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药物详细合成路线

Name Elocalcitol;Ro-26-9228;BXL-628
Chemical Name (23E)-1alpha-Fluoro-25-hydroxy-16,17,23,24-tetradehydro-26,27-bishomo-20-epivitamin D3
CAS 199798-84-0
Related CAS
Formula C29H43FO2
Structure
Formula Weight 442.66326
Stage II 期临床
Company Roche Bioscience (Originator)
Activity/Mechanism Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Osteoporosis, Vitamin D Analogs
Syn. Route 2
Route 1
the indenone intermediate (xiii) has been obtained as follows: the silylation of 3-methyl-1-pentyn-3-ol (i) with tes-cl and dmap in dmf gives the silyl ether (ii), which is condensed with paraformaldehyde and n-buli in thf to yield the propargyl alcohol (iii). partial reduction of (iii) with red-al in thf affords the allyl alcohol (iv), which is treated with ts-cl and dmap in dichloromethane to provide the allyl chloride (v). the condensation of (v) with the unsaturated ester (vi) (obtained by wittig condensation of perhydroindanone (vii) with triethyl phosphonoacetate (viii) by means of etona) by means of buli and dicyclohexylamine in hmpa gives the octenoic ester (ix), which is reduced with lialh4, yielding the corresponding primary alcohol (x). the reaction of (x) with tscl and pyridine affords the tosylate (xi), which is reduced with libet3h in thf with simultaneous opening of the epoxide ring to provide the hexahydroindenol (xii). finally, this compound is oxidized with pyridinium dichromate (pdc), yielding the target hexahydroindenone intermediate (xiii).
List of intermediates No.
methyl (1r,2r)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate (viii)
ethyl 2-[7-fluoro-2,3-dioxo-3,4-dihydro-1(2h)-quinoxalinyl]acetate (vii)
4-{[tert-butyl(diphenyl)silyl]oxy}-3-[(methylsulfonyl)amino]phenyl acetate (i)
tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-hydroxyphenyl(methylsulfonyl)carbamate (ii)
tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-[(2s)oxiranylmethoxy]phenyl(methylsulfonyl)carbamate (iii)
1,4-difluoro-2-(isocyanatomethyl)benzene; 2,5-difluorobenzyl isocyanate (iv)
tert-butyl 4-[(1-{[(2,5-difluorobenzyl)amino]carbonyl}-4-piperidinyl)amino]phenethylcarbamate (v)
4-[4-(2-aminoethyl)anilino]-n-(2,5-difluorobenzyl)-1-piperidinecarboxamide (vi)
3-[(12r,13r,22s,23s)-17-acetyl-12-ethyl-13,18,22,27-tetramethyl-3,5-dioxo-4-oxa-8,24,25,26-tetraazahexacyclo[19.2.1.1~6,9~.1~11,14~.1~16,19~.0~2,7~]heptacosa-1,6,9(27),10,14(26),15,17,19,21(24)-nonaen-23-yl]propanoic acid (ix)
propyl 3-[(12r,13r,22s,23s)-17-acetyl-12-ethyl-13,18,22,27-tetramethyl-3,5-dioxo-4-oxa-8,24,25,26-tetraazahexacyclo[19.2.1.1~6,9~.1~11,14~.1~16,19~.0~2,7~]heptacosa-1,6,9(27),10,14(26),15,17,19,21(24)-nonaen-23-yl]propanoate (x)
methyl (9r,10r,19s,20s)-14-acetyl-9-ethyl-2-[(hexylamino)carbonyl]-5,10,15,19-tetramethyl-20-(3-oxo-3-propoxypropyl)-21,22,23,24-tetraazapentacyclo[16.2.1.1~3,6~.1~8,11~.1~13,16~]tetracosa-1,3,5,7,11(23),12,14,16,18(21)-nonaene-4-carboxylate (xi)
methyl (9r,10r,19s,20s)-14-acetyl-9-ethyl-4-[(hexylamino)carbonyl]-5,10,15,19-tetramethyl-20-(3-oxo-3-propoxypropyl)-21,22,23,24-tetraazapentacyclo[16.2.1.1~3,6~.1~8,11~.1~13,16~]tetracosa-1,3,5,7,11(23),12,14,16,18(21)-nonaene-2-carboxylate (xii)
propyl 3-[(12r,13r,22s,23s)-17-acetyl-12-ethyl-4-hexyl-13,18,22,27-tetramethyl-3,5-dioxo-4,8,24,25,26-pentaazahexacyclo[19.2.1.1~6,9~.1~11,14~.1~16,19~.0~2,7~]heptacosa-1,6,9(27),10,14(26),15,17,19,21(24)-nonaen-23-yl]propanoate (xiii)
Reference 1:
    radinov, r.n.; daniewski, a.r. (f. hoffmann-la roche ag); process for preparing anti-osteoporotic agents. ep 1048661; jp 2000336094 .

Route 2
the reaction of the cyclohexylidene ethanol (xiv) with triphosgene gives the corresponding chloride (xv), which is condensed with diphenylphosphine oxide (xvi) by means of nah in dmf to yield the alkyldiphenylphosphine oxide (xvii) (2). the condensation of (xvii) with the hexahydroindenone intermediate (xiii) by means of buli in thf affords the disilylated precursor (xviii), which is finally deprotected by means of tbaf in thf.
List of intermediates No.
propyl 3-[(12r,13r,22s,23s)-17-acetyl-12-ethyl-4-hexyl-13,18,22,27-tetramethyl-3,5-dioxo-4,8,24,25,26-pentaazahexacyclo[19.2.1.1~6,9~.1~11,14~.1~16,19~.0~2,7~]heptacosa-1,6,9(27),10,14(26),15,17,19,21(24)-nonaen-23-yl]propanoate (xiii)
propyl 3-[(12r,13r,22s,23s)-12-ethyl-4-hexyl-17-(1-hydroxyethyl)-13,18,22,27-tetramethyl-3,5-dioxo-4,8,24,25,26-pentaazahexacyclo[19.2.1.1~6,9~.1~11,14~.1~16,19~.0~2,7~]heptacosa-1,6,9(27),10,14(26),15,17,19,21(24)-nonaen-23-yl]propanoate (xiv)
propyl 3-[(12r,13r,22s,23s)-17-(1-bromoethyl)-12-ethyl-4-hexyl-13,18,22,27-tetramethyl-3,5-dioxo-4,8,24,25,26-pentaazahexacyclo[19.2.1.1~6,9~.1~11,14~.1~16,19~.0~2,7~]heptacosa-1,6,9(27),10,14(26),15,17,19,21(24)-nonaen-23-yl]propanoate (xv)
propyl 3-[(12r,13r,22s,23s)-12-ethyl-4-hexyl-13,18,22,27-tetramethyl-3,5-dioxo-17-vinyl-4,8,24,25,26-pentaazahexacyclo[19.2.1.1~6,9~.1~11,14~.1~16,19~.0~2,7~]heptacosa-1,6,9(27),10,14(26),15,17,19,21(24)-nonaen-23-yl]propanoate (xvii)
4-(3-bromopropyl)-2,6-di(tert-butyl)phenol (xviii)
2,6-di(tert-butyl)-4-[3-(4-nitrophenoxy)propyl]phenol (xvi)
Reference 1:
    batcho, a.d.; bryce, g.f.; hennessy, b.m.; iacobelli, j.a.; uskokovic, m.r. (f. hoffmann-la roche ag); vitamin d3 analogs. ep 0808833; jp 1998045713; us 5939408 .
Reference 2:
    kabat, m.m. (f. hoffmann-la roche ag); phosphinoxide vitamin d precursors. ep 1050537 .

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艾洛骨化醇;英文名Elocalcitol;Ro-26-9228;BXL-628;CAS[199798-84-0]

 
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