4 hours. Check TLC and upon completion of reaction, remove THF under vacuum, add water and extract with ethyl acetate. Concentrate ethyl acetate under vacuum to obtain oily liquid. The product was identical to the product obtained in example- 1.

Example-3: Synthesis of 2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6- dichloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol 33

Figure imgf000035_0001

Iron powder (1.7g) was added to a solution of 2-(((3aR,4S,6R,6aS)-6-((2,6- dichloro-5-nitropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [l ,3]dioxol-4-yl)oxy)ethanol 32 (0.01 mole) in methanol (25ml) and acetic acid (15.27 mL). The reaction mixture was then stirred at 25-35° C for 2 hrs. The reaction was monitored by TLC. After the reaction was complete, the product was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give product 1.5 gm (95% yield) of 33. Satisfactory MS and Ή NMR were obtained. Some of the selective and characteristic peaks in Ή NMR were 6.4δ (d, l H,NH), 5.5 to 6.5δ (brs, 4H), 4.8δ (d, 2H), 4.5δ (d, 1H), 4.2δ (m, 2H), 1.4 (s,3H), 1.2 (s,3H).

Example-4: Synthesis of 2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloro pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4- yl)oxy)ethanol 33

Figure imgf000035_0002

To a solution of 2-(((3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin-4- yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)oxy)ethanol 32 (0.01 mole) in methanol (25 ml ) and acetic acid (15 ml) at less then 30°C, iron powder (1.7 g) was added and the reaction mixture was stirred at this temperature for 3-5 hrs. Additional warming and longer time was required for completion of reaction. The progress of reaction was monitored by TLC. The reaction mixture was worked up by adding water (5 mole) and by filtering the suspended particles. The filtrate was concentrated under reduced pressure at 40-50°C to produce a residue. The residue was extracted with ethyl acetate, organic layer was washed with aqueous sodium bicarbonate and concentrated under reduced pressure to give 1.6 g of 33, which was identical to the product obtained in Example-3.

Example-5: Synthesis of 2-(((3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[l ,2,3] triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol 34

Figure imgf000036_0001

2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)amino)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)oxy)ethanol 33 (0.75gm, 0.002 mole) in acetic acid (5 mL) was added sodium nitrite (0.002 mole) while maintaining the reaction temperature at 0-10°C. The reaction mixture was stirred for 30 minutes. It was then diluted with ethyl acetate (50 mL), washed with water (2 x 35 mL) and evaporated under reduced pressure. The crude product was triturated in hexane (20 mL) and filtered to give 0.68gm (90% yield) of 34. Satisfactory Ή NMR were obtained. Some of the selective and characteristic peaks were 5.5δ (d, lH), 5.2δ (dt,lH), 4,85δ (d, l H), 4.75 (1 H), 4.05 (m,4H), 2.5- 2.65 (m, l H), 1.95 (m,l H), 1.55 (s,3H), 1.45 (s,3H). Example-6: Synthesis of 2-(((3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[l,2,3] triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol 34

Figure imgf000037_0001

To a solution of 2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4- yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol 33 (0.002 mole) in acetonitrile( 5-10 vol.) was added isoamylnitrite (0.0022 mol) while maintaining the reaction temp, at 5-15°C. the reaction mixture was stirred at 40-60°C for 3-5 hrs. The progress of reaction was monitored by TLC. After completion, the reaction was quenched with NaHS03 solution in water and concentrated under reduced pressure to 80% of its total volume. The product was isolated from ethyl acetate extract and trituration with hexane to give a solid 34 (92% yield). The product was identical to the product obtained in example 5.

Example-7: Synthesis of 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-((( 1 R,2S)-2-(3 ,4- difluorophenyl)cyclopropyl)amino)-3H-[ l ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol 35

Figure imgf000037_0002
To a stirring solution of 2-(((3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[l ,2,3]triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4- yl)oxy)ethanol 34 (0.01 mol) in tetrahydrofuran (40 mL) at 20 °C was added a mixture of (lR,2S)-2-(3,4-difluorophenyl)cyclopropanamine 7 (0.01 mol) and triethylamine (1.4 mL, 0.012 mol). After 2 h, the mixture was diluted with Diethyl ether (60 mL) and washed with 1 % aqueous acetic acid (200 mL), water (75 mL) and evaporated under reduced pressure. The residue was triturated with n-hexane (40 mL) and toluene to get a solid and filtered to give 4.4 gm (85% yield) of 35. Some of the selective and characteristic peaks (δ value) in Ή-NMR (CDC13) for 35 are 7.23 (s,; lH), 6.93 - 7.2Ό (m, 3H), 5.45 (m, 1H), 5.14 (m, 1H), 4.83 (m, 1H), 3.95 (m, 1H), 3.41 - 3.56 (5H), 3.0 (1 H), 1.25 (s, 3H), 1.45 (s, 3H). Mol. Ion peak in MS at 522. \

Example-8: Synthesis of 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((lR,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol 35

Figure imgf000038_0001
To a solution of compound 34 (3.9 gm) in acetonitrile (5-10ml) was added diisopropyl ethylamine (2.83 gm). A solution of compound 7 HCl salt (2 gm) in acetonitrile (3-5 Vol.) was added slowly. The reaction mixture was stirred at 25°C-35°C for 3-5 hours. The progress of reaction was monitored by TLC and after complete disappearance of 34, the reaction was quenched by addition of water. The reaction mixture was extracted with ethyl acetate 3 times. The combined organic extract was washed with brine and concentrated to dryness. The crude product was purified by crystallization from ethyl acetate and toluene or hexane to give 35 (4.43gm, 85%). This product was identical to the product of example-7 in every respect. Example-9: Synthesis of protected ketal of Ticagrelor 28.

Figure imgf000038_0002
To a solution of 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((l R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxoI-4-yl)oxy)ethanol (solid) 35 (5.2gm, O.Olmol) in 70ml methanol, sodium salt of propanethiol (CH3CH2CH2SNa, O.O lmol) was added and the reaction mixture was stirred for 6 hr at room temperature, under nitrogen atmosphere. The progress of reaction was monitored by TLC. On completion of reaction, the solvent was removed under vacuum and the residue was treated with ethyl acetate and water. The layer were separated, organic layer was separated and washed with brine. Drying of organic layer over anhydrous sodium sulfate, filtering and removal of ethyl acetate gave a residue, which on treatment with a suitable solvent and addition of anti solvent (discussed in detail in the text) gave 1.68gm (30% yield) of protected ketal of Ticagrelor 28. Some of the characteristic and selective peaks (δ value) in Ή-NMR

(CDC13) for 28 are 7.5 (s, lH), 6.8 - 7.3 (m, 3H), 5.42 (m, 1H), 5.1 (m, 1H), 4.8 (m, 1H), 4.1 (m, 1H), 3.4 - 3.7 (m, 4H), 3.1 (t, 2H), 1.45 (s, 3H), 1.26 (s, 3H), 1.15 (t, 3H), 0.87 (m, 1H).

Examplc-10: Synthesis of protected ketal of Ticagrelor 28.

Figure imgf000039_0001

Charge 0.01 mole (5.62 gm) of 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((lR,2S)-2- (3,4-difluorophenyl)cyclopropyl)amino)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3- yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol 35 in mixture of 26 ml DMF and 0.02 mole (2.76 gm) potassium carbonate at room temperature. Charge 0.012 mole (0.91 gm) 1 -propanethiol drop wise at room temperature. Heat the reaction mass at 55-60°C for 2-3 hours. Upon completion of reaction, pour reaction mass in water and extract with Ethyl acetate. Wash organic layer with aq. sodium bisulfite. Concentrate organic layer to yield final product 28. This product was identical to the product obtained in example 9.

Example-ll: Synthesis of Ticagrelor 1.

Figure imgf000040_0001
Charge (2.6 gm) of compound 28 in (8-10 Vol.) of Methanol at Room temperature. Charge dilute HC1 (1.4 gm) at RT. Stir the reaction mass for 24 hours at RT. Upon completion of the reaction checked by TLC, the reaction mass was brought to slightly acidic pH of 6-6.5 by using dilute aq. NaOH. Upon removal of methanol under vacuum and extracting organic mass with ethyl acetate and further washing this organic layer with brine and concentration of ethyl acetate under vacuum gave crude Ticagrelor 1. Further purification of Ticagrelor 1. was carried out by crystallization from a mixture of ethyl acetate and heptane to provide white to off-white solid. The purity of Ticagrelor 1 was 99.6% (HPLC). Some of the characteristic and selective peaks (δ value) in Ή-NMR (CDG13) for 1 are 7.5 (s, 1H), 6.83 - 7.2 (m, 3H), 5.67 (m, 1 H), 5.04 (m, 1H), 4.82 (m, 1H), 4.13 (m, 1H), 3.6 - 3.9 (m, 4H), 3.2 (t, 2H), 1.57 (m, 2H), 0.79 (t, 3H).

Example-12: Synthesis of Ticagrelor 1 from 28.

To a cooled solution of protected Ticagrelor 28 (4gm), prepared in example 9/10, in 20ml of toluene, a solution of 6.5ml concentrated HC1 in 12ml methanol was added slowly, with constant stirring. The reaction mixture was stirred at 5-10°C for 2 hrs. The progress of deketalization was monitored by TLC. After completion of reaction, a solution of 7gm of sodium bicarbonate in water was added slowly, to get pH of around 7.5 to 8. The reaction mixture was extracted with :20ml of ethyl acetate and allowed for layer separation. The aqueous layer was re-extracted with ethyl acetate. All the ethyl acetate layers were combined and dried over anhydrous sodium sulfate, filtered, treated with small amount of charcoal, again filtered through hyflo. The filtrate was concentrated and purified, similar to example 1 1 to give 3gm of Ticagrelor 1 as off-white to yellow colored solid. This sample was identical to the product of example- 1 1. Example-13: Synthesis of (3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin-4- yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol. 45

Dissolve 0.G2 mole (4.53 gm) 2,4,6-Trichloro-5-Nitropyrimidine 31 in 40 ml THF keep at 10°C under stirring. Dissolve 0.02 mole (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol 10 (3.46 gm) in 25 ml THF. Charge (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d][l ,3]dioxol-4-ol solution dropwise in reaction mass. Stir for 3-4 hours. Check TLC and upon completion of reaction remove THF under vacuum, add water and extract with ethyl acetate. Concentrate ethyl acetate under vacuum to obtain oily liquid, 45, which can be taken directly to next step. Example-14: Synthesis of (3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin- 4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol. 48

Iron powder (1.7g) was added to a solution of 0.01 mole (3.64 gm) (3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin-4-yl)amino)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol 45 in methanol (25ml) and acetic acid (15.27 niL). The reaction mixture was then stirred at 25-35° C for 2 hrs. The reaction was monitored by TLC. After the reaction was. complete, the product was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give Product 48, which was used directly in the:next step.

Example-15: Synthesis of (3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[i 2,3]triazolo[4, 5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol.50

(3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)amino)-2,2-dimethyl tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol 48 (0.002 mole) in acetic acid (5 mL) was added sodium nitrite (0.002 mole) while maintaining the reaction temperature at 20-30 °C. The reaction mixture was stirred for 30 minutes. It was then diluted with ethyl acetate (50 mL), washed with water (2 x 35 mL) and evaporated under reduced pressure. The crude product was triturated in hexane (20 mL) and filtered to give Product, 50.

Example-16: Synthesis of (3aR,4S,6R,6aS)-6-(5-chloro-7-(((l R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol. 49

To a stirring solution of (3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[l ,2,3]triazolo[4,5- d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol 50 (0.01 mol) in tetrahydrofuran (40 mL) at 20 °C was added a mixture of (lR,2S)-2- (3,4-difluorophenyl)cyclopropanamine 7 (0.01 mol) and triethylamine (1.4 mL, 0.012 mol). After 2 h, the mixture was diluted with Diethyl ether (60 mL) and washed with 1 % aqueous acetic acid (200 mL), water (75 mL) and evaporated under reduced pressure. The residue was triturated under n-hexane (40 mL) and filtered to give the desired product 49, some of the selective and characteristic peak in Ή NMR were 8.6δ (s, 1 H), 7.0-7.2 δ (m, 3H), 5.4 (s, 1H), 5.3 (d, 1H), 4.79-4.83 (m, 2H), 4.4 (d, 1 H), 3.0 (m, 1 H), 2.82-2.89 (m, 1H), 1.4 (s, 3H), 1.2 (s, 3H).

Example-17: Synthesis of (3aR,4S,6R,6aS)-6-((2-chloro-6-(((l R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-5-nitropyrimidin-4-yl)amino)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol. 46

To a stirring solution of (3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin-4- yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol 45 (0.01 mol) from example 1 , in tetrahydrofuran (40 mL) at 20 °C was added a mixture of (lR,2S)-2-(3,4-difluorophenyl)cyclopropanamine 7: (0.01 mol) and triethylamine (1.4 mL, 0.012 mol). After 2 h, the mixture was diluted with Diethyl ether (60 mL) and washed with 1 % aqueous acetic acid (200 mL), water (75 mL) and evaporated under reduced pressure. The residue was triturated under n-hexane (40 mL) and product 46 was filtered, some of the selective and characteristic peak in Ή NMR were 10.08 (d, 1H), 9.28 δ (d, 1H), 7.0-7.2 (m, 3H), 4.84 (m, 1H), 4.52 (m, 2H), 4.33 (m, 1H), 2.99 (m, 1H), 1.39 (s, 3H), 1 :22 (s, 3H). Example-18: Synthesis of (3aR,4S,6R,6aS)-6-((5-amino-2-chloro-6-(((lR,2S)-2- (3,4-difluorophenyl)cyclopropyl)amino)pyrimidin-4-yl)amino)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol. 47

Iron powder (1.7g) was added :to a solution of 0.01 mole (4.97 gm) (3aR,4S,6R,6aS)-6-((2-chloro-6-(((l R,2S)-2-(3,4-difluorophenyl) cyclopropyl) amino)-5-nitropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l ,3]dioxol-4-ol 46 in methanol (25ml) and acetic acid (15.27 mL). The reaction mixture was then stirred at 25-35° C for 2 hrs. The reaction was monitored by TLC. After the reaction was complete, the product was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give Product 47.

Example-19: Synthesis of (3aR,4S,6R,6aS)-6-(5-chloro-7-(((lR,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[l ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-ol 49 (3aR,4S,6R,6aS)-6-((5-amino-2-chloro-6-(((l R,2S)-2-(3,4-difluorophenyl) cyclopropyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l ,3]dioxol-4-ol 30 (0.002 mole) in acetic acid (5 mL) was added sodium nitrite (0.002 mole) while maintaining the reaction temperature at 20-30 °C. The reaction mixture was stirred for 30 minutes. It was then diluted with ethyl acetate (50 mL), washed with water (2 x 35 mL) and evaporated under reduced pressure. The crude product was triturated in hexane (20 mL) and filtered to give Product 49. The characterization data of 49 is provided in Example 16.

ExampIe-20: Synthesis of ethyl 2-(((3a^,45,6i?,6aS)-6-((2,6-dichloro-5- nitropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH- cyclopenta[i ][l ,3]dioxol-4-yl)oxy)acetate. 52

Figure imgf000044_0001

To. a cooled and stirring solution of 2,4,6-trichloro-5-nitropyrimidine 31 (6.1 g) and potassium carbonate (7.4 gm) in 50 mL of THF, was added a solution of 56 (7 g) in 20 mL THF dropwise. The reaction mixture was slowly warm to room temperature and stirred for 3-4 hrs. The progress of reaction was monitored by TLC. After completion of the reaction, THF was removed under reduced pressure. Water was added (100 mL) to the residue and extracted with ethyl acetate (2x100 mL). The organic layer was separated and concentrated under reduced pressure to give crude product. This crude product was purified by column chromatography to give 4.8 g of oily liquid 52 (59%). Ή NMR (400 MHz, CDCI3): δ 8.47 (d, 1 H), 4.75-4.71 (m, 1 H), 4.61 (d, 1H), 4.49 (d, 1 H), 4.21 -4.09 (m, 4H), 3.66-3.59 (m, 1H), 2.28-2.22 (m, 1H), 1.95 (d, 1H), 1.35 (s, 3H), 1.23-1.15 (m, 6H).

Example-21: Synthesis of ethyl 2-(((3a7?,45',6i?,6a1S,)-6-((5-amino-2,6- dichloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH- cyclopenta[flT][ l ,3]dioxol-4-yl)oxy)acetate. 53

Figure imgf000044_0002

Iron powder (3 g) was added to a solution of 52 (3.3 g) in methanol (50 mL) and acetic acid (20 mL) at 5-10°C. The reaction mixture was then stirred at 25-35° C for 2 hrs. After completion of the reaction, water (100 mL) was added and the product was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulfate and concentrated under vacuum to give crude product, which was purified by column chromatography to obtained 2.3 gm (75% yield) of 53. Ή NMR (400 MHz, CDC13): δ 6.52 (d, 1H), 4.60 (t, 1H), 4.50-4.45 (m, 2H), 4.27 (d, 1H), 4.18-3.99 (m, 5H), 3.94 (d, 1H), 2.22-2.16 (m, 1H), 1.81 (d, 1H), 1.34 (s, 3H), 1.23-1.14 (m, 6H). Example-22: Synthesis of ethyl 2-(((3ai?,45,6i?,6a5)-6-(5,7-dichloro-3H- [l,2,3]triazolo[4,5-i¾pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH- cycIopenta[</J[l,3]dioxol-4-yl)oxy)acetate. 54

Figure imgf000045_0001

To a solution of compound 53 (2 g) in acetic acid (15 mL) was added NaN02 (0.5 g) in small portions while maintaining the temp to 10-15°C. The reaction mixture was then stirred at room temperature for lh. It was then diluted with ethyl acetate (100 mL), washed with water (2 x 100 mL) and evaporated under reduced pressure. The crude product was purified by column chromatography to give 1.7 g (85% yield) of 54. Ή NMR (400 MHz, CDC13): δ 5.53 (d, 1H), 5.21 -5.17 (m, 1H),;4.82 (d, 1H), 4.1-3.97 (m, 5H), 2.76-2.61 (m, 2H), 1.47 (s, 3H), 1.29 (s, 3H), 1 .15 (t, 311).

Example-23; Synthesis of ethyl 2-(((3ai?,45,6i?,6aS)-6-(5-chloro-7-(((l ?,2S)-2- (3,4-difluorophenyl)cyclopropyl)amino)-3H-[l ,2,3]triazolo[4,5-flT]pyrimidin-3- yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[if][l ,3]dioxol-4-yl)oxy)acetate. 51

Figure imgf000045_0002
To a stirring solution of 54 (1.6 g) in dichloromethane (16 mL) at room temperature was added a mixture of (lR,2S)-2-(3,4-difluorophenyl)cyclo propanamine 7 (0.8 g) and triethylamine (1.2 g). After 3 h, the mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL) and evaporated under reduced pressure. The residue was purified by column chromatography to give 1.5 g (68% yield) of 51. Ή NMR (400 MHz, CDC13): δ 8.52 (s, 1 H), 7.31 - 7.25 (m, 1H), 7.12-7.08 (m, 2H), 5.47-5.45 (m, 1 H), 5.15-5.12 (m, 1 H), 4.84-4.82 (m, 1 H), 4.22-4.08 (m, 7H), 3.12-3.09 (m, 1 H), 2.76-2.62 (m, 3H), 2.26-2.23 (m, 1 H), 1.61 (s, 3H), 1.49-1.45 (m,lH), 1.30-1.25 (m, 4H). ExampIe-24: Synthesis of ethyl 2-(((3ai?,45,,6i?,6a5)-6-(7-(((l/?,2.S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-( ] pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[(f][l ,3]dioxol-4-yl)oxy) acetate. 55

Figure imgf000046_0001
To a solution of 51 (1.5 g) in 15ml DMF, potassium carbonate (2.4 gm) and propane thiol (0.5 mL) was added. The reaction mixture was heated to 60-65°C and stirred at the same temp for 3h. After completion of the reaction as observed by TLC, the solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine. Drying of organic layer over anhydrous sodium sulfate, removal of ethyl acetate under reduced pressure gave a residue, which was purified by column chromatography to give 1.1 gm (61% yield) of 55. Ή NMR (400 MHz, CDC13): δ 7.96 (d, 1H), 7.36 (m, 1H), 7.0 (m, 2H), 5.36 (dd, lH), 5.04 (m, 1 H), 4.73 (dd, 1H), 4.14 (q, 2H), 4.07 (m, 4H), 2.99 (m, 2H), 2.64 (t, 2H), 2.1 1 (m, 1H), 1.61 (m, 1H), 1.46 (s, 3H), 1.36 (m, 1 H), 1.25 (s, 3H), 1.19 (m, 5H), 0.89 (t, 3H).

Example 25: Synthesis of 2-(((3a/?,45,6i?,6aS)-6-(7-(((l/?,25)-2-(3,4- difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[l ,2,3]triazolo[4,5-i ] pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[c/][l ,3]dioxol-4-yl)oxy) ethanol. 28

Figure imgf000047_0001

To a solution of Compound 55 (1.1 g) in THF (30 mL) was added lithium borohydride (0.216 g) at 5-10°C. The reaction mixture was then stirred at 15-20°C for 8-10 h. The reaction was monitored by TLC. After completion, the reaction was quenched with water (50 mL), and the THF was distilled off under reduced pressure to provide a residue. The residue was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated at reduced pressure to provide the crude product (0.8 g). This crude product was found to be identical to 28 (by TLC), prepared in example 9, by another route and was used for the next step without further purification.

Example-26: Synthesis of Ticagrelor 1.

Figure imgf000047_0002

To a cooled solution of protected ticagrelor 28 (0.8 g) in methanol (10 mL) was added a solution of HCl (1 mL) in water (2 mL). The reaction mixture was stirred at rt for 3-4 h. After completion the methanol was distilled off under reduced pressure. The residue was added water (50 mL) and extracted with ethyl acetate(2*50 mL). The combined organic layers was dried over anhydrous sodium sulfate, filtered, treated with small amount of charcoal, and again filtered through hyflo. The filtrate was concentrated to give 0.6 gm of Ticagrelor 1 as off-white solid. The sample was found to be identical to the sample prepared in example 1 1 and 12.

Example 27; Synthesis of 2-(((3a<S,4i?,65,6aR)-4-((2,6-dichloro-5-nitropyrimidin- 4-yl)amino)tetrahydro-3aH-spiro[cyclopenta[ii][l,3]dioxole-2,r-cyclopentan]-6- yl)oxy)ethanol. 38

Figure imgf000048_0001

A solution of compound 37 (3.33 gm) in water (30 mL) and NaHC03 was added dropwise to a solution of 2,4,6-trichloro-5-nitropyrimidine 31 in THF (40 mL) at 5-10°C. The resulting reaction mixture was stirred at RT for 2h and layers were separated. The THF layer was then distilled off and the residue was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography to obtain 4.8 gm of 38. Ή NMR (400

MHz, CDC13): 5 8.55 (d, 1H), 4.84-4.82 (m, 1 H), 4.61 (d, 1 H), 4.46 (d, 1 H), 4.0 (d, lH), 3.83-3.75 (m, 3H), 3.66-3.63 (m, 1H), 3.34 (bs, 1 H), 2.37-2.32 (m, 1 H), 1.95-1.88 (m, 3H), 1.72-1.62 (m, 6H).

Example 28: 2-(((3a5,4i2,65,,6a ?)-4-((5-amino-2,6-dichloropyrimidin-4-yl) am'ino)tetrahydro-3aH-spiro[cyclopenta[(i][l ,3]dioxole-2,r-cyclopentan]-6- yl)oxy)ethanol. 39

Figure imgf000049_0001

Iron powder (3 g) was added to a solution of 38 (3.3g, 0.01 mole) in methanol (50 mL) and acetic acid (20 mL) at 5-10°C. The reaction mixture was then stirred at 25-35° C for 2 hrs. After completion of the reaction, water (100 mL) was added and the product was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulfate and concentrated under vacuum to give compound 39 (2.4 g). The crude product was used for the next step without further purification.

Example 29: Synthesis of 2-(((3a5,4^,6S',6ai?)-4-(5,7-dichloro-3H-[ 1 ,2,3] triazolo[4,5-c/]pyrimidin-3-yl)tetrahydro-3aH-spiro[cyclopenta[(5 ] [ 1 ,3] dioxole- 2, 1 '-cyclopentan]-6-yl)oxy)ethanol. 40

Figure imgf000049_0002

To a solution of compound 39 (2.2 g) in acetic acid (15 mL) was added NaN02 (0.6 g) in small portions while maintaining the temp to 10-15°C. The reaction mixture was then stirred at room temperature for lh. It was then diluted with ethyl acetate (50 mL), washed with water (2 x 35 mL) and evaporated under reduced pressure to give compound 40 (2.1 g). The crude product was used for the next step without further purification.

Example 30: Synthesis of 2-(((3aS,4i?,65,6ai?)-4-(5-chloro-7-(((l/?,25)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[l,2,3]triazolo[4,5-c ]pyrimidin-3- yl)tetrahydro-3 aH-spiro [cyclopenta[if] [ 1 ,3] dioxole-2, 1 '-cyclopentan] -6- yl)oxy)ethanol. 41

Figure imgf000050_0001

40

To a stirring solution of 40 (1.8 g) in THF (30 mL) at 20 °C was added (l R,2S)-2- (3,4-difluorophenyl)cyclopropanamine 7 (0.9 g). After 2 h, water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography to give 1 .9 g of 41. Ή NMR (400 MHz, CDC13): δ 8.0 (d, 1 H), 7.30-7.26 (m, 1H), 7.12-7.05 (m, 2H), 5.42-5.39 (m, 1H), 5.21-5.19 (m, 1 H), 4.78 (d, 1H), 4.1 1-4.09 (m, 1 H), 3.67-3.53 (m, 4H), 3.09-3.08 (m, 1 H), 2.71 -2.66 (m, 1H), 2.47-2.41 (m, 1H), 2.26-2.23 (m, l H), 2.04- 1.98 (m, 2H), 1.76-1.65 (m, 5H), 1.49-1.39 (m, 2H), 1.28-1.21 (m, 2H).

Example 31: Synthesis of 2-(((3aS,4/?,65,6a^)-4-(7-(((li?,2S)-2-(3,4-difluoro phenyl)cyclopropyl)amino)-5-(propylthio)-3H-[l ,2,3]triazolo[4,5-fiT]pyrimidin-3- yl)tetrahydro-3aH-spiro[cyclopenta[if][l ,3]dioxole-2, -cyclopentan]-6-yl)oxy) ethanol. 42

Figure imgf000050_0002

To a solution of 41 (1.5 g) and K2C03 (1 g) in DMF (20 mL) was propane thiol (0.5 mL) at rt. The .reaction mixture was then stirred at 60-70 °C for 8 h. The progress of reaction was monitored by TLC. After completion of the reaction, the solvent was removed under vacuum and the residue was treated with ethyl acetate and water. The layer were separated, organic layer was washed with brine. Drying of organic layer over anhydrous sodium sulfate, filtering and removal of ethyl acetate gave a residue, which was purified by column chromatography to obtain 1.4 g of protected ketal Ticagrelor 45. Ή NMR (400 mHz, CDC13): δ 7.41 (m, 1 H), 7.03-6.93 (m, 3H), 5.33 (d, 1H), 5.09 (s, 1H), 4.70 (d, 1H), 3.97-3.94 (m, 1H), 3.57-3.43 (m, 3H), 3.04-2.92 (m, 3H), 2.62-2.57 (m ,1 H), 2.46-2.30 (m, 1H), 2.10-2.08 (m, 1H), 1.97-1.91 (m, 2H), 1.7-1.51 (m, 6H), 1.4-1.1 (m, 6H), 0.95- 0.71 (m, 3H).

Example 32: Synthesis of Ticagrelor 1

Figure imgf000051_0001

To a cooled solution of protected ticagrelor 42 (1.4 g) in methanol (14 mL) was added a solution of HC1 (1.2 mL) in water (2 mL). The reaction mixture was stirred at rt for 3-4 h. After completion the methanol was distilled off under reduced pressure. The residue was added water (70 mL) and extracted with ethyl acetate (2* 100 mL). The combined organic layers was dried over anhydrous sodium sulfate, filtered, treated with small amount of charcoal, and again filtered through hyflo. The filtrate was concentrated to give 1.1 g of Ticagrelor 1 as off- white solid. The sample of 1 was found to be identical in all respect i.e. TLC, HPLC-RT purity and spectroscopically to the sample of Example 1 1 and 12.

Claims

We claim:
1. A process for preparing Ticagrelor of Formula 1
Figure imgf000052_0001
1 or a pharmaceutically acceptable salts, polymorph or co-crystal there of comprising
(a) coupling a compound according to formula 1_1
Figure imgf000052_0002
11
a compound of formula 23 (scheme 6)
Figure imgf000052_0003
where X is independently electron withdrawing group type leaving group such as chloro, bromo, iodo, mesylate, tosylate, besylate, brosylate, nosylate and the like and their permutation, combination there of. where R ,R is both oxygen (such as N02 in 31 in scheme 7), where R is -H and R is electron withdrawing group type amine protecting groups such as formyl, acetyl, mesyl, tosyl, besyl, nosyl etc. to produce a compound according to formula 24 (Scheme 6).
Figure imgf000053_0001
24 and converting the compound of formula 24 to a compound formula 1 (Ticagrelor);
( ) reducing the compound of formula 24 (-NR' ,R2=N02) or hydrolyzing (-NR' ,R2, R'=H, R2 as mentioned above) or deprotecting NHR2 to produce a compound of formula 25;
Figure imgf000053_0002
(c) diazotizing the compound of formula 25 to produce a compound of formula 26;
Figure imgf000053_0003
(d) reacting the formula 26 compound with (lR,2S)-2-(3,4- difluorophenyl)cyclopropyl amine 7, to produce a compound of formula 27;
Figure imgf000054_0001
27 reacting the compound of formula 27 with propyl thio- nucleophiles/reagents (alkali or alkali earth metal salts of 1- propanethiol) or thiourea and trapping the intermediate with propyl -X (X is chloro, bromo, iodo, mesylate, tosylate, etc) to produce a compound of formula 28;
Figure imgf000054_0002
(f) hydrolyzing the compound of formula 28 to produce Ticagrelor 1.
2. A compound according to formula 24j wherein X and R1, R2 are as discussed above in claim 1 (a)
Figure imgf000054_0003
3. A compound according to formula 25, wherein X and R1, R2 are as discussed above in claim 1 (a)
Figure imgf000055_0001
4. A compound according to formula 26, wherein the meaning of X is discussed above in claim 1 (a)
Figure imgf000055_0002
5. A compound according to formula 27, Wherein the meaning of X is discussed above in claim 1(a)
Figure imgf000055_0003
A process of preparing Ticagrelor, comprising
(a) coupling a compound according to formula 11 (scheme-7)
Figure imgf000055_0004
11 with a compound of formula 31
Figure imgf000056_0001
31 to produce a compound of formula 32
Figure imgf000056_0002
and converting the compound of formula 32 to a compound of formula l_(Ticagrelor);
reducing the compound of formula 32 to produce a compound of formula 33;
Figure imgf000056_0003
33 diazotizing the compound of formula 33_ to produce a compound of formula 34;
Figure imgf000056_0004
reacting the compound of formula 34 with (l R,2S)-2-(3,4- difluorophenyl)cyclopropyl amine 7, to produce a compound of formula 35;
Figure imgf000057_0001
35
(e) reacting the compound of formula 35 with propylthio-reagents (as discussed in claim 1(e), to produce a compound of formula 28;
Figure imgf000057_0002
(f) hydrolyzing the compound of formula 28 to produce Ticagrelor _1.
A compound according to formula 32
Figure imgf000057_0003
8. A compound according to formula 33
Figure imgf000058_0001
9. A compound according to formula 34
Figure imgf000058_0002
34
A compound according to formula 35
Figure imgf000058_0003
Figure imgf000058_0004
12. A compound according to formula 36
Figure imgf000059_0001
36
A compound according to formula 38
Figure imgf000059_0002
A compound according to formula 40
Figure imgf000059_0003
40
15. A compound according to formula 41
Figure imgf000060_0001
A compound according to formula 45
Figure imgf000060_0002
45
17. A compound according to formula 46
Figure imgf000060_0003
46
18. A compound according to formula 49
Figure imgf000061_0001
19. A compound according to formula 50
Figure imgf000061_0002
50
20. A compound according to formula 51
Figure imgf000061_0003
compound according to formula 52
Figure imgf000062_0001
22. A compound according to formula 54
Figure imgf000062_0002
23. A compound according to formula 58
Figure imgf000062_0003
58
24. A compound according to formula 59
Figure imgf000062_0004
compound according to formula
Figure imgf000063_0001
61
A compound according to formula 63
Figure imgf000063_0002
63
A compound according to formula 64
Figure imgf000063_0003
Various processes, route of synthesis, reagents, solvents, reactions conditions such as herein described in the description for steps 'a', 'b', 'c', 'd', 4e', , 'g', 'h' and 'i' to prepare above novel compounds.
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