Synthesis Of Maxacalcitol?Eldecalcitol And La,25-Dihydroxyvitamin D3 Analogues

As the most active form of vitamin D3,1?,25-dihydroxyvitamin D3 exerts various physiological activities,such as calcium and phosphorus regulation,immunoregulation,anti-cancer,cardiovascular regulation,etc.There are ten 1?,25-dihydroxyvitamin D3 drugs on the market,which are used for the treatment of osteoporosis,psoriasis and hyperparathyroidism.However,only two drugs,calcitriol and alfacalcitol,are marked in China.The development of new methods for the synthesis of 1?,25-dihydroxyvitamin D3 analogues is beneficial for the application and development of vitamin D drugs in China.Maxacalcitol and eldecalcitol are two marked 1?,25-dihydroxyvitamin D3 analogues in Japan,which were developed by Chugai Pharmaceutical Co.,Ltd.Maxacalcitol is used for the treatment of hyperparathyroidism and psoriasis,while eldecalcitol is used for the treatment of osteoporosis.They are prepared from steroids in multiple steps industrially with many shortcomings,such as the instability of the conjugated diene,the low yield in the photochemical ring-opening and thermal rearrangement process,the use of HPLC in the purification of the products,etc.Therefore,new synthetic methods of maxacalcitol and eldecalcitol are investigated in this study.In chapter I,the discovery,clinical application and synthetic routes of maxacalcitol are briefly described.In this study,the convergent strategy through the Wittig-Horner coupling of the CD-ketone moiety with the A-ring phosphine oxide synthon furnished the gram-scale synthesis of maxacalcitol in 13 steps.The22-oxa-25-hydroxy Grundmann's ketone was prepared from vitamin D2 via the multiple-step transformations.A key intermediate,the(20S)-alcohol,was prepared by the asymmetric reduction of the corresponding ketone using the Corey's(R)-CBS reagents.The environmentally benign reagent Oxone was used instead of PDC or PCC in the convertion of the secondary alcohol into the ketone.This new synthetic approach was favorable for the industrial production of maxacalcitol,and may be used for the synthesis of a variety of 1?,25-dihydroxyvitamin D3 analogues.Chapter II introduced the discovery,clinical application and synthetic routes of eldecalcitol.In this study,eldecalcitol was successfully synthesized for the first time applying the stereochemistry of D-mannitol.In the Michael addition of the secondary alcohol with ethyl acrylate to introduce the C-2 substituent at the A-ring of eldecalcitol,an unusual transfer of TBS protecting group from the 1?-to 2?-position occured,and the major Michael addition happened at the la-position.Therefore,a structural revision of the reported A-ring phosphine oxide synthon for eldecalcitol(JACS,2001,123,3716-3722)was made.By using the more stable methoxymethyl(MOM)as the hydroxyl protective group,the A-ring phosphine oxide synthon was successfully prepared from D-mannitol in 23 steps.The preparation of eldecalcitol and its la-isomer was finally achieved through the Wittig-Horner coupling of the A-ring synthon with the CD-ring ketone.In chapter III,the biological chemistry of 1?,25-dihydroxyvitamin D3 and structural modification and synthetic strategies were summaized.In order to separate the calcemic effects from prodifferentiating action and find novel 1 a,25-dihydroxyvitamin D3 derivatives for the treatment of osteoporosis,a conformational restriction strategy was used in the drug design.Cycloketone moiety was introduced into the side chain of 1?,25-dihydroxyvitamin D3,and the carbonyl group at C-24 position was expected not to be easily metabolized by CYP24A1.Two fluorine atoms were introduced at the a-position of cycloketone,and they have the ability to form hydrogen bondings with VDR and can mimic the terminal dimethyl at the side chain of 1?,25-dihydroxyvitamin D3.Considering the importance of the 2?-3-hydroxypropoxyl group of eldecalcitol in the enhancement of the bone mineral density,the eldecalcitol analogues containing ?,?-difluorocycloketone at the side chain were also designed.To investigate the influences of the stereochemistry at the C-2 position on the biological activity,the 2?-epimers of the eldecalcitol analogues were also designed.To test the rationality of the drug design,molecular docking and dot map simulations were carried out.The synthesis of the 1?,25-dihydroxyvitamin D3 analogues was achieved by the Wittig-Horner reaction of the corresponding A-ring phosphine oxide synthons with the CD-ketone moiety to build the conjugated triene system,followed by the introduction of ?,?-difluorocycloketone at the side chain.Ozonolysis of vitamin D2 and subsequent reduction with NaBH4 resulted in the formation of a diol,which underwent selective acetylation of the primary alcohol and Oxone oxidation to furnish the CD-ring ketone.Coupling of the CD-ring ketone with the 1?,25-dihydroxyvitamin D3 A-ring phosphine oxide synthon,the 2?-or 2?-3-(methoxymethoxy)propoxyl A-ring phosphine oxide synthon,respectively,followed by deacetylation,provided the primary alcohol,which was converted into an aldehyde via Swern oxidation.The aldol condensation of the aldehyde with cyclohexanone or cyclopentanone generated a secondary alcohol that was mesylated followed by elimination to afford the unsaturated cyclic ketone.?,?-Difluorinateion of the ketone was achieved by the treatment of the corresponding silyl enol ether with Selectfluor.After the removal of the MOM or TBS protective group,six 1?,25-dihydroxyvitamin D3 analogues containing the ?,?-difluorocycloketone at the side chain were prepared.In addition,the 2?-hydroxyl configuration in the A-ring phosphine oxide synthon of eldecalcitol was successfully inverted into the 2?-form via the reaction of its trifluoromesylate with KO2.