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【结 构 式】 
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【分子编号】49696 【品名】(S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol 【CA登记号】60827-45-4 |
【 分 子 式 】C3H7ClO2 【 分 子 量 】110.54008 【元素组成】C 32.6% H 6.38% Cl 32.07% O 28.95% |
合成路线1
该中间体在本合成路线中的序号：(I)Treatment of (R)-1-chloro-2,3-propanediol (I) with either K2CO3 or Cs2CO3 in CH2Cl2, followed by O-protection with Trt-Cl and Et3N in CH2Cl2, yields (S)-trityl glycidol (II). Alternatively, derivative (II) can also be obtained either by direct O-protection of (R)-glycidol (III) by means of Trt-Cl and Et3N in refluxing CH2Cl2 or by cyclization of protected propanediol derivative (IV)--obtained from treatment of compound (I) with Trt-Cl and Et3N in CH2Cl2--by means of KOH in EtOH. Reaction of (S)-trityl glycidol (II) with vinyl magnesium bromide (V) by means of CuI in THF provides (S)-1-(triphenylmethoxy)-4-penten-2-ol (VI), which is then condensed with allyl bromide (VII) with KOtBu or NaH in THF to afford compound (VIII). Ozonolysis of (VIII) in CH2Cl2/MeOH, followed by reductive quench with NaBH4 in NaOH, gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (IX), which is then treated with MsCl/Et3N in CH2Cl2 to yield bismesylate (X). Coupling of compound (X) with 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) [obtained by treatment of dichloromaleic anhydride (XII) with methylamine hydrochloride by means of NaOMe in HOAc to furnish dichloro-N-methylmaleimide (XIII), followed by Grignard reaction of (XIII) with indole (XIV) in toluene/THF by means of EtMgBr in Et2O] by means of Cs2CO3 in DMF gives the 14-membered macrocycle (XV).
| 【1】 Faul, M.M.; Sullivan, K.A.; Neel, D.A.; Krumrich, C.A.; Jirousek, M.R.; Winneroski, L.L.; Gillig, J.R.; Rito, C.J.; Macrocyclic bisindolylmaleimides: Synthesis by inter- and intramolecular alkylation. J Org Chem 1998, 63, 6, 1961. |
| 【2】 Engel, G.L.; Farid, N.A.; Faul, M.M.; Jirousek, M.R.; Richardson, L.A.; Winneroski, L.L. Jr. (Eli Lilly and Company); Protein kinase C inhibitor. EP 0776895; JP 1999500149; US 5710145; WO 9718809 . |
| 【3】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. US 5721272 . |
| 【4】 Rito, C.J.; Mcdonald, J.H. III; Jirousek, M.R.; Winneroski, L.L. Jr.; Heath, W.F. Jr.; Faul, M.M. (Eli Lilly and Company); Improved synthesis of bisindolylmaleimides. EP 0657411; US 5541347 . |
| 【5】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. EP 0776899 . |
| 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) | 49696 | (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol | 60827-45-4 | C3H7ClO2 | 详情 | 详情 |
| (II) | 41006 | (2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane | C22H20O2 | 详情 | 详情 | |
| (III) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (IV) | 51942 | (2R)-1-chloro-3-(trityloxy)-2-propanol | C22H21ClO2 | 详情 | 详情 | |
| (V) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (VI) | 41007 | (2S)-1-(trityloxy)-4-penten-2-ol | C24H24O2 | 详情 | 详情 | |
| (VII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VIII) | 41008 | 1-[[[(2S)-2-(allyloxy)-4-pentenyl]oxy](diphenyl)methyl]benzene; allyl (1S)-1-[(trityloxy)methyl]-3-butenyl ether | C27H28O2 | 详情 | 详情 | |
| (IX) | 41010 | (3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol | C25H28O4 | 详情 | 详情 | |
| (X) | 51943 | (7S)-2,11-dimethyl-2,11-dimethylene-7-[(trityloxy)methyl]-3,6,10-trioxa-2lambda(6),11lambda(6)-dithia-1,11-dodecadiene; 2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl (1S)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(trityloxy)methyl]propyl ether | C31H40O4S2 | 详情 | 详情 | |
| (XI) | 51012 | 5-(tert-butyl) 1-(2,3,5,6-tetrafluorophenyl) (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]pentanedioate | C32H38F4N2O9 | 详情 | 详情 | |
| (XII) | 21947 | 3,4-dichloro-2,5-furandione | 1122-17-4 | C4Cl2O3 | 详情 | 详情 |
| (XIII) | 41029 | 3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione | C5H3Cl2NO2 | 详情 | 详情 | |
| (XIV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (XV) | 41016 | (18S)-4-methyl-18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione | C46H39N3O4 | 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 reaction of 3-fluoroaniline (I) with isobutyl chloroformate (II) by means of K2CO3 in dichloromethane/water gives the carbamate (III), which is brominated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) to yield the 4-bromo-3-fluorophenyl carbamate (IV). The condensation of (IV) with tetrahydrothiopyran-4-one (V) by means of EtMgBr and BuLi in THF affords the tertiary alcohol (VI), which is dehydrated by means of TFA in dichloromethane and oxidized with NaIO4 in methanol/water to provide the unsaturated sulfoxide (VII). The stereoselective reduction of (VII) by means of H2 over Pt/C in DMF gives the cis sulfoxide (VIII). The cyclization of the carbamate (VIII) with (S)-3-chloropropane-1,2-diol (IX) by means of Li t-amylate in DMF gives the oxazolidinone (X), whose free OH group is activated with 2,5-dichlorobenzenesulfonyl chloride (XI) and TEA in dichloromethane to yield the sulfonate (XII). The reaction of (XII) with NH4OH in methanol/acetonitrile affords the aminomethyl derivative (XIII), which is finally acylated with acetic anhydride (XIV) to provide the target sulfoxide.
| 【1】 Gage, J.R.; et al.; Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics. Tetrahedron Lett 2000, 41, 22, 4301. |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (III) | 49690 | isobutyl 3-fluorophenylcarbamate | C11H14FNO2 | 详情 | 详情 | |
| (IV) | 49691 | isobutyl 4-bromo-3-fluorophenylcarbamate | C11H13BrFNO2 | 详情 | 详情 | |
| (V) | 49692 | Tetrahydrothiopyran-4-one; Tetrahydro-4H-thiopyran-4-one; 4-Oxothiane | 1072-72-6 | C5H8OS | 详情 | 详情 |
| (VI) | 49693 | isobutyl 3-fluoro-4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenylcarbamate | C16H22FNO3S | 详情 | 详情 | |
| (VII) | 49694 | 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]-3,6-dihydro-2H-thiopyranium-1-olate | C16H20FNO3S | 详情 | 详情 | |
| (VIII) | 49695 | 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]tetrahydro-2H-thiopyranium-1-olate | C16H22FNO3S | 详情 | 详情 | |
| (IX) | 49696 | (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol | 60827-45-4 | C3H7ClO2 | 详情 | 详情 |
| (X) | 49697 | 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate | C15H18FNO4S | 详情 | 详情 | |
| (XI) | 49698 | 2,5-Dichlorobenzenesulfonic acid | 88-42-6 | C6H4Cl2O3S | 详情 | 详情 |
| (XII) | 49699 | 4-[4-[(5R)-5-([[(2,5-dichlorophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate | C21H20Cl2FNO6S2 | 详情 | 详情 | |
| (XIII) | 49700 | 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate | C15H19FN2O3S | 详情 | 详情 | |
| (XIV) | 49701 | Acetic anhydride; Acetyl oxide | 108-24-7 | C4H6O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The reaction of 3-fluoroaniline (I) with isobutyl chloroformate (II) by means of K2CO3 in dichloromethane/water gives the carbamate (III), which is brominated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) to yield the 4-bromo-3-fluorophenyl carbamate (IV). The condensation of (IV) with tetrahydrothiopyran-4-one (V) by means of EtMgBr and BuLi in THF affords the tertiary alcohol (VI), which is dehydroxylated by means of poly(methylhydrosiloxane) (PMHS), (Me3Si)2O and Ts-OH in toluene to provide the intermediate (VII). The stereoselective oxidation of (VII) to the trans sulfoxide (VIII) is performed by means of Ti(OiPr)4 and tert-butyl hydroperoxide in the presence of diisopropyl D-tartrate. The cyclization of the carbamate (VIII) with (S)-3-chloropropane-1,2-diol (IX) by means of Li t-amylate in DMF gives the oxazolidinone (X), whose free OH group is activated with 3-nitrobenzenesulfonyl chloride and TEA in dichloromethane to yield the sulfonate (XII). The reaction of (XII) with NH4OH in methanol/acetonitrile affords the aminomethyl derivative (XIII), which is finally acylated with propionic anhydride (XIV) to provide the target sulfoxide.
| 【1】 Gage, J.R.; et al.; Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics. Tetrahedron Lett 2000, 41, 22, 4301. |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (III) | 49690 | isobutyl 3-fluorophenylcarbamate | C11H14FNO2 | 详情 | 详情 | |
| (IV) | 49691 | isobutyl 4-bromo-3-fluorophenylcarbamate | C11H13BrFNO2 | 详情 | 详情 | |
| (V) | 49692 | Tetrahydrothiopyran-4-one; Tetrahydro-4H-thiopyran-4-one; 4-Oxothiane | 1072-72-6 | C5H8OS | 详情 | 详情 |
| (VI) | 49693 | isobutyl 3-fluoro-4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenylcarbamate | C16H22FNO3S | 详情 | 详情 | |
| (VII) | 49702 | isobutyl 3-fluoro-4-tetrahydro-2H-thiopyran-4-ylphenylcarbamate | C16H22FNO2S | 详情 | 详情 | |
| (VIII) | 49706 | 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]tetrahydro-2H-thiopyranium-1-olate | C16H22FNO3S | 详情 | 详情 | |
| (IX) | 49696 | (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol | 60827-45-4 | C3H7ClO2 | 详情 | 详情 |
| (X) | 49707 | 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate | C15H18FNO4S | 详情 | 详情 | |
| (XI) | 49703 | m-nitrobenzenesulfonic acid; 3-nitrobenzenesulfonic acid | 98-47-5 | C6H5NO5S | 详情 | 详情 |
| (XII) | 49704 | 4-[2-fluoro-4-[(5R)-5-([[(3-nitrophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate | C21H21FN2O8S2 | 详情 | 详情 | |
| (XIII) | 49705 | 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate | C15H19FN2O3S | 详情 | 详情 | |
| (XIV) | 49701 | Acetic anhydride; Acetyl oxide | 108-24-7 | C4H6O3 | 详情 | 详情 |