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Name Maxacalcitol;22-Oxacalcitriol;Sch-209579;MC-1275;22-Oxa-1;25(OH)2D3;OCT;Oxarol;Prezios
Chemical Name 1alpha,25-Dihydroxy-22-oxavitamin D3
      22-Oxacalcitriol
      20(S)-(3-Hydroxy-3-methylbutoxy)-9,10-secopregna-5(Z),7(E),10(19)-trien-1alpha,3beta-diol
CAS 103909-75-7
Related CAS
Formula C26H42O4
Structure
Formula Weight 418.62224
Stage 上市-2000
Company Chugai (Originator), Maruho (Licensee), Schering-Plough (Licensee)
Activity/Mechanism Antipsoriatics, Dermatologic Drugs, ENDOCRINE DRUGS, Keratolytics, Thyroid Disease Therapy, Treatment of Hyperparathyroidism, Vitamin D Analogs
Syn. Route 7
Route 1
1) the microbiological oxidation of 3beta-hydroxyandrost-5-en-17-one (i) gives 1alpha,3beta-dihydroxyandrost-5-en-17-one (ii), which is silylated with tert-butyldimethylsilyl (tbs) chloride and imidazole to the bis(silyloxy) compound (iii). the dehydrogenation of (iii) by bromination with n-bromosuccinimide (nbs) and dehydrobromination with 2,4,6-trimethylpyridine (tmpyr) yields 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androsta-5,7-dien-17-one (iv). the wittig condensation of (iv) with ethyltriphenylphosphonium bromide (v) by means of nah in dms gives the corresponding ethylidene derivative (vi), which is treated first with 9-borabicyclo[3.3.1]nonane (9-bbn) and then with h2o2 and naoh in thf yielding a mixture of the 20(s)- and 20(r)-isomers of 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20-ol that was separated by preparative tlc. the 20(s)-isomer (vii) was condensed with 1-bromo-3-butene (viii) by means of nah in refluxing xylene affording 20(s)-(3-butenyloxy)-1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-diene (ix), which is oxidized with o2 gas in dmf/water catalyzed by cu2cl2 and pdcl2 to give the corresponding 3-oxobutoxy derivative (x). the grignard alkylation of (x) with methylmagnesium bromide in thf afforded the 20(s)-(3-hydroxy-3-methylbutoxy) derivative (xi), which was submitted to uv irradiation with a 200 w high-pressure mercury lamp in ethanol yielding the silylated 22-oxavitamin d3 derivative (xii). finally, this compound is desilylated by a treatment with tetrabutylammonium fluoride (tbaf) in thf.2) the addition of ethyl acrylate (xiii) to the previously reported pregna-5,7-dien-20(s)-ol (vii) by means of tetrabutylammonium hydroxide/naoh in water/toluene gives the 2-(ethoxycarbonyl)ethoxy derivative (xiv), which by alkylation of the carbonyl function with methyllithium yields the 3-hydroxy-3-methylbutoxy derivative (xi), already obtained.3) the addition of n,n-dimethylacrylamide (xv) to the previously reported pregna-5,7-dien-20(s)-ol (vii) by means of nah gives the corresponding propionamide derivative (xvi), which by a grignard alkylation with methylmagnesium bromide and cecl3 is converted into the 3-hydroxy-3-methylbutoxy derivative (xi), already obtained.
List of intermediates No.
[5-(1-piperazinyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl benzoate (xiii)
[8-(hydroxymethyl)-2-methoxy-1-naphthyl]methanol (i)
1,8-bis(bromomethyl)-2-naphthyl methyl ether; 1,8-bis(bromomethyl)-2-methoxynaphthalene (ii)
diethyl 4-methoxy-1h-phenalene-2,2(3h)-dicarboxylate (iii)
4-methoxy-2,3-dihydro-1h-phenalene-2-carboxylic acid (iv)
4-methoxy-2,3-dihydro-1h-phenalene-2-carboxylic acid ethoxycarbonyl anhydride (v)
4-methoxy-2,3-dihydro-1h-phenalene-2-carbonyl azide (vi)
4-methoxy-2,3-dihydro-1h-phenalen-2-yl isocyanate; 2-isocyanato-4-methoxy-2,3-dihydro-1h-phenalene (vii)
4-methoxy-2,3-dihydro-1h-phenalen-2-amine; 4-methoxy-2,3-dihydro-1h-phenalen-2-ylamine (viii)
2-bromoacetic acid (ix)
benzyl (2s)-2-[(2-bromoacetyl)amino]-4-methylpentanoate (x)
benzyl (2s)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate (xi)
(2s)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid (xii)
benzyl (2s)-2-[[(4s)-4-amino-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate (xiv)
(2s,3s)-2-[(tert-butoxycarbonyl)amino]-3-[((2r)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid (xv)
benzyl (5r,8s,9s,12s,17s)-9-[(tert-butoxycarbonyl)amino]-1-(9h-fluoren-9-yl)-12,17-diisobutyl-5,8-dimethyl-3,6,10,13,15-pentaoxo-14-(triphenylphosphoranylidene)-2,7-dioxa-4,11,16-triazaoctadecan-18-oate (xvi)
Reference 1:
    murayama, e.; miyamoto, k.; kubodera, n.; mori, t.; matsunaga, i.; synthetic studies of vitamin d3 analogues. viii. synthesis of 22-oxavitamin d3 analogues. chem pharm bull 1986, 34, 10, 4410-3.
Reference 2:
    kubodera, n.; watanabe, h.; kawanishi, t.; matsumoto, m.; synthetic studies of vitamin d analogues. xi. synthesis and differentiation-inducing activity of 1alpha,25-dihydroxy-22-oxavitamin d3 analogues. chem pharm bull 1992, 40, 6, 1494-9.
Reference 3:
    leeson, p.a.; martel, a.m.; castaner, j.; 22-oxacalcitriol. drugs fut 1996, 21, 12, 1229.
Reference 4:
    kubodera, n.; miyamoto, k.; ochi, k.; matsunaga, i.; murayama, e. (chugai pharmaceutical co. ltd.); novel vitamin d derivs. and process for producing the same. ep 0184112; jp 1986267548; jp 1986267550 .

Route 2
4) the wittig condensation of the previously reported 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androst-5-en-17-one (iii) with ethyltriphenylphosphonium bromide and potassium tert-butoxide gives the corresponding 17-ethylidene derivative (xvii), which is treated first with 9-borabicyclo[3.3.1]nonane (9-bbn) and then with h2o2 and naoh in thf yielding a mixture of the 20(s)- and 20(r)-isomers of the 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregn-5-en-20-ol that was separated by preparative tlc. the 20(s)-isomer (xviii) was condensed with n,n-dimethylacrylamide (xv) by means of nah affording the propionamide derivative (xix), which by a grignard condensation with methylmagnesium bromide catalyzed by cecl3 is converted into 1alpha,3beta-bis(tert-butyldimethylsilyloxy)-20(s)-(3-hydroxy-3-methylbutoxy)pregn-5-ene (xx). finally, this compound is dehydrogenated as before by bromination with n-bromosuccinimide (nbs) and dehydrobromination with 2,4,6-trimethylpyridine (tmpyr) to afford the 3-hydroxy-3-methylbutoxy derivative (xi), already obtained.
List of intermediates No.
diethyl 4-methoxy-1h-phenalene-2,2(3h)-dicarboxylate (iii)
4-methoxy-2,3-dihydro-1h-phenalene-2-carboxylic acid ethoxycarbonyl anhydride (v)
benzyl (2s)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate (xi)
(2s,3s)-2-[(tert-butoxycarbonyl)amino]-3-[((2r)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid (xv)
(xvii)
(xviii)
(xix)
2-[(3r,6s,9s,14s,17s,18s)-17-amino-9,14-diisobutyl-3,18-dimethyl-2,5,8,11,13,16-hexaoxo-12-(triphenylphosphoranylidene)-1-oxa-4,7,10,15-tetraazacyclooctadecan-6-yl]acetamide (xx)
Reference 1:
    kubodera, n.; active vitamin d analogs. important and various roles by medicinal chemists during the course of development of promising candidates as useful medicines. jpn j org chem 1996, 54, 2, 139-45.
Reference 2:
    leeson, p.a.; martel, a.m.; castaner, j.; 22-oxacalcitriol. drugs fut 1996, 21, 12, 1229.
Reference 3:
    kato, m.; mikami, t.; ochi, k.; watanabe, h.; kubodera, n. (chugai pharmaceutical co. ltd.); 22-oxacalciferol deriv. and production thereof. wo 9312083 .

Route 3
5) the acetylation of 20(s)-(3-hydroxy-3-methylbutoxy)pregna-5,7-diene-1alpha,3beta-diol (xxi) with acetic anhydride and dimethylaminopyridine (dmap) in pyridine gives the 1alpha,3beta-diacetoxy derivative (xxii), which was submitted to uv irradiation with a 400 w high-pressure mercury lamp in thf yielding the corresponding 22-oxavitamin d3 derivative (xxiii). finally, this compound is deacetylated by a treatment with koh in methanol.
List of intermediates No.
(2s,3s)-3-hydroxy-2-([(2s)-3-phenyl-2-[(2-phenylacetyl)amino]propanoyl]amino)butyric acid (xxi)
(2s,3s)-n-[(3r,6s,9s,14s,17s,18s)-6-(2-amino-2-oxoethyl)-9,14-diisobutyl-3,18-dimethyl-2,5,8,11,13,16-hexaoxo-12-(triphenylphosphoranylidene)-1-oxa-4,7,10,15-tetraazacyclooctadecan-17-yl]-3-hydroxy-2-([(2s)-3-phenyl-2-[(2-phenylacetyl)amino]propanoyl]amino)butanamide (xxii)
(2s,3s)-3-hydroxy-2-([(2s)-2-[(3-methylbutanoyl)amino]-3-phenylpropanoyl]amino)butyric acid (xxiii)
Reference 1:
    leeson, p.a.; martel, a.m.; castaner, j.; 22-oxacalcitriol. drugs fut 1996, 21, 12, 1229.
Reference 2:
    mikami, t. (chugai pharmaceutical co. ltd.); vitamin d deriv. and process for producing the same. wo 9408958 .

Route 4
the synthesis of 22-oxacalcitriol labeled with tritium at the 26-methyl group has been performed as follows: the starting compound is the previously obtained 3-oxobutoxy derivative (x), which is submitted to a grignard alkylation with 3ch3mgi giving the labeled 3-hydroxy-3-methylbutoxy derivative (xxiv). the deprotection of (xxiv) with tetrabutylammonium fluoride affords the triol derivative (xxv), which is finally irradiated with a 400 w high-pressure mercury lamp with a vycor filter.
List of intermediates No.
benzyl (2s)-2-[(2-bromoacetyl)amino]-4-methylpentanoate (x)
benzyl (2s)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate (xxiv)
(2s,3s)-3-hydroxy-2-([(2s)-3-phenyl-2-[(2-phenylacetyl)amino]propanoyl]amino)butyric acid (xxv)
(3s)-1,3,8-octanetriol (xxiv)
5-[(4s)-2,2-dimethyl-1,3-dioxan-4-yl]-1-pentanol (xxv)
Reference 1:
    leeson, p.a.; martel, a.m.; castaner, j.; 22-oxacalcitriol. drugs fut 1996, 21, 12, 1229.
Reference 2:
    watanabe, h.; akiyama, m.; kawanishi, t.; kubodera, n.; synthesis of tritiated 1alpha,25-dihydroxy-22-oxavitamin d3. j label compd radiopharm 1995, 36, 7, 645-54.

Route 5
the synthesis of 22-oxacalcitriol labeled with tritium at the 2beta-position has been performed as follows:the condensation of 3beta-(tert-butyldimethylsilyloxy)pregn-5-en-20(s)-ol (xxvi) with n,n-dimethylacrylamide (xv) by means of nah in thf gives the propionamide derivative (xxvii), which is submitted to a grignard alkylation with ch3mgbr and cecl3 in ethyl ether yielding the 3-hydroxy-3-methylbutoxy derivative (xxviii). the desilylation of (xxviii) with tetrabutylammonium fluoride in thf affords the 3beta-hydroxy compound (xxix), which is oxidized with cyclohexanone in refluxing toluene catalyzed by aluminum isopropoxide giving the enone compound (xxx). the dehydrogenation of (xxx) with dichlorodicyanobenzoquinone (ddq) in refluxing dioxane yields the 1,4-dien-3-one compound (xxxi), which is isomerized by means of sodium ethoxide in dmso to the 1,5-dien-3-one isomer (xxxii). the reduction of (xxxii) with nabh4 in methanol affords the corresponding 3beta-hydroxy compound (xxxiii), which is selectively acetylated with acetic anhydride in pyridine to the 3beta-acetoxy compound (xxxiv). the dehydrogenation of (xxxiv) with n-bromosuccinimide (nbs) and tetrabutylammonium fluoride in refluxing ccl4 affords the 1,5,7-triene compound (xxxv), which is deacetylated with lialh4/naoh in thf giving the corresponding 3beta-hydroxy compound (xxxvi). the protection of the conjugated diene system of (xxxvi) by a diels-alder cycloaddition with 4-phenyl-2,5-dihydro-1h-1,2,4-triazole-2,5-dione (xxxvii) in dichloromethane yields the adduct (xxxviii), which is treated with trimethylsilyl chloride and imidazole in dmf (in order to protect the 3beta-hydroxy group) affording (xxxix). the selective epoxidation of the 1-double bond of (xxxix) with m-chloroperbenzoic acid (mcpba) in dichloromethane gives the 1alpha,2alpha-epoxy derivative (xl), which is desilylated with tbaf in thf to the 1alpha,2alpha-epoxy-3beta-hydroxy adduct (xli). the deprotection of the conjugated diene system of (xli) by a retro diels-alder reaction (heating at 140 c in 1,3-dimethylimidazolidin-2-one) yields 1alpha,2alpha-epoxy-3beta-hydroxy-20(s)-(3-hydroxy-3-methylbutoxy) pregna-5,7-diene (xlii), which is submitted to a epoxy ring opening with tritiated nab3h4 affording the 2beta-tritiated pregnadiene (xliii). finally, this compound is irradiated in ethanol with a 400 w high-pressure mercury lamp provided with a vycor filter.
List of intermediates No.
(2s,3s)-2-[(tert-butoxycarbonyl)amino]-3-[((2r)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid (xv)
[4-methoxy-3-(phenethyloxy)phenyl]methanol (xxvi)
4-(chloromethyl)-1-methoxy-2-(phenethyloxy)benzene; 5-(chloromethyl)-2-methoxyphenyl phenethyl ether (xxvii)
2-[4-methoxy-3-(phenethyloxy)phenyl]acetonitrile (xxviii)
2-[4-methoxy-3-(phenethyloxy)phenyl]acetic acid (xxix)
2-[4-methoxy-3-(phenethyloxy)phenyl]acetyl chloride (xxx)
2-[4-methoxy-3-(phenethyloxy)phenyl]-n,n-dipropylacetamide (xxxi)
2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione (xxxii)
propyl 3-oxo-3-phenylpropanoate (xxxiii)
propyl (e)-3-amino-3-phenyl-2-propenoate (xxxiv)
butyraldehyde (xxxv)
propyl 6-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-4-propyl-1,4-dihydro-3-pyridinecarboxylate (xxxvi)
s-ethyl 3-oxopentanethioate (xxxvii)
ethyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-1,4-dihydro-3-pyridinecarboxylate (xxxviii)
propylhydrosulfide; 1-propanethiol (xxxix)
s-propyl 3-oxopentanethioate (xl)
propyl 3-(3-chlorophenyl)-3-oxopropanoate (xli)
propyl (e)-3-amino-3-(3-chlorophenyl)-2-propenoate (xlii)
propyl 2-(3-chlorophenyl)-4,6-diethyl-5-[(propylsulfanyl)carbonyl]-1,4-dihydro-3-pyridinecarboxylate (xliii)
5-[(4s)-2,2-dimethyl-1,3-dioxan-4-yl]pentanal (xliii)
Reference 1:
    watanabe, h.; akiyama, m.; kawanishi, t.; kubodera, n.; synthesis of tritiated 1alpha,25-dihydroxy-22-oxavitamin d3. j label compd radiopharm 1995, 36, 7, 645-54.
Reference 2:
    leeson, p.a.; martel, a.m.; castaner, j.; 22-oxacalcitriol. drugs fut 1996, 21, 12, 1229.

Route 6
synthesis of phosphine oxide (xiv): epoxidation of l-carvone (i) with h2o2 and lioh in methanol gives the epoxide (ii), which is reduced with l-selectride in thf to yield the alcohol (iii). oxidation of the isopropenyl group of (iii) with oso4, kio4, mcpba and hoac affords the acetate (iv), which is hydrolyzed to the diol (v) with meona in methanol. protection of the two oh groups of (v) with tbdms-cl and imidazole provides the bis-silyl ether (vi), which is oxidized with periodic acid in ethyl ether to give the aldehyde (vii). compound (vii) is submitted to a wittig condensation with cbr4, pph3 and zn in dichloromethane to yield the dibromovinyl compound (viii), which is converted into the acetylenic vinyl triflate (x) by treatment with lda in thf followed by the triflic imide (ix). cyclization of triflate (x) by means of pd(oac)2 and pph3, followed by carbonylation with co in methanol provides the methyl ester (xi) as a 2:1 mixture of the z- and e-isomers. photoisomerization of this mixture (xia-b) under the hoffman-la roche conditions (presence of 9-fluorenone) gives the z-isomer (xii) in a high yield. reduction of ester (xii) with dibal in toluene provides the primary alcohol (xiii), which is finally converted into the phosphine oxide (xiv) by known methods.
List of intermediates No.
(1s)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2s,3s)-3-[[(3r,4s)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoate (i)
ethyl (2e,4e,6s,7r,8s)-7-[(4-methoxybenzyl)oxy]-2,4,6,8-tetramethyl-2,4-octadecadienoate (ix)
[(2s,4r,5r)-5-(6-chloro-9h-purin-9-yl)-4-hydroxytetrahydro-2-furanyl]methyl acetate (xiv)
(2s,3r,4r)-2-[(diphenylphosphoryl)methyl]-4-(2-hydroxyphenoxy)tetrahydro-2h-pyran-3-ol (xiii)
Reference 1:
    mourino, a.; et al.; efficient and versatile synthesis of a-ring precursors of 1alpha,25-dihydroxyvitamin d3 and analogues. application to the synthesis of lythgoe-roche phosphine oxide. tetrahedron lett 1997, 38, 26, 4713.

Route 7
synthesis of ketone (xxiv): reaction of the known diol (xv) - obtained by degradation of vitamin d2 - with tsoh in pyridine gives, regioselectively, the monotosylate (xvi), which is protected at the secondary oh group by silylation with tbdms-cl and imidazole to yield the silyl ether (xvii). oxidation of the tosyloxy group of (xvii) with o2 and t-buok in dmso/t-buoh affords ketone (xviii), which is reduced with k and i-proh providing alcohol (xix). condensation of compound (xix) with ethyl prop-ynoate (xx) by means of nmm in benzene gives the alkoxyacrylate (xxi), which is reduced with h2 over pd/c in etoh to yield the alkoxypropionate (xxii). deprotection of the oh group of (xxii) with hf in acetonitrile affords alcohol (xxiii), which is oxidized with pyridinium dichromate (pdc) in ch2cl2 providing ketone (xxiv). wittig-horner condensation of ketone (xxiv) with phosphine oxide (xiv) by means of buli in thf yields the corresponding adduct (xxv), which is submitted to a grignard reaction with meli in thf to give the protected maxacalcitol precursor (xxvi). finally, this compound is desilylated by means of tbaf in thf.
List of intermediates No.
(2s)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid (xxvi)
(3s,6r,7s,8s)-11-[(2r,3s)-3-[(2s,3e)-2-azido-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid (xx)
[(2s,4r,5r)-5-(6-chloro-9h-purin-9-yl)-4-hydroxytetrahydro-2-furanyl]methyl acetate (xiv)
Reference 1:
    vidal, b.; fall, y.; mourino, a.; gonzalez, v.; stereoselective synthesis of 22-oxacalcitriol (oct) and analogues modified at c25. tetrahedron lett 2002, 43, 3, 427.
Reference 2:
    fall, y.; a new approach to the synthesis of the 25-hydroxy-22-oxa-vitamin d3 side chain. tetrahedron lett 1997, 38, 27, 4909.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名馬沙骨化醇;英文名Maxacalcitol;22-Oxacalcitriol;Sch-209579;MC-1275;22-Oxa-1;25(OH)2D3;OCT;Oxarol;Prezios;CAS[103909-75-7]

 
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