|
【结 构 式】 
|
【分子编号】13805 【品名】(4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one 【CA登记号】 |
【 分 子 式 】C11H20O2Si 【 分 子 量 】212.3641 【元素组成】C 62.21% H 9.49% O 15.07% Si 13.23% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 3(R)-(tert-butyldimethylsilyloxy)-4(R)-methoxy-4(R)-methyl-1-(tributylstannyl)-1(E)-octene (II) with butyllithium, cuprous iodide and tributylphosphine gives an intermediate copper derivative which is condensed first with 4(R)-(tert-butyldimethylsilyloxy)-2-cyclopentenone (I) and then with methyl 6-formylhexanoate (III) to give the 7-hydroxy PGE1 derivative (IV). The dehydration of (IV) with mesyl chloride yields the unsaturated PGE compound (V), which is reduced with tributystannyl hydride and finally deprotected with acetic acid in THF. The starting products (I) and (II) are obtained as follows: 1) The oxidation of cyclopentadiene (VI) gives 2-cyclopentene-1,4-diol (VII), which is acetylated to the diacetate (VIII). Selective hydrolysis of (VIII) yields (1S, 4R)-4-hydroxy-2-cyclopentenyl acetate (IX), which is protected with tert-butyldimethylsilyl chloride to the protected acetate (X). Partial hydrolysis of (X) affords the semiprotected alcohol (XI), which is finally oxidized to the cyclopentenone (I).
| 【1】 Kolb, M.; Van Hijfte, L.; Ireland, R.E.; A highly convergent synthesis of mexiprostil: 16(R) 16-methoxy 16-methyl PGE1 methyl ester. Tetrahedron Lett 1988, 29, 51, 6769. |
| 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) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (II) | 21528 | (1R,2R,3E)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(tributylstannyl)-3-butenyl methyl ether | C28H60O2SiSn | 详情 | 详情 | |
| (III) | 21529 | methyl 7-oxoheptanoate | 35376-00-2 | C8H14O3 | 详情 | 详情 |
| (IV) | 21530 | methyl 7-[(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentyl]-7-hydroxyheptanoate | C35H68O7Si2 | 详情 | 详情 | |
| (V) | 21531 | methyl 7-[(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentylidene]heptanoate | C35H66O6Si2 | 详情 | 详情 | |
| (VI) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (VII) | 21533 | 4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (VIII) | 21534 | 4-(acetoxy)-2-cyclopenten-1-yl acetate | C9H12O4 | 详情 | 详情 | |
| (IX) | 21535 | (1R,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (X) | 21536 | (1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl acetate | C13H24O3Si | 详情 | 详情 | |
| (XI) | 21537 | (1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The photooxidation of cyclopentadiene (I) gives cis-4-cyclopentene-1,3-diol (II), which is acylated with Ac2O to yield the diacetate (II). Enzymatic selective hydrolysis of (II) using porcine pancreas lipase (PPL) affords the chiral monoacetate (IV), which is protected with dihydropyran (DHP) and Ts-OH to provide the tetrahydropyranyl ether (V). The hydrolysis of the acetate group of (V) with KOH in methanol gives the alcohol (VI), which is silylated with TbdmsCl and imidazole to yield the silyl ether (VII). Elimination of the THP-protecting group of (VII) with Me2AlCl in dichloromethane affords the cyclopentenol (VIII), which is oxidized with PCC to the cyclopentenone (IX). The condensation of (IX) with chloroiodomethane and BuLi in THF gives the chiral chloromethyl derivative (X), which is treated with potassium methoxide in THF to obtain the chiral epoxide (XI). Stereocontrolled opening of the epoxide ring of (XI) by means of DIBAL in hexane provides the cyclopentenyl-methanol derivative (XII), which is desilylated with TBAF in THF to give the chiral diol (XIII). The esterification of the diol (XIII) with methyl chloroformate and pyridine yields the bis-carbonate (XIV), which is condensed with 2-amino-6-chloropurine (XV) by means of Pd(PPh3)4 in DMF to afford the carbocyclic purine derivative (XVI). Finally, this compound is hydrolyzed with NaOH in refluxing water to provide the target carbocyclic guanine.
| 【1】 Nokami, J.; et al.; Palladium-catalyzed chemoselective reaction of allylic carbonate with nucleoside bases and its application for the synthesis of carbocyclic nucleosides. (-)-and (+)-carbovirs. Chem Lett 1994, 1071. |
| 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) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (II) | 33168 | (1R,3S)-4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (III) | 45374 | (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate | C9H12O4 | 详情 | 详情 | |
| (IV) | 45407 | (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol | 60410-16-4 | C7H10O3 | 详情 | 详情 |
| (V) | 45339 | C8H11N | 详情 | 详情 | ||
| (VI) | 45400 | (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-ol | C11H18O3 | 详情 | 详情 | |
| (VII) | 45401 | tert-butyl(dimethyl)([(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl]oxy)silane; tert-butyl(dimethyl)silyl (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl ether | C17H32O3Si | 详情 | 详情 | |
| (VIII) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (IX) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (X) | 45402 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-(chloromethyl)-2-cyclopenten-1-ol | C12H23ClO2Si | 详情 | 详情 | |
| (XI) | 45403 | tert-butyl(dimethyl)silyl (3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yl ether; tert-butyl(dimethyl)[(3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yloxy]silane | C12H22O2Si | 详情 | 详情 | |
| (XII) | 45404 | ((1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl)methanol | C12H24O2Si | 详情 | 详情 | |
| (XIII) | 45405 | (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XIV) | 45406 | [(1S,4R)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XV) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (XVI) | 45398 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate | C13H14ClN5O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(LXXXI)8) The condensation of the cyclopentenone (LXXXI) with the organocuprate (LXXXII) gives the condensed enolate (LXXXIII), which is coupled with 3-(trimethylsilyl)-2-propynyl iodide (LXXXIV) to yield the acetylenic cyclopentanone (LXXXV). The methylenation of (LXXXV) with Zn/CH2Br2/TiCl4 as before gives compound (LXXXVI), which by selective hydroboration as usual is converted into the hydroxymethyl derivative (LXXXVII). The selective desilylation of the protected acetylene of (LXXXVII) affords (LXXXVIII), which is oxidized as usual to the corresponding aldehyde (LXXXIX). The reductive cyclization of (LXXXIX) gives the bicyclic alcohol (XC), which is treated with tosyl chloride and DMAP in dichloromethane to yield (XCI). Finally, this compound is alkylated with methyl 4-iodobutyrate (XCII)/Zn/Cu2(CN)2 in THF affording the bisilylated clinprost derivative (XCIII) that was desilylated with TBAF as usual. 9) The alkylation of the exocyclic methylene double bond of the bicyclic alcohol (XC) can also be performed by treating (XC) first with diethyl chlorophosphate and BuLi, and then with 4-iodobutyrate (XCII)/Zn/Cu2Cl2 in THF to obtain the previously reported bisilylated clinprost (XCIII). 10) The preceding alkylation of bicyclic alcohol (XC) can also be performed using p-toluenesulfonyl chloride instead of diethyl chlorophosphate.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【2】 Tanaka, T.; Bannai, K.; Hazato, A.; Koga, M.; Kurozumi, S.; Kato, Y.; Short synthesis of isocarbacyclin by regioselective SN2' alkylation of bicyclic allylic esters with zinc-copper reagents. Tetrahedron 1991, 47, 10-11, 1861-76. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LXXXI) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (LXXXII) | 13806 | Bis[3(S)-(tert-Butyldimethylsilyloxy)-1(E)-octenyl] copper magnesium chloride | C39H82O5 | 详情 | 详情 | |
| (LXXXIII) | 13807 | (3R,4R)-4-[[(tert-Butyl)(dimethyl)silyl]oxy]-3-((E,3S)-3-[[(tert-butyl)(dimethyl)silyl]oxy]-1-octenyl)-1-cyclopenten-1-ol chloromagnesium salt | C25H49ClMgO3Si2 | 详情 | 详情 | |
| (LXXXIV) | 13808 | (3-Iodo-1-propynyl)(trimethyl)silane | C6H11ISi | 详情 | 详情 | |
| (LXXXV) | 13809 | (2R,3R,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-[3-(trimethylsilyl)-2-propynyl]cyclopentanone | C31H60O3Si3 | 详情 | 详情 | |
| (LXXXVI) | 13810 | tert-Butyl[((1S,2E)-3-[(1R,2R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-methylene-2-[3-(trimethylsilyl)-2-propynyl]cyclopentyl]-1-pentyl-2-propenyl)oxy]dimethylsilane | C32H62O2Si3 | 详情 | 详情 | |
| (LXXXVII) | 13811 | [(1S,2S,3S,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-[3-(trimethylsilyl)-2-propynyl]cyclopentyl]methanol | C32H64O3Si3 | 详情 | 详情 | |
| (LXXXVIII) | 13812 | [(1S,2S,3S,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(2-propynyl)cyclopentyl]methanol | C29H56O3Si2 | 详情 | 详情 | |
| (LXXXIX) | 13813 | (1S,2R,3R,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(2-propynyl)cyclopentanecarbaldehyde | C29H54O3Si2 | 详情 | 详情 | |
| (XC) | 13814 | (1R,3aS,4S,5R,6aS)-5-[[tert-Butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-methyleneoctahydro-1-pentalenol | C29H56O3Si2 | 详情 | 详情 | |
| (XCI) | 13815 | ([(1S,2E)-3-[(1S,2R,3aS,6aS)-2-[[tert-Butyl(dimethyl)silyl]oxy]-5-(chloromethyl)-1,2,3,3a,6,6a-hexahydro-1-pentalenyl]-1-pentyl-2-propenyl]oxy)(tert-butyl)dimethylsilane | C29H55ClO2Si2 | 详情 | 详情 | |
| (XCII) | 13816 | Methyl 4-iodobutyrate; Methyl 4-iodobutanoate | 14273-85-9 | C5H9IO2 | 详情 | 详情 |
| (XCIII) | 13817 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C34H64O4Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The rearrangement of furfuryl alcohol (XI) in acidic medium (KH2PO4, H3PO4) gives 4-hydoxy-2-penten-1-one (XII), which is silylated with TBDMS-Cl, Et3N and DMAP in THF yielding the silyl ether (XIII). The reduction of (XIII) with LiAlH4 in toluene affords the (rac)(cis)-4-(tert-butyldimethylsilyloxy)-2-penten-1-ol (XIV), which is submitted to optical resolution by digestion with pancreatin (8xUSP) and vinyl acetate in tert-butyl methyl ether yielding a mixture of (1S,4R)-4-(tert-butyldimethylsilyloxy)-2-cyclopentenyl acetate (XV) and (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI), which were separated by column chromatography. Both compounds (XV) and (XVI) were used by independent routes to obtain the target compound: a) The desilylation of (XV) with TBAF in THF gives the previously described (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is converted into the target compound by the previously described route (VI) - (VII) - (VIII) - (X) - target adenine derivative. b) The hydrogenation of (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI) with H2 over Ni2B in ethanol gives the corresponding saturated alcohol (XVII), which is treated with methanesulfonyl chloride and triethylamine in tert-butyl methyl ether yielding the mesylate (XVIII). The condensation of (XVIII) with adenine (IX) by means of NaH in hot DMA affords the silylated target compound (XIX), which is finally deprotected with HCl in ethanol.
| 【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615. |
| 【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)(XIV) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (VII) | 33170 | (1R,3S)-3-hydroxycyclopentyl acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 33171 | (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate | C8H14O5S | 详情 | 详情 | |
| (IX) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (X) | 33172 | (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate | C12H15N5O2 | 详情 | 详情 | |
| (XI) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (XII) | 33173 | 4-hydroxy-2-cyclopenten-1-one | C5H6O2 | 详情 | 详情 | |
| (XIII) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XV) | 33175 | (1S)-2-cyclopenten-1-yl acetate | C7H10O2 | 详情 | 详情 | |
| (XVI) | 64705 | (1R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (XVII) | 33176 | (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentanol | C11H24O2Si | 详情 | 详情 | |
| (XVIII) | 33177 | (1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl methanesulfonate | C12H24O4SSi | 详情 | 详情 | |
| (XIX) | 33178 | 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-amine; 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-ylamine | C16H27N5OSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)The tetrahydropyranyl protecting group of (XII) is removed under acidic conditions, and the resultant alcohol (XIII) is then reprotected as the silyl ether (XIV) by treatment with tert-butyldimethylsilyl chloride and imidazole. Alkyne (XIV) is converted into the vinyl iodide (XV) employing zirconocene chloride hydride and iodine. Metalation of (XV) with tert-butyllithium and 2-(thienyl)cyanocuprate, followed by Michael addition to cyclopentenone (XVI) produces the intermediate enol adduct (XVII), which is further condensed with aldehyde (XVIII) to furnish the hydroxy ketone (XIX). Dehydration of (XIX) to enone (XX) is accomplished by treatment with methanesulfonyl chloride and 4-(dimethylamino)pyridine. Selective reduction of the conjugated olefin of (XX) with tributyltin hydride and tert-butyl peroxide leads to the saturated ketone (XXI). Then, desilylation of (XXI) with HF in pyridine produces diol (XXII). The methyl ester group of (XXII) is finally hydrolyzed to the target carboxylic acid by using pig liver esterase (PLE) in a buffered medium.
| 【2】 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 . |
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 56405 | (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran | C17H22O3 | 详情 | 详情 | |
| (XIII) | 56406 | (2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol | C12H14O2 | 详情 | 详情 | |
| (XIV) | 56407 | tert-butyl(dimethyl)silyl (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl ether; tert-butyl({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)dimethylsilane | C18H28O2Si | 详情 | 详情 | |
| (XV) | 56408 | tert-butyl(dimethyl)silyl (1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl ether; tert-butyl({(1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)dimethylsilane | C18H29IO2Si | 详情 | 详情 | |
| (XVI) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XVII) | 56986 | lithium (3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-1-cyclopenten-1-olate | C29H49LiO4Si2 | 详情 | 详情 | |
| (XVIII) | 56410 | methyl 4-[(2-oxoethyl)sulfanyl]butanoate | C7H12O3S | 详情 | 详情 | |
| (XIX) | 56411 | methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)-2-hydroxyethyl]sulfanyl}butanoate | C36H62O7SSi2 | 详情 | 详情 | |
| (XX) | 56412 | methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentylidene)ethyl]sulfanyl}butanoate | C36H60O6SSi2 | 详情 | 详情 | |
| (XXI) | 56413 | methyl 4-{[2-((1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate | C36H62O6SSi2 | 详情 | 详情 | |
| (XXII) | 56987 | methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate | C24H34O6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XV)After acidic cleavage of the tetrahydropyranyl group of (XI), the resultant alcohol (XII) is reprotected as the silyl ether (XIII). Hydroiodination of acetylene (XIII) is effected by treatment with iodine and zirconocene chloride hydride, yielding vinyl iodide (XIV). The organolithium derivative generated from iodide (XIV) undergoes conjugate addition to cyclopentenone (XV), producing the intermediate lithium enolate (XVI) which, upon quenching with aldehyde (XVII), leads to the substituted cyclopentanone adduct (XVIII). Dehydration of aldol (XVIII) to dienone (XIX) is performed by treatment with mesyl chloride and DMAP. The conjugated double bond of (XIX) is selectively reduced to (XX) by means of tributyltin hydride and t-butyl hydroperoxide. Finally, desilylation of (XX) with HF in pyridine affords the title prostaglandin derivative.
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743. |
| 【2】 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 . |
| 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) | 56405 | (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran | C17H22O3 | 详情 | 详情 | |
| (XII) | 56406 | (2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol | C12H14O2 | 详情 | 详情 | |
| (XIII) | 56407 | tert-butyl(dimethyl)silyl (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl ether; tert-butyl({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)dimethylsilane | C18H28O2Si | 详情 | 详情 | |
| (XIV) | 56408 | tert-butyl(dimethyl)silyl (1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl ether; tert-butyl({(1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)dimethylsilane | C18H29IO2Si | 详情 | 详情 | |
| (XV) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XVI) | 56409 | lithium (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-1-cyclopenten-1-olate | C29H49LiO4Si2 | 详情 | 详情 | |
| (XVII) | 56410 | methyl 4-[(2-oxoethyl)sulfanyl]butanoate | C7H12O3S | 详情 | 详情 | |
| (XVIII) | 56411 | methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)-2-hydroxyethyl]sulfanyl}butanoate | C36H62O7SSi2 | 详情 | 详情 | |
| (XIX) | 56412 | methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentylidene)ethyl]sulfanyl}butanoate | C36H60O6SSi2 | 详情 | 详情 | |
| (XX) | 56413 | methyl 4-{[2-((1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate | C36H62O6SSi2 | 详情 | 详情 |