TH77094A - Epimerization of Allicin - Google Patents

Abstract

DC60 (26/10/48) This invention relates to a process for polymerizing the alkalinity of compounds. Containing asymmetric hydroxyl carbon on the allyic carbon as a useful compound. For the synthesis of vitamin D equivalents in which epimeric hydroxyl substitutes are at position 24, the invention involves a method of producing useful intermediates for The synthesis of calcipotriol by the aforementioned imitation process. The invention involved a process for the polymerization of the compound alkaline. Containing asymmetric hydroxyl-allicocarbon substitutes, such as beneficial compounds For the synthesis of vitamin D equivalents in which epimeric hydroxyl substitutes are at position 24, the invention involves a method of producing useful intermediates for The synthesis of calcipotriol by the aforementioned immerization process.

Claims (31)

1. Epimerizing method: Epimerizing or epimeric mixing of compounds containing side chains of general structure A and/or B (chemical formula) (chemical formula) A B at the position of the carbon atom to which the hydroxyl group and R3 are attached by contact. Such epimers or epimeric mixtures are mixed with an acid in the presence of water, where R3 is an alkyl, alkenyl, alkynyl, or cycloalkyl, which may be selected to be replaced by one or more substitutes chosen from the groups consisting of alkyl, alkoxycarbonyl, halogen, hydroxyl, methoxy, and ethoxy, where the carbon marked with an asterisk is connected by a single bond to the carbon atom C-17 of the vitamin D analogue portion, or where the carbon marked with an asterisk is connected by a single bond to the initiator portion for the synthesis of the vitamin D analogue at its C-17 analogue position. 2. A method consistent with claim 1 where the precursor portion for the synthesis of a vitamin D analog is a portion of the steroid ring system or the CD ring system of steroids. 3. A method consistent with claim 2 where the portion of the steroid ring system is represented by the structure Q or R (chemical formula) (chemical formula) Q R 4. A method consistent with claim 2 or 3 where part of the CD ring system of the steroid is represented by structure E or P (chemical formula) (chemical formula) E P 5. A method consistent with Reputation 1 in which the vitamin D analogue is replaced by one of the parts F, G, H, J, K, or L (chemical formula) where R1 and/or R2 may be the same or different and replaces a hydrogen or hydroxyl protective group. 6. The method consistent with any of the claims 1-5 at R3 is cyclopropyl. 7. The method that is consistent with any of the claims 1-5 at R3 is -C(CH3)2-C(O)-O-CH(CH3)2. 8. A method that conforms to one of claims 1-7 where the arrangement at the carbon atom C-20 of the side chain marked with an asterisk is (R) and where the arrangement at C-17 or the equivalent C-17 position is the same as natural vitamin D3. 9. A method consistent with claim 1 of epimerizing the epimerizing of a compound of structure IIIba or an epimeric mixture consisting of compounds IIIaa and IIIba (chemical formula) IIIaa (chemical formula) IIIba by contacting such epimers or epimeric mixture with an acid in the presence of water. 10. A method consistent with one of Claims 1-9 where the acid is a mineral acid. 11. The method consistent with claim 10 for mineral acids is sulfuric acid. 12. A method consistent with one of claims 1-9 in which the acid is given as a solution of aqueous salt of a polyvalent acid. 13. A method consistent with claim 12 is to provide an acid as a solution of sodium hydrogen sulfate in water. 14. A method consistent with one of claims 1-13 where exposure is performed at a pH lower than 3.0. 15. A method consistent with claim 14 where exposure is achieved at a pH between 1.2 and 1.7. 16. A method consistent with one of Claims 1-15 where contact is made at a temperature of approximately 15-30°C. 17. A method consistent with one of Claims 1-16 where exposure is performed approximately 2-4 hours later. 18. A method consistent with one of the claims 1-17 where contact is made in a mixture of one or more water-compatible solvents and water. 19. A method consistent with claim 18 where contact is achieved in a mixture containing water, acetone, and tetrahydrofuran. 20. A method consistent with one of the claims 1-19 where the epimeric mixture after epimerization contains C-24 epimer in an epimeric (S):(R) ratio greater than 29:17. 21. A method consistent with claim 20, in which epimeric mixtures after epimerization are separated by chromatography. 22. A method for the preparation of calcipotriol or calcipotriol monohydrate consisting of one or more steps of any one of the methods of Claims 1-21. 23. A method for the production of calcipotriol {(5Z, 7E, 22E, 24S)-24-cyclopropyl-9,10-secozola-5,7,10(19),22-tetraene-1a-3beta-24-triol} or calcipotriol monohydrate consisting of the following steps: (i) Emerging the vitamin D equivalent of general structure IIb (chemical formula) IIb where R1 and R2 may be the same or different, and substituting the hydrogen or hydroxyl protective group with the acid in the presence of water to obtain a mixture of compounds of general structures IIa and IIb where R1 and R2 are as specified above (chemical formula) IIa (chemical formula) IIb; (ii) By selective separation of the compound of general structure IIa from the mixture of compounds of general structures IIa and IIb where R1 and R2 are as specified above; (iii) When R1 and/or R2 are not hydrogenated. Removal of the hydroxyl protective groups R1 and/or R2 of compounds of general structure IIa to produce calcipotriol and (iv) selective crystallization of calcipotriol from a mixture of organic solvent and water to obtain calcipotriol monohydrate. 24. A method for the production of calcipotriol {(5Z, 7E, 22E, 24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1a-3beta-24-triol} or calcipotriol monohydrate consisting of the following steps: (i) Emerging the vitamin D analog of general structure IIIb (chemical formula) IIIb at R1 and R2 may be the same or different, and substituting the hydrogen or hydroxyl protective group with an acid in the presence of water so that the mixture of compounds of general structure IIIa and IIIb at R1 and R2 is as specified above (chemical formula) IIIa (chemical formula) IIIb; (ii) By selective separation of the compound of general structure IIIa from the mixture of compounds of (iii) Photoisomerizing compounds of general structure IIIa into compounds of general structure IIa (chemical formula) IIa where R1 and R2 are as specified above; (iv) When R1 and/or R2 are non-hydroxygenated, removal of the protective hydroxyl groups R1 and/or R2 of the compounds of general structure IIa to produce calcipotriol; and (v) Selective crystallization of calcipotriol from a mixture of organic solvent and water may be possible so that calcipotriol monodrate at steps (iii) and (iv) may be achieved in reverse order. 25. A method for the production of calcipotriole {(5Z, 7E, 22E, 24S)-24-cyclopropyl-9,10-secozola-5,7,10(19),22-tetraene-1a-3beta-24-triol} or calcipotriole monohydrate consisting of the following steps: (i) Emerging a vitamin D analogue of the common structure IVba and/or IVbb (chemical formula) IVba (chemical formula) IVbb where R1 and R2 may be the same or different and replacing the hydrogen or hydroxyl protective group. (ii) Separating compounds of general structure IVaa and/or IVbb and IVaa and/or IVab at R1 and R2 as specified above (chemical formula) IVaa (chemical formula) IVab; (iii) Heating compounds of general structure IVaa and/or IVab above 60 °C in the presence of a base to produce compounds of general structure IIIa (chemical formula) IIIa at R1 and R2 as specified above; (iv) Photoisomerizing compounds of general structure IIIa into compounds of general structure IIa (chemical formula) IIa at R1 and R2 as specified above; (v) When R1 and/or R2 are not hydrogenated, removing the hydroxyl protective groups R1 and/or R2 of compounds of general structure IIa to produce calcipotriol; and (vi) Crystallizing calcipotriol from a mixture of organic solvent and water. So that calcipotriolemonohydrate at steps (iv) and (v) can be performed in reverse order. 26. A method consistent with claims 5, 23, 24, or 25 where R1 and R2 substitute for alkylylyl or hydrogen. 27. A method consistent with claim 26 where R1 and R2 substitute for tert-butyldimethylxylyl. 28. A method consistent with claim 1 for epimerizing the epimerism of a compound of structure IIIba or an epimeric mixture consisting of compounds IIIaa and IIIba (chemical formula) IIIaa (chemical formula) IIIba by exposing the epimer or such epimeric mixture for 2–4 hours to an acid in the presence of water at a pH below 3.0 at a temperature of approximately 15–30 °C, where the acid is provided as an aqueous sodium hydrogen sulfate solution. 29. The use of methods consistent with any of the claims 1-28 for the production of calcipotriol or calcipotriol monohydrate. 30. The use of methods consistent with any of the claims 1-28 in the manufacture of pharmaceutical formulations or medicines such as creams, ointments or gels containing calcipotriol or calcipotriol-monohydrate. 31. Calcipotriol or calcipotriol monohydrate obtained by a process comprising methods consistent with any of the claims 1-28.