TECHNICAL FIELD OF INVENTION:

The present invention relates to a novel, simple and short process for synthesis of the photosensitizer, 5-(3-pyridyl)-2,2'-bithiophene.

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.

(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.

In light of the advantageous feature of the said photosensitizer, 5-(3-pyridyl)-2,2’- bithiophene, the present inventors felt that there is a scope to provide a more simple, cost effective process for synthesis of 5-(3-pyridyl)-2,2’-bithiophene over the process disclosed in US5252191.

SUMMARY OF THE INVENTION:

In line with the above, the present invention provides a simple, short process for preparation of sensitizer 5-(3-pyridyl)-2,2’-bithiophene comprising;

i. Homo coupling of 2-iodothiophene under palladium catalysed Ullmann condition in presence of potassium acetate and acetone to obtain 2,2’bithiophene (1);

ii. Brominating intermediate (1) of step (i) to obtain 5-bromo-2,2’- bithiophene (2); followed by iii. Suzuki coupling of compound (2) of step (ii) with compound of formula (4)

when R ¹ and R ² are hydrogen; or with tris- 3-pyridyl boroxine or with a compound of formula (4) wherein R ¹ and R ² when taken together represent the group;

in presence of Pd(PPh ₃ ) ₄ base and solvent to yield the product.

In an aspect, the compound 5-bromo-2, 2' -bithiophene (2) may alternately be prepared in one pot comprising converting 2-bromothiophene to Grignard reagent followed by reaction with a solution of 2,5-dibromothiophene.

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In an embodiment, the present invention relates to a simple, short process for preparation of sensitizer 5-(3-pyridyl)-2,2’-bithiophene comprising;

i. Homo coupling of 2-iodothiophene under palladium catalyzed Ullmann condition in presence of potassium acetate and acetone to obtain 2,2’bithiophene (1);

ii. Brominating intermediate (1) of step (i) to obtain 5-bromo-2,2’- bithiophene (2); followed by iii. Suzuki coupling of compound (2) of step (ii) with compound of

formula (4)

when R ¹ and R ² are hydrogen; or with tris 3-pyridyl boroxine or with a compound of formula (4) wherein R ¹ and R ² when taken together represent the group;

in presence of Pd(PPh ₃ ) ₄ and base to yield the product.

The process is depicted in Scheme 1:

The present invention provides an improved Ullmann reaction for coupling of 2- iodothiophene to obtain 2,2’bithiophene (1). Typically, Ullmann reaction is carried out using copper or its complexes as catalyst. However, these copper- mediated transformations are usually conducted under harsh conditions (neat, >200°C) besides the requirement of a stoichiometric amount of Cu catalyst. To avoid the harsh conditions, the present invention discloses the use of palladium catalyst for Ullmann reaction and the reaction proceeds to completion at lower temperature range of 90-100°C to yield biaryl compound. Further, in the present invention Ullmann reaction is performed in presence of weak base such as potassium acetate which reduces the formation of undesired side products and improves the yield.

The present invention further successfully employs selective nuclear mono brominating agent N-bromosuccinimide in chloroform-gl. acetic acid. By optimizing the equivalents of NBS in chloroform-gl. acetic acid the reaction can be performed at room temperature which results in high yield of monobrominated intermediate (2). The bromination step of the present invention does not require the additional use of radical initiators or the use of UV lamp to initiate the reaction and the reaction proceeds smoothly to yield the desired product in good yield and purity.

Accordingly, mixture of 2-iodothiophene, palladium tetraacetate, potassium acetate were stirred in the solvent at a temperature ranging from 90-110°C until completion of the reaction as monitored by TLC and GC analysis. The mixture was filtered, washed with organic solvent and the organic layers were evaporated under vacuum, purified to obtain purified 2,2’bithiophene (1).

To the above solid (1) was added N-bromosuccinimide as brominating agent in mixture of glacial acetic acid and chloroform and the mixture was stirred at room temperature. The mixture was then poured into ice-water and extracted in solvent, washed, dried and purified by column chromatography to obtain 5-bromo-2,2’- bithiophene (2).

To the degassed aq. solution of sodium carbonate was added tris 3-pyridylboroxin (obtained from 3-pyridineboronic acid) or 3-Pyridylboronic Acid Pinacol Ester, 5-bromo-2,2'-bithiophene obtained above, catalyst Pd(PPh ₃ ) ₄ and the mixture was stirred at 70-80°C for about 14-17 hours. The mixture was then cooled to ambient temperature and poured in to solvent, washed sequentially, dried, filtered concentrated and purified to yield 5-(3-pyridyl)-2,2'-bithiophene as pale yellow solid.

In an embodiment of the present process, the process for preparing tris 3- pyridylboroxin comprises adding drop wise solution of n-butyl lithium to 3-neck flask charged with solvent cooled below -60°C. After the internal temperature reached to -60°C a solution of 3-bromopyridine was added drop wise to keep the internal temperature below -50°C. A brownish-black solid was precipitated and the resultant slurry was stirred for another 10-30 minutes. The solvent was added drop- wise to keep the internal temperature below -50°C and the resultant slurry was stirred for another 10 to 20 min. To the slurry was added triisopropyl borate in one portion via syringe. The solution was warmed to about -15°C, quenched with acid transferred to a separatory funnel. The aqueous layer was collected and the organic layer was washed severally with water. The aqueous layer was neutralized to pH 7 and extracted in solvent. The combined organic layer were concentrated and the residue was dissolved in solvent mixture, filtered, diluted, distilled the solvent, concentrated to afford 3-pyridineboronic acid (1). The 3- pyridineboronic acid (1) was taken up in the solvent for crystallization. The resulting slurry was heated to 60- 75°C for about an hour and allowed to cool slowly to RT and then cooled to 0°C. The solid obtained was filtered, washed, dried under vacuum to afford tris 3-pyridylboroxin (2) for further use in Suzuki- Miyaura cross coupling reaction with aryl/hetero aryl halides. In yet another embodiment, the present invention provides a process for preparation of 3-Pyridylboronic acid pinacol ester (3). Accordingly, 3- pyridylboroxin (2) as prepared above was refluxed with pinacol in the solvent using Dean -Stark apparatus for about 2-4h until the cloudy white reaction mixture became clear. The solution was then concentrated to provide solid which was crystallized in the solvent by heating at 80-85°C for about half an hour followed by slow cooling to RT, filtering and drying to afford 3-Pyridylboronic acid pinacol ester (3) for further use in Suzuki- Miyaura cross coupling reaction with aryl/hetero aryl halides.

The process for preparing 3-pyridylboroxin (2) and 3-Pyridylboronic acid pinacol ester (3) is depicted in Scheme 2 below:

Scheme 2:

In the alternate embodiment, the present invention provides a one pot process for preparation of the compound 5-bromo-2, 2' -bithiophene (2) comprising converting 2-bromothiophene to Grignard reagent followed by reaction with a solution of 2,5-dibromothiophene which is then converted to 5-(3-pyridyl)-2,2'-bithiophene as shown in Scheme 3.

Scheme 3:

Accordingly, 2-bromothiophene was added to a slurry of magnesium turnings in anhydrous THF at reflux temperature. After completion of reaction, the Grignard reagent was filtered to remove the excess of magnesium, and the resulting solution was kept under a blanket of argon prior to use. In the Kumada coupling reaction, the Grignard reagent added in a period of about 15 min to a solution of 2,5-dibromothiophene at room temperature. Catalyst was added and the mixture was stirred at room temperature until maximum completion of starting material. Reaction was quenched in aqu. ammonium chloride, extracted in solvent, dried and purified to yield 5-bromo-2, 2' -bithiophene (2) which was further converted to 5-(3-pyridyl)-2,2'-bithiophene by the process stated above.

The solvents for the process is selected from polar or non-polar; protic or aprotic solvent such as lower alcohols, ethers, esters, ketones, nitriles, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons and the like in suitable amount.

The base for the reaction is selected from organic or inorganic base and includes but is not limited to ethylamine, pyridine, alkali metal carbonate or bicarbonate and the like in suitable amount.

EXAMPLES:

Example 1: Synthesis of 2,2’-Bithiophene

A mixture of 2-iodothiophene (10g, 0. 047 mol), Pd(OAc) ₂ (10mol %), and KOAc (2.3g 0.24mol, 5 equiv) was stirred in acetone (100 mL) at 100°C until complete consumption of starting material as monitored by TLC and GC analysis. Then the mixture was filtered with a crude flash column chromatography and washed with diethyl ether. The organic layers were evaporated under vacuum, the residue was purified by flash column chromatography (hexane, or hexane/ethyl acetate) to afford the pure product. The colorless liquid solidifies on cooling and turns to dark brown with time.

Yield : 7.4g

Purity: 96%

¹ H NMR (300 MHz): 7.22-7.19 (m, 4H), 7.04-7.00 (m, 2H); ¹³ C NMR (75 MHz): 137.4, 127.8, 124.3, 123.8.

Example 2: Synthesis of 5-bromo-2,2'-bithiophene:

N-Bromosuccinimide (NBS, 9.6 g, 0.054mol) was added in small portions to a stirred solution of 2,2'-bithiophene (7.4g, 0.045mol) in 100 ml of glacial acetic acid and 100 ml of chloroform. After stirring for 1 h at room temperature, the mixture was poured into ice-water and extracted into chloroform (500 ml). The organic layer was washed with aqueous sodium bicarbonate solution, water, and then dried over magnesium sulfate and evaporated. The residue was subjected to flash chromatography on silica gel using hexane to give light green solid.

Yield: 9.5 g (88%) M.pt. 55-56°C

Example 2a: Alternate one pot synthesis of 5-bromo-2,2’-bithiophene:

2-bromothiophene, (10. Og, 0.06 mol) was added in 1 h to a slurry of 1.3 equiv of magnesium tumings(1.9g, 0.078mol) in anhydrous THF (50 mL). Addition was carried out at reflux temperature. After addition of all 2-bromothiophene the mixture was kept at reflux temperature during 1 h. The stirrer was stopped, the Grignard reagent was filtered to remove the excess of magnesium, and the resulting solution was kept under a blanket of argon prior to use.

In the Kumada coupling reaction, to a solution of 2,5-dibromothiophene (0.06 mol, 14.5 g) in diethylether (50 mL) at room temperature was added the catalyst, Pd(dppf)C1 ₂ (0.15 mmol, 60 mg). Grignard reagent (50 mL,1.4 M) was then added in 15 min to the mixture and the reaction mixture was stirred at room temperature until maximum completion of starting material. Reaction was quenched by adding aqueous NH ₄ CI and extracted with diethyl ether, dried over anhydrous Na ₂ SO ₄ and solvent removed to get crude mass which upon purification by flash chromatography on silica gel using heptane gave 5-bromo-2,2’-bithiophene as light green solid.

Yield: 8.0g(55%)

M.pt: 54-56°C

Example 3: Synthesis of tris 3-pyridylboroxin

To a 500mL 3-necked flask was charged toluene (85 mL), cooled to below -60°C and a solution of n-BuLi (1.6 M in hexane, 48.6 mL, 77.8 mmol) was added drop wise over 10 min. After the internal temperature reached -60°C a solution of 3- bromopyridine (6.8 mL, 70.7 m mol) in toluene (30 mL) was added drop wise to keep the internal temperature below -50°C. A brownish-black solid precipitated and the resultant slurry was stirred for 20 min. THF (30 mL) was added drop-wise to keep the internal temperature below -50°C and the resultant slurry was stirred for 15min. To the slurry was added triisopropyl borate (19.6 mL, 84.9 mmol) in one portion via syringe. The solution was warmed to -15°C, quenched with HC1 (aq) (2.7 N, 70.0 mL) and transferred to a separatory funnel. The aqueous layer was collected and the organic layer was washed with water (10 mL), the combined aqueous layers were neutralized to pH 7 with NaOH(aq) (10 N) and extracted with THF (200 mL x 1, 125 mL x 2). The combined organics were concentrated in vacuo to get pyridine-3-boronic acid as buff coloured solid.

To prepare tris 3-pyridylboroxin, the pyridine-3 -boronic acid solid obtained above was dissolved in THF/CH3OH (1: 1, 140 mL), filtered and diluted to 300 mL with CH3CN. The solvent was switched to CH3CN by distillation and concentrated to 100 mL. The resulting slurry was heated to 70°C for lh and allowed to cool slowly to RT before it was cooled to 0°C for 30 min. The solids were collected by filtration, washed the solid cake with cold acetonitrile, dried under vacuum to afford tris 3-pyridylboroxin as an off white solid which could also be used as such for further Suzuki-Miyaura cross coupling reactions.

Yield: 6.4g (73%)

¹ H NMR (CD3OD) 8.64 (br s, IH), 8.50 (m, IH), 8.38 (br s, IH), 7.65 (br s, IH).

Example 4: Synthesis of 3-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2- yl)pyridine (3-Pyridyl boronic Acid Pinacol Ester )

500-mL, one-necked, round-bottomed flask equipped with a magnetic stirbar and a Dean- Stark trap fitted with a condenser capped with a nitrogen inlet adaptor is charged with tris(3-pyridyl)boroxin (6.0 g, 18.2 mmol), pinacol (8.14 g, 68.8 mmol ) and 200 mL of toluene. The solution was heated at reflux for 3.0 h in a 120 °C oil bath. The reaction was complete when the mixture changes from cloudy-white to clear. The solution was concentrated under reduced pressure on a rotary evaporator to afford a solid residue. The solid was suspended in 15 mL of cyclohexane and the slurry was heated to 85°C, stirred at this temperature for 30 min, and then allowed to cool slowly to room temperature. The slurry was filtered, washed with cyclohexane, and dried under vacuum to afford 3-pyridylboronic acid pinacol ester as a white solid which could be used for further for Suzuki- Miyaura cross coupling reactions Yield: 9.0 g

M.Pt: 103-106°C

Example 5: Synthesis of 5-(3-pyridyl)-2,2'-bithiophene

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 3- pyridineboronic acid(5.28g , 0.043 moles) of example 3 or 3-pyridineboronic acid pinacol ester(8.8g, 0.043 moles) of example 4, 5-bromo-2,2'-bithiophene (9.5g, 0.039moles), and 1, 1'-bis(diphenyl phosphino) ferrocene]-dichloro palladium or tetrakis (triphenylphosphine)palladium (2.25 g, 5mol%) in DMF (250 mL). The mixture was stirred at 70-80°C for 16 hrs and then cooled to ambient temperature. The mixture was poured into dichloromethane (500 mL); washed sequentially with NaHCO ₃ (sat.) (75 mL) and NaCl(sat) (150 mL); dried over Na ₂ SO ₄ ; filtered; and concentrated. The crude material was purified by silica gel chromatography (eluting with 3: 1 hexanes :EtOAc) to give 5-(3-pyridyl)-2,2'-bithiophene as pale yellow solid.

Yield: 7.5 g (72%)

HPLC purity: >95%