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【结 构 式】 
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【分子编号】29069 【品名】1-pentynylcopper 【CA登记号】 |
【 分 子 式 】C5H7Cu 【 分 子 量 】130.65658 【元素组成】C 45.96% H 5.4% Cu 48.64% |
合成路线1
该中间体在本合成路线中的序号：(C)The reaction of 4-hydroxy-1-octyne (I), with chlorotrimethylsilane and imidazole in DMF gives 4-trimethylsilyloxy-1-octyne (II), which is converted into 1-iodo-4-trimethylsilyloxy-trans-1-octene (III) by reaction with bis(3-methyl-2-butyl)borane (A), trimethylamine oxide, NaOH and finally I2. The hydrolysis of (III) with acetic acid in THF affords 1-iodo-4-hydroxy-trans-1-octene (IV), which is oxidized with pyridinium chlorochromate in methylene chloride yielding 1-iodo-4-oxo-trans-1-octene (V). The Grignard reaction of (V) with vinylmagnesium bromide (B) in THF gives 4-hydroxy-4-vinyl-1-iodo-trans-1-octene (VI), which is protected with trimethylsilyl chloride as before yielding 4-trimethylsilyloxy-4-vinyl-1-iodo-trans-1-octene (VII). The reaction of (VII) with tert-butyllithium in ether and then with copper (1)-1-pentyne-tributylphosphine (C) in HMPT affords the copper salt (VIII), which is condensed with 2-(6-trimethylsilyloxycarbonyl-2-cis-hexenyl)-4-trimethylsilyloxycyclopent-2-en-1-one (IX) in ether - THF giving trimethylsilyl-9-oxo-11alpha,16-bistrimethylsilyloxy-16-vinyl-5-cis-13-trans-prostadienoate (X). The hydrolysis of (X) with acetic acid in THF-water yields 9-oxo-11alpha,16-dihydroxy-16-vinyl-5-cis-13-trans-prostadienoic acid (XI), which is finally methylated with diazomethane in ether.
| 【1】 Middlenton, B.F.; Martin, J.W.; Grudzinskas, C.V.; Chen, S.L. (American Cyanamid Co.); Novel prostaglandin compounds. ES 475787; FR 2410648; GB 2009173; US 4198521 . |
| 【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; CL-115,347. Drugs Fut 1983, 8, 4, 307. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (A) | 20452 | bis(1,2-dimethylpropyl)borane | 132509-17-2 | C10H23B | 详情 | 详情 |
| (I) | 29312 | 1-octyn-4-ol | C8H14O | 详情 | 详情 | |
| (II) | 36018 | [(1-butyl-3-butynyl)oxy](trimethyl)silane; 1-butyl-3-butynyl trimethylsilyl ether | C11H22OSi | 详情 | 详情 | |
| (III) | 36019 | (E)-1-butyl-4-iodo-3-butenyl trimethylsilyl ether; [[(E)-1-butyl-4-iodo-3-butenyl]oxy](trimethyl)silane | C11H23IOSi | 详情 | 详情 | |
| (IV) | 29315 | (E)-1-iodo-1-octen-4-ol | C8H15IO | 详情 | 详情 | |
| (V) | 29316 | (E)-1-iodo-1-octen-4-one | C8H13IO | 详情 | 详情 | |
| (VI) | 29317 | (5E)-3-butyl-6-iodo-1,5-hexadien-3-ol | C10H17IO | 详情 | 详情 | |
| (VII) | 36020 | (E)-1-butyl-4-iodo-1-vinyl-3-butenyl trimethylsilyl ether; [[(E)-1-butyl-4-iodo-1-vinyl-3-butenyl]oxy](trimethyl)silane | C13H25IOSi | 详情 | 详情 | |
| (VIII) | 36021 | [(1E)-4-butyl-4-[(trimethylsilyl)oxy]-1,5-hexadienyl](1-pentynyl)copper | C18H32CuOSi | 详情 | 详情 | |
| (IX) | 36022 | trimethylsilyl (Z)-7-[(3R)-5-oxo-3-[(trimethylsilyl)oxy]-1-cyclopenten-1-yl]-5-heptenoate | C18H32O4Si2 | 详情 | 详情 | |
| (X) | 36023 | trimethylsilyl (Z)-7-[(1R,2R,3R)-2-[(1E)-4-butyl-4-[(trimethylsilyl)oxy]-1,5-hexadienyl]-5-oxo-3-[(trimethylsilyl)oxy]cyclopentyl]-5-heptenoate | C31H58O5Si3 | 详情 | 详情 | |
| (XI) | 36024 | (Z)-7-[(1R,2R,3R)-2-[(1E)-4-butyl-4-hydroxy-1,5-hexadienyl]-3-hydroxy-5-oxocyclopentyl]-5-heptenoic acid | C22H34O5 | 详情 | 详情 | |
| (C) | 29069 | 1-pentynylcopper | C5H7Cu | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(C)The oxidation of 1-hepten-3-ol (XII) with pyridinium chlorochromate gives 1-hepten-3-one (XIII), which by a Grignard condensation with propargylmagnesium bromide (XIV) is converted into 4-hydroxy-4-vinyl-1-octyne (XV). The protection of (XV) with trimethylsilyl chloride and imidazole in DMF yields 4-trimethylsilyloxy-4-vinyl-1-octyne (XVI), which by reaction with tri-n-butyl-stannane and azobisisobutyronitrile at 125 C affords 1-(tri-n-butylstannyl)-4-vinyl-4-(trimethylsilyloxy)-1-octene (XVII). Finally, this compound by reaction with butyllithium and copper -1-pentyne-tributylphosphine (C) in HMPT yields the copper salt (VIII), already obtained.
| 【1】 Grudzinkas, C.V.; Bimbaum, J.E.; Chen. S.L.; Chan, P.S.; Floyd, M.B.; Weiss, M.J.; Cervoni, P.; Prostaglandins and congeners. 29. (16RS)-Rac-15-deoxy-16-hydroxy-16-vivyl-protaglandin E2, an orally and transdermally active hypotensive agent of prolonged duration. J Med Chem 1982, 25, 5, 492-494. |
| 【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; CL-115,347. Drugs Fut 1983, 8, 4, 307. |
| 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) | 36021 | [(1E)-4-butyl-4-[(trimethylsilyl)oxy]-1,5-hexadienyl](1-pentynyl)copper | C18H32CuOSi | 详情 | 详情 | |
| (XII) | 36025 | 1-hepten-3-ol | 4938-52-7 | C7H14O | 详情 | 详情 |
| (XIII) | 36026 | 1-hepten-3-one | C7H12O | 详情 | 详情 | |
| (XIV) | 29064 | bromo(2-propynyl)magnesium | C3H3BrMg | 详情 | 详情 | |
| (XV) | 29325 | 3-butyl-1-hexen-5-yn-3-ol | C10H16O | 详情 | 详情 | |
| (XVI) | 36027 | 1-butyl-1-vinyl-3-butynyl trimethylsilyl ether; [(1-butyl-1-vinyl-3-butynyl)oxy](trimethyl)silane | C13H24OSi | 详情 | 详情 | |
| (XVII) | 36028 | (E)-1-butyl-4-(tributylstannyl)-1-vinyl-3-butenyl trimethylsilyl ether; [[(E)-1-butyl-4-(tributylstannyl)-1-vinyl-3-butenyl]oxy](trimethyl)silane | C25H52OSiSn | 详情 | 详情 | |
| (C) | 29069 | 1-pentynylcopper | C5H7Cu | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)This compound can be obtained in two different ways: 1) By reaction of phthalic anhydride (I) with valeric anhydride (II) in the presence of sodium valerate (A). 2) By reaction of 2-iodobenzoic acid (III) with copper propylacetylide (IV).
| 【1】 Castro, C.E.; et al.; Indoles, benzofurans, phthalides and tolanes via copper (I) acetylides. J Org Chem 1966, 31, 12, 4071-78. |
| 【2】 Lardelli, G.; et al.; A new gamma-lactone found in butter. Recl Trav Chim Pays-Bas 1966, 85, 43-55. |
| 【3】 Castaner, J.; Blancafort, P.; Hillier, K.; Serradell, M.N.; Butylidenephthalide. Drugs Fut 1981, 6, 4, 216. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 31907 | Sodium valerate; Sodium pentanoate | C5H9NaO2 | 详情 | 详情 | |
| (I) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (II) | 27683 | pentanoic anhydride | 2082-59-9 | C10H18O3 | 详情 | 详情 |
| (III) | 37160 | 2-iodobenzoic acid | 88-67-5 | C7H5IO2 | 详情 | 详情 |
| (IV) | 29069 | 1-pentynylcopper | C5H7Cu | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The Grignard reaction of propargylmagnesium bromide (I) with 2-hexanone (II) in ether gives 4-methyloct-1-in-4-ol (III), which by reaction with diisobutylaluminum hydride and I2 is converted to 1-iodo-4-methyloct-1-en-4-ol (IV). The reaction of (IV) with dihydropyran and p-toluenesulfonic acid yields the corresponding tetrahydropyranyloxy derivative (V), which by reaction with tert-butyllithium and copper pentyne (VI) affords the corresponding organolithiocuprate (VII). The condensation of (VII) with 4R-(tetrahydropyranyloxy)-2-[7-(tetrahydropyranyloxyl)heptyl]cyclopent-2-en-1-one (VIII) in ether gives 1,11,16-tris(tetrahydropyranyloxy)-16-methylprost-13-en-9-one (IX), which is finally deprotected by a treatment with acetic acid in water THF.
| 【1】 Woessner, W.D.; Biddlecom, W.G.; Kluender, H.C. (Bayer Corp.); Preparation of 15-deoxy-16-hydroxyprostaglandins. US 4132738 . |
| 【2】 Castaner, J.; Serradell, M.N.; Rioprostil. Drugs Fut 1985, 10, 3, 207. |
| 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) | 29064 | bromo(2-propynyl)magnesium | C3H3BrMg | 详情 | 详情 | |
| (II) | 29065 | 2-hexanone | 591-78-6 | C6H12O | 详情 | 详情 |
| (III) | 29066 | 4-methyl-1-octyn-4-ol | C9H16O | 详情 | 详情 | |
| (IV) | 29067 | (E)-1-iodo-4-methyl-1-octen-4-ol | C9H17IO | 详情 | 详情 | |
| (V) | 29068 | (E)-2-butyl-5-iodo-2-methyl-4-pentenyl tetrahydro-2H-pyran-2-yl ether | C15H27IO2 | 详情 | 详情 | |
| (VI) | 29069 | 1-pentynylcopper | C5H7Cu | 详情 | 详情 | |
| (VIII) | 29070 | (4R)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[8-(tetrahydro-2H-pyran-2-yloxy)octyl]-2-cyclopenten-1-one | C24H40O5 | 详情 | 详情 | |
| (IX) | 29071 | (2R,3S,4R)-3-[(E)-4-methyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[8-(tetrahydro-2H-pyran-2-yloxy)octyl]cyclopentanone | C39H68O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The sililation of 4-methyl-1-octin-4-ol (I) with trimethylsilyl chloride by means of triethylamine in DMF gives the corresponding silyloxy derivative (II), which is treated with diisobutyl aluminum hydride and I2 in toluene - THF yielding 4-methyl-(RS)-4-trimethylsilyloxy-trans-1-octene-1-yl iodide (III). The condensation of (III) with the complex of copper 1-pentynilyde and HMPT (IV) by means of butyllithium in hexane affords the complex salt (V), which, without isolation, is allowed to react with methyl 7-[3-[(RS)-tetrahydropyranyl-2-oxy]-5-oxo-1-cyclopentenyl]-heptanoate (VI) in ethyl ether to give methyl 7-[3-(tetrahydropyranyl-2-oxy)-2-(4-methyl-4-trimethylsilyloxy-trans-1-octene-1-yl)-5-oxo-cyclopentyl]heptanoate (VII). Finally, this compound is hydrolyzed with a mixture acetic acid - water - THF at room temperature.
| 【1】 Collins P.W.; et al.; Influence of the position of the side-chain hydroxy group on the biological properties of prostaglandins. Tetrahedron Lett 1975, 48, 4217-20. |
| 【2】 Pappo, R.; Collins, P.W.; 16-Oxygenated prostanoic acid derivatives. BE 0827127; DE 2513212; FR 2274289; GB 1492426; JP 50135059; US 3965143 . |
| 【3】 Castaner, J.; Hillier, K.; SC-29333. Drugs Fut 1977, 2, 12, 817. |
| 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) | 29066 | 4-methyl-1-octyn-4-ol | C9H16O | 详情 | 详情 | |
| (II) | 33906 | 1-butyl-1-methyl-3-butynyl trimethylsilyl ether; [(1-butyl-1-methyl-3-butynyl)oxy](trimethyl)silane | C12H24OSi | 详情 | 详情 | |
| (III) | 33907 | [[(E)-1-butyl-4-iodo-1-methyl-3-butenyl]oxy](trimethyl)silane; (E)-1-butyl-4-iodo-1-methyl-3-butenyl trimethylsilyl ether | C12H25IOSi | 详情 | 详情 | |
| (IV) | 29069 | 1-pentynylcopper | C5H7Cu | 详情 | 详情 | |
| (V) | 33908 | C17H32CuLiOSi | 详情 | 详情 | ||
| (VI) | 33909 | methyl 7-[(1R,4S)-2-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate | C19H32O5 | 详情 | 详情 | |
| (VII) | 33910 | methyl 7-[(1R,2S,3R)-2-[(E)-4-methyl-4-[(trimethylsilyl)oxy]-1-octenyl]-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate | C31H56O6Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(B)The protection of the free hydroxy group of (X) with trimethylchlorosilane and hexamethyldisilazane in pyridine gives the trimethylsilyl derivative (XI), which is condensed with [3-(triphenylmethoxy)-1-octenyl](pentenyl)lithiocuprate (XII) in HMPT-ether to afford 11-deoxy-11alpha-(2-trimethyl-silyloxyethylthio)-15-triphenylmethoxy-PGE2 methyl ester (XIII). Finally, this compound is deprotected by treatment with acetic acid in THF. The lithium cuprate (XII) is prepared as follows: Hydrogen iodide addition to 3-triphenylmethoxy-1-octyne (XVII) gives 1-iodo-3-triphenylmethoxy-1-octene (XVIII), which is condensed with copper 1-pentyne (B) and butyllithium in ether.
| 【1】 Floyd, M.; et al.; Prostaglandins and congeners. 22. Synthesis of 11-substituted derivatives of 11-deoxyprostaglandins E1 and E2. Potential bronchodilators. J Med Chem 1980, 23, 8, 903-913. |
| 【2】 Hillier, K.; Serradell, M.N.; Blancafort, P.; Castañer, J.; DHET-PGE2. Drugs Fut 1982, 7, 4, 241. |
| 【3】 Weiss, M.J.; Siuta, G.J. (American Cyanamid Co.); 11-(2-Hydroxyethylthio)prostenoic acid E{HD 2 {B series derivatives. US 4085272 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 29069 | 1-pentynylcopper | C5H7Cu | 详情 | 详情 | |
| (X) | 36371 | methyl (Z)-7-[3-[(2-hydroxyethyl)sulfanyl]-5-oxo-1-cyclopenten-1-yl]-5-heptenoate | C15H22O4S | 详情 | 详情 | |
| (XI) | 36378 | methyl (Z)-7-[5-oxo-3-([2-[(trimethylsilyl)oxy]ethyl]sulfanyl)-1-cyclopenten-1-yl]-5-heptenoate | C18H30O4SSi | 详情 | 详情 | |
| (XII) | 36379 | C32H37IO | 详情 | 详情 | ||
| (XIII) | 36380 | methyl (Z)-7-[(1R,2R,3R)-5-oxo-3-([2-[(trimethylsilyl)oxy]ethyl]sulfanyl)-2-[(E,3S)-3-(trityloxy)-1-octenyl]cyclopentyl]-5-heptenoate | C45H60O5SSi | 详情 | 详情 | |
| (XVII) | 36376 | 1-pentyl-2-propynyl trityl ether; 1-[[(1-pentyl-2-propynyl)oxy](diphenyl)methyl]benzene | C27H28O | 详情 | 详情 | |
| (XVIII) | 36377 | 1-[[[(E)-3-iodo-1-pentyl-2-propenyl]oxy](diphenyl)methyl]benzene; (E)-3-iodo-1-pentyl-2-propenyl trityl ether | C27H29IO | 详情 | 详情 |