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EP-3906238-B1 - AN IMPROVED PROCESS TO SYNTHESIZE 5-(3-PYRIDYL)-2,2'-BITHIOPHENE(SENSITIZER)

EP3906238B1EP 3906238 B1EP3906238 B1EP 3906238B1EP-3906238-B1

Inventors

  • DATLA, ANUPAMA
  • NAGRE, Prashant
  • TAMORE, Jagdish
  • TRIVIKRAM, Sreenath
  • DEGAONKAR, Gajanan

Dates

Publication Date
20260506
Application Date
20200608

Claims (7)

  1. An improved catalytic process for synthesis of 5-(3-Pyridyl)-2, 2'-Bithiophene in high yield comprising; i. Reacting 2-acetyl Thiophene with paraformaldehyde and Dimethylamine hydrochloride in solvent to give 3-(Dimethylamino)-1-(2-Thienyl)-1-propanone hydrochloride; ii. Treating 3-(Dimethylamino)-1-(2-Thienyl)-1-propanone hydrochloride of step (1) with pyridine-3-carboxaldehyde in presence of the catalyst 3-Benzyl-5-(2-Hydroxyethyl)-4-methyl thiazolium hydrochloride, base and solvent to give 1-(2-Thienyl)-4-(3-Pyridyl)-1,4-Butanedione optionally followed by crystallization; and iii. Converting 1-(2-Thienyl)-4-(3-Pyridyl)-1,4-Butanedione of step (2) to 5-(3-pyridyl)-2,2'-bithiophene.
  2. The improved catalytic process as claimed in claim 1, wherein the solvent is selected from polar or non-polar, protic or aprotic solvent, optionally lower alcohols, ethers, ketones, esters, hydrocarbons, halogenated hydrocarbons alone or mixtures thereof.
  3. The improved catalytic process as claimed in claim 1, wherein the base in step (ii) is selected from ethylamine, triethylamine, or pyridine.
  4. The improved catalytic process as claimed in claim 1, wherein the temperature in step (i) is in the range of 50-120°C, preferably 70-100°C, more preferably 80-100°C.
  5. The improved catalytic process as claimed in claim 1, wherein the temperature in step (ii) is in the range of 70°C-140°C, preferably 80-135°C, more preferably 90-100°C.
  6. The improved catalytic process as claimed in claim 5, wherein the reaction of step (ii) at said temperature is carried out for 12-45 hours, more preferably for 20-30 hours.
  7. The improved catalytic process as claimed in claim 1, wherein the product of step (iii) is further purified/ crystallized from the solvents selected from polar or non-polar, protic or aprotic solvent, optionally water, nitriles, C1-C6 alcohols, aliphatic or aromatic hydrocarbons, ketones, ethers, esters alone or mixtures thereof.

Description

FIELD OF INVENTION: The present invention relates to an improved catalytic process for the synthesis of 5-(3-pyridyl)-2, 2'-bithiophene (Sensitizer) in high yield. BACKGROUND OF THE INVENTION: Vitamin D3 i.e. Cholecalciferol, is produced in the human body through the exposure to UVB light on its provitamin 7-dehydrocholesterol (7-DHC). Vitamin D3 is commercially produced from its isomers such as tachysterol, 7-DHC, cholesterol, phytosterol, ergosterol, lanosterol by subjecting the solution of said sterol/isomers to irradiation at suitable wavelength. However, irradiation processes have certain shortfalls such as it leads to formation of undesirable isomers and requires extensive separation and purification techniques to isolate vitamin D3 which is not industrially feasible as it leads to addition of 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. The drawbacks of irradiation processes in in the synthesis of vitamin D3 in the art are overcome by use of photosensitizers such that they block certain wavelengths and aid in resulting 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. One such photosensitizer encompassed in the general Markush structure of Formula (I) in US' 191 is 5-(3-pyridyl)-2,2'-bithiophene. The photosensitizer was observed to block certain undesired wavelengths resulting in good yield and purity of the irradiated/ photosynthesis products. Moreover, the said sensitizer can be easily removed from the reaction mixture after the irradiation is complete. The present inventors while following the general method of preparation of substituted thiophene derivatives of general formula (I) and particularly 5-(3-pyridyl)-2,2'-bithiophene disclosed in US'191worked out the method for preparation of 5-(3-pyridyl)-2,2'-bithiophene which comprises reacting 3-dimethylamino-1-(2-thienyl)1-propanone with pyridine-3-carboxaldehyde in presence of sodium cyanide and DMF to yield 1-(3-pyridyl)-4-(2-thienyl)-1, 4 butadione which is further reacted with Lawesson reagent to get the final product, 5-(3-pyridyl)-2,2'-bithiophene. The inventors observed that following the method described in US' 191 has certain drawbacks viz. the conversion rate is very low i.e. in the range of 30-40%. Moreover, 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. In light of the need to employ the photosensitizer, 5-(3-pyridyl)-2,2'-bithiophene, during photochemical conversion to vitamin D compounds the present inventors felt that there remains a scope to synthesize the said photosensitizer in economical and industrially feasible manner over the process disclosed in US' 191. SUMMARY OF THE INVENTION: It is therefore the object of the present invention to provide an improved catalytic method for the preparation of the photosensitizer, 5-(3-pyridyl)-2,2'-bithiophene using safe and easy to handle catalyst i.e. N-Benzyl-4-methyl-5-Hydroxyethyl thiazole hydrochloride. In accordance with the above, the present invention provides an improved catalytic process for synthesis of 5-(3-Pyridyl)-2, 2'-Bithiophene (Sensitizer) in high yield and purity which comprises; i. Reacting 2-acetyl Thiophene with paraformaldehyde and Dimethylamine hydrochloride in solvent to give 3-(Dimethylamino)-1-(2-Thienyl)-1-propanone hydrochloride;ii. Treating 3-(Dimethylamino)-1-(2-Thienyl)-1-propanone hydrochloride of step (1) with pyridine-3-carboxaldehyde in presence of the catalyst 3-Benzyl-5-(2-Hydroxyethyl)-4-methyl thiazolium hydrochloride, base and solvent to give 1-(2-Thienyl)-4-(3-Pyridyl)-1,4-Butanedione optionally followed by crystallization; andiii. Converting 1-(2-Thienyl)-4-(3-Pyridyl)-1,4-Butanedione of step (2) to 5-(3-pyridyl)-2,2'-bithiophene. 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. The present invention discloses an improved process for the preparation of the photosensitizer, 5-(3-p