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藥物詳細合成路線

Name Calcipotriene;Calcipotriol;BMS-181161;MC-903;Psorcutan;Divonex;Dovonex;Daivonex
Chemical Name 20(R)-[3(S)-Cyclopropyl-3-hydroxyprop-1(E)-enyl]-1(S),3(R)-dihydroxy-9,10-secopregna-5(Z),7(E),10(19)-triene
      1(S),24(S)-Dihydroxy-22,23:26,27-tetradehydrovitamin D3
CAS 112828-00-9
Related CAS 112965-21-6 (no stereoch. at C24)
Formula C27H40O3
Structure
Formula Weight 412.61805
Stage 上市-1991
Company Leo (Originator), Bristol-Myers Squibb (Licensee), CSL (Licensee), Fujisawa (Licensee), Schering AG (Licensee), Teikoku Seiyaku (Licensee), Galen (Comarketer)
Activity/Mechanism Antipsoriatics, DERMATOLOGIC DRUGS, Vitamin D Analogs
Syn. Route 2
Route 1
the reaction of vitamin d2 (i) with refluxing liquid so2 gives a mixture of the 6(r)- and 6(s)-so2-adducts (ii), which by treatment with tert-butyl-dimethylsilyl chloride (tbdmsci) and imidazole in dmf yields the corresponding mixture of silylated adducts (iii). the reaction of the mixture (iii) with nahco3 in ethanol affords the silylated 5(e)-vitamin d2 (iv), which by oxidation with seo2 and n-methylmorpholine n-oxide in refluxing methanol-dichloromethane is converted into a mixture of silylated 1(s)- and 1(r)-hydroxy-5(e)-vitamin d2 (v). the silylation of (v) as before, followed by crystallization in ethyl ether-ethanol gives the 1(s)-isomer of the fully silylated compound (vi), which is treated with refluxing so2 as before to yield the mixture of the 6(r)- and 6(s)-so2-adducts (vii). the ozonolysis of the mixture (vii) in dichloromethane-methanol at -65 c affords the corresponding mixture of the 6(r)- and 6(s)-so2-aldehydic adducts (viii).
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 (i)
ethyl (e,4s)-4-[((2r,5s)-2-benzyl-5-[[(cyclopentylsulfanyl)carbonyl]amino]-6-methyl-4-oxoheptanoyl)amino]-7-oxo-7-(tritylamino)-2-heptenoate (ii)
n-(5-bromo-2-pyridinyl)-1h-imidazole-1-carbothioamide (iii)
2-(1-piperidinyl)-1-ethanamine (iv)
2-(1-piperazinyl)-1-ethanamine (v)
4-(dimethylamino)-3-methylbenzoic acid (vi)
1-(chloromethyl)-2,3,4,5,6-pentamethylbenzene (vii)
2,3,4,5,6-pentamethylbenzyl 4-(dimethylamino)-3-methylbenzoate (viii)
Reference 1:
    calverley, m.j.; synthesis of mc 903, a biologically active vitamin d metabolite analogue. tetrahedron 1987, 43, 20, 4609-19.
Reference 2:
    binderup, e.; calcipotriol. drugs fut 1990, 15, 1, 15.

Route 2
the treatment with nahco3 of the corresponding mixture of the 6(r)- and 6(s)-so2-aldehydic adducts (viii) gives a mixture of the 20(r) and 20(s) epimeric aldehydes (ix). the wittig condensation of the aldehyde mixture (ix) with cyclopropylcarbonylmethylenetriphenylphosphorane (x) [prepared from acetylcyclopropane (xi) by bromination to bromoacetylcyclopropane (xii), reaction with triphenylphosphine (xiii) to the phosphonium salt (xiv) and treatment with naoh] in dmso at 105 c, followed by chromatographic separation yields the epimeric 20(r)-enone (xv). the reduction of (xv) with nabh4 and cecl3 in thf-methanol, followed by chromatographic purification affords the epimeric 3(r)-allylic alcohol (xvi), which is isomerized by irradiation with uv-light from a tq 718z2 hanau lamp in toluene in the presence of anthracene to give the corresponding 5(z)-derivative (xvii). finally, this compound is deprotected by a treatment with tetrabutylammonium fluoride in thf at 60 c.
List of intermediates No.
2,3,4,5,6-pentamethylbenzyl 4-(dimethylamino)-3-methylbenzoate (viii)
n,n,n,2-tetramethyl-4-[[(2,3,4,5,6-pentamethylbenzyl)oxy]carbonyl]benzenaminium (ix)
2,3,4,5,6-pentamethylbenzyl 4-fluoro-3-methylbenzoate (x)
4-fluoro-3-methylbenzoic acid (xi)
4-fluoro-3-methylbenzoyl chloride (xii)
n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinamine (xiii)
ethyl 4-hydroxycyclohexanecarboxylate (xiv)
4-hydroxycyclohexanecarboxylic acid (xv)
2,3,4,5,6-pentamethylbenzyl 4-hydroxycyclohexanecarboxylate (xvi)
2,3,4,5,6-pentamethylbenzyl 4-[[(4-nitrophenyl)sulfonyl]oxy]cyclohexanecarboxylate (xvii)
Reference 1:
    calverley, m.j.; synthesis of mc 903, a biologically active vitamin d metabolite analogue. tetrahedron 1987, 43, 20, 4609-19.
Reference 2:
    binderup, e.; calcipotriol. drugs fut 1990, 15, 1, 15.

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鈣泊三醇;英文名Calcipotriene;Calcipotriol;BMS-181161;MC-903;Psorcutan;Divonex;Dovonex;Daivonex;CAS[112828-00-9]

 
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