Vitamin D3 and its analogue Calcifediol from Ergosterol
AssigneeFermenta Biotech Limited
InventorsAnupama Datla, Prashant Nagre, Jagdish Tamore, Manojkumar Sadanand Prabhu, Sachin Vasant Kadam
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Abstract
Disclosed herein is an improved and efficient process for synthesis of vitamin D3 and its analogue Calcifediol from Ergosterol. Particularly, the present invention discloses the synthesis of key intermediate 3β-tert-Butyldimethylsilyloxy-22-hydroxy-23,24-bisnorchola-5,7-diene (5), and novel intermediate β-tert-Butyldimethylsilyloxy-22-iodo-23,24-bisnorchola-5,7-diene (9) by a simple and cost effective process. The industrially viable processes for preparation of said intermediate(s) results in providing provitamins with various side chains and the desired products in high yield.
Claims14
A process for the conversion of ergosterol to vitamin D3 of formula (I), wherein R=H, or calcifediol of formula (I), wherein R=OH:
- via a provitamin precursor of formula (II), wherein R=H or OH:
- wherein the process comprises:
- i. silylating ergosterol to obtain 3β-tert-butyldimethylsilyloxy-ergosta-5,7,22-triene;
- ii. reacting 3β-tert-butyldimethylsilyloxy-ergosta-5,7,22-triene with 1,4-dihydrophthalazine-1,4-dione to obtain the Diels Alder adduct 3β-tert-Butyldimethylsilyloxy-5α,8α-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)-23,24-bisnorchol-6-en-22-al;
- iii. converting 3β-tert-Butyldimethylsilyloxy-5α,8α-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)-23,24-bisnorchol-6-en-22-al to 3β-tert-Butyldimethylsilyloxy-22-hydroxy-23,24-bisnorchola-5,7-diene in one step with LiAlH4;
- iv. tosylating 3β-tert-Butyldimethylsilyloxy-22-hydroxy-23,24-bisnorchola-5,7-diene to obtain 3β-tert-Butyldimethylsilyloxy-22-tosyloxy-23,24-bisnorchola-5,7-diene;
- v. converting 3β-tert-Butyldimethylsilyloxy-22-tosyloxy-23,24-bisnorchola-5,7-diene to the provitamin precursor of formula (II);
- and
- vi. irradiating the provitamin precursor of formula (II) in the presence of a photosensitizer, wherein the photosensitizer is 5-(3-pyridyl)-2,2′-bithiophene, to obtain the compound of formula (I);
- and
- vii. crystallizing the compound of formula (I).
A process for the conversion of ergosterol to calcifediol of formula (I), wherein R=OH, via a provitamin precursor of formula (II), wherein R=OH:
- wherein the process comprises:
- iii. silylating ergosterol to obtain 3β-tert-butyldimethylsilyloxy-ergosta-5,7,22-triene;
- iv. reacting 3β-tert-butyldimethylsilyloxy-ergosta-5,7,22-triene with 1,4-dihydrophthalazine-1,4-dione to obtain the Diels Alder adduct 3β-tert-Butyldimethylsilyloxy-5α,8α-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)-23,24-bisnorchol-6-en-22-al;
- iii. converting 3β-tert-Butyldimethylsilyloxy-5α,8α-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)-23,24-bisnorchol-6-en-22-al to 3β-tert-Butyldimethylsilyloxy-22-hydroxy-23,24-bisnorchola-5,7-diene in one step with LiAlH4;
- iv. tosylating 3β-tert-Butyldimethylsilyloxy-22-hydroxy-23,24-bisnorchola-5,7-diene to obtain 3β-tert-Butyldimethylsilyloxy-22-tosyloxy-23,24-bisnorchola-5,7-diene;
- V. converting 3β-tert-Butyldimethylsilyloxy-22-hydroxy-23,24-bisnorchola-5,7-diene into an iodo compound;
- and converting the iodo compound to the provitamin precursor of formula (II), wherein R=OH;
- and
- vi. irradiating the provitamin precursor of formula (II) in the presence of a photosensitizer, wherein the photosensitizer is 5-(3-pyridyl)-2,2′-bithiophene, to obtain the compound of formula (I);
- wherein converting the iodo compound to the provitamin precursor of formula (II), wherein R=OH, comprises:
- alkylating the iodo compound with a reaction product of NiCl2 and ethyl acrylate to yield ethyl-3β-tert-butyldimethylsilyloxy-chola-5,7-diene-24-carboxylate, wherein the reaction product is prepared in situ;
- reacting ethyl-3β-tert-butyldimethylsilyloxy-chola-5,7-diene-24-carboxylate with methyl magnesium bromide to obtain 3β-tert-Butyldimethylsilyloxy-25-hydroxychola-5,7-diene, followed by desilylation with TBAF in THF to yield 25-OH-provitamin D3 of formula (II), wherein R=OH.
Dependencies are inferred from the claim text.