FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION: HETEROARYL BORONIC ACIDS
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to the novel heteroaryl boronic acids.
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 the novel heteroaryl boronic acids. The invention also relates to processes for the preparation of compounds of the present invention.
Background of the Invention
Boronic acid compounds and their derivatives, e.g. esters, are used extensively in organic chemistry as chemical building blocks and intermediates. Arylboronic acids and their esters are highly popular synthetic intermediates in organic synthesis for their ease of conversion to other functional groups (such as phenols and aryl halides as described in, Tetrahedron Lett. 1995, 36, 5117 and Synlett 1998, 141.
Aryl boronic acids are now in substantial commercial use to synthesize biaryl compounds by the palladium catalyzed cross-coupling "Suzuki" reaction as described by Suzuki, A. Pure Appl. Chem. 1994, 66, 213, A. Suzuki, et al, Syn. Commun.(1981) 513519; Y. Young, et al., Acta Chem. Scand.. (1939) 47:221230; G.B. Smith, et al., J. Org. Chem. (1994) 598:81518156; S. Sengupta, et al., J. Org. Chem. (1997)62:34053406.
Summary of the Invention
The present invention relates to the novel heteroaryl boronic acids of Formula I.
R3
A~^q R2>=\ /OH
hr\ ^ 0H Ri
Formula I
wherein,
Ri is selected from the group of hydrogen, Ci-C6 alkyl, halogen and CN;
R.2 is halogen or OR5, wherein R5 is selected from the group of hydrogen, C|-C6
alkyl;
R3 is selected from the group of hydrogen, Ci-C6 alkyl, and halogen;
X is selected from the group of CH2, S, O, -NR4 wherein R4 is selected from the
group of hydrogen and alkoxy carbonyl;

p and q each and independently selected from 0, 1, or 2.
Detailed Description of the Invention
The present invention relates to the novel heteroaryl boronic acids of Formula I.
R3
R2,)=\ £>H

Ri
Formula I wherein,
R1 is selected from the group of hydrogen, C1-C6 alkyl, halogen and CN;
R2 is halogen or OR5, wherein R5 is selected from the group of hydrogen, C1-C6
alkyl;
R3 is selected from the group of hydrogen, C]-C6 alkyl, and halogen;
X is selected from the group of CH2, S, O, -NR4 wherein R4 is selected from the
group of hydrogen and alkoxy carbonyl; p and q each and independently selected from 0, 1, or 2.
Description of terms In above definitions
"C1-C6 alkyl" refers to saturated, straight or branched chain hydrocarbon having C1-C6 number of carbon atoms such as methyl, ethyl, propyl, isopropyl and so on.; "Alkoxy carbonyl" refers to an
-C(O)O- C1-C6 alkyl
for example methoxy carbonyl, ethoxy carbonyl, propoxy carbonyl, isopropyloxy carbonyl, butyloxy carbonyl and so on.; "halogen" means atom selected from atom such as fluorine, chlorine, bromine;
Some examples of heteroaryl boronic acids represented by the general Formula-1 are as follows:
1. (RS)-[6-(3-Hydroxytetrahydro-3-thienyl)pyridin-3-yl]boronic acid,
2. (RS)-[6-(3-Methoxytetrahydro-3-thienyl)pyridin-3-yl]boronic acid,
3. (RS)-[6-(3-Hydroxytetrahydrofuran-3-yl)pyridin-3-yl]boronic acid,

4. (RS)-{6-[l-(tert-Butoxycarbonyl)-3-hydroxypyrrolidin-3-yl]pyridin-3-yl} boronic acid,
5. 3[6-(3-Hydroxythietan-3-yl)pyridin-3-yl]boronic acid,
6. [6-(3-Hydroxyoxetan-3-yl)pyridin-3-yl]boronic acid,
7. {6-[l-(tert-Butoxycarbonyl)-3-hydroxyazetidin-3-yl]pyridin-3-yl}boronic acid,
8. [6-(4-Hydroxytetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]boronic acid,
9. 1,5-Anhydro-2,4-dideoxy-3-C-[5-(dihydroxyboryl)pyridin-2-yl]-2-methyl-1 -thiopentitol,
10. [6-(4-Hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl]boronic acid,
11. {6-[l-(tert-Butoxycarbonyl)-4-hydroxypiperidin-4-yl]pyridin-3-yl}boronic acid,
12. {6-[l-(tert-Butoxycarbonyl)-4-methoxypiperidin-4-yl]pyridin-3-yl} boronic acid,
13. [6-(4-Methoxytetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]boronic acid,
14. [6-(4-Fluorotetrahydro-277-thiopyran-4-yl)pyridin-3-yl]boronic acid,
15. (RS)-[6-(3-Hydroxytetrahydro-3-thienyl)-5-methylpyridin-3-yl]boronic acid,
16. [6-(3-Hydroxythietan-3-yl)-5-methylpyridin-3-yl]boronic acid,
17. [6-(4-Hydroxytetrahydro-2H-thiopyran-4-yl)-5-methylpyridin-3-yl]boronic acid.
The compounds of present invention are useful as chemical building blocks and intermediates in the preparation of chemicals, agrochemicals & pesticides, drugs & drug intermediates, dyes & dye intermediates, fertilizers, petrochemicals, speciality chemicals, textile chemicals and the like.
The present invention further provides a method of preparation of the compound of formula I, which comprises:
(i) reacting compound of formula V either with halogenating reagent such as DAST in organic solvent such as dichloromethane and chloroform or reacting compound of formula V with alkyl halides in an organic solvent such as dimethyl formamide and mixture of dimethyl sulphoxide and tetrahydrofuran in presence of base such as sodium hydride or sodium hydroxide or potassium hydroxide to provide compound of formula VI;

Formula VI, R2= F or -O-alkyl
(ii) reacting the compound of formula V or compound obtained either in step (i) with trialkyl borate, for example trimethyl borate, triethyl borate, in the presence of a base such as n-butyl lithium in an organic solvent mixture such as tetrahydrofuran and toluene, wherein a reaction mixture containing an heteroaryl boronic acid alkyl diester is produced and,



,0-alkyl O-alkyl

(iii) subjecting said reaction mixture of step (ii) for effective hydrolysis by acid such as aqueous hydrochloric acid, followed by isolation of compound of formula-I by adjusting the pH of the reaction mixture

An embodiment of the invention is to provide methods of preparation of the compound of formula I as depicted in scheme-I. As per scheme-I, heteroatom bearing ketone compound of formula III is reacted with unsubstituted or substituted 2,5-dibromopyridine compound of formula IV in the presence of a base such as n-butyl lithium in a solvent such as toluene at a temperature between -70 °C to 35 °C for 4 to 6 hours to provide heterocyclic aromatic hydroxyl compound of formula V (Tetrahedron Lett., 41, 4335, 2000). The compound of formula V is optionally reacted with fluorinating reagent such as DAST in a solvent such as dichloromethane or chloroform at a temperature between -40 °C to 30 °C for 1 to 4 hour to furnish fluoroheterocyclic bromo aryl compound of formula VI., Compound of formula V is optionally reacted with alkyl halides for example methyl iodide in presence of a base such as sodium hydride in a solvent such as N,N-dimethylformamide at a temperature between 0 °C to 30 °C for 3 to 4 hour to furnish methoxyheterocyclic bromo aryl

compound of formula VI. The compound of formula V-VI is reacted with trialkyl borate for example triethyl borate, in the presence of a base such as n-butyl lithium in a solvent mixture such as tetrahydrofuran and toluene at a temperature between -40 °C to +10 °C for 1 to 4 hour followed by treatment with aqueous hydrochloric acid and adjusting the pH to 7 to furnish heterocyclic aryl boronic acid of formula I.



■*► X
Ri
Formula VI, R2=-OR5



R,
Tialkyl borate v
Br ► X
-»► X
(FRi
Formula I

Br-tx /-Br N-
Formula IV

Scheme-1
wherein,
Ri is selected from the group of hydrogen, CpC6 alkyl, halogen and CN;
R.2 is halogen or OR5, wherein R5 is selected from the group of hydrogen, CrC6
alkyl;
R3 is selected from the group of hydrogen, C1-C6 alkyl, and halogen;
X is selected from the group of CH2, S, O, -NR4 wherein R4 is selected from the
group of hydrogen and alkoxy carbonyl; p and q each and independently selected from 0, 1, or 2.
A further embodiment of the invention is to provide methods of preparation of the compound of formula I, which comprises:

(i) reacting the compound of formula V with trialkyl borate, for example triethyl borate, in the presence of a base such as n-butyl lithium in a solvent mixture such as tetrahydrofuran and toluene at a temperature between -40 °C to -20 °C for 1-4 hour, wherein a reaction mixture containing an heteroaryl boronic acid alkyl diester is produced; and,
(ii) subjecting said reaction mixture of step (i) for effective hydrolysis by acid such as aqueous hydrochloric acid, followed by adjustment of pH to 7 and isolation to provide aryl boronic acid of formula I as depicted in following structure.
R3 A~*VR2/
Ri wherein R.2 is OH Formula-I

A further embodiment of the invention is to provide methods of preparation of the compound of formula I, which comprises:

(i) reacting compound of formula V either with halogenating reagent such as DAST in organic solvent such as dichloromethane and chloroform to provide compound of formula VI (where R2 is F),
(ii) reacting the compound obtained in step (i) with trialkyl borate, for example triethyl borate, in the presence of a base such as n-butyl lithium in a solvent mixture such as tetrahydrofuran and toluene at a temperature between -40 °C to -20 °C for 1 -4 hour, wherein a reaction mixture containing an heteroaryl boronic acid alkyl diester is produced; and,
(iii) subjecting said reaction mixture of step (ii) for effective hydrolysis by acid such as aqueous hydrochloric acid, followed by adjustment of pH to 7 and isolation to provide aryl boronic acid of formula I as depicted in following structure.
R3

A further embodiment of the invention is to provide methods of preparation of the compound of formula I, which comprises:
(i) reacting compound of formula V with alkyl halides or alkenyl halide for example methyl iodide, ethyl iodide and the like in presence of a base such as sodium hydride in a solvent such as N,N-dimethylformamide at a temperature between 0 °C to 30 °C for 3-4 hour to provide compound of formula VI,
(ii) reacting the compound obtained in step (i) with trialkyl borate, for example triethyl borate, in the presence of a base such as n-butyl lithium in a solvent mixture such as tetrahydrofuran and toluene at a temperature between -40 °C to -20 °C for 1-4 hour, wherein a reaction mixture containing an aryl boronic acid alkyl diester is produced; and,
(iii) subjecting said reaction mixture of step (ii) for effective hydrolysis by acid such as aqueous hydrochloric acid, followed by adjustment of pH to 7 and isolation to provide aryl boronic acid of formula I as depicted in following structure.
R3

Ri Formula-I While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. Following examples illustrate the methods of preparation of the compounds of the invention and are provided only as examples, but not to limit the scope of the compounds of the present invention.
Experimental
All of the starting materials are prepared by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the following schemes are as defined above. Optically pure material could be obtained either by one of a number of asymmetric synthesis or alternatively by resolution from a racemic mixture. Mass spectra were recorded on Waters Micromass Quatro- II instrument.

General method to prepare intermediates of invention
General Method-1: Preparation of 2-substituted-3-(unsubstituted/substituted)-5-bromopyridine:
R3 R3
. r° Br-( /^Br - * r~i )~Br
R1 R1
To the mixture of 2,5-dibromo-3-(unsubstituted/substituted)-pyridine (10 mmol) in toluene (40 times volume) was added a base such as n-butyllithium, lithiumhexmethyldilazane, sec-butyllithium, methyllithium, preferably n-butyllithium (11.5 mmol) at -40 °C to -78 °C, preferably -78 °C, over a period of 30 minutes. The reaction mixture was stirred at -78 °C for 1 to 4 hours, preferably 2 hours. Heteroatom bearing cyclic ketone (11.6 mmol) was added over a period of 10 to 45 minutes, preferably 20 minutes. The reaction mixture was gradually allowed to warm at 25 °C to 35 °C and stirred for 1 to 10 hours preferably 6 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. Layers were separated. Organic layer was concentrated in vacuum and residue was purified on silica gel column chromatography to provide title compound in 40% to 70% yield.
General Method-2: Preparation of 2-substituted-3-(unsubstituted/substituted)-pyridin-5-yl-boronic acid:

0r< N-^ OH
Ri
To the mixture of (2-substituted-3-(unsubstituted/substituted)-5-bromopyridine (10.0 mmol) and trialkylborate ester such as trimethylborate, triethyl borate, tri-n-butylborate, preferably triethylborate (11.6 mol) suspended in toluene :tetrahydrofuran mixture (20 times volumes in 4:1 ratio) was added n-butyllithium (29.0 mol) at -40 °C to - 78 °C, preferably -78 °C over period of 30 minutes. The mixture was stirred at -40 °C to -78 °C for 1 to 3 hours, preferably 2 hours. The reaction mixture was quenched by addition of 4N aqueous hydrochloric acid at -40 °C and was stirred at 25 °C to 35 °C for 1to 3 hours, preferably 1 hour. Layers were

separated and aqueous layer was adjusted to pH 7 by the addition of ION aqueous sodium hydroxide solution. The suspension was stirred for 1 to 12 hours to provide complete precipitation. The precipitated solid was filtered at suction and washed with water to provide title compound in 42% to 80% yield.
Example-1 : Preparation of (RS)-3-(5-bromopvridin-2-vl)tetrahvdrothiophene-3-ol To the mixture of 2,5-dibromo pyridine (60 g, 0.253 mol) in toluene (2.4 lit) was added n-butyl lithium (190 ml, 0.288 mol) at -78 °C over a period of 30 minutes. The reaction mixture was stirred at -78 °C for 2 hours. Dihydrothiophen-3(2H)-one (30 g, 0.294 mol) was added over a period of 10 minutes. The reaction mixture was gradually allowed to warm at 25 °C to 35 °C and stirred for 6 to 8 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (500 ml). Layers were separated. Organic layer was concentrated in vacuum to provide oily residue, which was purified on silica gel column chromatography to provide title compound in 50% (32 g) yield as oil. Mass (M+l) for C9H,oBrNOS = 261.1
Example-2 : Preparation of (RS)-3-(5-bromopyridin-2-yl)tetrahvdrofuran-3-ol
By using the procedure described in Example-1 and by using dihydrofuran-3(2H)-one
in the place of dihydrothiophen-3(2H)-one, title compound was obtained in 42%
yield.
Mass (M+l) for C9H10BrNO2 = 245.1
Example-3 : Preparation of (RS)-tert-butyl 3-(5-bromopyridin-2-yl)-3-hydroxy
pyrrolidine-1 -carboxylate
By using the procedure described in Example-1 and by using tert-butyl 3-
oxopyrrolidine-1-carboxylate in the place of dihydrothiophen-3(2H)-one, title
compound was obtained in 48% yield.
Mass (M+l) for C,4H,9BrN203 = 344.1
Example-4 : Preparation of 3-(5-bromopyridin-2-yl)thietan-3-ol
By using the procedure described in Example-1 and by using thietan-3-one in the place of dihydrothiophen-3(2H)-one, title compound was obtained in 40%o yield. Mass (M+l) for C8H8BrNOS = 247.1

Example-5 : Preparation of 3-(5-bromopyridin-2-yl)oxetan-3-ol By using the procedure described in Example-1 and by using oxetan-3-one in the place of dihydrothiophen-3(2H)-one, title compound was obtained in 42% yield. Mass (M+l) for C8H8BrN02 = 231.1
Example-6 : Preparation of tert-butyl 3-(5-bromopyridin-2-yl)-3-hydroxyazetidine-l-
carboxylate
By using the procedure described in Example-1 and by using tert-butyl 3-
oxoazetidine-1 -carboxylate in the place of dihydrothiophen-3(2H)-one, title
compound was obtained in 48% yield.
Mass (M+l) for Ci3Hi7BrN203 = 330.1
Example-7 : Preparation of 4-(5-bromopyridin-2-yl)tetrahvdro-2H-thiopvran-4-ol By using the procedure described in Example-1 and by using
tetrahydro-4H-thiopyran-4-one in the place of dihydrothiophen-3(2H)-one, title compound was obtained in 50%) yield. Mass (M+l) for C,oH,2BrNOS = 275.1
Example-8 : Preparation of l,5-anhydro-3-C-(5-bromopyridin-2-yl)-2,4-dideoxy-2-
methyl-1 -thiopentitol
By using the procedure described in Example-1 and by using 3-methyltetrahydro-4//-
thiopyran-4-one (prepared as per procedure described in J. Org. Chem.; 48(6), 1983, p
794) in the place of dihydrothiophen-3(2H)-one, the title compound was obtained in
49% yield.
Mass (M+l) for C11H14BrNOS = 289.1
Example-9 : Preparation of 4-(5-bromopyridin-2-yl)tetrahydro-2H-pyran-4-ol
By using the procedure described in Example-1 and by using tetrahydro-4H-pyran-4-
one in the place of dihydrothiophen-3(2H)-one, title compound was obtained in 40%>
yield.
Mass (M+l) for C10H12BrNO2 = 259.1

Example-10 : Preparation of tert-butyl 4-(5-bromopyridin-2-vl)-4-hydroxypiperidine-
1-carboxylate
By using the procedure described in Example-1 and by using tert-butyl 4-
oxopiperidine-1-carboxylate in the place of dihydrothiophen-3(2H)-one, title
compound was obtained in 52% yield.
Mass (M+l) for Ci5H2iBrN203 = 358.1
Example-11 : Preparation of 5-bromo-2-(4-methoxytetrahydro-2H-thiopyran-4-yPpyridine
A mixture of 4-(5-bromopyridin-2-yl)tetrahydro-2H-thiopyran-4-ol (13.0 mmol) and
powdered potassium hydroxide (26.1 mmol) was stirred at 0 °C in the 1 :1
mixture of dimethylsulfoxide and tetrahydrofuran (35 ml) for 1 hour. Methyl iodide (19 mmol) was added at 0 °C, and the reaction mixture was stirred for 12 hours. Reaction mixture was poured in water and extracted with ethyl acetate. Organic layer was concentrated under vacuum and residue was purified over silica gel column chromatography to provide title compound in 61% yield. Mass (M+l) for C,,Hl4BrNOS = 289.1
Example-12 : Preparation of tert-butyl 4-(5-bromopyridin-2-yl)-4-methoxypiperidine-1 -carboxylate
By using procedure described in Example-11 and using tert-butyl 4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-l -carboxylate in place of 4-(5-bromopyridin-2-yl)tetrahydro-2H-thiopyran-4-ol, title compound was synthesized in 70% yield. Mass (M+l) for C11H14BrNOS = 372.1
Example-13 : Preparation of (RS)- 5-bromo-2-(3-methoxytetrahvdro-3-
Thienyl)pyridine
By using the procedure described in Example-11 and by using (RS)-3-(5-
bromopyridin-2-yl)tetrahydrothiophene-3-ol in the place of 4-(5-bromopyridin-2-
yl)tetrahydro-2H-thiopyran-4-ol, title compound was obtained in 40% yield.
Mass (M+l) for C,0H|2BrNOS = 275.1
Example-14 : Preparation of 5-bromo-2-(4-fluorotetrahydro-2H-thiopyran-4-vDpyridine

To a mixture of 4-(5-bromopyridin-2-yl)tetrahydro-2H-thiopyran-4-ol (15 mmol) in dichloromethane (50 ml) was added diethylaminosulfurtrifluoride (DAST, 21.5 mmol) at 0 °C, the reaction mixture was stirred at 35 °C for 12 hours. The reaction mixture was quenched with water and extracted with dichloromethane. Evaporation of organic layer and purification of resultant residue using silica gel column chromatography provided title compound in 27% yield.
Mass (M+l) for C10H11BrFNS = 277.1
Example-15 : Preparation of (RS)-3-(5-bromo-3-methvlpvridin-2-yl)tetrahydro
thiophene-3-ol
By using the procedure described in Example-1 and by using 2,5-dibromo-3-
methylpyridine in the place of 2,5-dibromopyridine, title compound was obtained in
52% yield.
Mass (M+l) for C10H12BrNOS = 275.1
Example-16 : Preparation of 3-(5-bromo-3-methvlpvridin-2-yl)thietan-3-ol
By using the procedure described in Example-1 and by using 2,5-dibromo-3-
methylpyridine in the place of 2,5-dibromoyridine, and thietan-3-one in the place of
dihydrothiophen-3(2H)-one, the title compound was obtained in 48% yield.
Mass (M+l) for C9H10BrNOS = 261.1
Example-17 : Preparation of 4-(5-bromo-3-methylpyridin-2-yl)tetrahvdro-2H-
thiopyran-4-ol
By using the procedure described in Example-1 and by using 2,5-dibromo-3-
methylpyridine in the place of 2,5-dibromoyridine, and tetrahydro-4H-thiopyran-4-
one in the place of dihydrothiophen-3(2H)-one, the title compound was obtained in
62% yield.
Mass (M+l) for CnH14BrNOS = 289.1
Example-18 : Preparation of (RS)-[6-(3-hydroxytetrahydro-3-thienvl)pvridin-3-yllboronic acid
To the mixture of (RS)-3-(5-bromopyridin-2-yl)tetrahydrothiophene-3-ol (25 g, 0.961 mmol) and triethyl borate (60.82 g, 1.15 mol) suspended in toluene :tetrahydrofuran mixture (400 ml :100 ml) was added n-butyllithium (179 ml, 2.88 mol) at - 78 °C

over period of 30 minutes. The mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched by addition of 4N aqueous hydrochloric acid (225 ml) at -40 °C and was stirred at 25 °C to 35 °C for 1 hour. Layers were separated and aqueous layer was adjusted to pH 7 by the addition of ION aqueous sodium hydroxide solution (50 ml). The suspension was stirred for 1 hour to provide complete precipitation. The precipitated solid was filtered at suction and washed with water to provide title compound in 72% (15 g) yield. Mass (M+l) for C9H,2BN03S = 226.1
Example-19 : Preparation of (RS)-[6-(3-methoxytetrahydro-3-thienvl)pvridin-3-
Yl]boronic acid
By using the procedure described in Example-18 and by using (RS)-5-bromo-2-(3-
methoxytetrahydro-3-thienyl)pyridine in the place of (RS)-3-(5-bromopyridin-2-
yl)tetrahydrothiophene-3-ol, the title compound was obtained in 71% yield.
Mass (M+l) for Cl0Hi4BNO3S = 240.1
Example-20 : Preparation of (RS)-[6-(3-hydroxytetrahydrofuran-3-thienyl)pyridin-3-
yl]boronic acid
By using the procedure described in Example-18 and by using (RS)-3-(5-
bromopyridin-2-yl)tetrahydrofuran-3-ol in the place of (RS)-3-(5-bromopyridin-2-
yl)tetrahydrothiophene-3-ol, the title compound was obtained in 76% yield.
Mass (M+l) for C9H12BN04 = 210.1
Example-21 : Preparation of (RS)-{6-[l-(tert-butoxycarbonyl)-3-hydroxypyrrolidin-
3-yl]pvridin-3-yl}boronic acid
By using the procedure described in Example-18 and by using (RS)-tert-butyl 3-(5-
bromopyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate in the place of (RS)-3-(5-
bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 70%
yield.
Mass (M+l) for C14H21BN2O5 = 309.1
Example-22 : Preparation of 3[6-(3-hydroxvthietan-3-vl)pvridin-3-vl~|boronic acid

By using the procedure described in Example-18 and by using 3-(5-bromopyridin-2-yl)thietan-3-ol in the place of (RS)-3-(5-bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 65% yield. Mass (M+l) for C8Hi0BNO3S = 212.1
Example-23 : Preparation of [6-(3-hydroxyoxetan-3-yl)pyridin-3-yllboronic acid
By using the procedure described in Example-18 and by using 3-(5-bromopyridin-2-yl)oxetan-3-ol in the place of (RS)-3-(5-bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 48% yield.
Mass (M+l) for C8H10BNO4 = 196.1
Example-24 : Preparation of {6-[l-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-
yl]pyridin-3-vl}boronic acid
By using the procedure described in Example-18 and by using tert-butyl 3-(5-
bromopyridin-2-yl)-3-hydroxyazetidine-l-carboxylate in the place of (RS)-3-(5-
bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 54%
yield.
Mass (M+l) for C13H19BN2O5 = 295.1
Example-25 : Preparation of [6-(4-hydroxytetrahydro-2H-thiopyran-4-yl)pyridin-3-
yl]boronic acid
By using the procedure described in Example-18 and by using 4-(5-bromopyridin-2-
yl)tetrahydro-2H-thiopyran-4-ol in the place of (RS)-3-(5-bromopyridin-2-
yl)tetrahydrothiophene-3-ol, the title compound was obtained in 76% yield.
Mass (M+l) for C|0Hi4BNO3S = 240.1
Example-26 ; Preparation of 1,5-anhydro-2,4-dideoxy-3-C-[5-
(dihydroxyboryl)pyridin-2-yl]-2-methyl-1 -thiopentitol
By using the procedure described in Example-18 and by using l,5-anhydro-3-C-(5-bromopyridin-2-yl)-2,4-dideoxy-2-methyl-l-thiopentitol in the place of (RS)-3-(5-bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 68% yield. Mass (M+l) for C, 1H16BN03S = 254.1

Example-27 : Preparation of |"6-(4-hvdroxytetrahydro-2H-pyran-4-yl)pyridin-3-
yl]boronic acid
By using the procedure described in Example-18 and by using 4-(5-bromopyridin-2-
yl)tetrahydro-2H-pyran-4-ol in the place of (RS)-3-(5-bromopyridin-2-
yl)tetrahydrothiophene-3-ol, the title compound was obtained in 42% yield.
Mass (M+l) for C,oH,4BN04 = 224.1
Example-28 : Preparation of {6-[l-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-
yl]pyridin-3-yl}boronic acid
By using the procedure described in Example-18 and by using tert-butyl 4-(5-
bromopyridin-2-yl)-4-hydroxypiperidine-l-carboxylate in the place of (RS)-3-(5-
bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 77%
yield.
Mass (M+l) for C15H23BN2O5 = 323.1
Example-29 : Preparation of {6-[l-(tert-butoxycarbonyl)-4-mefhoxypiperidin-4-
vnpvridin-3-yllboronic acid
By using the procedure described in Example-18 and by using tert-butyl 4-(5-
bromopyridin-2-yl)-4-methoxypiperidine-l-carboxylate in the place of (RS)-3-(5-
bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 70%
yield.
Mass (M+l) for C16H25BN2O5 = 337.1
Example-30 : Preparation of [6-(4-methoxytetrahvdro-2H-thiopyran-4-yl)pyridin-3-
yl]boronic acid
By using the procedure described in Example-18 and by using 5-bromo-2-(4-
methoxytetrahydro-2H-thiopyran-4-yl)pyridine in the place of (RS)-3-(5-
bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 80%
yield.
Mass (M+l) for CnHi6BN03S = 254.1
Example-31 : Preparation of [6-(4-fluorotetrahvdro-2H-thiopyran-4-vl)pyridin-3-yllboronic acid

By using the procedure described in Example-18 and by using 5-bromo-2-(4-fluorotetrahydro-2H-thiopyran-4-yl)pyridine in the place of (RS)-3-(5-bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 42% yield. Mass (M+l) for C,oH,3BFN02S = 242.1
Example-32 : Preparation of (RS)-[6-(3-hydroxytetrahvdro-3-thienyl)-5-methylpyridin-3-yl]boronic acid
By using the procedure described in Example-18 and by using (RS)-3-(5-bromo-3-methylpyridin-2-yl)tetrahydrothiophene-3-ol in the place of (RS)-3-(5-bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 78% yield. Mass (M+l) for C|0H14BNO3S = 240.1
Example-33 : Preparation of [6-(3-hydroxythietan-3-yl)-5-methylpyridin-3-yl]boronic
acid
By using the procedure described in Example-18 and by using 3-(5-bromo-3-
methylpyridin-2-yl)thietan-3-ol in the place of (RS)-3-(5-bromopyridin-2-
yl)tetrahydrothiophene-3-ol, the title compound was obtained in 52% yield.
Mass (M+l) for C9H12BNO3S = 226.1
Example-34 : Preparation of [6-(4-hydroxytetrahydro-2H-thiopyran-4-yl)-5-
methylpyridin-3-vl]boronic acid
By using the procedure described in Example-18 and by using 4-(5-bromo-3-
methylpyridin-2-yl)tetrahydro-2H-thiopyran-4-ol in the place of (RS)-3-(5-
bromopyridin-2-yl)tetrahydrothiophene-3-ol, the title compound was obtained in 60%
yield.
Mass (M+l) for CuHi6BN03S = 254.1

We Claim:

1. A compound of Formula I,
R3
/—t\q,R2 X
h
Ri
Formula I wherein,
Ri is selected from the group of hydrogen, Ci-C6 alkyl, halogen and CN;
R.2 is halogen or OR5, wherein R5 is selected from the group of hydrogen, Q-C6
alkyl;
R3 is selected from the group of hydrogen, C1-C6 alkyl, and halogen;
X is selected from the group of CH2, S, O, -NR4 wherein R4 is selected from the
group of hydrogen and alkoxy carbonyl; p and q each and independently selected from 0, 1, or 2.
2. A compound of Formula ,

R1 is selected from the group of hydrogen, C1-C6 alkyl, halogen and CN;
R2 is halogen or OR5, wherein R5 is selected from the group of hydrogen, C1-C6
alkyl;
R3 is selected from the group of hydrogen, C1-C6 alkyl, and halogen;
X is selected from the group of CH2, S, O, -NR4 wherein R4 is selected from the
group of hydrogen and alkoxy carbonyl; p and q each and independently selected from 0, 1, or 2.
3. A method of preparation of the compound of formula I, which comprises:
(i) reacting compound of formula V either with halogenating reagent or with alkyl
halides in an organic solvent to provide corresponding compound of formula VI.

(ii) reacting the compound obtained in step (i) with trialkyl borate, in the presence of a base in an organic solvent, wherein a reaction mixture containing an heteroaryl boronic acid alkyl diester is produced; and,
(iii) subjecting said reaction mixture of step (ii) for effective hydrolysis by acid such as aqueous hydrochloric acid, followed by adjustment of pH to 7 and isolation to provide aryl boronic acid of formula I.
R3
X \=0 + Br~C />~Br ► X
Ri
Formula III
Formula IV
Tialkyl borate
Ri
Formula VI, R2 = F, OCH3
Formula I
Scheme-1
wherein,
R1 is selected from the group of hydrogen, C1-C6 alkyl, halogen and CN;
R2 is halogen or OR5, wherein R5 is selected from the group of hydrogen, C1-C6
alkyl;
R3 is selected from the group of hydrogen, C1-C6 alkyl, and halogen;
X is selected from the group of CH2, S, O, -NR4 wherein R4 is selected from the
group of hydrogen and alkoxy carbonyl; p and q each and independently selected from 0, 1, or 2.
4. The method of claim 3, wherein the preparation of the compound of formula I,
which comprises:
(i) reacting the compound of formula V with trialkyl borate in the presence of a base
in a solvent, wherein a reaction mixture containing an heteroaryl boronic acid alkyl
diester is produced; and,
(ii) subjecting said reaction mixture of step (i) for effective hydrolysis by acid such as
aqueous hydrochloric acid, followed by adjustment of pH to 7 and isolation to provide
aryl boronic acid of formula I as depicted in following structure.

R3
/-M 0H>=\ OH
Ri Formula I
5. The method of claim 3, wherein the preparation of the compound of formula I,
which comprises:
(i)reacting compound of formula V with halogenating reagent in an organic solvent to
provide halo derivatives of compound of formula VI.
(ii) reacting the compound obtained in step (i) with trialkyl borate in the presence of a
base in a solvent, wherein a reaction mixture containing an heteroaryl boronic acid
alkyl diester is produced; and,
(iii) subjecting said reaction mixture of step (ii) for effective hydrolysis by acid such
as aqueous hydrochloric acid, followed by adjustment of pH to 7 and isolation to
provide aryl boronic acid of formula I as depicted in following structure..
Ri Formula I
6. The method of claim 3, wherein the preparation of the compound of formula I,
which comprises:
(i) reacting compound of formula V with alkyl halides in presence of a base in a
solvent to provide alkoxy derivative compound of formula VI.
(ii) reacting the compound obtained in step (i) with trialkyl borate in a solvent
wherein a reaction mixture containing an aryl boronic acid alkyl diester is produced;
and,
(iii) subjecting said reaction mixture of step (ii) for effective hydrolysis by acid such
as aqueous hydrochloric acid, followed by adjustment of pH to 7 and isolation to
provide aryl boronic acid of formula I as depicted in following structure.

Formula I
7. The method of claim 3, 4, 5 and 6, wherein the a base is such as n-butyllithium, lithiumhexmethyldilazane, sec-butyllithium, methyllithium, preferably n-butyllithium
8. The method of claim 3, 4, 5 and 6, wherein the organic solvent is toluene.
9. The method of claim 3, 4, 5 and 6, wherein the halogenating agent DAST.
10. The method of claim 3, 4, 5 and 6, wherein the trialkyl borate is trimethyl borate,
triethyl borate and the like.

Abstract
The present invention relates to the novel aryl boronic acids of the general formula-I. The invention also relates to processes for the preparation of compounds of the present invention.

R1 Formula I wherein,
R1 is selected from the group of hydrogen, C1-C6 alkyl, halogen and CN;
R2 is halogen or OR5, wherein R5 is selected from the group of hydrogen, C1-C6 alkyl;
R3 is selected from the group of hydrogen, C1-C6 alkyl, and halogen;
X is selected from the group of CH2, S, O, -NR4 wherein R4 is selected from the
group of hydrogen and alkoxy carbonyl; p and q each and independently selected from 0, 1, or 2.