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【结 构 式】

【药物名称】Squalamine, MSI-1256F(lactate)

【化学名称】3beta-[3-(4-Aminobutylamino)propylamino]-7alpha-hydroxy-24(R)-(sulfooxy)-5alpha-cholestane

【CA登记号】148717-90-2, 320725-47-1 (lactate)

【 分 子 式 】C34H65N3O5S

【 分 子 量 】627.97825

【开发单位】Genaera (Orphan Drug), Genaera (Originator)

【药理作用】Bone Diseases, Treatment of, Lung Cancer Therapy, METABOLIC DRUGS, Non-Small Cell Lung Cancer Therapy, OCULAR MEDICATIONS, Oncolytic Drugs, Ophthalmic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Treatment of Age-Related Macular Degeneration, Angiogenesis Inhibitors, Inhibitors of Signal Transduction Pathways, Mitogen-Activated Protein (MAP) Kinase Inhibitors, Na+/H+ Exchange (NHE) Inhibitors, Vascular Endothelial Growth Factor (VEGF) Inhibitors
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26合成路线27合成路线28

合成路线1

Protection of 3-beta-hydroxy-5-cholenic acid (I) with 2,3-dihydropyran in the presence of pyridinium p-toluenesulfonate provided the bis-tetrahydropyranyl derivative (II). Reduction of the tetrahydropyranyl ester group of (II) with LiAlH4 gave alcohol (III), which was further oxidized to aldehyde (IV) under Swern conditions. Addition of isopropylmagnesium bromide to the aldehyde (IV) yielded the secondary alcohol (V). After silylation of alcohol (V) with t-butyldimethylsilyl chloride and imidazole to (VI), the tetrahydropyranyl protecting group was removed under acidic conditions to afford alcohol (VII). This was further esterified with Ac2O in pyridine to provide acetate ester (VIII).

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103.
【2】 Pechulis, A.D.; et al.; Synthesis of 24xi-squalamine, an anti-infective steroidal polyamine. J Org Chem 1995, 60, 16, 5121.
【3】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 53687 5-Cholenic acid-3beta-ol; 3beta-Hydroxy-5-cholen-24-oic acid 5255-17-4 C24H38O3 详情 详情
(II) 53688 tetrahydro-2H-pyran-2-yl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate n/a C34H54O5 详情 详情
(III) 53689 (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-pentanol n/a C29H48O3 详情 详情
(IV) 53690 (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanal n/a C29H46O3 详情 详情
(V) 53691 (6R)-6-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanol n/a C32H54O3 详情 详情
(VI) 53692 tert-butyl(dimethyl)silyl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl ether; tert-butyl({(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl}oxy)dimethylsilane n/a C38H68O3Si 详情 详情
(VII) 53693 (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol n/a C33H60O2Si 详情 详情
(VIII) 53694 (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H62O3Si 详情 详情

合成路线2

Allylic oxidation of (VIII) by means of t-butyl hydroperoxide and chromium hexacarbonyl produced enone (IX). Subsequent Birch reduction of (IX) employing lithium metal in liquid ammonia gave the saturated ketone (X), which was further reduced to alcohol (XI) with K-Selectride in cold THF. Removal of the acetate ester of (XI) was achieved by treatment with NaCN in MeOH, giving diol (XII). The 3-beta hydroxyl group of (XII) was then selectively oxidized to ketone (XIII) under Oppenauer conditions. Ketone (XIII) was converted to the primary amine (XV) via formation of the O-benzyl oxime (XIV), which was reduced by LiAlH4.

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103.
【2】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 53694 (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H62O3Si 详情 详情
(IX) 53695 (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H60O4Si 详情 详情
(X) 53696 (3S,5R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H62O4Si 详情 详情
(XI) 53697 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H64O4Si 详情 详情
(XII) 53698 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol n/a C33H62O3Si 详情 详情
(XIII) 53699 (5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C33H60O3Si 详情 详情
(XIV) 53700 (5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one O-benzyloxime n/a C40H67NO3Si 详情 详情
(XV) 53701 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-amino-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol n/a C33H63NO2Si 详情 详情

合成路线3

The condensation between 4-bromobutyronitrile (XVI) and 3-amino-1-propanol (XVII) gave the hydroxy amino nitrile (XVIII), which was further converted to the N,O-bis-tosylated derivative (XIX). Displacement of the tosylate ester group of (XIX) with NaI in boiling acetone afforded the alkyl iodide (XX). Alkylation of amine (XV) with iodide (XX) provided the secondary amine adduct (XXI). The p-toluenesulfonamido group of (XXI) was reductively removed by sodium in liquid ammonia, yielding diamine (XXII). Subsequent nitrile reduction by means of LiAlH4 furnished triamine (XXIII).

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103.
【2】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 53701 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-amino-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol n/a C33H63NO2Si 详情 详情
(XVI) 34789 4-bromobutanenitrile 5332-06-9 C4H6BrN 详情 详情
(XVII) 18522 3-amino-1-propanol 156-87-6 C3H9NO 详情 详情
(XVIII) 53702 4-[(3-hydroxypropyl)amino]butanenitrile n/a C7H14N2O 详情 详情
(XIX) 53703 3-{(3-cyanopropyl)[(4-methylphenyl)sulfonyl]amino}propyl 4-methylbenzenesulfonate n/a C21H26N2O5S2 详情 详情
(XX) 53704 N-(3-cyanopropyl)-N-(3-iodopropyl)-4-methylbenzenesulfonamide n/a C14H19IN2O2S 详情 详情
(XXI) 53705 N-(3-{[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]amino}propyl)-N-(3-cyanopropyl)-4-methylbenzenesulfonamide n/a C47H81N3O4SSi 详情 详情
(XXII) 53706 4-[(3-{[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]amino}propyl)amino]butanenitrile n/a C40H75N3O2Si 详情 详情
(XXIII) 53707 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol n/a C40H79N3O2Si 详情 详情

合成路线4

After protection of triamine (XXIII) as the tris-benzyloxycarbonyl derivative (XXIV), its 7-hydroxyl was acetylated by means of Ac2O and DMAP. Further hydrogenolysis of the benzyloxycarbonyl groups in ethanolic HCl also removed the O-silyl group, yielding (XXV). Treatment of alcohol (XXV) with sulfur trioxide in pyridine generated the pyridinium sulfate salt (XXVI). The 7-acetate ester of (XXVI) was finally hydrolyzed with NaOH to furnish the title compound.

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103.
【2】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 53707 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol n/a C40H79N3O2Si 详情 详情
(XXIV) 53708 benzyl 4-{[(benzyloxy)carbonyl]amino}butyl(3-{[(benzyloxy)carbonyl][(3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]amino}propyl)carbamate n/a C64H97N3O8Si 详情 详情
(XXV) 53709 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-[(1R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-yl acetate n/a C36H67N3O3 详情 详情
(XXVI) 53710 pyridinium (3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(acetyloxy)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-[(1R)-1,5-dimethyl-4-(sulfonatooxy)hexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene n/a C41H72N4O6S 详情 详情

合成路线5

In an alternative preparation of intermediate (VIII), 3-beta-acetoxy-5-cholenic acid (XXVII) was converted to the corresponding acid chloride, to which was added isopropylcadmium bromide, yielding ketone (XXVIII). Subsequent reduction of (XXVIII) with calcium borohydride in THF, followed by silylation of the resultant alcohol (XXIX), provided intermediate (VIII).

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 53694 (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H62O3Si 详情 详情
(XXVII) 53711 (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-3-(acetyloxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C26H40O4 详情 详情
(XXVIII) 53712 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethyl-4-oxohexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C29H46O3 详情 详情
(XXIX) 53713 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C29H48O3 详情 详情

合成路线6

In a different method, protection of alcohol (III) as the tert-butyldimethylsilyl ether (XXX), followed by allylic oxidation by means of CrO3 in the presence of 3,5-dimethylpyrazole (DMP), gave enone (XXXI). Hydrogenation of (XXXI) using Adams catalyst resulted in the formation of the saturated ketone (XXXII). Some undesired 7-beta alcohol byproduct was reoxidized to ketone (XXXII) by means of Collin's reagent. Stereoselective reduction of ketone (XXXII) with K-Selectride afforded the 7-alpha alcohol (XXXIII), which was protected as the benzyl ether (XXXIV) by treatment with benzyl bromide and NaH. After desilylation of (XXXIV) with Bu4NF, the deprotected alcohol was subjected to Swern oxidation to provide aldehyde (XXXV). Addition of isopropylmagnesium chloride to aldehyde (XXXV) gave alcohol (XXXVI) as a mixture of epimers.

参考文献 中间体
【1】 Pechulis, A.D.; et al.; Synthesis of 24xi-squalamine, an anti-infective steroidal polyamine. J Org Chem 1995, 60, 16, 5121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 53689 (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-pentanol n/a C29H48O3 详情 详情
(XXX) 53714 tert-butyl(dimethyl)silyl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl ether; tert-butyl({(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl}oxy)dimethylsilane n/a C35H62O3Si 详情 详情
(XXXI) 53715 (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4,8,9,10,11,12,13,14,15,16,17-tetradecahydro-7H-cyclopenta[a]phenanthren-7-one n/a C35H60O4Si 详情 详情
(XXXII) 53716 (3S,5R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-7H-cyclopenta[a]phenanthren-7-one n/a C35H62O4Si 详情 详情
(XXXIII) 53717 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-7-ol n/a C35H64O4Si 详情 详情
(XXXIV) 53718 benzyl (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-7-yl ether; ({(4R)-4-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl}oxy)(tert-butyl)dimethylsilane n/a C42H70O4Si 详情 详情
(XXXV) 53719 (4R)-4-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanal n/a C36H54O4 详情 详情
(XXXVI) 53720 (6R)-6-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanol n/a C39H62O4 详情 详情

合成路线7

After silylation of alcohol (XXXVI) to silyl ether (XXXVII), its tetrahydropyranyl protecting group was selectively removed by treatment with magnesium bromide in Et2O. The resultant 3-beta alcohol (XXXVIII) was oxidized to ketone (XXXIX) employing Collin's reagent. The polyamino side-chain was then introduced in (XXXIX) by reductive amination with the di-Boc-protected spermidine (XL) in the presence of NaBH3CN, giving (XLI) as a mixture of 3-alpha and 3-beta isomers.

参考文献 中间体
【1】 Pechulis, A.D.; et al.; Synthesis of 24xi-squalamine, an anti-infective steroidal polyamine. J Org Chem 1995, 60, 16, 5121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXVI) 53720 (6R)-6-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanol n/a C39H62O4 详情 详情
(XXXVII) 53721 ({(4R)-4-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl}oxy)(tert-butyl)dimethylsilane; benzyl (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-7-yl ether n/a C45H76O4Si 详情 详情
(XXXVIII) 53722 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol n/a C40H68O3Si 详情 详情
(XXXIX) 53723 (5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C40H66O3Si 详情 详情
(XL) 53724 tert-butyl 3-aminopropyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C17H35N3O4 详情 详情
(XLI) 53725 tert-butyl 3-{[(5R,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]amino}propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C57H101N3O6Si 详情 详情

合成路线8

Removal of the Boc and silyl protecting groups of (XLI) was accomplished by treatment with trifluoroacetic acid in chloroform to provide, after chromatographic separation, the 3-alpha-polyamino sterol (XLII). Subsequent catalytic hydrogenation removed the benzyl protecting group of (XLVII), yielding (XLIII). Finally, sulfation of alcohol (XLIII) with sulfur trioxide-pyridine gave rise to the title compound.

参考文献 中间体
【1】 Zhang, X.; et al.; Synthesis of squalamine utilizing a readily accessible spermidine equivalent. J Org Chem 1998, 63, 23, 8599.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLI) 53725 tert-butyl 3-{[(5R,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]amino}propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C57H101N3O6Si 详情 详情
(XLII) 53726 (6R)-6-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-7-(benzyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanol n/a C41H71N3O2 详情 详情
(XLIII) 53727 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-[(1R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol n/a C34H65N3O2 详情 详情

合成路线9

Preparation of the key intermediate (XIII) starting from chenodeoxycholic acid (XLIV) was also reported. Diacetylation of (XLIV), followed by selective hydrolysis of diacetate (XLV), gave the C-3 alcohol (XLVI). This was oxidized to dienone (XLVII) following a previously reported procedure. Reduction of (XLVII) by lithium in liquid ammonia yielded the saturated ketone (XLVIII). Protection of the 7-hydroxyl group of (XLVIII) using methoxymethyl chloride, followed by ketalization of the 3-ketone, afforded (XLIX). Side-chain elongation in (XLIX) as in Scheme 20248401a produced (L), which was then deprotected giving (XIII).

参考文献 中间体
【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IL) 53733 　 n/a C28H46O6 详情 详情
(VIII) 53699 (5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C33H60O3Si 详情 详情
(XLIV) 53728 (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C24H40O4 详情 详情
(XLV) 53729 (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-bis(acetyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C28H44O6 详情 详情
(XLVI) 53730 (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-(acetyloxy)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C26H42O5 详情 详情
(XLVII) 53731 (4R)-4-[(7R,8S,9S,10S,13R,14S,17R)-7-(acetyloxy)-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C26H36O5 详情 详情
(XLVIII) 53732 (4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C24H38O4 详情 详情
(L) 53734 　 n/a C31H54O5 详情 详情

合成路线10

Alternatively, intermediate (XLVIII) can also be obtained by Oppenauer oxidation of chenodeoxycholic acid (XLIV) to yield ketone (LI), which is further oxidized employing SeO2 to provide conjugate ketone (LII). Birch reduction of (LII) with lithium in liquid ammonia led to the trans-fused A-B ring compound (XLVIII).

参考文献 中间体
【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLIV) 53278 (2R)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol n/a C11H9F3O2 详情 详情
(XLVIII) 53732 (4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C24H38O4 详情 详情
(LI) 53735 (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C24H38O4 详情 详情
(LII) 53736 (4R)-4-[(7R,8S,9S,10R,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid n/a C24H36O4 详情 详情

合成路线11

In a different synthesis of intermediate (XI), compound (LIV) (prepared by acetylation of fucosterol (LIII)) was subjected to ozonolysis to produce ketone (LV). Protection of the keto group by ketalization yielded (LVI), which was allylically oxidized to the conjugated ketone (LVII). Double bond reduction in (LVII) by lithium in ammonia, followed by stereoselective reduction of resulting ketone with K-Selectride, yielded alcohol (LVIII). Acid-catalyzed hydrolysis of the ethylene ketal group of (LVIII) gave ketone (LIX). This was converted to intermediate (XI) by reduction with Ca(BH4)2 and subsequent silylation of the resulting alcohol.

参考文献 中间体
【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 53697 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H64O4Si 详情 详情
(LIII) 53737 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4Z)-4-isopropyl-1-methyl-4-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol n/a C29H48O 详情 详情
(LIV) 53738 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4Z)-4-isopropyl-1-methyl-4-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H50O2 详情 详情
(LV) 53712 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethyl-4-oxohexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C29H46O3 详情 详情
(LVI) 53739 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H50O4 详情 详情
(LVII) 53740 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H48O5 详情 详情
(LVIII) 53741 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H52O5 详情 详情
(LIX) 53742 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R)-1,5-dimethyl-4-oxohexyl]-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C29H48O4 详情 详情

合成路线12

Optionally, acetate ester hydrolysis of intermediate (LVIII), followed by regioselective alcohol oxidation with Collin's reagent, yielded ketone (LX). The 7-hydroxyl group of (LX) was then protected by benzylation to afford (LXI). Reductive amination of ketone (LXI) with the di-Boc-protected spermidine (XL) provided the polyamino sterol (LXII). After hydrolysis of the ethylidene ketal group of (LXII), the resultant ketone was reduced by NaBH4 to give alcohol (LXIII).

参考文献 中间体
【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XL) 53724 tert-butyl 3-aminopropyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C17H35N3O4 详情 详情
(LVIII) 53741 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H52O5 详情 详情
(LX) 53743 (5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C29H48O4 详情 详情
(LXI) 53744 (5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C36H54O4 详情 详情
(LXII) 53745 tert-butyl 3-({(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl}amino)propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C53H89N3O7 详情 详情
(LXIII) 53746 tert-butyl 3-({(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-[(1R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl}amino)propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C51H87N3O6 详情 详情

合成路线13

Sulfation of alcohol (LXIII) with SO3-pyridine yielded (LXIV). After acidic Boc group cleavage, the resultant compound (LXV) was subjected to benzyl group hydrogenolysis to give the title compound.

参考文献 中间体
【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LXIII) 53746 tert-butyl 3-({(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-[(1R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl}amino)propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C51H87N3O6 详情 详情
(LXIV) 53747 tert-butyl 3-({(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-17-[(1R)-1,5-dimethyl-4-(sulfooxy)hexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl}amino)propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C51H87N3O9S 详情 详情
(LXV) 53748 (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-7-(benzyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate n/a C41H71N3O5S 详情 详情

合成路线14

In a synthetic route starting from dehydroepiandrosterone (LXVI), Wittig reaction of ketone (LXVI) with ethyl triphenylphosphonium bromide (LXVII) and potassium tert-butoxide gave the C-17 ethylidene derivative (LXVIII). Condensation of (LXVIII) with isopropyl vinyl ketone (LXIX) in the presence of dimethylaluminum chloride, followed by catalytic hydrogenation over Pt/C, yielded (LV), which was then converted into ethylene ketal (LVI). Catalytic hydrogenation of (LVI) gave compound (LXX), whose acetate ester was hydrolyzed to afford alcohol (LXXI). Oxidation of (LXXI) by means of chromic acid furnishes ketone (LXXII), from which intermediate (LX) was obtained by introduction of the 7-alpha hydroxyl group by means of microbiological oxidation employing several microorganism strains.

参考文献 中间体
【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LV) 53712 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethyl-4-oxohexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C29H46O3 详情 详情
(LVI) 53739 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H50O4 详情 详情
(LX) 53754 (3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C25H38O4 详情 详情
(LXVI) 20083 Prasterone acetate;3b-Hydroxy-5-androstene-17-one acetate；Dehydroisoandrosterone acetate;Dehydroepiandrosterone 3-acetate;Dehydroepiandrosterone acetate;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate 853-23-6 C21H30O3 详情 详情
(LXVII) 11717 Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide 1530-32-1 C20H20BrP 详情 详情
(LXVIII) 53749 (3S,8S,9S,10R,13S,14S)-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C23H34O2 详情 详情
(LXIX) 53750 4-methyl-1-penten-3-one 1606-47-9 C6H10O 详情 详情
(LXX) 53751 (3S,5S,8R,9S,10S,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H52O4 详情 详情
(LXXI) 53752 (3S,5S,8R,9S,10S,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol n/a C29H50O3 详情 详情
(LXXII) 53753 (5S,8R,9S,10S,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C29H48O3 详情 详情

合成路线15

In another synthetic route from pregnenolone acetate (LXXIII), its ketalization to (LXXIV) followed by allylic oxidation led to enone (LXXV). Sequential reduction of (LXXV) with lithium in liquid ammonia and then with K-Selectride gave alcohol (LXXVI), which was further protected as the methoxymethyl derivative (LXXVII). Selective deprotection of the C-20 ketal of (LXXVII) yielded ketone (LXXVIII). Ylide (LXXX) was prepared by condensation of bromide (LXXIX) with triphenylphosphine, followed by deprotonation with n-BuLi. Wittig condensation of ketone (LXXVIII) with phosphorane (LXXX) furnished olefin (LXXXI). Then, double-bond hydrogenation and deprotection of the 7-hydroxyl group of (LXXXI) gave rise to the intermediate (XI).

参考文献 中间体
【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 53697 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C35H64O4Si 详情 详情
(LXXIII) 35173 (3S,8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate 1778-02-5 C23H34O3 详情 详情
(LXXIV) 53754 (3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C25H38O4 详情 详情
(LXXV) 53755 (3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C25H36O5 详情 详情
(LXXVI) 53756 (3S,5S,7R,8R,9S,10S,13S,14S,17S)-7-hydroxy-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C25H40O5 详情 详情
(LXXVII) 53757 (3S,5S,7R,8R,9S,10S,13S,14S,17S)-7-(methoxymethoxy)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C27H44O6 详情 详情
(LXXVIII) 53758 (3S,5S,7R,8R,9S,10S,13S,14S,17S)-17-acetyl-7-(methoxymethoxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C25H40O5 详情 详情
(LXXIX) 53759 1-(2-bromoethyl)-2-methylpropyl tert-butyl(dimethyl)silyl ether; [1-(2-bromoethyl)-2-methylpropoxy](tert-butyl)dimethylsilane n/a C12H27BrOSi 详情 详情
(LXXX) 53760 (3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentylidene)(triphenyl)phosphorane; tert-butyl(dimethyl)silyl 2-methyl-1-[2-(triphenylphosphoranylidene)ethyl]propyl ether n/a C30H41OPSi 详情 详情
(LXXXI) 53761 (3S,5S,7R,8R,9S,10S,13S,14S,17R)-17-((Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethyl-1-hexenyl)-7-(methoxymethoxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C37H66O5Si 详情 详情

合成路线16

A stereoselective synthesis of the (24R)-epimer of squalamine dessulfate (CIII) has been reported starting from stigmasterol (LXXXII). Tosylate (LXXXIII) prepared from (LXXXII) was rearranged in the presence of potassium acetate in methanol to afford the cyclopropane compound (LXXXIV). Ozonization of the double bond produced aldehyde (LXXXV), which was subsequently reduced to alcohol (LXXXVI) by means of NaBH4. The primary alcohol (LXXXVI) was converted into the corresponding mesylate, which was further displaced by NaI to provide the alkyl iodide (LXXXVII). Condensation of iodide (LXXXVII) with sodium benzenesulfinate furnished sulfone (LXXXVIII).

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Stereoselective synthesis of squalamine dessulfate. Tetrahedron Lett 1995, 36, 29, 5139.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LXXXII) 53762 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,2E,4S)-4-ethyl-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol n/a C29H48O 详情 详情
(LXXXIII) 53763 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,2E,4S)-4-ethyl-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-methylbenzenesulfonate n/a C36H54O3S 详情 详情
(LXXXIV) 53764 (1aR,3aR,3bS,5aR,6R,8aS,8bS,10R,10aR)-6-[(1R,2E,4S)-4-ethyl-1,5-dimethyl-2-hexenyl]-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-10-yl methyl ether; (1aR,3aR,3bS,5aR,6R,8aS,8bS,10R,10aR)-6-[(1R,2E,4S)-4-ethyl-1,5-dimethyl-2-hexenyl]-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalene n/a C30H50O 详情 详情
(LXXXV) 53765 (2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]propanal n/a C23H36O2 详情 详情
(LXXXVI) 53766 (2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]-1-propanol n/a C23H38O2 详情 详情
(LXXXVII) 53767 (1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-6-[(1S)-2-iodo-1-methylethyl]-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-10-yl methyl ether; (1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-6-[(1S)-2-iodo-1-methylethyl]-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalene n/a C23H37IO 详情 详情
(LXXXVIII) 53768 (2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]propyl phenyl sulfone; {(2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]propyl}(dioxo)phenyl-lambda~6~-sulfane n/a C29H42O3S 详情 详情

合成路线17

Diazotization of (S)-valine (LXXXIX) gave rise to the alpha-hydroxyacid (XC), which was reduced to diol (XCI) using LiAlH4. Tosylation of the primary hydroxyl of (XCI), followed by cyclization of the resulting tosylate (XCII) under basic conditions, furnished epoxide (XCIII). Condensation of epoxide (XCIII) with the lithium anion derived from sulfone (LXXXVIII) gave adduct (XCIV). Reductive elimination of the phenylsulfonyl group and then acidic rearrangement of the cyclopropane ring provided the dihydroxy steroid (XCV). After protection of (XCV) as the diacetate (XCVI), allylic oxidation with CrO3 in the presence of dimethylpyrazole yielded enone (XCVII).

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Stereoselective synthesis of squalamine dessulfate. Tetrahedron Lett 1995, 36, 29, 5139.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LXXXVII) 53768 (2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]propyl phenyl sulfone; {(2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]propyl}(dioxo)phenyl-lambda~6~-sulfane n/a C29H42O3S 详情 详情
(LXXXIX) 37828 L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid 72-18-4 C5H11NO2 详情 详情
(XC) 37829 (2S)-2-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(XCI) 53769 (2S)-3-methyl-1,2-butanediol n/a C5H12O2 详情 详情
(XCII) 53770 (2S)-2-hydroxy-3-methylbutyl 4-methylbenzenesulfonate n/a C12H18O4S 详情 详情
(XCIII) 53771 (2S)-2-isopropyloxirane 123731-68-0 C5H10O 详情 详情
(XCIV) 53772 (3R,6S)-6-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]-2-methyl-5-(phenylsulfonyl)-3-heptanol n/a C34H52O4S 详情 详情
(XCV) 53773 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol n/a C27H46O2 详情 详情
(XCVI) 53774 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate n/a C31H50O4 详情 详情
(XCVII) 53775 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate C31H48O5 详情 详情

合成路线18

Birch reduction of enone (XCVII), followed by reduction of the saturated ketone (XCVIII) with K-Selectride, provided alcohol (XCIX). Acetylation of (IC) gave the triacetate (C). Selective hydrolysis of the C-3 acetate group of (C) with NaCN in MeOH yielded alcohol (CI), which was oxidized to ketone (CII) by using the Jones reagent.

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Stereoselective synthesis of squalamine dessulfate. Tetrahedron Lett 1995, 36, 29, 5139.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IC) 53777 (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate C31H52O5 详情 详情
(CI) 53779 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-yl acetate C31H52O5 详情 详情
(CII) 53780 (5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl acetate C31H50O5 详情 详情
(XCVII) 53775 (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate C31H48O5 详情 详情
(XCVIII) 53776 (3S,5R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate C31H50O5 详情 详情
(C) 53778 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-(acetyloxy)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-yl acetate C33H54O6 详情 详情

合成路线19

Reductive amination of ketone (CII) with the deprotected spermidine (XL) in the presence of NaBH3CN provided the triamino derivative (CIII). The Boc protecting groups of (CIII) were then removed by acidic treatment to furnish the target precursor (CIV).

参考文献 中间体
【1】 Moriarty, R.M.; et al.; Stereoselective synthesis of squalamine dessulfate. Tetrahedron Lett 1995, 36, 29, 5139.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CII) 53780 (5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl acetate C31H50O5 详情 详情
(CIII) 53781 (1R,4R)-4-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(acetyloxy)-3-{[3-((tert-butoxycarbonyl){4-[(tert-butoxycarbonyl)amino]butyl}amino)propyl]amino}-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-isopropylpentyl acetate C48H85N3O8 详情 详情
(CIV) 53782 (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol C34H65N3O2 详情 详情
(XL) 53724 tert-butyl 3-aminopropyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C17H35N3O4 详情 详情

合成路线20

In a further synthetic procedure, ketalization of enone (CV) with ethyleneglycol afforded (CVI). After silylation of the primary alcohol group of (CVI) to (CVII), allylic oxidation by means of tert-butyl hydroperoxide and Cr(CO)6 furnished ketone (CVIII). Catalytic hydrogenation of the double bond of (CVIII) to (CIX), followed by ketone reduction with K-Selectride, gave the C-7 alcohol (CX), which was esterified with benzoyl chloride, yielding benzoate ester (CXI). Subsequent desilylation of (CXI) using tetrabutylammonium fluoride provided (CXII).

参考文献 中间体
【1】 Kinney, W.A.; Meckler, H.; Zhang, X.; Lee, N.; Jones, S.; Rao, M.N.; Bulliard, M. (Genaera Corp.); Stereoselective synthesis of 24-hydroxylated cpds. useful for the preparation of aminosterols, vitamin D analogs, and other cpds.. WO 9824800 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CV) 53783 (8S,9S,10R,13S,14S,17R)-17-[(1S)-2-hydroxy-1-methylethyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C22H34O2 详情 详情
(CVI) 53784 　 n/a C24H38O3 详情 详情
(CVII) 53785 　 n/a C30H52O3Si 详情 详情
(CVIII) 53786 　 n/a C30H50O4Si 详情 详情
(CIX) 53787 　 n/a C30H52O4Si 详情 详情
(CX) 53788 　 n/a C30H54O4Si 详情 详情
(CXI) 53789 　 n/a C37H58O5Si 详情 详情
(CXII) 53790 　 n/a C31H44O5 详情 详情

合成路线21

Alcohol (CXII) was converted to aldehyde (CXIII) either by Swern oxidation or by means of NaOCl and TEMPO. The Horner-Emmons condensation of phosphonate (CXV) (prepared from bromo ketone (CXIV) and triethyl phosphite) with aldehyde (CXIII) furnished the unsaturated ketone (CXVI). Asymmetric reduction of the carbonyl group of (CXVI) was accomplished by means of borane-dimethyl sulfide complex in the presence of (S)-MeCBS, yielding (CXVII). Catalytic hydrogenation of the resultant allylic alcohol (CXVII) afforded (CXVIII). The ethylene ketal group of (CXVIII) was then hydrolyzed under acidic conditions to the ketone (CXIX).

参考文献 中间体
【1】 Zhang, X.; et al.; Synthesis of squalamine utilizing a readily accessible spermidine equivalent. J Org Chem 1998, 63, 23, 8599.
【2】 Kinney, W.A.; Meckler, H.; Zhang, X.; Lee, N.; Jones, S.; Rao, M.N.; Bulliard, M. (Genaera Corp.); Stereoselective synthesis of 24-hydroxylated cpds. useful for the preparation of aminosterols, vitamin D analogs, and other cpds.. WO 9824800 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CXII) 53790 　 n/a C31H44O5 详情 详情
(CXIII) 53791 　 n/a C31H42O5 详情 详情
(CXIV) 53792 1-bromo-3-methyl-2-butanone 19967-55-6 C5H9BrO 详情 详情
(CXV) 53793 diethyl 3-methyl-2-oxobutylphosphonate n/a C9H19O4P 详情 详情
(CXVI) 53794 　 n/a C36H50O5 详情 详情
(CXVII) 53795 　 n/a C36H52O5 详情 详情
(CXVIII) 53796 　 n/a C36H54O5 详情 详情
(CXIX) 53797 (5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl benzoate n/a C34H50O4 详情 详情

合成路线22

Treatment of the OH group of (CXIX) with SO3-pyridine provided sulfate (CXX). The benzoate ester of (CXX) was subsequently hydrolyzed under basic conditions to give (CXXI). Reductive amination of (CXXI) with the cyanodiamine (CXXII) afforded (CXXIII). The cyano group of (CXXIII) was finally reduced to the target amine by catalytic hydrogenation.

参考文献 中间体
【1】 Zhang, X.; et al.; Synthesis of squalamine utilizing a readily accessible spermidine equivalent. J Org Chem 1998, 63, 23, 8599.
【2】 Kinney, W.A.; Meckler, H.; Zhang, X.; Lee, N.; Jones, S.; Rao, M.N.; Bulliard, M. (Genaera Corp.); Stereoselective synthesis of 24-hydroxylated cpds. useful for the preparation of aminosterols, vitamin D analogs, and other cpds.. WO 9824800 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CXIX) 53797 (5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl benzoate n/a C34H50O4 详情 详情
(CXX) 53798 (5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-1,5-dimethyl-4-(sulfooxy)hexyl]-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl benzoate n/a C34H50O7S 详情 详情
(CXXI) 53799 (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate n/a C27H46O6S 详情 详情
(CXXII) 53800 4-[(3-aminopropyl)amino]butanenitrile n/a C7H15N3 详情 详情
(CXXIII) 53801 (1R,4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(3-cyanopropyl)amino]propyl}amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate n/a C34H61N3O5S 详情 详情

合成路线23

In a further synthetic strategy, an azido precursor of spermidine (CXXX) was used in the reductive amination step. Condensation between 1,3-diaminopropane (CXXIV) and 4-chloro-1-butanol (CXXV) provided the diamino alcohol (CXXVI). Protection of the amino groups of (CXXVI) with di-tert-butyl dicarbonate yielded alcohol (CXXVII), which was converted to mesylate (CXXVIII) by treatment with methanesulfonyl chloride and triethylamine. Subsequent mesylate displacement in (CXXVIII) with NaN3 in DMF furnished the di-Boc-protected azide (CXXIX). The Boc protecting groups of (CXXIX) were then removed by treatment with HCl to give the desired diamino azide (CXXX). Reductive amination of the 3-keto steroid (CXXI) with amine (CXXX) yielded the 3-beta amino steroid (CXXXI). The azido group of (CXXXI) was finally reduced to the title triamino compound by catalytic hydrogenation over Raney-Ni.

参考文献 中间体
【1】 Weis, A.L.; et al.; Synthesis of an azido spermidine equivalent. Tetrahedron Lett 1999, 40, 26, 4863.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CXXIV) 19331 3-aminopropylamine; 1,3-propanediamine 109-76-2 C3H10N2 详情 详情
(CXXV) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(CXXI) 53799 (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate n/a C27H46O6S 详情 详情
(CXXVI) 53802 3-[(3-aminopropyl)amino]-1-propanol n/a C6H16N2O 详情 详情
(CXXVII) 53803 tert-butyl 3-[(tert-butoxycarbonyl)amino]propyl(3-hydroxypropyl)carbamate n/a C16H32N2O5 详情 详情
(CXXVIII) 53804 3-((tert-butoxycarbonyl){3-[(tert-butoxycarbonyl)amino]propyl}amino)propyl methanesulfonate n/a C17H34N2O7S 详情 详情
(CXXIX) 53805 tert-butyl 3-azidopropyl{3-[(tert-butoxycarbonyl)amino]propyl}carbamate n/a C16H31N5O4 详情 详情
(CXXX) 53806 N-(3-aminopropyl)-N-(3-azidopropyl)amine; N1-(3-azidopropyl)-1,3-propanediamine n/a C6H15N5 详情 详情
(CXXXII) 53807 (1R,4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(3-azidopropyl)amino]propyl}amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate n/a C33H61N5O5S 详情 详情

合成路线24

Steroid (CV) was treated with the fungal species Diplodia gossipina to yield the 7-hydroxylated compound (CXXXII) as a fermentation metabolite. Reduction of enone (CXXXII) by lithium in liquid ammonia afforded the saturated ketone (CXXXIII), which was subsequently protected as the ethylene ketal (CXXXIV) by treatment with ethylene glycol and chlorotrimethylsilane. Selective oxidation of the C-22 alcohol group of (CXXXIV) with NaOCl in the presence of TEMPO provided aldehyde (CXXXV). Wadsworth-Emmons condensation of (CXXXV) with phosphonate (CXV) gave enone (CXXXVI). Stereoselective reduction of (CXXXVI) to the 24-(S)-alcohol (CXXXVII) was achieved by treatment with borane-tetrahydrofuran complex in the presence of the chiral catalyst (R)-MeCBS. After catalytic hydrogenation of the double bond of (CXXXVII), the resultant ketal (CXXXVIII) was hydrolyzed to ketone (CXXXIX) under acidic conditions. Sulfation of (CXXXIX) by means of sulfur trioxide-pyridine furnished the key precursor (CXXI), which was then reductively aminated as in the precedent Scheme

参考文献 中间体
【1】 Kinney, W.A.; et al.; A short formal synthesis of squalamine from a microbial metabolite. Org Lett 2000, 2, 19, 2921.
【2】 Kinney, W.A.; Zhang, X.; Michalak, R. (Genaera Corp.); A process for the preparation of 7alpha-hydroxy 3-aminosubstd. sterols using intermediates with an unprotected 7alpha-hydroxy group. WO 0179255 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CV) 53783 (8S,9S,10R,13S,14S,17R)-17-[(1S)-2-hydroxy-1-methylethyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C22H34O2 详情 详情
(CXV) 53793 diethyl 3-methyl-2-oxobutylphosphonate n/a C9H19O4P 详情 详情
(CXXI) 53799 (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate n/a C27H46O6S 详情 详情
(CXXXII) 53808 (7R,8S,9S,10R,13R,14S,17R)-7-hydroxy-17-[(1S)-2-hydroxy-1-methylethyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C22H34O3 详情 详情
(CXXXIII) 53809 (5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1S)-2-hydroxy-1-methylethyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C22H36O3 详情 详情
(CXXXIV) 53810 　 n/a C24H40O4 详情 详情
(CXXXV) 53811 　 n/a C24H38O4 详情 详情
(CXXXVI) 53812 　 n/a C29H46O4 详情 详情
(CXXXVII) 53813 　 n/a C29H48O4 详情 详情
(CXXXVIII) 53814 　 n/a C29H50O4 详情 详情
(CXXXIX) 53815 (5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C27H46O3 详情 详情

合成路线25

Intermediate (CXXXIX) has been prepared by a new synthetic procedure:The known methyl 3-keto-5-alpha-chenodeoxycholanate (CXL) was protected as the methoxymethyl ether (CXLI) by treatment with dimethoxymethane and P2O5. Further protection of the keto group of (CXLI) as the ethylene ketal (CXLII), followed by reduction with LiAlH4, afforded alcohol (CXLIII). Swern oxidation of alcohol (CXLIII) yielded aldehyde (CXLIV). This was subjected to Wittig condensation with isopropylidene triphenylphosphorane to give olefin (CXLV). Sharpless asymmetric dihydroxylation of olefin (CXLV) furnished the target diol (CXLVI). Selective esterification of the secondary alcohol of (CXLVI) with Ac2O in pyridine gave rise to acetate (CXLVII).

参考文献 中间体
【1】 Zhou, X.D.; et al.; A new highly stereoselective construction of the sidechain of squalamine through improved Sharpless catalytic asymmetric dihydroxylation. Tetrahedron Lett 2001, 42, 13, 2537.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CXL) 53816 methyl (4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate n/a C25H40O4 详情 详情
(CXLI) 53817 methyl (4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-(methoxymethoxy)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate n/a C27H44O5 详情 详情
(CXLII) 53818 　 n/a C29H48O6 详情 详情
(CXLIII) 53819 　 n/a C28H48O5 详情 详情
(CXLIV) 53820 　 n/a C28H46O5 详情 详情
(CXLV) 53821 　 n/a C31H52O4 详情 详情
(CXLVI) 53822 　 n/a C31H54O6 详情 详情
(CXLVII) 53823 　 n/a C33H56O7 详情 详情

合成路线26

The tertiary alcohol group of (CXLVII) was dehydrated to (CXLVIII) upon treatment with methanesulfonyl chloride and triethylamine. Diimide reduction of the olefin double bond of (CXLVIII) produced (CXLIX). The acetate ester of (CXLIX) was further hydrolyzed to alcohol (CL) by methanolic KOH. Then, acidic hydrolysis of the ketal protecting groups of (CL) furnished the key precursor (CXXXIX).

参考文献 中间体
【1】 Zhou, X.D.; et al.; A new highly stereoselective construction of the sidechain of squalamine through improved Sharpless catalytic asymmetric dihydroxylation. Tetrahedron Lett 2001, 42, 13, 2537.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(CXXXIX) 53815 (5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C27H46O3 详情 详情
(CXLVII) 53823 　 n/a C33H56O7 详情 详情
(CXLVIII) 53824 　 n/a C33H54O6 详情 详情
(CXLIX) 53825 　 n/a C33H56O6 详情 详情
(CL) 53826 　 n/a C31H54O5 详情 详情

合成路线27

The oxidation of chenodeoxycholanic acid methyl ester (I) by known methods gives the 3-oxo derivative (II), which is treated with CH2(OMe)2 and P2O5 in chloroform to yield the 7-O-Mom protected compound (III). The reaction of (III) with ethyleneglycol and TsOH in refluxing benzene affords the ethyleneketal (IV), whose ester group is reduced with LiAlH4 in THF to provide the pentanol derivative (V). The oxidation of (V) with oxalyl chloride and DMSO in dichloromethane gives the aldehyde (VI), which is condensed with the phosphonium iodide (VII) by means of BuLi in THF to yield steroid (VIII) with an unsaturated side chain. The dihydroxylation of (VIII) by means of (DHQD)2PHAL, K2OsO2(OH)4 and K3Fe(CN)6 affords the 24(R),25-dihydroxysteroid (IX), which is monoacylated with Ac2O and pyridine to provide the monoacetate (X). The dehydration of (X) by means of MsCl and TEA gives the unsaturated acetoxy compound (XI), which is reduced and hydrolyzed by means of hydroxylamine and KOH to yield the 24(R)-hydroxysteroid (XII). Elimination of the ethylene ketal and Mom protecting groups of (XII) by means of TsOH in t-butanol affords the ketosteroid (XIII).

参考文献 中间体
【1】 Zhou, X.D.; et al.; A stereoselective synthesis of squalamine. Tetrahedron 2002, 58, 52, 10293.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62193 (3R,5S,7R,10R,13R,17R)-17-[(1R)-4-ethyl-1-methyl-4-pentenyl]-3,5,7,10,13-pentamethylhexadecahydro-1H-cyclopenta[a]phenanthrene C30H52 详情 详情
(II) 62194 (5R,7R,10R,13R,17R)-17-[(1R)-4-ethyl-1-methyl-4-pentenyl]-5,7,10,13-tetramethyl-3-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene C30H50 详情 详情
(III) 62195 (5R,7R,10R,13R,17R)-7-ethyl-17-[(1R)-4-ethyl-1-methyl-4-pentenyl]-5,10,13-trimethyl-3-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene C31H52 详情 详情
(IV) 62196 　 C29H48O6 详情 详情
(V) 62197 　 C28H48O5 详情 详情
(VI) 62198 　 C28H46O5 详情 详情
(VII) 62199 Isopropyltriphenylphosphonium iodide; Isopropyltriphenylphosphonium iodide; Isopropyl triphenylphosphonium iodide; (2-Propyl)triphenylphosphonium bromide 24470-78-8 C21H22IP 详情 详情
(VIII) 62200 　 C31H52O4 详情 详情
(IX) 62201 　 C31H54O6 详情 详情
(X) 62202 　 C33H56O7 详情 详情
(XI) 62203 　 C33H54O6 详情 详情
(XII) 62204 　 C31H54O5 详情 详情
(XIII) 62205 (5R,7R,10S,13R,17R)-7-hydroxy-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one C27H46O3 详情 详情

合成路线28

The reductocondensation of (XIII) with protected amine (XIV) by means of NaBH4 in methanol gives a mixture of the 3-beta and 3-alpha steroids, easily separated by flash chromatography. The desired 3-beta isomer (XV) is deprotected by means of HCl in methanol, yielding intermediate (XVI), which is finally treated with SO3 and pyridine to afford the target 24(R)-O-sulfate steroid

参考文献 中间体
【1】 Zhou, X.D.; et al.; A stereoselective synthesis of squalamine. Tetrahedron 2002, 58, 52, 10293.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 62205 (5R,7R,10S,13R,17R)-7-hydroxy-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one C27H46O3 详情 详情
(XIV) 53724 tert-butyl 3-aminopropyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate n/a C17H35N3O4 详情 详情
(XV) 62206 tert-butyl 4-[(tert-butoxycarbonyl)amino]butyl[3-({(3S,5S,7R,10S,13R,17R)-7-hydroxy-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl}amino)propyl]carbamate C44H81N3O6 详情 详情
(XVI) 62207 (3S,5S,7R,10S,13R,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol C34H65N3O2 详情 详情
Extended Information