Claims:
1. An efficient process for synthesis of the sensitizer, 5-(3-pyridyl)-2,2’-bithiophene comprising;
i. converting 3-bromopyridine to 3-(thiophene-2-yl) pyridine (1);
ii. brominating 3-(thiophene-2-yl) pyridine (1) of step (i) with bromine in DCM to obtain 3-(5-bromothiophen-2-yl) pyridine (2); and
iii. Suzuki coupling of 3-(5-bromothiophen-2-yl) pyridine (2) of step (ii) with thiophene-2-boronic acid in presence of Pd(PPh3)2Cl2 as catalyst to yield the product.

2. The efficient process according to claim 1, wherein the compound 3-(thiophene-2-yl) pyridine (1) is prepared by a process, comprising;
A) Suzuki reaction of 3-bromopyridine with thiophene-2-boronic acid in presence of sodium carbonate, Pd(PPh3)4 as catalyst and THF;
OR
B) (i) Adding 3-bromopyridine to the suspension of active zinc (Rieke zinc) followed by addition of 10-20 mol% lithium chloride to form 3-pyridylzinc bromide; and
(ii) in-situ cross coupling of 3-pyridylzinc bromide with 2-iodo/bromo thiophene in presence of THF and Pd(PPh3)4 as catalyst.

3. The efficient process according to claims 1 and 2 comprising;
i. Suzuki reaction of 3-bromopyridine with thiophene-2-boronic acid in presence of sodium carbonate, Pd(PPh3)4 as catalyst and THF to obtain 3-(thiophene-2-yl) pyridine (1);
ii. brominating 3-(thiophene-2-yl) pyridine (1) of step (i) with bromine dissolved in DCM to obtain 3-(5-bromothiophen-2-yl) pyridine (2); followed by Suzuki coupling with thiophene-2-boronic acid in presence of Pd(PPh3)2 Cl2 as catalyst to yield the product.

4. The efficient process according to claims 1 and 2 comprising;
i. Adding 3-bromopyridine to the suspension of active zinc (Rieke zinc) followed by addition of 10-20 mol% lithium chloride to form 3-pyridylzinc bromide;
ii. in-situ cross coupling of 3-pyridylzinc bromide of step (i) with 2-iodo/bromo thiophene in presence of solvent and Pd(PPh3)4 as catalyst to obtain 3-(thiophene-2-yl) pyridine (1);
iii. brominating 3-(thiophene-2-yl) pyridine (1) of step (ii) with bromine dissolved in DCM to obtain 3-(5-bromothiophen-2-yl) pyridine (2) followed by Suzuki coupling with thiophene-2-boronic acid in presence of Pd(PPh3)2Cl2 as catalyst to yield the product.

5. The efficient process according to any one of the preceding claims 1 to 4, wherein the solvent is selected from lower alcohols such as C1-C6 alcohols, aliphatic or aromatic hydrocarbons, aliphatic halogenated hydrocarbons, ethers, esters, ketones, nitriles, THF, DMF and the like or mixtures thereof.

6. Sensitizer, 5-(3-pyridyl)-2,2’-bithiophene prepared by the process according to claims 1 to 5.
, Description:TECHNICAL FIELD OF INVENTION:
The present invention relates to an efficient process for synthesis of the photosensitizer 5-(3-pyridyl)-2,2'-bithiophene in high yield and purity.

BACKGROUND OF THE INVENTION:
Vitamin D3 is commercially produced from its precursors such as 7-dehydrocholesterol and other isomers such as cholesterol, phytosterol, ergosterol, lanosterol by irradiation at suitable wavelengths. The irradiation processes has certain disadvantages such as it results in the formation of undesired isomers/ impurities and requires additional purification leading to escalation in costs.

With the intended use of vitamin D3, viz. for human or veterinary administration, the final vitamin D3 compound obtained should be produced free from detrimental contaminants. It is therefore essential that the photochemical conversion preferably yields a single well-defined product with the desired properties. Insufficient conversion and/or the formation of by-products during the conversion reaction produce(s) contaminated end product which is often tedious, sometimes even impossible, to purify such reaction products up to a purity suitable for human or veterinary use.

Photosensitizers are nowadays used in the irradiation process for production of vitamin D3 since they block certain wavelengths and aid in obtaining the desired end product with minimum or no contamination.

US5252191 discloses substituted thiophene derivatives of general formula (I) having a substantial absorption in the wavelength region of approx. 300-1,000 nm as improved photosensitizer over the art during photochemical conversion of tachysterol compounds into previtamin D compounds and of trans vitamin D compounds into cis-vitamin D compounds.
(I)
(variables are as defined in US’191)
One such photosensitizer encompassed in the general Markush structure of Formula (I) in US’191 is 5-(3-pyridyl)-2,2’-bithiophene.

The said sensitizer can be easily removed from the reaction mixture after the irradiation is complete. The process described in US’191 has low conversion rate and the process employs sodium cyanide which is a highly hazardous chemical and extra precaution is needed to be taken while storing, handling and disposing the chemical.

The advantages of the said sensitizer during preparation of vitamin D3 from its precursors have pursued the present inventors to provide alternate yet efficient process for the synthesis of said sensitizer, 5-(3-pyridyl)-2,2’-bithiophene in high yield and purity.

The present inventors found that by optimizing the process parameters of the known chemical reactions such as the use of solvents, base or temperature conditions the said sensitizer 5-(3-pyridyl)-2,2’-bithiophene could be prepared efficiently in high yield and purity.


SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides a novel and efficient process for preparation of 5-(3-pyridyl)-2,2’-bithiophene comprising;
i. converting 3-bromopyridine to 3-(thiophene-2-yl) pyridine (1);
ii. brominating 3-(thiophene-2-yl) pyridine (1) of step (i) with Br2 in dichloromethane (DCM) to obtain 3-(5-bromothiophen-2-yl) pyridine (2); and
iii. Suzuki coupling of 3-(5-bromothiophen-2-yl) pyridine (2) of step (ii) with thiophene-2-boronic acid in presence of Pd(PPh3)2Cl2 as catalyst to yield the product.
In an aspect, the 3-bromopyridine is converted to 3-(thiophene-2-yl) pyridine (1) by a process which comprises;
A) Suzuki reaction of 3-bromopyridine with thiophene-2-boronic acid in presence of base, Pd(PPh3)4 as catalyst and the solvent;
OR
B) (i) Adding 3-bromopyridine to the suspension of active zinc (Rieke zinc) followed by addition of 10-20 mol% lithium chloride to form 3-pyridylzinc bromide; and
(ii) in-situ cross coupling of 3-pyridylzinc bromide with 2-iodo/bromo thiophene in presence of solvent and Pd(PPh3)4 as catalyst.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an efficient process for synthesis of 5-(3-pyridyl)-2,2’-bithiophene comprising;
i. converting 3-bromopyridine to 3-(thiophene-2-yl) pyridine (1);
ii. brominating 3-(thiophene-2-yl) pyridine (1) of step (i) with Br2 in DCM to obtain 3-(5-bromothiophen-2-yl) pyridine (2); and
iii. Suzuki coupling of 3-(5-bromothiophen-2-yl) pyridine (2) of step (ii) with thiophene-2-boronic acid in presence of Pd(Ph3)2Cl2 as catalyst to yield the product.

The process is depicted in Scheme 1 below:

Scheme 1
In an embodiment, the compound 3-(thiophene-2-yl) pyridine (1) is obtained from 3-bromopyridine as starting material by a process which comprises;
A) Suzuki reaction of 3-bromopyridine with thiophene-2-boronic acid in presence of Pd(PPh3)4 (Palladium-tetrakis(triphenylphosphine) as catalyst;
OR
B) (i) Adding 3-bromopyridine to the suspension of active zinc (Rieke zinc) followed by addition of 10-20 mol% lithium chloride to form 3-pyridylzinc bromide; and
(ii) in-situ cross coupling of 3-pyridylzinc bromide with 2-iodo/bromo thiophene in presence of THF and Pd(PPh3)4 as catalyst.

The Suzuki reaction in the present process is performed in base and solvent. The base for the reaction is selected from alkali metal carbonate in suitable amount.
The solvent in the present process as well as for Suzuki reaction is selected from lower alcohols such as C1-C6 alcohols, aliphatic or aromatic hydrocarbons, aliphatic halogenated hydrocarbons, ethers, esters, ketones, nitriles, THF, DMF and the like or mixtures thereof in suitable amount.

Accordingly, the efficient process for synthesis of 5-(3-pyridyl)-2,2’-bithiophene comprises;
i. Suzuki reaction of 3-bromopyridine with thiophene-2-boronic acid in presence of sodium carbonate, Pd(PPh3)4 as catalyst in THF to obtain 3-(thiophene-2-yl) pyridine (1);
ii. brominating 3-(thiophene-2-yl) pyridine (1) of step (i) with bromine dissolved in DCM to obtain 3-(5-bromothiophen-2-yl) pyridine (2) followed by Suzuki coupling with thiophene-2-boronic acid in presence of Pd(PPh3)2Cl2 as catalyst to yield the product.
The process is shown schematically below:

Scheme 2
According to Scheme 2, to a degassed aqueous solution of the base was added a mixture of 2-thiopheneboronic acid, 3-bromopyridine and the catalyst tetrakis(triphenylphosphine)palladium Pd(PPh3)4 in the solvent. The mixture was stirred for 65-80oC for about 15-17 hours and then cooled to ambient temperature. The mixture was poured in to the solvent, washed sequentially, dried and concentrated, purified to obtain the intermediate 3-(thiophene-2-yl) pyridine (1).
The intermediate (1) was brominated in a vessel wrapped in foil to prevent exposure to light. To the vessel was added solution of intermediate, 3-(thiophene-2-yl) pyridine (1) and a solution of bromine was added drop wise over the period. The mixture was stirred and aqueous solution of the base was added and the mixture was stirred vigorously until the precipitates dissolved. The layers were separated, extracted in solvent, dried the organic layers, filtered and concentrated to give 3-(5-bromothiophen-2-yl) pyridine (2).

A mixture of 2-thienylboronic acid, 3-(5-bromothiophen-2-yl) pyridine, catalyst Bis (triphenyl phosphine) palladium(II) dichloride, Pd(PPh3)2Cl2 in degassed solvent was stirred at 65-80oC for about 15-17 hours and then cooled to ambient temperature. The mixture was filtered over celite bed, washed, extracted in solvent, further washed, dried, concentrated and purified to obtain 5-(3-pyridyl)-2,2'-bithiophene as pale yellow solid.

In another embodiment, the present invention relates to an efficient process for preparation of 5-(3-pyridyl)-2,2’-bithiophene which comprises;
i. Adding 3-bromopyridine to the suspension of active zinc (Rieke zinc) followed by addition of 10-20 mol% lithium chloride to form 3-pyridylzinc bromide;
ii. in-situ cross coupling of 3-pyridylzinc bromide of step (i) with 2-iodo/bromo thiophene in presence of THF and Pd(PPh3)4 as catalyst to obtain 3-(thiophene-2-yl) pyridine (1);
iii. brominating 3-(thiophene-2-yl) pyridine (1) of step (ii) with bromine dissolved in DCM to obtain 3-(5-bromothiophen-2-yl) pyridine (2) followed by Suzuki coupling with thiophene-2-boronic acid in presence of sodium carbonate, Pd(PPh3)2Cl2 (bis-triphenyl phosphine) palladium(II) dichloride as catalyst and DMF to yield the product.

The process is shown in Scheme 3 below:

According to Scheme 3, the first step comprises direct insertion of active zinc in 3-bromopyridine. The improvement in the oxidative addition of active zinc (Rieke zinc) has been achieved by adding 10-20 mol% of lithium chloride wherein more than 99% conversion of 3-bromopyridine to 3-pyridylzinc bromide occurs.

To the suspension of active zinc (Rieke zinc) was added 3-bromopyridine followed by LiCl and the mixture was refluxed for about 2-3 hours. 3-pyridylzinc bromide formed (in order to confirm the formation of 3-pyridylzinc bromide, the resulting organozinc reagent was first treated with iodine, affording 90% 3-iodopyridine and 3% pyridine) is siphoned to another flask containing the solution of 2-Iodothiophene ,via cannula without any exposure to air, followed by addition of the catalyst tetrakis(triphenylphosphine)palladium Pd(PPh3)4 , stirred and monitored by TLC. The reaction mass was filtered over celite bed, washed, extracted in suitable solvent dried, concentrated and purified to obtain 3-(thiophen-2-yl)pyridine (1).

The intermediate (1) was brominated in a vessel wrapped in foil to prevent exposure to light. To the vessel was added solution of intermediate, 3-(thiophene-2-yl) pyridine (1) and bromine dissolved in DCM was added drop wise over the period. The mixture was stirred and aqueous solution of the base was added and the mixture was further stirred vigorously until the precipitate is dissolved. The layers were separated, extracted in solvent, dried the organic layers, filtered and concentrated to give3-(5-bromothiophen-2-yl) pyridine (2).

A mixture of 2-thienylboronic acid, 3-(5-bromothiophen-2-yl) pyridine, catalyst Bis (triphenyl phosphine) palladium (II) dichloride, Pd (PPh3)2Cl2 in degassed solvent was stirred at 65-80oC for about 15-17 hours and then cooled to ambient temperature. The mixture was filtered over celite bed, washed, extracted in solvent, further washed, dried, concentrated and purified to obtain 5-(3-pyridyl)-2,2'-bithiophene as pale yellow solid.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit scope of the invention.

EXAMPLES:
Example 1(A): Synthesis of 3-(thiophen-2-yl) pyridine
Only degassed solvents were used under air-free conditions. A degassed 2M aqueous solution of sodium carbonate (75 mL) was added to a mixture of 2-thiopheneboronic acid(7.68 g, 60.0 mmoles), 3-bromopyridine(5.84mL,60.0 mmoles), and tetrakis(triphenylphosphine)palladium (2.10 g, 1.80 mmoles) in THF (150 mL). The mixture was stirred at 70oC for 16 hrs and cooled to ambient temperature. The mixture was poured into dichloromethane (400 mL); washed sequentially with NaHCO3(sat.) (75mL) and NaCl(sat.) (150mL); dried over Na2SO4; filtered; and concentrated. The crude material was purified by silica gel chromatography (eluting with 3:1 hexane: EtOAc) to give 3-(thiophen-2-yl) pyridine.
Yield: 7.0 g (72%)

Example 1(B): Alternate method for synthesis of 3-(thiophen-2-yl) pyridine
Only degassed solvents were used under air-free conditions. To the suspension of active zinc (Rieke zinc)(3.0g,0.047mol) in dry THF(50mL) was added 3-bromopyridine (5.0g, 0.032mol) followed by addition of LiCl(0.5g, 10-20% mole) and refluxed the reaction mixture for 2h. (In order to confirm the formation of 3-pyridylzinc bromide, the resulting organozinc reagent was first treated with iodine, affording 90% 3-iodopyridine and 3% pyridine).The 3-pyridylzinc bromide so formed was siphoned to another flask containing solution of 2-iodothiophene(5.3g, 0.026mol, 0.8 equiv) in THF(100mL) via cannula without any exposure to air. This was followed by addition of Pd (PPh3)4 (0.6g, 2mol%) in the said flask and stirred the reaction mixture at room temperature for 2h. Reaction was monitored by TLC. The reaction mass was filtered over celite bed and washed the filter bed with ethyl acetate (EtOAc). To the filtrate, water was added and extracted with EtOAc, washed EtOAc layer with water followed by brine and dried over anhydrous Na2SO4. The solvent was concentrated to get crude mass. The crude mass was purified by silica gel chromatography (eluting with 3:1 hexane: EtOAc) to give 3-(thiophen-2-yl) pyridine.
Yield: 3.0 g (70%)

Example 2: Synthesis of 3-(5-bromothiophen-2-yl) pyridine:
Example 2A:
The reaction vessels were wrapped in foil to prevent exposure to light. Compound 3-(thiophen-2-yl) pyridine (7.0 g, 0.043mol) of example 1A was dissolved in dichloromethane (DCM, 200 mL). A solution of bromine (2.4 mL, 0.047mol) in dichloromethane (100 mL) was added drop wise over 30 min. The reaction was stirred at ambient temperature for 2 hrs. A 1M aqueous solution of sodium carbonate (150 mL) was added, and the mixture was stirred vigorously until the precipitate dissolved. The layers were separated. The aqueous phase was extracted with additional dichloromethane (150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 3-(5-bromothiophen-2-yl) pyridine.
Yield: 9.3 g (90%)

Example 2B:
Compound 3-(thiophen-2-yl) pyridine (3.0 g, 0.019mol) of example 1B was dissolved in DCM (100 mL). A solution of bromine (1.1 mL, 0.021mol) in dichloromethane (50 mL) was added drop wise over 30 min. The reaction mixture was stirred at ambient temperature for 2 hrs. A 1M aqueous solution of sodium carbonate (75 mL) was added, and the mixture was stirred vigorously until the precipitate dissolved. The layers were separated. The aqueous phase was extracted with additional dichloromethane (150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 3-(5-bromothiophen-2-yl) pyridine.
Yield: 4.1 g (90%)

Example 3: Synthesis of 5-(3-pyridyl)-2,2'-bithiophene
Example 3A:
Only degassed solvents were used under air-free conditions. Sodium carbonate (4.34g, 0.041mol) was added to a mixture of 2-thienylboronic acid(5.2g, 0.041 moles), 3-(5-bromothiophen-2-yl)pyridine (9.0g, 0.037moles) of example 2A, and bis triphenylphosphine palladium(II) dichloride (1.35 g, 5mol%) in DMF (100 mL). The mixture was stirred at 70-80oC for 16 hrs and then cooled to ambient temperature. The mixture was filtered over celite bed, washed the celite bed thoroughly with dichloromethane. To the filtrate, water (50mL) was added and extracted with dichloromethane (250 mL); washed sequentially with NaHCO3(sat.) (75mL) and NaCl(sat.)(150 mL); dried over Na2SO4; filtered; and concentrated. The crude material was purified by silica gel chromatography (eluting with 3:1 hexane: EtOAc) to yield 5-(3-pyridyl)-2,2'-bithiophene as pale yellow solid.
Yield: 7.2 g (80%)
HPLC purity: >95%.

Example 3B:
Only degassed solvents were used under air-free conditions. Sodium carbonate (2.0g, 0.019mol) was added to a mixture of 2-thienylboronic acid(2.43g , 0.019 mol), 3-(5-bromothiophen-2-yl)pyridine (4.0 g, 0.017mol) of example 2B and bis triphenylphosphine palladium(II) dichloride (0.7 g, 5mol%) in DMF (100 mL). The mixture was stirred at 70-80oC for 16 hrs and then cooled to ambient temperature. The mixture was filtered over celite bed, washed celite bed thoroughly with dichloromethane. To the filtrate, water (50mL) was added and extracted with dichloromethane (200 mL); washed sequentially with NaHCO3(sat.) (75 mL) and NaCl(sat.) (150 mL); dried over Na2SO4; filtered; and concentrated. The crude material was purified by silica gel chromatography (eluting with 3:1 hexane: EtOAc) to give 5-(3-pyridyl)-2,2'-bithiophene as pale yellow solid.
Yield: 3.3 g (82%)
HPLC purity: >95%.

It will be understood that the above description is intended to be illustrative and not restrictive. The embodiments will be apparent to those in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description but should instead be determined by the appended claims along with full scope of equivalents to which such claims are entitled.