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药物详细合成路线

Name Doxercalciferol;TSA-840;One-alpha D2;1alpha-D2;Hectorol
Chemical Name 1alpha-Hydroxyvitamin D2
      1alpha-Hydroxyergocalciferol
      9,10-Secoergosta-5(Z),7(E),10(19),22(E)-tetraene-1alpha,3beta-diol
CAS 54573-75-0
Related CAS
Formula C28H44O2
Structure
Formula Weight 412.66168
Stage 上市-1999
Company Wisconsin Alumni Research Foundation (Originator), Bone Care International (Licensee), Draxis Health (Licensee), Shire Pharmaceuticals (Licensee)
Activity/Mechanism Antipsoriatics, Bone Diseases, Treatment of, DERMATOLOGIC DRUGS, ENDOCRINE DRUGS, METABOLIC DRUGS, Oncolytic Drugs, Prostate Cancer Therapy, Thyroid Disease Therapy, Treatment of Hyperparathyroidism, Treatment of Osteoporosis, Vitamin D Analogs
Syn. Route 6
Route 1
the reaction of ergosta-4,6,22-trien-3-one (i) with ddq and 5-sulfosalicylic acid in refluxing dioxane gives ergosta-1,4,6,22-tetraen-3-one (ii), which is acylated with isopropenyl acetate and ts-oh in refluxing butyl acetate yielding 3-acetoxyergosta-1,3,5,7,22-pentaene (iii). the reduction of (iii) with calcium borohydridde in ethanol affords ergosta-1,5,7,22-tetraen-3beta-ol (iv), which is condensed with 4-phenyl-3h-4,5-dihydro-1,2,4-triazole-3,5-dione (v) in ethyl acetate yielding the diels-alder adduct (vi). the silylation of (vi) with tbdms-cl and imidazole affords the silyl ether (vii), which is epoxidized with mcpba in chloroform giving the 1alpha,2alpha-22,23-diepoxide (viii). the elimination of the silyl group with tbaf in thf gives the 3beta-alcohol (ix).
List of intermediates No.
s-ethyl 3-oxopentanethioate (v)
benzhydryl (2r,6r)-3-formyl-8-oxo-7-[(z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate (i)
benzhydryl (2r,6r)-8-oxo-3-[(e)-2-(2-pyridinyl)ethenyl]-7-[(z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate (ii)
2-((e)-2-[(6r)-2-[(benzhydryloxy)carbonyl]-5,5,8-trioxo-7-[(z)-2-pyridinylmethylidene]-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]ethenyl)-1-pyridiniumolate (iii)
(1r,2r,3s,4r,5s)-4-(6-amino-9h-purin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (iv)
6-amino-9-[(1s,2r,3s,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)bicyclo[3.1.0]hex-2-yl]-1-(3-iodobenzyl)-9h-purin-1-ium bromide (vi)
ethyl (z)-3-amino-3-(4-morpholinyl)-2-propenoate (vii)
ethyl 4-hydroxy-2-(4-morpholinyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (viii)
methyl 3-methoxyphenethylcarbamate (ix)
Reference 1:
    tachibana, y.; a convenient syntesis of a 1alpha-hydroxyvitamin d2. bull chem soc jpn 1988, 61, 11, 3915.

Route 2
the reduction of (ix) with lialh4 in refluxing thf eliminates the diels-alder adduct and opens the 1alpha,2alpha-epoxide giving the 1alpha,2beta-diol (x), which is acylated with acetyl chloride in pyridine yielding the diacetoxy epoxide (xi). the reaction of (xi) with nai and trifluoroacetic anhydride in acetonitrile/thf regenerates the 22,23-double bond affording 1alpha-acetoxyergosteryl acetate (xii), which is submitted to uv irradiation with a high pressure mercury lamp in ethyl ether to provide the diacetate of 1alpha-hydroxyvitamin d2 (xiii). finally, this compound is deacylated with koh in refluxing ethanol.
List of intermediates No.
methyl 3-methoxyphenethylcarbamate (ix)
6-methoxy-3,4-dihydro-1(2h)-isoquinolinone (x)
methyl 1,2,3,4-tetrahydro-6-isoquinolinyl ether; 6-methoxy-1,2,3,4-tetrahydroisoquinoline (xi)
3-(4-oxocyclohexyl)-1h-indole-5-carbonitrile (xii)
di(tert-butyl) (2s,3s)-2,3-dihydroxybutanedioate (xiii)
Reference 1:
    tachibana, y.; a convenient syntesis of a 1alpha-hydroxyvitamin d2. bull chem soc jpn 1988, 61, 11, 3915.

Route 3
the methanolysis of vitamin d2 tosylate (xiv) gives the cyclovitamin (xv), which is oxidized with seo2 and tert-butyl hydroperoxide in dichloromethane yielding the 1alpha-hydroxy cyclovitamin (xvi). the acylation of (xvi) with acetic anhydride affords the acetate (xvii), which is rearranged with tsoh in hot dioxane to provide 1alpha-acetodyvitamin d2 (xviii). finally, this com-pound is hydrolyzed with koh in aqueous methanol.
List of intermediates No.
2-(acetoxy)-4-[(e)-3-chloro-3-oxo-1-propenyl]phenyl acetate (xiv)
di(tert-butyl) (2s,3s)-2,3-bis([(e)-3-[3,4-bis(acetoxy)phenyl]-2-propenoyl]oxy)butanedioate (xv)
1,3-thiazolidine-2-carboxylic acid (xvi)
3-[2-([2-[(2-carboxy-1,3-thiazolidin-3-yl)carbonyl]phenyl]disulfanyl)benzoyl]-1,3-thiazolidine-2-carboxylic acid (xvii)
3-(2-sulfanylbenzoyl)-1,3-thiazolidine-2-carboxylic acid (xviii)
Reference 1:
    paaren, h.e.; et al.; direct c-1 hydroxylation of vitamin d compounds: convenient preparation of 1alpha-hydroxyvitamin d3, 1alpha,25-dihydroxyvitamin d3, and 1alpha-hydroxyvitamin d2. proc natl acad sci usa 1978, 75, 5, 2080.
Reference 2:
    paaren, h.e.; hamer, d.e.; deluca, h.f.; schnoes, h.k. (wisconsin alumni research foundation); process for preparing 1alpha-hydroxylated cpds.. be 0873512; us 4195027; wo 7900513 .

Route 4
the oppenauer oxidation of ergosterol (xix) gives ergosta-4,6,22-trien-3-one (i), which is dehydrogenated with seo2 to ergosta-1,4,6,22-tetraen-3-one (ii). the epoxidation of (ii) with h2o2 and naoh in dioxane affords the 1alpha,2alpha-epoxide (xx), which is reduced with li in liquid nh3 to give ergost-5-ene-1alpha,3beta-diol (xxi). the acylation of (xxi) with acetic anhydride and pyridine yields the diacetate (xxii), which is dehydrogenated by the bromination dehydrobromination method to provide the previously reported 1alpha-acetoxyergosteryl acetate (xii). the uv irradiation of (xii) with a high pressure hg lamp gives the 1alpha-hydroxyvitamin d2 diacetate (xiii), which is finally, deacylated with koh in methanol.
List of intermediates No.
benzhydryl (2r,6r)-3-formyl-8-oxo-7-[(z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate (i)
benzhydryl (2r,6r)-8-oxo-3-[(e)-2-(2-pyridinyl)ethenyl]-7-[(z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate (ii)
3-(4-oxocyclohexyl)-1h-indole-5-carbonitrile (xii)
di(tert-butyl) (2s,3s)-2,3-dihydroxybutanedioate (xiii)
4-oxo-4h-chromene-3-carbaldehyde (xix)
2-amino-5h-chromeno[4,3-d]pyrimidin-5-ol (xx)
dibenzyl 2-methylenepentanedioate (xxi)
5-(benzyloxy)-2-[(benzyloxy)carbonyl]-5-oxopentylphosphinic acid (xxii)
Reference 1:
    lam, h.y.; et al.; synthesis of 1alpha-hydroxyergocalciferol. steroids 1977, 30, 5, 671.
Reference 2:
    schnoes, h.k.; deluca, h.f.; lam, h.-y. (wisconsin alumni research foundation); 1alpha-hydroxyergocalciferol and processes for preparing same. us 3907843 .

Route 5
the silylation of vitamin d2 (xxiii) with tbdms-cl and imidazole in dichloromethane gives the silyl ether (xxiv), which is cyclized with n-sulfinyl-p-toluenesulfonamide yielding the diels-alder adduct (xxv). the oxidation of (xxv) with seo2 and n-methylmorpholine-oxide in ethanol affords the trans-1alpha-hydroxy-3-o-(tert-butyldimethylsilyl)vitamin d2 (xxvi), which is irradiated with uv light in benzene containing anthracene yielding 1alpha-hydroxy-3-o-(tert-butyldimethylsilyl)vitamin d2 (xxvii). finally, this compound is desilylated with tbaf in thf.the cyclization of the silyl ether (xxiv) can also be performed with ts-n=se=n-ts yielding the corresponding adduct (xxviii), which is oxidized with seo2 as before to afford the trans-1alpha-hydroxy-3-o-(tert-butyldimethylsilyl) vitamin d2 (xxvi) already reported.
List of intermediates No.
ethyl (e,4s)-4-[[(2r,5s)-5-amino-2-benzyl-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate (xxiii)
dibenzyl 2-[[(benzyloxy)(oxo)phosphoranyl]methyl]pentanedioate (xxviii)
dibenzyl 2-[((benzyloxy)[5-(benzyloxy)-2-[(benzyloxy)carbonyl]-5-oxopentyl]phosphoryl)methyl]pentanedioate (xxv)
(2s)-5-(benzyloxy)-2-methylpentanal (xxvi)
(5s,6r,9s)-5-[(1s)-4-(benzyloxy)-1-methylbutyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadecan-7-one (xxiv)
(5s,8r,9s)-9-[(1s)-4-(benzyloxy)-1-methylbutyl]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one (xxvii)
Reference 1:
    guo, l.; moriarty, r.m.; penmasta, r.a. (lunar corp.); synthesis of 1alpha-hydroxy vitamin d. wo 9602501 .

Route 6
by allylic oxidation of vitamin d2 (xxiii) with seo2 and tert-butyl hydroperoxide in pyridine followed by purification by tlc over silicagel. the allylic oxidation of trans-vitamin d2 (xxix) with seo2, tert-butyl hydroperoxide and octahydroacridine in dichloromethane gives the trans-1alpha-hydroxyvitamin d2 (xxx), which is isomerized to the target compound by irradiation with uv light with anthracene as photosensitizer.
List of intermediates No.
ethyl (e,4s)-4-[[(2r,5s)-5-amino-2-benzyl-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate (xxiii)
(4r,5s,6s)-9-(benzyloxy)-2-[(4s)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-3-nonanone (xxx)
(3s,6r,7s,8s)-11-(benzyloxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxoundecanal (xxix)
Reference 1:
    schnoes, h.k.; paaren, h.e.; deluca, h.f.; hamer, d.e. (wisconsin alumni research foundation); process for preparing 1-hydroxylated vitamin d cpds. from 5,6-trans-vitamin d cpds.. us 4265822 .
Reference 2:
    deluca, h.f.; hamer, d.e.; paaren, h.e.; schnoes, h.k. (wisconsin alumni research foundation); process for preparing 1alpha-hydroxylated cpds.. us 4202829 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名度骨化醇;英文名Doxercalciferol;TSA-840;One-alpha D2;1alpha-D2;Hectorol;CAS[54573-75-0]

 
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