FIELD OF INVENTION
The present invention relates to an improved process for the synthesis of 3, 4-difluorophenyl cyclopropanamine and its use for the synthesis of triazolopyrimidine compounds viz Ticagrelor. The present invention in particular relates to the synthesis of 3, 4-difluorophenyl cyclopropanamine via novel intermediates.
BACKGROUND OF INVENTION
Ticagrelor is triazolopyrimidine compound, chemically known as 3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-7,2,3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy)-(lS',2S',3i?,5S)-l,2-,cyclopentanediol) which is disclosed in EP1135391 (WO 00/34283).
Ticagrelor is an important triazolopyrimidine compound. It has a trade name Brilinta in the US and Brilique and Possia in the EU. Ticagrelor is a platelet aggregation inhibitor having the following structural formula:

Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infarction with ST elevation, other coronary artery diseases and arterial

thrombosis as well as other disorders related to platelet aggregation (WO 00/34283).
Basic patent application WO 00/34283 discloses various methods for preparation of Ticagrelor. An improved process for preparation of ticagrelor is disclosed in patent application WO 01/92263, and a further improved process in patent application WO 10/030224 respectively derived from the originator AstraZeneca, while two are published in a "deutero" patent application WO 11/017108 of Auspex Pharmaceuticals. Further, there is one synthetic path published in a scientific journal (Bioorg. Med. Chem. Lett. 2007,17, 6013-6018).
All synthetic approaches mentioned in the aforesaid publication utilize trans-(\R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine (CPA); compound of formula IX as one of the key intermediate for the preparation of Ticagrelor.

There are several synthetic paths for preparation of intermediate CPA, compound of formula (IX) known in the literature.
According to WO 01/92200 and WO 01/92263, CPA is prepared as shown in Scheme-1. According to the process disclosed in aforesaid publication 3, 4-Difluorobenzaldehyde is reacted with malonic acid in the presence of pyridine and piperidine to yield (E)-3-(3, 4-difluorophenyl)-2-propenoic acid, which is converted to (E)-3-(3, 4-difiuorophenyl)-2-propenoyl chloride by using thionyl chloride in the presence of toluene and pyridine. A solution of Z-menthol in toluene is added to the obtained compound in the presence of pyridine to yield (lR,2S,5R)-2-isopropyl-5-rnethylcyclohexyl (E)- 3- (3, 4-difluorophenyl)-2-propenoate, which is then converted to (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-Difluorophenyl)cyclo-propanecarboxylate using

dimethylsulfoxonium methylide, sodium iodide and NaOH in DMSO. The latter is then hydrolysed to trans-(1R, 2R)-2-(3, 4-difluorophenyl)-cyclopropanecarboxylic acid, which is subsequently converted to trans-(1R, 2R)-2-(3, 4-difluorophenyl) cyclopropanecarbonyl chloride with thionyl chloride. In the last two steps, the obtained carbonyl chloride is first converted to the corresponding azide by addition of sodium azide and tertbutylammonium bromide, which is finally converted to CPA.

Scheme 1: Synthesis of CPA as described in WO 01/92200 and WO 01/92263.
The 8 steps synthesis of CPA disclosed in Scheme 1 is very long, utilizes toxic compounds like sodium azide and pyridine, and is not economical as expensive reagents like trimethylsulfoxonium iodide are used. Moreover, the overall yield of the reaction is low.
Another process for the preparation of CPA is described in Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018. The synthesis of the trans-(1R,2S)-phenylcyclopropylamine begins with derivatisation of substituted cinnamic acid A with Oppolzer's sultam to give B. Diastereoselective cyclopropanation then provides, after recrystallisation, cyclopropylamide C in high chiral purity which is readily saponified to acid D. A four-step Curtius rearrangement gives CPA.


Scheme 2: Synthesis of CPA as described in Bioorg. Med. Chem. Lett. 2007,17, 6013-6018.
This 4 steps synthesis presented in Scheme 2 involves the use of hazardous and explosive materials like sodium hydride, diazomethane and sodium azide. Moreover, highly expensive chiral sultam and palladium acetate are used. In addition, this lengthy process involves column chromatographic purifications, which are generally undesirable in view of large scale industrial applicability.
According to WO 08/018822 and WO 08/018823, CPA is prepared as shown in Scheme 3. First step involves reacting 1, 2-difluorobenzene with chloroacetyl chloride in the presence of aluminium trichloride to produce 2-chloro-l-(3, 4-difluorophenyl) ethanone. The keto group of the latter is then reduced by the use of chiral oxazaborolidine catalyst and borane dimethylsulfide complex to yield 2-chloro-l-(3, 4-difluorophenyl) ethanol, which is then reacted with triethylphosphoacetate in the presence of sodium hydride in toluene to produce trans-(1R, 2R) - 2-(3, 4-difluorophenyl) cyclopropyl carboxylate. In the final two steps the ester compound is first converted to amide by methyl formate in the presence of ammonia, said amide is then reacted with sodium hydroxide and sodium hypochlorite to produce CPA.


Scheme 3: Synthesis of CPA as described in WO 08/018822 and WO 08/018823.
The disadvantages of the process described in WO 08/018822 and WO 08/018823 are the use of expensive chiral oxazaborolidine catalyst and toxic borane dimethylsulfide complex as well as use of explosive materials like sodium hydride.
According to WO 11/017108, CPA is prepared by a process as described in Scheme 4. First, (E)-3-(3,4-difluorophenyl) acrylic acid is reacted with oxalyl dichloride in the presence of N,N-dimethylformamide and dichloromethane to produce the corresponding acryloyl chloride, which is then reacted with a mixture of (2R)-bornane-10,2-sultam and triethylamine to yield [3aS-[l(E),3a,6,7a]]-l-[3-(3,4-Difluorophenyl)-l-oxo-2-propenyl]-hexahydro-8, 8- dimethyl -3H-3a, 6-methano - 2,l-benzisothiazole-2,2-dioxide. Said intermediate is then reacted with methyl-1-nitrosourea in NaOH and ethyl ether, and with palladium acetate reagent to convert the propenyl group into cyclopropyl group. In the final two steps the obtained intermediate is first converted to (1R, 2R)-trans-2-(3, 4-difluorophenyl) cyclopropyl carboxylic acid by lithium hydroxide in the presence of tetrahydrofuran, said acid is then reacted with diphenylphosphoryl azide and triethylamine in toluene and HC1 to produce CPA.


Scheme 4: Synthesis of CPA as described in WO 11/017108.
The disadvantage of the process described in WO 11/017108 is the use of expensive chiral sultam and palladium acetate reagent.
Another synthetic route for preparing CPA is described in WO 11/132083 (Scheme 5). 1, 2-Difluoro benzene is reacted with 3-chloropropionyl chloride to produce 3-chloro-l-(3', 4'-difluorophenyl)-propan-l-one, which is by addition of N, N-dimethylformamide, phloroglucinol and sodium iodide in the next step converted to l-(3', 4'-difluorophenyl)-3-nitro-propan-l-one. The keto group of the latter intermediate is in the subsequent step stereochemically reduced to hydroxyl group by the use of chiral oxazaborolidine together with borane dimethyl sulfide or borane-N, N, diethyl aniline complex in the presence of tetrahydrofuran. The obtained (lR)-l-(3',4'-difluorophenyl)-3-nitro-propan-l-ol is then added to a mixture of triphenylphosphine and diethylazodicarboxylate in benzene to yield trans-(1S,2R)-2-(3',4,-difluorophenyl)-l-nitrocyclopropane, which is in the last step converted to CPA by reduction of the nitro group by catalytic hydrogenation with palladium catalyst and zinc dust.


Scheme 5: Synthesis of CPA as described in WO 11/132083.
The disadvantage of the process described in WO 11/132083 is the use of expensive chiral oxazaborolidine and palladium catalyst, sodium iodide, toxic borane dimethylsulfide complex, heavy metals and hazardous diethyl azodicarboxylate.
WO 12/001531 describes another alternative synthetic path for preparation of CPA (Scheme 6). In this case the starting reagent 3, 4-difluorobenzaldehyde is reacted with a mixture of methyltriphenylphosphonium bromide, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and toluene to yield 3, 4-difluorostyrene. The obtained intermediate is then added to dichloro (p-cymene)ruthenium(II) dimer and (S,S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine, which is followed by addition of ethyl diazoacetate to yield ethyl trans-(1R,2R)-2-(3,4-difluorophenyl)-l-cyclopropane-carboxylate, which is converted to trans-(1R,2R)-2-(3,4-difluorophenyl)-l-cyclopropane-carboxylic acid by hydrolysis in the presence of sodium hydroxide and methanol. The obtained carboxylic acid is with aqueous hydroxylamine solution further converted to trans-(1R, 2R)-2-(3, 4-difluorophenyl)-l-cyclopropanecarboxamide, which is mixed with pyridine and acetic anhydride to yield trans-(1R, 2R)-N-(acetyloxy)-2-(3, 4-difluorophenyl)-l-cyclopropane carboxamide. To the obtained intermediate in the presence of tetrahydrofurane then 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) is added,

which is followed by addition of isopropyl acetate and ammonium chloride to finally yield CPA.

Scheme 6: Synthesis of CPA as described in WO 12/001531.
The disadvantage of the process described in WO 12/001531 is the use of expensive chiral ligand, dichloro (p-cymene) ruthenium (II) dimer, and use of toxic pyridine.
There are also some processes for synthesis of 3, 4- difluorophenyl cyclopropanamine known in literature which involves synthesis of 3, 4-difluorophenyl cyclopropane carboxylic acid methyl ester which is converted into 3, 4- difluorophenyl cyclopropane carboxylic acid which is further converted into 3,4- difluorophenyl cyclopropanamine.
The product obtained after cyclopropanation is usually a mixture of trans and cis compounds. In order to increase the yield, the methyl ester is isolated, and subjected to base treatment to increase the diastereomeric excess. The process of isolation of 3, 4-difluorophenyl cyclopropane carboxylic acid methyl ester is hazardous and time consuming. Besides, there are number of steps involved in the conversion of 3, 4-difluorophenyl cyclopropane carboxylic acid methyl ester to 3, 4- difluorophenyl cyclopropanamine. Also, the reported overall yield in prior art is low.

A more convenient method for the preparation of 3, 4- difiuorophenyl cyclopropanamine is to prepare a 3, 4- difiuorophenyl cyclopropancarboxamide and then converting this amide into 3, 4- difiuorophenyl cyclopropanamine. However, cyclopropanation of 3, 4 difiuorophenyl cinnamic acid amide does not proceed easily and there are few reports of such cyclopropanation reactions. The ones reported in literature mentions the use of Samarium metal along with Diazomethane while others mention Chromium (II) chloride along with diazomethane. The reagents are very expensive and not commercially viable.
A major drawback of the hitherto known synthesis schemes for the preparation of CPA is that the synthesis is long and/or expensive or environmentally unfriendly reagents are used, which makes the prior art processes unsuitable for large scale preparation of CPA' compound of formula IX. Therefore there is a need for an alternative but commercially viable process for preparation of CPA.
The present inventors have found that the process of the present invention for preparation of CPA, compound of formula IX via novel intermediate 2-(3, 4-difluorophenyl)-N-methoxy-N-methyl cyclopropanecarboxamide, compound of formula (IV)

which can be easily prepared and isolated in good yield and purity by the cyclopropanation of the novel compound (E)-3-(3,4-difluorophenyl)-N-methoxy-N-methylacrylamide, compound of formula III as depicted below:


is commercially viable. Cyclopropanation of (E)-3-(3,4-difluorophenyl)-N-methoxy-N-methylacrylamide, compound of formula III in the present invention is carried out using inexpensive and commercially viable reagents like Trimethylsulphoxonium iodide and a base.
The present inventors have found that the intermediate alpha beta unsaturated amide (III) was prepared very easily by a one pot process starting from 3,4 difluorophenyl cinnamic acid and N,0- Dimethyl hydroxylamine in very good yield and purity.
The present invention further found that the novel intermediate of formula (VI) of the present invention can be easily converted into 3, 4- difluorophenyl cyclopropanamine in good yield and purity.
The main advantages of this process over prior art are:
1) Shorter synthesis route
2) Good yield and purity of all intermediates
3) Easily upscaleable process with ease of operation.
OBJECT OF THE INVENTION
It is an object of the present invention to provide an industrially applicable and economical process for obtaining trans-(1R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine, compound of formula (IX), which is an important intermediate in preparation of ticagrelor (TCG).
It is another object of the present invention to provide an improved process for obtaining trans-(1R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine, compound of formula (IX), which does not employ any hazardous reagent and that is safer to carry out.

It is yet another object of the present invention to provide novel intermediates which can be used in the preparation of ticagrelor (TCG).
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided an improved process for the preparation of a compound of formula (IX) which comprises the step of:
(i) Reacting a compound of formula (I)

Formula (I)
with thionyl chloride or oxalyl chloride in the presence of dimethylformamide in an organic solvents to obtain compound of formula (II);

Formula (II)
(ii) Reacting compound of formula (II) with N, O-dimethylhydroxylamine hydrochloride to obtain compound of formula (III);

Formula (III)

(iii) Cyclopropanation of compound of formula (III) with trimethyl suphoxonium iodide in the presence of base and DMSO to obtain compound of formula (IV);

Formula (IV)
(iv) converting the compound of formula (IV) to compound of formula (VI) using hydrazine hydrate;

Formula VI
(v) converting the compound of formula (VI) to azide compound of formula (VII) using sodium nitrite in the presence of hydrochloric acid;

Formula VII
(vi) converting compound of formula (VII) to compound of formula (VIII);

Formula VIII
(vii) Hydrolyzing compound of formula (VIII) to obtain compound of formula (IX) or a salt thereof.


Formula IX
According to another aspect of the present invention there is provided novel intermediates of formula III; formula IV and formula VI.

Formula III

Formula IV

Formula VI
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the synthesis of 3, 4-difluorophenyl cyclopropanamine and its use for the synthesis of triazolopyrimidine compounds viz Ticagrelor. The present invention in particular relates to the synthesis of 3, 4-difluorophenyl cyclopropanamine via novel intermediates.

The process of the present invention provides a method for preparation or synthesis of the compound of formula IX with an industrially applicable and economical process while using environmentally friendly reagents. Preferred embodiments will be described below. The present invention further provides novel compounds that are useful intermediates in the preparation of ticagrelor (TCG).
In an embodiment of the present invention there is provided an improved process for the preparation of compound of formula III comprising the steps of converting (E)-3-(3, 4-Difluorophenyl) acrylic acid; compound of formula I into its acid halide; compound of formula II, said acid halide is then reacted with N, O-dimethyl hydroxylamine hydrochloride to obtain (E) - 3- (3, 4-difluorophenyl) -N-methoxy-N-methylacrylamide; compound of formula III.
In another embodiment of the present invention there is provided an improved process for the preparation of compound of formula IV, which is prepared by cyclopropanation of compound of formula III.
Suitable reagents for the above reaction are for example trimethylsulfoxonium iodide and trimethylsulfoxonium bromide. Preferred reagent is trimethylsulfoxonium iodide.
The process for preparation of compound of formula IV is represented by Scheme A.
Scheme A:


In another embodiment of the present invention, the compound of formula IV is further converted to the hydrazide compound of formula VI.
The step of conversion of compound of formula IV to compound of formula VI can be performed directly by reacting the compound of formula IV with hydrazine hydrate. Alternatively, the compound of formula IV can be hydrolyzed into 2-(3, 4-difluorophenyl) cyclopropanecarboxylic acid, compound of formula (V), which is then converted into its ester, compound of formula (Va). Said ester compound of formula (Va), which is for example ester with a linear or branched alkyl, preferably (C1 to C6) alkyl ester, is then reacted with hydrazine hydrate giving the compound of formula VI. The reaction can be represented Scheme B.
Scheme B:

In an another embodiment of the present invention, the compound VI is first converted to an azide compound of formula VII, which is further converted to a compound of formula VIII, which is subsequently converted to the compound of formula IX. The reaction can be represented by Scheme C.

Scheme C;

The present invention provides a one pot synthesis of compound of formula IX from compound of formula VI i.e. the above three steps can be conducted in the same pot without isolating the intermediates VII and VIII.
In yet another embodiment, the compound of formula IX can be further converted to a stereochemically pure (IR, 2S)-2-(3, 4-difluorophenyl) cyclopropanamine in a form of a salt, for example by chiral resolution of the racemic amine, compound of formula IX with an optically active acid. A preferred optically active acid is R-mandelic acid.
In a preferred embodiment of the present invention. (E)-3-(3, 4-Difluorophenyl) acrylic acid, compound of formula (I) is converted into its acid chloride by reaction with thionyl chloride or oxalyl chloride in DMF. The obtained acid chloride' compound of formula (II) is reacted with N, O-dimethyl hydroxylamine hydrochloride in the presence of pyridine to obtain (E)-3-(3, 4-difluorophenyl)-N-methoxy-N-methylacrylamide, compound of formula (III).
Compound of formula (III) is then cyclopropanated with trimethyl suphoxonium iodide in sodium hydride and DMSO to give 2-(3, 4-difluorophenyl)-N-methoxy-

N-methylcyclopropanecarboxamide, compound of formula (IV). Alternatively, sodium hydroxide can be used instead of sodium hydride to perform this step.
The compound of formula (IV) can be converted into 2-(3, 4-difluorophenyl) cyclopropanecarbohydrazide, compound of formula (VI) by either
(i) reacting IV with hydrazine hydrate to directly obtain VI, or
(ii) hydrolyzing IV into 2-(3, 4-difluorophenyl)cyclopropanecarboxylic acid, compound of formula (V), which is then converted into its methyl ester and then further reacted with hydrazine hydrate to obtain, compound of formula VI.
2-(3,4-difiuorophenyl)cyclopropanecarbohydrazide, compound of formula (VI) is then reacted with sodium nitrite in the presence of HC1 to obtain the corresponding acyl azide (VII) which is then subjected to the Curtius rearrangement to obtained, compound of formula (VIII). Compound of formula VIII is then hydrolyzed to obtain 2-(3, 4-difluorophenyl) cyclopropanamine, compound of formula (IX).
The reaction path from conversion of compound of (VI) into compound of formula (IX) is carried in the same pot, without isolating intermediates VII and VIII.
The desired isomer (1R, 2S)-2-(3, 4-difluorophenyl) cyclopropanamine is then isolated in the form of its salt (IX') by reacting with R-mandelic acid.
The preferred embodiment of the present invention can be represented by Scheme D.

Scheme D;

Further aspect of the present invention resides in the provision of providing valuable intermediate compounds of formula III, IV and VI or its stereochemical isomeric forms thereof, useful in the synthesis of ticagrelor (TCG).
In an embodiment of the present invention there is provided compound of formula III, formula IV and formula VI.



The following examples are meant to illustrate the present invention. The examples are presented to exemplify the invention and are not to be considered as limiting the scope of the invention.
Examples
Example 1: Preparation of (E)-3-(3, 4-difluorophenvl)-N-methoxv-N-methvlacrylamide, compound of formula (III)
a) Preparation of (E)-3-(3, 4-difluorophenyl) acrylovl chloride: compound of formula II
100 g (0.54 moles) of (E)-3-(3, 4-Difluorophenyl) acrylic acid, compound of formula (I) was dissolved in 250 ml dichloromethane at about 25°C to 30°C. A solution of the 276 g of oxalyl chloride (2.17 moles) in 100 ml dichloromethane was added slowly to reaction mixture in about 15 minutes. This was followed by the addition of a solution of 20 ml. DMF in 150 ml dichloromethane at 25°C to 30°C in about 15 minutes. The reaction mixture stirred for about 2 h, solvent was distilled under reduced pressure below 40°C to obtain product in the form of a semisolid.

The semisolid obtained was dissolved in about 100 ml acetone and used as such in step (b).
b) Conversion of (E)-3-(3. 4-difluorophenyl) acrylovl chloride, compound of formula II into (2E)-3-(3. 4-difluorophenyl)-N-methoxy-N-methylacrylamide, compound of formula III.
In another reaction flask, was prepared a solution of 59 g (0.597 moles) N, O-dimethyl hydroxylamine hydrochloride in acetone. The solution was cooled to 0 to 5°C. Pyridine 128 g (1.62 moles) was added to this solution and the reaction mixture was stirred at 25°C to 30°C for about 10 minutes. The solution of the acid chloride in acetone previously prepared in step (a) was added slowly to the reaction mixture maintaining the temperature between 0 to 5°C. After completion of the reaction solvent from the reaction mixture was distilled out under vacuum below 40°C. To the residue was added 500 ml dichloromethane followed by hydrochloric acid (dilute) till pH of aqueous layer was about 2 to 3. The resultant biphasic mixture was stirred for about 15 minutes and then the layers were allowed to settle for about 10 minutes. The lower organic layer was separated and washed 500 ml with saturated bicarbonate solution followed by 250 ml water. The solvent was distilled under reduced pressure below 40°C to obtain 114.5 g of title product.
1H NMR in (400MHz, CDC13) 5 3.30 (3H, s), 3.76 (3H, s), 6.91-6.95 (1H, d),
7.12-7.19
(1H, m), 7.26- 7.28 (1H, m), 7.34-7.40 (1H, m), 7.59-7.63 (1H, d)
Example 2: Preparation of 2-(3, 4-difluorophenyl)-N-methoxv-N-methvl cyclopropane carboxamide; compound of formula (IV)
To 500 ml of dimethylsulphoxide was added 242 g (1.1 moles) of trimethylsulphoxonium iodide at 25 °C to 30°C. To the resultant slurry was

charged 17 g (0.66 moles) of sodium hydride in portions carefully to avoid exotherm. The reaction mixture was then stirred at 25°C to 30°C for about 1 hr. Then, to the reaction mixture was added a solution of 100 g (E)-3-(3,4-difluorophenyl)-N-methoxy-N-methylaciylamide, compound of formula (III) as obtained in example 1, step (b) dissolved in 100 ml of dimethylsulphoxide, slowly between 25°C and 30°C.
The reaction mixture was stirred at 25°C to 30°C for 3 h and diluted with about 2.5 L water and extracted with toluene. The toluene solution was washed with brine followed by water and distilled under vacuum to obtain 106 g of the cyclopropanated product in the form of oil. This oil was used as such for the next step.
1H NMR in (400MHz,DMSO d6) 8 1.33-1.37 (lH,m), 1.40-1.44 (lH,m), 2.32-2.39 (2H, m), 3.13 (3H,s), 3.65 (3H, s), 7.04-7.08 (1H, m), 7.25 -7.33 (2H, m)
Example 3: Preparation of 2-(3. 4-difluorophenyl) cyclopropane carbohydrazide (VI)
To the oil obtained in the example 2 were added 250 ml of methanol and 140.25
(2.8 moles) g of hydrazine hydrate. The resultant reaction mixture was heated to
about 60°C to 65°C for 12 hour. After completion of the reaction, solvent was
distilled from reaction mixture under reduced pressure. The reaction mixture was
diluted with ethyl acetate and washed with brine.
The ethyl acetate was distilled completely under reduced pressure to obtain 62 g
(yield = 70%) title compound in the form of a solid.
1H NMR in (400MHz, DMSO d6)& 1.27-1.37 (2H, m), 1.74- 1.78 (1H, m), 2.25-
2.28
(1H, m), 4.22(2H, s), 7.00 (1H, m), 7.19-7.34(2H, m), 9.10 (1H, s)

Example 4: Preparation of 2-(3, 4-difluorophenyl) cyclopropanamine, compound of formula (IX).
20 g (94.3 mmoles) 2-(3, 4-difluorophenyl) cyclopropanecarbohydrazide, compound of formula VI was added to 50 ml of water and the slurry was cooled to 0-5 °C. 100 ml (6N) Hydrochloric acid was added slowly and stirred to dissolve the solid. To the resultant clear solution sodium nitrite solution (6.5 g dissolved in 100 ml) was added slowly at 0-5 °C over a period of 30 min. followed by 200 ml of toluene. The reaction mixture was stirred for 15 min, stirring stopped to separate layers. Toluene layer containing azide intermediate, compound of formula (VII) collected and was added slowly over one hour to 50 ml of toluene at 110 °C. The reaction mixture was refluxed for 1 hour at 110 °C and the hot toluene solution was transferred to 200 ml (6N) hydrochloric acid at 100 °C under stirring and the reflux continued for another 2 hour. The reaction mixture was cooled to 25 °C and the layers were allowed to separate. Aqueous layer collected and the pH was adjusted to 10. 200 ml of methylene dichloride was added and stirred for 15 min. The dichloromethane layer separated and concentrated under vacuum below 40 °C to obtained 10 g of 2-(3,4-difluorophenyl)-cyclopropanamine, compound of formula IX as an oil.
Example 5: Preparation of (1R, 2S)-2-(3.4-difluorophenvl)cyclopropanamine R-mandelic acid salt (IX')
To a solution of 9 g R-mandelic acid in 300 ml of methanol at 45 °C, was added a solution of 10 g of 2-(3,4-difluorophenyl)cyclopropanamine in 300 ml of methanol slowly over a period of 30 minutes. The reaction mixture was slowly cooled to 25 °C, stirred for 1 h, then further cooled slowly to 18°C and maintained for another 1 hour. The crystallized product was filtered off and washed with 20 ml of chilled methanol. The product was dried under vacuum to obtain 7.56 gms of title compound as a white crystalline solid.

1H NMR in (400MHz, DMSO d6) & 1.13 -1.16 (2H, m), 1.25 - 1.28 (2H, m), 2.20-
2.23
(1H, m), 2.65 - 2.67 (1H, m), 4.64(1H, s), 6.94 -6.96 (1H, m), 7.11-7.36 (8H, m)
Example 6: Preparation of 2-(3, 4-difluorophenyl) cyclopropane
carbohvdrazide, compound of formula (VI) from 2-(3, 4-
difluorophenyl) cvclopropanecarboxvlic acid, compound of
formula (V)
a) Preparation of 2-(3. 4-difluorophenyl) cvclopropanecarboxvlic acid: compound
of formula (V).
To 9gms (0.420 moles) of 2-(3,4-difluorophenyl)-N-methoxy-N-methylcyclopropane carboxamide, compound of formula IV in 120 ml of methanol was added a solution of 180 ml HC1 in dioxane (0.720 moles) at 25-30°C. The resulting clear solution was stirred at 25- 30°C for 16 h and then concentrated under vacuum. The resulting oil was dissolved in aqueous 1.5 N potassium hydroxide solution (160 ml) and heated to 50°C for 3 h. After cooling to 25- 30°C the mixture was diluted with water 500 ml and 10 % aqueous HC1 was added till pH 3 to 4. The solid that separated out was filtered and dried under vacuum to obtain 7.35g (90%) title compound.
b) Conversion of 2-(3. 4-difluorophenvl) cvclopropanecarboxvlic acid, compound
of formula V into 2-(3. 4-difluorophenvl)-cvclopropanecarbohydrazide,
compound of formula VI.
To 200 ml of methylene dichloride was added 20 g (100 mmoles) 2-(3,4-difluorophenyl)-cyclopropane carboxylic acid, 1.0 ml of DMF at ambient temperature and to the solution slowly added 10 ml of (116 mmoles) oxalyl chloride over a period of 30 min under stirring. After completion of reaction, 200 ml methanol was added slowly over 30-45 min. The reaction mixture was then subjected to vacuum distillation at 60-65°C to get yellow oil.

To the oil was added 100 ml methanol slowly under stirring followed by 40 ml of hydrazine hydrate was added with vigorous stirring at 20-25°C. After complete addition the reaction mixture was refluxed at 65 °C for 3 h. The reaction mixture was distilled at 60-65°C to remove solvent completely. A concentrated reaction mass was obtained. To the residue was added 200 ml water followed by 200 ml dichloromethane and stirred to dissolve the solid. The organic layer was separated and washed with 200 ml water. The organic layer was then concentrated under vacuum at 35-40°C to give 20 gms of 2-(3,4-difluorophenyl) cyclopropanecarbohydrazide (yield= 87% of theory).
1H NMR in (400MHz,DMSO d6) & 1.27-1.37 (2H, m), 1.74- 1.78 (1H, m), 2.25-2.28 (1H, m), 4.22(2H, s), 7.00 (1H, m), 7.19-7.34 (2H, m), 9.10 (1H, s)
Example 7: Preparation of 2-(3.4-difluorophenyl) cvclopropanamine (IX).
To 50 ml of water was added 20 g (94.3 mmoles) 2-(3, 4-difluorophenyl) cyclopropanecarbohydrazide, compound of formula VI and the slurry was cooled to 0-5 °C. 100 ml (6N) Hydrochloric acid was added slowly to the above slurry and stirred to dissolve the solid. To the resultant clear solution was then added sodium nitrite solution (6.5 g dissolved in 100 ml) slowly at 0-5 °C over a period of 30 min followed by 200 ml toluene. The reaction mixture was stirred for 15 min and then the layers were separated. The organic layer containing azide intermediate, compound of formula VII was then added slowly to 50 ml of hot toluene at 110 °C over a period of 1 h. The reaction mass was refluxed for 1 h at 110 °C and then transferred to 200 ml (6N) hydrochloric acid at 110 ° under stirring. The reflux was continued for 2 hrs. After completion of reaction the reaction mixture was cooled to 25 °C and the layers were separated. To the aqueous layer, sodium hydroxide solution was added to adjust to pH 10. 200 ml Methylene dichloride was added and stirred for 15 min. The layers were separated and the organic layer was distilled under vacuum below 40 °C to get 10 gms of 2-(3,4-difluorophenyl)cyclopropanamine as an oil (yield= 63 % theory).

Example 8: Preparation of (1R, 2S)-2-(3,4-difluorophenyl)cvclopropanamine R-mandelic acid salt (IX').
To a solution of 4.5 g R-mandelic acid in 150 ml of methanol at 45°C, was added a solution of 5 g of 2-(3,4-difluorophenyl)cyclopropanamine, compound of formula (IX) in 150 ml of methanol slowly over a period of 30 minutes. The reaction mixture was slowly cooled to 25°C and stirred for 1 h, then further cooled slowly to 18°C and maintained for another 1 h. The crystallized product was filtered off and washed with 20 ml of chilled methanol. The product was dried under vacuum to obtain 3.8 g of title compound as a white crystalline solid.
1H NMR in (400MHz, DMSO d6) & 1.13 -1.16 (2H, m), 1.25 -1.28 (2H, m), 2.20-
2.23
(1H, m), 2.65 - 2.67 (1H, m), 4.64(1H, s), 6.94 -6.96 (1H, m), 7.11-7.36 (8H, m)

WE CLAIM
1. An improved process for the preparation of a compound of formula (IX) which comprises the step of:
(i) Reacting a compound of formula (I)

Formula (I)
with thionyl chloride or oxalyl chloride in the presence of dimethylformamide in an organic solvents to obtain compound of formula (II);

Formula (II)
(ii) Reacting compound of formula (II) with N, O-dimethylhydroxylamine hydrochloride to obtain compound of formula (III);

Formula (III)
(iii) Cyclopropanation of compound of formula (III) with trimethylsulfoxonium iodide in the presence of base and DMSO to obtain compound of formula (IV);


Formula (IV)
(iv) converting the compound of formula (IV) to compound of formula (VI) using hydrazine hydrate;

Formula VI
(v) converting the compound of formula (VI) to azide compound of formula (VII) using sodium nitrite in the presence of hydrochloric acid;

Formula VII
(vi) converting compound of formula (VII) to compound of formula (VIII);

Formula VIII
(vii) Hydrolyzing compound of formula (VIII) to obtain compound of formula (IX) or a salt thereof.

Formula IX

7. A compound of formula III or stereochemical isomeric forms thereof.
2. The process as claimed in claim 1 step (iv), wherein the compound of formula IV is optionally converted compound of formula (V) by hydrolyzing compound of formula IV to obtain compound of formula (V) which is further reacted with Methanol and hydrazine hydrate to obtain compound of formula VI.
3. The process as claimed in claim 1 step (iii), wherein the base is selected from sodium hydride or sodium hydroxide.
4. The process as claimed in claim 1 step (vi), wherein the compound of formula VII is converted to formula VIII through Curtius rearrangement reaction.
5. The process as claimed in claim 1, wherein the process step (v) to step (vii) is conducted as a one-pot process.
6. The process as claimed in claim 1, wherein the compound of formula IX is reacted with R-mandelic acid to yield (1R, 2S)-2-(3, 4-difluorophenyl) cyclopropanamine R-mandelic acid salt, compound of formula IX'.



8.A compound of formula IV or stereochemical isomeric forms thereof.

Formula IV
9. A compound of formula VI or stereochemical isomeric forms thereof.

Formula VI
10. Use of the compound as claimed in claim 6 in the preparation of
Ticagrelor.

ABSTRACT

The present invention relates to an improved process for the synthesis of 3, 4-difluorophenyl cyclopropanamine and its use for the synthesis of triazolopyrimidine compounds viz Ticagrelor. The present invention in particular relates to the synthesis of 3, 4-difluorophenyl cyclopropanamine via novel intermediates.