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【结 构 式】 
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【分子编号】36317 【品名】thiomorpholine 【CA登记号】123-90-0 |
【 分 子 式 】C4H9NS 【 分 子 量 】103.1882 【元素组成】C 46.56% H 8.79% N 13.57% S 31.08% |
合成路线1
该中间体在本合成路线中的序号：(V)The cyclization of ethyl acetoacetate (I) with 3-amino-2-butenenitrile (II) gives 4-hydroxy-2,6-dimethylpyridine-3-carbonitrile (III), which is treated with SOCl2 and oxidized with MCPBA to yield 4-chloro-2,6-dimethylpyridine-3-carbonitrile N-oxide (IV). Finally, this compound is condensed with thiomorpholine (V) to afford the target compound.
| 【1】 Greve, W.; Schindler, U.; Elben, U.; Rudolphi, K. (Aventis Pharma AG); Substd. pyridin-1-oxides, process for their preparation, medicines containing them and their use. DE 3514073 . |
| 【2】 Nemcova, D.; Janata, V.; 4-Hydroxy-2,6-dimethylnicotinic acid esters. CS 147252 . |
| 【3】 Elben, U.; SUBSTITUTED DIALKYLPYRIDINES AND THEIR N-OXIDES WITH AN ELECTRON-WITHDRAWING SUBSTITUENT. Drugs Fut 1989, 14, 10, 981. |
| 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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 28381 | (E)-3-amino-2-butenenitrile | 1118-61-2 | C4H6N2 | 详情 | 详情 |
| (III) | 43658 | 4-hydroxy-2,6-dimethylnicotinonitrile | C8H8N2O | 详情 | 详情 | |
| (IV) | 43659 | 4-chloro-3-cyano-2,6-dimethyl-1-pyridiniumolate | C8H7ClN2O | 详情 | 详情 | |
| (V) | 36317 | thiomorpholine | 123-90-0 | C4H9NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Adenine (I) was oxidized with hydrogen peroxide in aqueous acetic acid to give adenine 1-N-oxide (II). Diazotization of (II) with sodium nitrite and acetic acid, followed by hydrolysis of the diazonium salt provided hypoxanthine 1-N-oxide (III). 2,6-Dichloropurine (IV) was then obtained by treatment of (III) with phosphoryl chloride in the presence of triethylamine. Displacement of the 6-chlorine atom of (IV) by benzylamine (V) in boiling n-butanol yielded 6-benzylamino-2-chloropurine (VI), which was subsequently alkylated at the 9-N with isopropyl iodide and NaH to give (VII). Finally, the remaining 2-chloro atom of (VII) was displaced by thiomorpholine (VIII) to furnish the title compound.
| 【1】 Woo, E.-R.; Baek, D.J.; Lee, s.-C.; Hong, C.Y.; Lee, K.-S.; Yang, B.-S.; Cho, J.-H.; Oh, C.-H.; Synthesis and biological activities of C-2, N-9 substituted 6-benzylaminopurine derivatives as cyclin-dependent kinase inhibitor. Arch Pharm 1999, 332, 6, 187. |
| 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) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 36313 | 6-amino-9H-purin-1-ium-1-olate | C5H5N5O | 详情 | 详情 | |
| (III) | 36314 | 6-hydroxy-9H-purin-1-ium-1-olate | C5H4N4O2 | 详情 | 详情 | |
| (IV) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 36315 | N-benzyl-2-chloro-9H-purin-6-amine; N-benzyl-N-(2-chloro-9H-purin-6-yl)amine | C12H10ClN5 | 详情 | 详情 | |
| (VII) | 36316 | N-benzyl-2-chloro-9-isopropyl-9H-purin-6-amine; N-benzyl-N-(2-chloro-9-isopropyl-9H-purin-6-yl)amine | C15H16ClN5 | 详情 | 详情 | |
| (VIII) | 36317 | thiomorpholine | 123-90-0 | C4H9NS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 6-(2,6-difluorobenzyl)-2-(methylsulfanyl)pyrimidin-4(3H)-one (I) with thiomorpholine (II) gives the target thiomorpholino-pyrimidinone.
合成路线4
该中间体在本合成路线中的序号：(V)The condensation of phthalic anhydride (I) with aniline (II) in refluxing HOAc produced N-phenyl phthalimide (III). Aromatic sulfonation of (III) with chlorosulfonic acid in the presence of PCl5 afforded the sulfonyl chloride (IV). This was finally condensed with thiomorpholine (V) to furnish the target sulfonamide.
| 【1】 Legora, A.M.; et al.; Anti-inflammatory effects of thalidomide-derived compounds on LPS-induced inflammation in mouse lung. Inflamm Res 2001, 50, Suppl. 3, Abst 083. |
| 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) | 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 53124 | N-Phenylphthalimide | 520-03-6 | C14H9NO2 | 详情 | 详情 |
| (IV) | 53125 | 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzenesulfonyl chloride | n/a | C14H8ClNO4S | 详情 | 详情 |
| (V) | 36317 | thiomorpholine | 123-90-0 | C4H9NS | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Two synthetic methods have been reported for the title compound. Coupling of aryl triflate (I) with thiomorpholine (II) affords the N-aryl thiomorpholine (III). Reduction of the nitroaryl group of (III) by catalytic hydrogenation in the presence of Raney nickel furnishes aniline (IV). This is then condensed with benzyl chloroformate under Schotten-Baumann conditions, yielding carbamate (V). Reaction of carbamate (V) with (S)-N-(2-acetoxy-3-chloropropyl)acetamide (VI) in the presence of lithium tert-butoxide and MeOH leads to the (S)-oxazolidine (VII). Finally, oxidation of the thiomorpholine sulfide group of (VII) with N-methylmorpholine-N-oxide in the presence of a catalytic amount of OsO4 gives rise to the title sulfone compound.
| 【1】 Greene, M.L.; et al.; Synthetic studies leading to the identification of PNU-288034, a potent new oxazolidinone antibacterial agent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1333. |
| 【2】 Zurenko, G.E.; Barbachyn, M.R. (Pharmacia Corp.); A thiazine oxazolidinone. EP 1294717; US 2002156072; US 6605609; WO 0198297 . |
| 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) | 62749 | 2,6-difluoro-4-nitrophenyl trifluoromethanesulfonate | C7H2F5NO5S | 详情 | 详情 | |
| (II) | 36317 | thiomorpholine | 123-90-0 | C4H9NS | 详情 | 详情 |
| (III) | 62750 | 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine | C10H10F2N2O2S | 详情 | 详情 | |
| (IV) | 62751 | 3,5-difluoro-4-(4-thiomorpholinyl)phenylamine; 3,5-difluoro-4-(4-thiomorpholinyl)aniline | C10H12F2N2S | 详情 | 详情 | |
| (V) | 62752 | benzyl 3,5-difluoro-4-(4-thiomorpholinyl)phenylcarbamate | C18H18F2N2O2S | 详情 | 详情 | |
| (VI) | 61915 | (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate | C7H12ClNO3 | 详情 | 详情 | |
| (VII) | 62753 | N-({(5S)-3-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide | C16H19F2N3O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Condensation between 1-phenyl-1,4-pentanedione (I) and 4-fluoroaniline (II) under Paal-Knorr reaction conditions provides the pyrrole derivative (III). This is then subjected to Mannich reaction with thiomorpholine (IV) and formaldehyde to furnish the target thiomorpholimomethyl pyrrole.
| 【1】 Biava, M.; Porretta, G.C.; Deidda, D.; Pompei, R.; Tafi, A.; Manetti, F.; Importance of the thiomorpholine introduction in new pyrrole derivatives as antimycobacterial agents analogues of BM 212. Bioorg Med Chem 2003, 11, 4, 515. |
合成路线7
该中间体在本合成路线中的序号：(II)Condensation of 1,2-difluoro-4-nitrobenzene (I) with thiomorpholine (II) using DIEA in refluxing acetonitrile at 85 °C yields 4-(2-fluoro-4-nitrophenyl)thiomorpholine (III) , which is then reduced by means of either Na2S2O4 in THF , Fe in the presence of NH4Cl in refluxing H2O/EtOH/dioxane , or by catalytic hydrogenation over Raney-Ni in THF/H2O (1) or sulfided Pd/C in MeOH , providing 3-fluoro-4-thiomorpholin-4-ylaniline (IV) . Acylation of amine (IV) with benzyl chloroformate (V), optionally in the presence of DMA , in THF affords carbamate (VI) , which then cyclizes with (R)-(–)-glycidyl butyrate (VII) using BuLi in THF at –78 °C to produce the 5-(hydroxymethyl)-2-oxazolidinone derivative (VIII). Reaction of the primary alcohol (VIII) with MsCl using Et3N in CH2Cl2 or with TsCl in pyridine yields the corresponding mesylate (IXa) or tosylate (IXb) , respectively, which by substitution with NaN3 in DMF at 65-85 °C provides azide (X). Staudinger reduction of azide (X) with PPh3 in THF/H2O then yields the corresponding amine (XIa). Finally, amine (XIa) or its hydrochloride (XIb) are acylated with acetic anhydride (XII) in the presence of pyridine in CH2Cl2 or NaOH in H2O/MeOH/CH2Cl2 .
| 【1】 Barbachyn, M.R., Hutchinson, D.K., Brickner, S.J. et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J Med Chem 1996, 39(3): 680-5. |
| 【2】 Brickner, S.J., Barbachyn, M.R., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. US 5880118. |
| 【3】 Barbachyn, M.R., Brickner, S.J., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. EP 0717738, JP 1997502436, US 5688792, WO 1995007271. |
| 【4】 Brickner, S.J., Nuermberger, E., Stover, C.K. (Pfizer, Inc.). Combination therapy for tuberculosis. CN 102143748, EP 2340022, JP 20122502017, KR 2011063518, US 2011190199, WO 2010026526. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 68063 | (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate | C15H19FN2O5S2 | 详情 | 详情 | |
| (IXb) | 68064 | (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate | C21H23FN2O5S2 | 详情 | 详情 | |
| (XIa) | 68066 | (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one | C14H18FN3O2S | 详情 | 详情 | |
| (XIb) | 68067 | (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one hydrochloride | C14H18FN3O2S.HCl | 详情 | 详情 | |
| (I) | 17013 | 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene | 369-34-6 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 36317 | thiomorpholine | 123-90-0 | C4H9NS | 详情 | 详情 |
| (III) | 68060 | 4-(2-fluoro-4-nitrophenyl)thiomorpholine | C10H11FN2O2S | 详情 | 详情 | |
| (IV) | 68061 | 3-fluoro-4-thiomorpholinoaniline | C10H13FN2S | 详情 | 详情 | |
| (V) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VI) | 68062 | benzyl (3-fluoro-4-thiomorpholinophenyl)carbamate | C18H19FN2O2S | 详情 | 详情 | |
| (VII) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (VIII) | 56305 | (5R)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C14H17FN2O3S | 详情 | 详情 | |
| (X) | 68065 | (R)-5-(azidomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one | C14H16FN5O2S | 详情 | 详情 | |
| (XII) | 49701 | Acetic anhydride; Acetyl oxide | 108-24-7 | C4H6O3 | 详情 | 详情 |