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【结 构 式】 
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【分子编号】28793 【品名】(Z)-1,2-dichloroethene 【CA登记号】156-59-2 |
【 分 子 式 】C2H2Cl2 【 分 子 量 】96.94328 【元素组成】C 24.78% H 2.08% Cl 73.14% |
合成路线1
该中间体在本合成路线中的序号：(XII)Reaction of 4,9(11)-androstadien-3,17-dione (III) with trimethyl orthoformate and TsOH in dioxane gives 3-methoxy-3,5,9(11)-androstatrien-17-one (XI), which is condensed with 1,2-dichloroethylene (XII) by means of MeLi in ethyl ether/THF to yield 17a-(chloroethynyl)-17b-hydroxy-4,9(11)-androstadien-3-one (XIII). Esterification of the OH group of (XIII) with fuming HNO3 and acetic anhydride affords the 17b-(nitrooxy) derivative (XIV), which is treated with formic acid and AgNO3 in N-methylpyrrolidone to provide 21-chloro-17a-(formyloxy)-4,9(11)-pregnadien-3,20-dione (XV). Hydrolysis of the formyloxy group of (XV) by means of KHCO3 in methanol/water gives 21-chloro-17a-hydroxy-4,9(11)-pregnadien-3,20-dione (XVI), which is finally acetylated by means of AcOK and KI in hot DMF.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Annen, K.; Laurent, H.; Wiechert, R.; Hofmeister, H. (Schering AG); Process for the preparation of pregnane deriv.. DE 3434448; EP 0181442; US 4708823 . |
| 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) | 56595 | (8S,10R,13S,14S)-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H24O2 | 详情 | 详情 | |
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XII) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (XIII) | 56603 | (8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H25ClO2 | 详情 | 详情 | |
| (XIV) | 56604 | (8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-10,13-dimethyl-17-(nitrooxy)-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H24ClNO4 | 详情 | 详情 | |
| (XV) | 50605 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C18H34N2O5SSi | 详情 | 详情 | |
| (XVI) | 56606 | (8S,10R,13S,14S,17R)-17-(2-chloroacetyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H27ClO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with (E)-1,2-dichloroethylene (XII) by means of BuLi in toluene gives 17a-[(E)-1,2-dichloro-vinyl]-17b-hydroxyandrosta-4,9(11)-dien-3-one (XXX), which is treated with phenylsulfenyl chloride and TEA in dichloromethane to yield 20,21-dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (XXXI). Reac-tion of compound (XXXI) with MeONa in acetone/MeOH at 0 C affords 21-chloro-20-methoxy-21-(phenylsulfinyl)-pregna-4,9(11),17(20)-trien-3-one (XXXII), which by treatment with more MeONa at 35 C provides 21-chloro-17a-hydroxy-20-methoxypregna-4,9(11),20-trien-3-one (XXXIII). Hydrolysis of the enol ether of (XXXIII) with HCl in THF/acetone/MeOH gives the 3,20-dione derivative (XVI), which is finally treated with AcOK and KI in hot acetone/dichloromethane.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Walker, J.A.; Hessler, E.J. (Pharmacia Corp.); Preparation of corticoids from 17-keto steroids. US 4357279 . |
| 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) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XII) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (XVI) | 56606 | (8S,10R,13S,14S,17R)-17-(2-chloroacetyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H27ClO3 | 详情 | 详情 | |
| (XXX) | 56619 | (8S,10R,13S,14S,17S)-17-[(E)-1,2-dichloroethenyl]-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26Cl2O2 | 详情 | 详情 | |
| (XXXI) | 56620 | (8S,10R,13S,14S)-17-[(Z)-1,2-dichloro-2-(phenylsulfinyl)ethylidene]-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3(2H,6H)-one | C27H30Cl2O2S | 详情 | 详情 | |
| (XXXII) | 56621 | (8S,10R,13S,14S)-17-[(Z)-2-chloro-1-methoxy-2-(phenylsulfinyl)ethylidene]-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3(2H,6H)-one | C28H33ClO3S | 详情 | 详情 | |
| (XXXIII) | 56622 | (8S,10R,13S,14S,17R)-17-[(E)-2-chloro-1-methoxyethenyl]-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C22H29ClO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The addition of 2-(trimethylsilyl)ethylmercaptane (I) to 2,4-hexadiyn-1,6-diol (II) catalyzed by KOH in DMF gives the addition product (III), which is oxidized with Dess-Martin periodinane in dichloromethane or oxalyl chloride in DMSO yielding the dialdehyde (IV). The condensation of (IV) with tetrabromomethane by means of triphenylphosphine in dichloromethane affords the tetrabromo derivative (V), which is treated with butyllithium in THF to give the diacetylenic dianion (VI). The reaction of (V) with methyl iodide yields the mono methylated compound (VII), which is condensed with cis-1,2-dichloroethylene (VIII) by means of Pd(PPh3)4/CuI/butylamine in benzene affording the cis-chlorovinyl compound (IX). THe reaction of (IX) with vinylmagnesium bromide (X) catalyzed by Pd(PPh3)4 in benzene gives precursor (XI), which is finally submitted to an oxidative cyclization by means of tetrabutylammonium fluoride/trifluoroacetic acid and iodine.
| 【1】 Wang, Y.M.; et al.; Total synthesis and DNA-cleaving properties of thiarubrine C. J Org Chem 1998, 63, 24, 8644. |
| 【2】 Yang, W.; Koreeda, M.; Chemistry of 1,2-dithiins. Synthesis of the potent antibiotic thiarubrine A. J Am Chem Soc 1994, 116, 10793. |
| 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) | 28780 | 2,4-hexadiyne-1,6-diol | 3031-68-3 | C6H6O2 | 详情 | 详情 |
| (II) | 28781 | 2-(trimethylsilyl)-1-ethanethiol | 18143-30-1 | C5H14SSi | 详情 | 详情 |
| (III) | 28782 | (2Z,4Z)-2,5-bis[[2-(trimethylsilyl)ethyl]sulfanyl]-2,4-hexadiene-1,6-diol | C16H34O2S2Si2 | 详情 | 详情 | |
| (IV) | 28783 | (2Z,4Z)-2,5-bis[[2-(trimethylsilyl)ethyl]sulfanyl]-2,4-hexadienedial | C16H30O2S2Si2 | 详情 | 详情 | |
| (V) | 28784 | (1Z,3Z)-6,6-dibromo-1-(2,2-dibromovinyl)-4-[[2-(trimethylsilyl)ethyl]sulfanyl]-1,3,5-hexatrienyl 2-(trimethylsilyl)ethyl sulfide | C18H30Br4S2Si2 | 详情 | 详情 | |
| (VI) | 28785 | 3,6-Bis[2-(trimethylsilyl)ethylsulfanyl]octa-3,5-dien-1,7-diyne dilithium salt | C18H28Li2S2Si2 | 详情 | 详情 | |
| (VII) | 28786 | ((3Z,5Z)-3,6-bis[[2-(trimethylsilyl)ethyl]sulfanyl]-3,5-nonadiene-1,7-diynyl)lithium | C19H31LiS2Si2 | 详情 | 详情 | |
| (VIII) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (IX) | 28792 | (1Z,3Z)-1-[(Z)-4-chloro-3-buten-1-ynyl]-4-[[2-(trimethylsilyl)ethyl]sulfanyl]-1,3-heptadien-5-ynyl 2-(trimethylsilyl)ethyl sulfide | C21H33ClS2Si2 | 详情 | 详情 | |
| (X) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XI) | 28794 | (1Z,3Z)-1-[(3Z)-3,5-hexadien-1-ynyl]-4-[[2-(trimethylsilyl)ethyl]sulfanyl]-1,3-heptadien-5-ynyl 2-(trimethylsilyl)ethyl sulfide | C23H36S2Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Alkylation of uracil (I) with propargyl bromide (II) in the presence of DBU affords the N1-alkylated product (III). Palladium-catalyzed coupling of the terminal alkyne (III) with cis-1,2-dichloroethene (IV) furnishes the chlorovinyl adduct (V). Subsequent alkylation at the N3-position of (V) with propargyl bromide (II) and DBU leads to the open-chain enediyne (VI). This is finally cyclized to the target bicyclic compound in the presence of Pd(PPh3)4, CuI and butylamine.
| 【1】 Hakimelahi, G.H.; et al.; A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics. Bioorg Med Chem 2002, 10, 5, 1321. |
| 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) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (II) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (III) | 60461 | 1-(2-propynyl)-2,4(1H,3H)-pyrimidinedione | C7H6N2O2 | 详情 | 详情 | |
| (IV) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (V) | 60462 | 1-[(Z)-5-chloro-4-penten-2-ynyl]-2,4(1H,3H)-pyrimidinedione | C9H7ClN2O2 | 详情 | 详情 | |
| (VI) | 60463 | 1-[(Z)-5-chloro-4-penten-2-ynyl]-3-(2-propynyl)-2,4(1H,3H)-pyrimidinedione | C12H9ClN2O2 | 详情 | 详情 |