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【结 构 式】 
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【分子编号】31277 【品名】1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione 【CA登记号】77-48-5 |
【 分 子 式 】C5H6Br2N2O2 【 分 子 量 】285.92292 【元素组成】C 21% H 2.12% Br 55.89% N 9.8% O 11.19% |
合成路线1
该中间体在本合成路线中的序号：(C)The starting product being 21-acetoxy-11alpha,17alpha-dihydroxy-pregn-4-ene-3,20-dione (I). The first step is the ketalization of (I) giving the ethylenedioxy derivative (II), which is epoxidized with monoperphthalic acid (B) to the epoxide (III), then the epoxide ring is opened with HF giving the fluoro derivative (IV); its bromination in dioxane affords (V), which by reaction with methanesulfonyl chloride gives the mesyl ester (VI). This compound is acetylated with acetic anhydride to the triacetoxy derivative (VII), which by treatment first with sodium acetate and then with bromine gives the mono unsaturated dibromo compound (VIII). This product by treatment with lithium carbonate and lithium bromide is converted into the triene derivative (IX); this product by treatment with 1,3-dibromo-5,5-dimethylhydantoine (C) adds BrOH giving (X), which is epoxidized by treatment with potassium carbonate yielding (Xl). This epoxide ring is finally opened with HF.
| 【1】 Riva, M.; Toscano, L.; 2-Bromo-6beta-fluoropregna-1,4-3,20-diones. BE 0826030; DE 2533377; ES 455934; FR 2261776; GB 1499822 . |
| 【2】 Castaner, J.; de Angelis, L.; Halopredone diacetate. Drugs Fut 1976, 1, 11, 526. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (B) | 34077 | 2-carboperoxybenzoic acid | C8H6O5 | 详情 | 详情 | |
| (I) | 34075 | 2-[(8S,10R,11R,14S,17R)-11,17-dihydroxy-10-methyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C22H30O6 | 详情 | 详情 | |
| (II) | 34076 | C25H36O7 | 详情 | 详情 | ||
| (III) | 34078 | (5α,6α,11α)-21-(acetyloxy)-5,6-epoxy-11,17-dihydroxypregnane-3,20-dione cyclic 3-(1,2-ethanediyl acetal) | 57781-08-5 | C25H36O8 | 详情 | 详情 |
| (IV) | 34079 | 2-[(5R,6R,8S,10R,11R,13S,14S,17R)-6-fluoro-5,11,17-trihydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | 913-49-5 | C23H33FO7 | 详情 | 详情 |
| (V) | 34080 | 2-[(2R,5R,6R,8S,10R,11R,13S,14S,17R)-2-bromo-6-fluoro-5,11,17-trihydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | 57781-10-9 | C23H32BrFO7 | 详情 | 详情 |
| (VI) | 34081 | 2-((2R,5R,6R,8S,10R,11R,13S,14S,17R)-2-bromo-6-fluoro-5,17-dihydroxy-10,13-dimethyl-11-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate | C26H38BrFO7S | 详情 | 详情 | |
| (VII) | 34082 | (2R,5R,6R,8S,10R,11R,13S,14S,17R)-5-(acetoxy)-17-[2-(acetoxy)acetyl]-2-bromo-6-fluoro-10,13-dimethyl-11-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate | C30H42BrFO9S | 详情 | 详情 | |
| (VIII) | 34083 | (6R,8S,10R,11R,13S,14S,17R)-17-[2-(acetoxy)acetyl]-2,2-dibromo-6-fluoro-10,13-dimethyl-11-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate | C28H37Br2FO7S | 详情 | 详情 | |
| (IX) | 34084 | (6R,8S,10R,13S,14S,17R)-17-[2-(acetoxy)acetyl]-2-bromo-6-fluoro-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl acetate | 57808-78-3 | C25H28BrFO6 | 详情 | 详情 |
| (X) | 34085 | (6R,8S,9R,10S,11S,13S,14S,17R)-17-[2-(acetoxy)acetyl]-2,9-dibromo-6-fluoro-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl acetate | 57781-13-2 | C25H29Br2FO7 | 详情 | 详情 |
| (XI) | 34086 | (4aS,4bS,5aS,6aS,7R,9aS,9bS,11R)-7-[2-(acetoxy)acetyl]-3-bromo-11-fluoro-4a,6a-dimethyl-2-oxo-2,4a,5a,6,6a,7,8,9,9a,9b,10,11-dodecahydrocyclopenta[7,8]phenanthro[4b,5-b]oxiren-7-yl acetate | C25H28BrFO7 | 详情 | 详情 | |
| (C) | 31277 | 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione | 77-48-5 | C5H6Br2N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(G)The less polar major isomer (IVa) was reduced to lactone (IVb) with 10 eq of tri-n-butyltin hydride (tetrahydrofuran, room temperature, 4 h) in 88% yield. Treatment of the lactone (IVb) with a catalytic amount of HCl in methanol at 50 C for 5 h gave the diol (IVc) in 88% yield. Reaction of (IVc) with ethyl chloroformate (16 eq) in the presence of 4-dimethylaminopyridine (17 eq) at room temperature for 15 h afforded ethyl carbonate (IVd) in 82% yield. Allylic bromination of (IVd) with 0.6 eq of 1,3-dibromo-5,5-dimethylhydantoin in n-hexane under reflux followed by dehydrobromination with collidine in refluxing xylene gave the 5,7-diene (V) as the major product. Alkaline hydrolysis (KOH, methanol, room temperature, 15 h) and purification by preparative thin-layer chromatography (TLC) gave the 5,7-diene in 53% yield from (IVd).
| 【1】 Morris, D.S.; Norris, A.F.; Williams, D.H.; Structure and synthesis of 25-hydroxycholecalciferol-26,23-lactone, a metabolite of vitamin D3. J Org Chem 1981, 46, 3422-28. |
| 【2】 Seino, Y.; Ishizuka, S.; 23(S),25(R)-1alpha,25-(OH)2-D3-26,23-Lactone. Drugs Fut 1992, 17, 8, 655. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 31272 | 5-[(2S)-2-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-iodopropyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C31H49IO7 | 详情 | 详情 | |
| (IVb) | 31273 | 5-[(2R)-2-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]propyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C31H50O7 | 详情 | 详情 | |
| (IVc) | 31274 | 5-[(2R)-2-[(1S,8S,9S,10R,13R,14S,17R)-1,3-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]propyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C27H42O5 | 详情 | 详情 | |
| (F) | 31275 | N,N-dimethyl-N-(4-pyridinyl)amine; N,N-dimethyl-4-pyridinamine | 1122-58-3 | C7H10N2 | 详情 | 详情 |
| (IVd) | 31276 | (1S,8S,9S,10R,13R,14S,17R)-1-[(ethoxycarbonyl)oxy]-17-[(1R)-2-(4-hydroxy-4-methyl-5-oxotetrahydro-2-furanyl)-1-methylethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ethyl carbonate | C33H50O9 | 详情 | 详情 | |
| (G) | 31277 | 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione | 77-48-5 | C5H6Br2N2O2 | 详情 | 详情 |
| (V) | 31278 | ethyl (1S,9S,10S,13R,14R,17R)-3-[(ethoxycarbonyl)oxy]-17-[(1R)-2-(4-hydroxy-4-methyl-5-oxotetrahydro-2-furanyl)-1-methylethyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1-carboxylate | C33H48O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXI)In an alternative route to morpholine (XVIII), bromination of 1,3-bis(trifluoromethyl)benzene (XX) by means of 1,3-dibromo-5,5-dimethylhydantoin (XXI) yielded bromide (XXII). The Grignard reagent prepared from aryl bromide (XXII) was acylated with acetic anhydride at -15 C to produce acetophenone (XXIII). Enantioselective reduction of ketone (XXIII) with ruthenium(II) chloride in the presence of (1S,2R)-cis-1-amino-2-indanol furnished the (R)-alcohol (XXIV). N-Benzyl ethanolamine (XXV) was condensed with glyoxylic acid (XXVI) to give the hydroxy oxazinone (XXVII). This was coupled with the chiral alcohol (XXIV) using trifluoroacetic anhydride and boron trifluoride etherate to afford the target (R,R)-adduct (XXVIII) as the main diastereoisomer. Addition of 4-fluorophenylmagnesium bromide (XXIX) to the lactam function of (XXVIII), followed by catalytic hydrogenation of the intermediate (XXX), provided the required disubstituted morpholine (XVIII).
| 【1】 Wang, J.; Crocker, L.; Cai, D. (Merck & Co., Inc.); Polymorphic form of a tachykinin receptor antagonist. WO 0132656 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (XX) | 53293 | 1,3-Bis(trifluoromethyl)benzene; 1,3-Di(trifluoromethyl)benzene; alpha,alpha,alpha,alpha',alpha',alpha'-Hexafluoro-m-xylene; m-Xylene hexafluoride | 402-31-3 | C8H4F6 | 详情 | 详情 |
| (XXI) | 31277 | 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione | 77-48-5 | C5H6Br2N2O2 | 详情 | 详情 |
| (XXII) | 53294 | 1,3-Bis(trifluoromethyl)-5-bromobenzene; 1-Bromo-3,5-bis(trifluoromethyl)benzene; 3,5-Bis(trifluoromethyl)bromobenzene | 328-70-1 | C8H3BrF6 | 详情 | 详情 |
| (XXIII) | 40778 | 1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanone | 30071-93-3 | C10H6F6O | 详情 | 详情 |
| (XXIV) | 53295 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanol | n/a | C10H8F6O | 详情 | 详情 |
| (XXV) | 53296 | 4-benzyl-2-hydroxy-3-morpholinone | 287930-73-8 | C11H13NO3 | 详情 | 详情 |
| (XXVI) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXVII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXVIII) | 53297 | (2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-morpholinone | n/a | C21H19F6NO3 | 详情 | 详情 |
| (XXIX) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XXX) | 53298 | (2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)-3-morpholinol | n/a | C27H24F7NO3 | 详情 | 详情 |