Claims:We Claim:
1. An improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts

Formula I
wherein R1 is selected from substituted or unsubstituted cycloalkyl group optionally containing N, O or S, which comprises:
a) converting compound of Formula III or its salts

Formula III
to compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
b) optionally isolating compound of Formula IV or its salts and
c) converting compound of Formula IV or its salts to compound of Formula I or its pharmaceutically acceptable salts.

2. An improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts

Formula I
wherein R1 is selected from substituted or unsubstituted cycloalkyl group optionally containing N, O or S, which comprises:
a) reacting compound of Formula II

Formula II
wherein X represents a suitable leaving group, with malononitrile optionally in the presence of a base to give compound of Formula III or its salts

Formula III
b) converting compound of Formula III or its salts to compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
c) optionally isolating compound of Formula IV or its salts and
d) converting compound of Formula IV or its salts to compound of Formula I or its pharmaceutically acceptable salts.
3. An improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts,

Formula I
wherein R1 is selected from substituted or unsubstituted cycloalkyl group optionally containing N, O or S, which comprises:
a) providing compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
b) reacting compound of Formula IV or its salts with hydrazine hydrate optionally in the presence of a base to give compound of Formula V or its salts,

Formula V
c) converting compound of Formula V or its salts to compound of Formula I or its pharmaceutically acceptable salts.

4. An improved process for the preparation of compound of Formula IV or its salts:
a) reacting compound of Formula II

Formula II
wherein X represents a suitable leaving group, with malononitrile optionally in the presence of a base to give compound of Formula III or its salts,

Formula III
b) converting compound of Formula III or its salts to compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group.

5. An improved process for the preparation of compound of Formula IV or its salts:
a) providing compound of Formula III or its salts,

Formula III
b) reacting compound of Formula III or its salts with a sulfonyl derivative to give compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group.

6. An improved process for the preparation of compound of Formula V or its salts
a) providing compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
b) reacting compound of Formula IV or its salts with hydrazine hydrate optionally in the presence of a base to give compound of Formula V or its salts.

Formula V

7. The process as claimed in any of the preceding claims, wherein R' represents sulfonyl group selected from methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, 4-chlorobenzenesulfonyl group, p-toluenesulfonyl group, naphthalene-sulfonyl group, and dimethylaminonaphthylsulfonyl group, trimsyl, tripsyl, brosyl or nosyl groups prefereably nosyl.

8. The process as claimed in any of the preceding claims, wherein the base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or organic bases such as triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicyclo[2,2,2]octane.

9. The process as claimed in any of the preceding claims, wherein the compound of Formula V is further converted to compound of Formula VI

Formula VI
by reacting compound of Formula V with formamide optionally in the presence of a solvent to give compound of Formula VI followed by converting compound of Formula VI to Ibrutinib or its salts.

10. Compound of Formula IV or its salts.

Formula IV
wherein R' is sulfonyl group.

11. The compound as claimed in claim 10, wherein the compound of Formula IV can exist in crystalline or amorphous.

12. An improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts

wherein R1 is selected from substituted or unsubstituted cycloalkyl group optionally containing N, O or S, which comprises converting compound of Formula IV or its salts to compound of Formula I or its pharmaceutically acceptable salts.

Dated this Thirtieth (30th) day of June 2016.
__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883 , Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL INTERMEDIATES OF BRUTON’S TYROSINE KINASE INHIBITOR

We, SUVEN LIFE SCIENCES LIMITED,
a company incorporated under the companies act, 1956 having address at Serene Chambers, Road No 5, Avenue 7, Banjara Hills, Hyderabad, Telangana 500034, India

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to novel intermediates of Bruton’s Tyrosine Kinase inhibitor.
The present invention particularly relates to novel intermediates of Ibrutinib and PCI-29732.
The present invention more particularly relates to an improved process for the preparation of the intermediates which is commercially feasible.
The present invention also relates to a process for the preparation of Ibrutinib and PCI-29732 using the novel intermediates of the present invention.

BACKGROUND OF THE INVENTION
IBRUTINIB is an inhibitor of Bruton’s tyrosine kinase (BTK). It is sold under brand name Imbruvica® used for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia and waldenström’s macroglobulinemia. The chemical name for Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:

PCI-29732 is the reversible BTK inhibitor which has the following structure:

Ibrutinib is first disclosed in US 7,514,444 B2. This patent discloses process for the preparation of Ibrutinib which comprises, reacting 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine with tert-Butyl 3-hydroxypiperidine-1-carboxylate to give piperidine intermediate followed by reaction in presence of 1,4 dioxane and acryl chloride to give Ibrutinib.

The process is shown in the scheme given below:

Scheme I
US 7,718,662 B1 & US 6,921,763 B2 disclose a process for the preparation of Ibrutinib intermediate, which is shown in the scheme given below:

Scheme II
Bioinorganic & Medicinal Chemistry, 2010, 20(1), 112-116 also discloses a process for preparing Ibrutinib intermediate, which is shown in the scheme given below:

Scheme III
The process is also disclosed in IP.COM 14(7A), 1-3, 2014 and in WO 2014/082598 A1 which is shown in the scheme given below:
Scheme IV
WO 2015/172713 A1 discloses a process for preparing Ibrutinib intermediates which is shown in the schemes given below:
Scheme V
US 2015/0005277 A1 also discloses similar process for preparing Ibrutinib intermediates, which is shown in the scheme given below:
Scheme VI
The process enabled in the above literature is not applicable for industrial scale use as the reagents used in the above reactions are industrially not safe and environmentally not advisable, for example trimethylsilyl diazomethane is toxic and POCl3 generates more effluents in the plants and the yield of the final products were very low.

There is consequently a need for a more advantageous alternative method of preparing Ibrutinib and its intermediates. Said novel method should in particular be simpler and involves less number of steps, more industrially scalable, involves the use of cheaper reagents, employ mild reaction conditions, and at the same time provide Bruton’s tyrosine kinase inhibitors and its intermediates with high yields, high chemical purity and efficiency.

The present inventors have surprisingly found an improved process for preparing Ibrutinib and its intermediates, which involves less number of steps, more industrially scalable with high yields.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide novel intermediates of Bruton’s Tyrosine Kinase inhibitors.
Another objective of the present invention is to provide novel intermediates of Ibrutinib and PCI-29732.
Yet another objective of the present invention is to provide an improved process for the preparation of Ibrutinib intermediate which is environmentally safe and industrially feasible.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts,

Formula I
wherein R1 is selected from substituted or unsubstituted cycloalkyl group optionally containing N, O or S, which comprises:
a) converting compound of Formula III or its salts

Formula III
to compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
b) optionally isolating compound of Formula IV or its salts,
c) converting compound of Formula IV or its salts to compound of Formula I or its pharmaceutically acceptable salts.

In a preferred aspect, the present invention provides an improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts,

Formula I
wherein R1 is selected from substituted or unsubstituted cycloalkyl group optionally containing N, O or S, which comprises:
a) reacting compound of Formula II

Formula II
wherein X represents a suitable leaving group, with malononitrile optionally in the presence of a base to give compound of Formula III or its salts,

Formula III
b) converting compound of Formula III or its salts to compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
c) optionally isolating compound of Formula IV or its salts,
d) converting compound of Formula IV or its salts to compound of Formula I or its pharmaceutically acceptable salts.
In a more preferred aspect, the present invention provides an improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts,

Formula I
wherein R1 is selected from substituted or unsubstituted cycloalkyl group optionally containing N, O or S, which comprises:
a) providing compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
b) reacting compound of Formula IV or its salts with hydrazine hydrate optionally in the presence of a base to give compound of Formula V or its salts,

Formula V
c) converting compound of Formula V or its salts to compound of Formula I or its pharmaceutically acceptable salts.

In yet another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula IV or its salts:
a) reacting compound of Formula II

Formula II
wherein X represents a suitable leaving group, with malononitrile optionally in the presence of a base to give compound of Formula III or its salts

Formula III
b) converting compound of Formula III or its salts to compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group.

In yet another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula IV or its salts:
a) providing compound of Formula III or its salts,

Formula III
b) reacting compound of Formula III or its salts with a sulfonyl derivative to give compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group.

In still another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula V or its salts
a) providing compound of Formula IV or its salts

Formula IV
wherein R' is sulfonyl group,
b) reacting compound of Formula IV or its salts with hydrazine hydrate optionally in the presence of a base to give compound of Formula V or its salts.

Formula V
In still another preferred aspect, the present invention provides compound of Formula IV or its salts.

Formula IV
wherein R' is sulfonyl group.
In still another preferred aspect, the present invention provides use of compound of Formula IV or its salts in the preparation of compound of Formula I or its pharmaceutically acceptable salts.

In still another preferred aspect, the present invention provides crystalline or amorphous compound of Formula IV or its salts.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention provides an improved process for preparing compound of Formula I or its pharmaceutically acceptable salts.
The present invention further provides an improved process for preparing Ibrutinib or PCI-29732 intermediates.
In a preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula I or its pharmaceutically acceptable salts, which is commercially feasible, does not involve any side reactions, and contains fewer impurities.
In a preferred embodiment, the present invention provides an improved process for the preparation of Ibrutinib or its pharmaceutically acceptable salts, which is commercially feasible, does not involve any side reactions, and contains fewer impurities.
In yet another preferred embodiment, R' represents sulfonyl group, there are no particular restrictions on the sulfonyl group or derivative as long as it satisfies the definition. Examples include a methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, 4-chlorobenzenesulfonyl group, p-toluenesulfonyl group, naphthalene-sulfonyl group, and dimethylaminonaphthylsulfonyl group, trimsyl, tripsyl, brosyl or nosyl groups. Among these nosyl is preferable.

In yet another preferred embodiment, R1 in compound of Formula I represents

According to the reported literature and the inventor’s knowledge compound of Formula IV containing sulfonyl group and their use in the preparation of Ibrutinib is not known.

Accordingly the present invention provides an improved process for preparing Ibrutinib or its pharmaceutically acceptable salts, which comprises:
a) converting compound of Formula III or its salts

Formula III
to compound of Formula IVA or its salts

Formula IVA
wherein Ns represents nosyl group,
b) optionally isolating compound of Formula IVA or its salts,
c) converting compound of Formula IVA or its salts to Ibrutinib or its pharmaceutically acceptable salts.

In a preferred embodiment, the present invention provides an improved process for preparing Ibrutinib or its pharmaceutically acceptable salts, which comprises:
a) reacting compound of Formula III or its salts

Formula III
with nosyl chloride in the presence of a base, in a solvent to give compound of Formula IVA or its salts

Formula IVA
wherein Ns represents nosyl group,
b) optionally isolating compound of Formula IVA or its salts,
c) converting compound of Formula IVA or its salts to Ibrutinib or its pharmaceutically acceptable salts.

In a preferred embodiment, the present invention provides an improved process for the preparation of Ibrutinib or its pharmaceutically acceptable salts, which comprises:
a) reacting compound of Formula III or its salts

Formula III
with nosyl chloride in the presence of a base, in a solvent to give compound of Formula IVA or its salts

Formula IVA
wherein Ns represents nosyl group,
b) optionally isolating compound of Formula IVA or its salts,
c) reacting compound of Formula IV or its salts with hydrazine hydrate optionally in the presence of a base to give compound of Formula V or its salts,

Formula V
d) converting compound of Formula V or its salts to Ibrutinib or its pharmaceutically acceptable salts.

In a more preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula IVA or its salts, which comprises:
a) reacting compound of Formula IIA

Formula IIA
with malononitrile optionally in the presence of a base to give compound of Formula III or its salts

Formula III
b) reacting compound of Formula III or its salts

Formula III
with nosyl chloride in the presence of a base, in a solvent to give compound of Formula IVA or its salts

Formula IVA
wherein Ns represents nosyl group.
In a more preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula IVA or its salts, which comprises reacting compound of Formula III or its salts

Formula III
with nosyl chloride in the presence of a base, in a solvent to give compound of Formula IVA or its salts

Formula IVA
wherein Ns represents nosyl group.

In still another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula V or its salts
a) providing compound of Formula IVA or its salts

Formula IVA
wherein Ns represents nosyl group,
b) reacting compound of Formula IVA or its salts with hydrazine hydrate optionally in the presence of a base to give compound of Formula V or its salts.

Formula V
In still another preferred embodiment, the present invention provides compounds of Formulae IVA, IVB, IVC, IVD, IVE or IVF.

Formula IVA Formula IVB Formula IVC Formula IVD

Formula IVE Formula IVF
In still another preferred embodiment, the present invention provides the use of compounds of Formulae IVA, IVB, IVC, IVD, IVE or IVF in the preparation of Ibrutinib or its pharmaceutically acceptable salts.
In yet another preferred embodiment, the present invention provides a process for the preparation of Ibrutinib intermediate of Formula IV or V, wherein any of the reactions may be carried out in-situ in order to prepare the intermediates of Formulae IV or V.
In yet another preferred embodiment compound of Formula II is reacted with malononitrile in the presence of base in a solvent to give compound of Formula III in the amount of 86 % yield with HPLC purity >99%.
In yet another preferred embodiment compound of Formula III is reacted with nosyl chloride in the presence of a base and in a solvent or mixture of solvents to give compound of Formula IV which is isolated and purified to give highly pure compound of Formula IV.
In yet another preferred embodiment, compound of Formula III is reacted with nosy chloride in the presence of a base and in a solvent or mixture of solvents to give compound of Formula IV which in-situ reacts with hydrazine hydrate to give compound of Formula V, which is isolated as a crystalline solid with the 98.4% yield with >99% HPLC.

In a preferred embodiment, compound of Formula V is converted to compound of Formula VI

Formula VI
by reacting compound of Formula V with formamide optionally in the presence of a solvent to give compound of Formula VI.
In a preferred embodiment, compound of Formula VI is converted to Ibrutinib or its pharmaceutically acceptable salts using the process disclosed in US 7,514,444 B2.
In yet another preferred embodiment, compound of Formula V is treated with N-protecting group to give N-protected derivative of compound of Formula V which is converted to Ibrutinib or its pharmaceutically acceptable salts.
In yet another embodiment suitable base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or organic bases such as triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.
In yet another embodiment suitable solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.
In yet another embodiment of the present invention X represents a suitable leaving group which is selected from chlorine, bromine, iodine, fluorine, amino acid, substituted or unsubstitutedaryloxy, alkoxyalkyloxy, aryloxyalkyloxy, C1 to C4 alkoxy, sulfonate esters, mono, di, or triphosphate ester, trityl, monomethoxy-trityl, trialkylsilyl, isopropyldialkylsilyl, alkyldiisopropylsilyl, triisopropylsilyltetraisopropyldisilyl, t-butyldialkylsilyl or t-butyldiphenylsilyl or trifluoroacetate or alkylsulfonyloxy group such as methanesulfonyloxy and the like or trifluoroalkylsulfonyloxy such as a trifluoromethanesulfonyloxy and the like or arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy, fluorosulfonyl, camphorsulfonyl and the like or phenoxides such as pentafluorophenoxide, p-NO2-phenoxide and the like or thio phenyls and the like or 2,2-dimethyl-3-(3-(trifluoromethyl)phenyl)propanoyl chloride and the like; bicyclic compounds such as indole, benzotriazoles or tricyclic compounds

As used herein the term “pharmaceutical acceptable salts or salts” refers to acid addition salts such as hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, maleic, succinic, and citric.
In yet another embodiment N-protection is carried out by reacting free amine of compound of Formula V with Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), p-Methoxybenzyl carbonyl (Moz or MeOZ), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), benzyl Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), sulfonamides and R2 represents ethyl group to give suitable N-protected derivatives.

In yet another embodiment N-deprotection may be carried out in the presence of metal catalyst, hydrogen source, wherein the metal catalyst is selected from Pd, Ni, Pt, Rh or the deprotection may carried out in the presence of an acid which is selected from strong acids such as HCl or CF3COOH or the deprotection may carried out in the presence of a base, which is selected from primary or secondary amines.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:
EXAMPLE 1: Preparation of 2-(hydroxy(4-phenoxyphenyl)malononitrile, compound of Formula III:
Method A:
To a mixture of toluene (20 mL), THF (5 mL), malononitrile (1.41g. 0.021 mol) and 4-phenoxybenzoyl chloride (5g, 0.021 mol), triethylamine (4.24 g, 0.042 mol) was added and stirred for 1hr at (-)10 to 0°C. The resulting mixture allowed to RT and stirred for 12 hrs. After completion of reaction, mass quenched into ice-water (50 mL), pH adjusted to 2.0-2.5 with conc.HCl and then extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine solution (25 mL), dried and concentrated to give the crude product Formula III (3.5 g 60% yield) with HPLC Purity 88%.

Method B:
To a suspension of sodium methoxide(SMO) powder (119 g, 2.20 mol) in THF (10 vol) was added a solution of malononitrile (90.8 g, 1.37 mol) in THF (40 mL) at (-) 5 to 0°C over a period of 30 minutes. The resulting mixture allowed to warm to RT and stirred for 30 minutes. The 4-phenoxybenzoyl chloride (128 g, 0.55 mol)was added over a period of 1hr and stirred for 30 minutes at (-) 5 to 0°C. The resulting mixture allowed to come to RT and stirred for 12 hrs. After completion of reaction, the reaction mass quenched into ice-water (1.0 Lts), and pH adjusted to 2.0-2.5 with conc.HCl then extracted with ethyl acetate (2x250 mL). The combined organic layers were washed with brine solution (100 mL), dried and concentrated to give the crude product. To the crude product, water (500 mL) was added and stirred for 2 hrs at RT. Filtered the precipitate and washed with water (2x150 m), the product is dried to get off white solid of Formula III (123 g, 86 % yield) with HPLC purity >99%.
MR: 160-162°C; IR (KBr cm-1): 2961, 2225, 2240, 1579, 1391 and 1254; 1H-NMR (400 MHz, DMSO): d 7.01 (d, 2H), 7.08 (d, 2H), 7.21 (t, 1H), 7.44 (t, 2H), 7.66 (d, 2H), 8.50 (s, 1H); 13 C-NMR (100 mHz, DMSO): d 54.79, 117.53, 120.24, 125.02, 130.12, 130.69, 130.76, 155.70, 160.25 and 185.76; MS: m/z 261 [M]-1.

EXAMPLE 2: Preparation of compound of Formula V:
Method A:
To a suspension of 2-(Hydroxy(4-phenoxyphenyl)malononitrile (1 g, 0.0038 mol) and dimethylaminopyridine (DMAP) (0.046g 0.00038 mol) in dichloromethane (6 vol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.16g, 0.0076 mol) was added and stirred for 10 minutes at 0-5 °C. 4-nitrobenzenesulfonyl chloride (1.5 g, 0.0067 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (5 mL), followed by brine solution (5 mL) and concentrated to get the crude bisyl derivative, which is dissolved in methanol (5 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (1 mL) was added 0-10°C and stirred for 6 hrs at RT. Water (4 mL) was added and stirred for 1 hr at RT to give product Formula V, 37% conversion was observed by HPLC.

Method B:
To a suspension of 2-(Hydroxy(4-phenoxyphenyl)malononitrile (1 g, 0.0038 mol) and dimethylaminopyridine (DMAP) (0.046g 0.00038 mol) in dichloromethane (6 vol), Triazabicyclodecene (TBD) (1.g, 0.0071 mol) was added and stirred for 10 minutes at 0-5 °C. 4-nitrobenzenesulfonyl chloride (1.5 g, 0.0067 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (5 mL), followed by brine solution (5 mL) and concentrated to get the crude nosyl derivative, which is dissolved in methanol (5 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (1 mL) was added 0-10°C and stirred for 6 hrs at RT. Water ( 4 mL) was added and stirred for 1 hr at RT to give product Formula V, 20% conversion was observed by HPLC.

Method C:
To a suspension of 2-(Hydroxy(4-phenoxyphenyl)malononitrile (1 g, 0.0038 mol) in dichloromethane (6 vol) dimethylaminopyridine (DMAP) (0.46g 0.0038 mol) was added and stirred for 10 minutes at 0-5 °C. 4-nitrobenzenesulfonyl chloride (1.5 g, 0.0067 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (5 mL), followed by brine solution (5 mL) and concentrated to get the crude nosyl derivative, which is dissolved in methanol (5 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (1 mL) was added 0-10°C and stirred for 6 hrs at RT. Water ( 4 mL) was added and stirred for 1 hr at RT. Filtered the precipitate and washed with 10 % methanol and water mixture (5 mL) and product is dried to get solid Formula V (0.5 g, 48 % yield with 88% purity).

Method D:
To a suspension of 2-(Hydroxy (4-phenoxyphenyl) malononitrile (60 g, 0.229 mol) and dimethylaminopyridine (DMAP) (2.76 g 0.0226 mol) in dichloromethane (6 vol), diisopropylethylamine (DIPEA) (59.19 g, 0.458 mol) was added and stirred for 10 minutes at 0-5°C. 4-nitrobenzenesulfonyl chloride (Nosyl chloride) (88.39 g, 0.398 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (50 mL), followed by brine solution (50 mL) and concentrated to get the crude nosyl derivative, which is dissolved in methanol (300 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (60 mL) was added 0-10°C and stirred for 6 hrs at RT. Water (240 mL) was added and stirred for 1 hr at RT. Filtered the precipitate and washed with 10 % methanol and water mixture (100 mL) and dried the precipitate to obtain crude product (62 g, 98.4% yield).The product was purified with methanol to obtain crystalline solid Formula V with >99% HPLC Purity.
IR (KBr cm-1): 3424, 3347, 3146, 2211, 1638 and 1244: 1H-NMR (400 MHz, DMSO): d 6.46 (s, 2H), 7.06-7.19 (m, 5H), 7.41 (t, 2H), 7.79 (d, 2H) and 12.10 (s, 1H); 13 C-NMR (100 mHz, DMSO): d 69.87, 116.80, 119.06, 119.40, 124.24, 127.89, 130.60, 150.01, 155.09, 156.71 and 157.45; MS: m/z 277 [M]+1.

EXAMPLE 3: Preparation of compound of Formula V:
To a suspension of 2-(hydroxy(4-phenoxyphenyl)malononitrile (0.5 g, 0.002 mol) and dimethylaminopyridine (DMAP) (0.024g, 0.0024 mol) in dichloromethane (6 vol), diisopropylethylamine (DIPEA) (0.5 g, 0.004 mol) was added and stirred for 10 minutes at 0-5 °C. 4-methylbenzenesulfonyl chloride (1.6 g, 0.003 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (5 mL), followed by brine solution (5 mL) and concentrated to get the crude tosyl derivative, which is dissolved in methanol (5 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (1 mL) was added 0-10°C and stirred for 6 hrs at RT. Water (4 mL) was added and stirred for 1 hr at RT to give product Formula V, 25% conversion was observed by HPLC.

EXAMPLE 4: Preparation of compound of Formula V:
To a suspension of 2-(Hydroxy(4-phenoxyphenyl)malononitrile (0.5 g, 0.0020mol) and dimethylaminopyridine (DMAP) (0.024 g 0.0002 mol) in dichloromethane (6 vol), diisopropylethylamine (DIPEA) (0.5 g, 0.004 mol) was added and stirred for 10 minutes at 0-5°C. Methanesulfonyl chloride (0.34 g, 0.0030 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (5 mL), followed by brine solution (5 mL) and concentrated to get the crude mesyl derivative, which is dissolved in methanol (5 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (0.5 mL) was added 0-10°C and stirred for 6 hrs at RT. Water (4.5 mL) was added and stirred for 1 hr at RT to give product Formula V, 38% conversion was observed by HPLC.

EXAMPLE 5: Preparation of compound of Formula V:
Method A:
To a suspension of 2-(hydroxy(4-phenoxyphenyl)malononitrile (0.5g, 0.0020 mol) and dimethylaminopyridine (DMAP) (0.023 g 0.00019 mol) in dichloromethane (6 vol), diisopropylethylamine (DIPEA) (0.5 g, 0.004 mol) was added and stirred for 10 minutes at 0-5 °C. benzenesulfonyl chloride (0.42 g, 0.0023 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (5 mL), followed by brine solution (5 mL) and concentrated to get the crude bisyl derivative, which is dissolved in methanol (5 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (1 mL) was added 0-10°C and stirred for 6 hrs at RT. Water (4 mL) was added and stirred for 1 hr at RT to give product Formula V, 30% conversion was observed by HPLC.

Method B:
To a suspension of 2-(Hydroxy(4-phenoxyphenyl)malononitrile (0.5 g, 0.0020mol) and dimethylaminopyridine (DMAP) (0.024 g 0.0002 mol) in methyl tert-butylether (MTBE) (6 vol), diisopropylethylamine (DIPEA) (0.5 g, 0.004 mol) was added and stirred for 10 minutes at 0-5 °C. benzenesulfonyl chloride (0.42 g, 0.0023 mol) was added to reaction mixture and stirred for 15 minutes at 0-5°C. The resulting mixture allowed to warm to RT and stirred for 36 hrs. After completion of reaction, mass cooled and washed with water (5 mL), followed by brine solution (5 mL) and concentrated to get the crude bisyl derivative, which is dissolved in methanol (5 mL) and cooled to 0°C. To the crude solution hydrazine hydrate (1 mL) was added 0-10°C and stirred for 6 hrs at RT. Water ( 4 mL) was added and stirred for 1 hr at RT to give product Formula V, 7% conversion was observed by HPLC.

EXAMPLE 6: Preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine:
Method A:
The mixture of formamide (30 mL) and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (5 g, 0.018 mol) were heated and maintained at 180-185°C for 4-5 hrs. After completion of reaction, reaction mass cooled and maintained for 1 hr at RT. Filtered the solid and washed with methanol (2 x 10 mL), the product is dried to get ash color solid (4 g, 74% yield) with >98% HPLC purity. The product was purified with methanol to obtain crystalline solid compound of Formula VI with 99.66% HPLC Purity & Individual Impurity 0.08%).
Method B:
The mixture of formamide (100 mL) and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (10 g, 0.036 mol) were heated and maintained at 180-185°C for for 4-5 hrs. After completion of reaction, reaction mass cooled and maintained for 1 hr at RT. Water (100 mL) was added to reaction mass and stirred for 1 hr at RT. Filtered the solid and washed with water (2 x 50 mL) and then methanol (2 x 10 mL), the product is dried to get ash color solid (9.7 g, 88.9% yield) with >97% HPLC purity. The product was purified with dimethylformamide (DMF) to obtain crystalline solid 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine with 99.78% HPLC Purity & Individual Impurity 0.08%).