|
【结 构 式】 
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【分子编号】15713 【品名】Oxalic acid 【CA登记号】144-62-7 |
【 分 子 式 】C2H2O4 【 分 子 量 】90.03548 【元素组成】C 26.68% H 2.24% O 71.08% |
合成路线1
该中间体在本合成路线中的序号：(B)1,4-Dihydroestronemethylether (I) was reacted with dimethylsulfonium-methylide (A) in a highly stereoselective manner to give the oxirane (II), which formed the cyanomethyl compound (III) by the addition of sodium cyanide. (III) was hydrolyzed with oxalic acid (B) in methanol and the product (IV) treated with pyridine perbromide hydrobromide to the dibromoketone, which yielded STS-557 after dehydrobromination.
| 【1】 Cook, C.E.; et al.; Synthesis and reactions of oxiranes obtained from 3- and 17-keto steroids. J Org Chem 1968, 33, 2789. |
| 【2】 Hubner, M.; et al.; Ein vereinfachtes Verfahren zur Darstellung von Steroid-Spirooxiranen. J Prakt Chem 1972, 314, 667. |
| 【3】 Ponsold, K.; et al.; Prostagene vom Typ 17alpha-CH2X-substituierter 19-Nortestossteronderivate. Pharmazie 1978, 33, 792. |
| 【4】 Perelman, M.; et al.; A new class of active steroids: the 19-nor-delta(4,9)-3-ketosteroids. J Am Chem Soc 1960, 82, 2402. |
| 【5】 Unterhalt, B.; STS-557. Drugs Fut 1980, 5, 6, 311. |
| 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) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (A) | 16180 | Dimethyl(methylene)-lambda(4)-sulfane; Dimethylsulfonium-methylide | C3H8S | 详情 | 详情 | |
| (I) | 32635 | 1,4-Dihydroestronemethylether; (8R,9S,13S,14S)-3-methoxy-13-methyl-1,4,6,7,8,9,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H26O2 | 详情 | 详情 | |
| (II) | 32637 | 3-Methoxyspiro[estra-2,5(10)-diene-17(S),2'-oxirane] | C20H28O2 | 详情 | 详情 | |
| (III) | 32636 | 2-[(8R,9S,13S,14S,17R)-17-hydroxy-3-methoxy-13-methyl-4,6,7,8,9,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]acetonitrile | C21H29NO2 | 详情 | 详情 | |
| (IV) | 32638 | 2-[(8R,9S,13S,14S,17R)-17-hydroxy-13-methyl-3-oxo-2,3,4,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]acetonitrile | C20H27NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)2) The condensation of quinolone (III) with 3 methylbutyl oxalate (X) [obtained from 3 methyl butanol (VIII) and oxalic acid (IX)] by means of NaH yields 3-methylbutyl-4-(4 hydroxy-7,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-2,4-dioxobutanoate (XI), which is then cyclized by means of sulfuric acid. ([*]-labeled compound).
| 【1】 Esumi, A.; Jin, Y.; Uohama, K.; Study in vivo of MY-5116. Absorption, distribution and elimination in rats. Clin Rep 1985, 20, 2, 391. |
| 【2】 Castaner, J.; Prous, J.; Repirinast. Drugs Fut 1987, 12, 1, 37. |
| 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) | 23027 | 3-acetyl-4-hydroxy-7,8-dimethyl-2(1H)-quinolinone | C13H13NO3 | 详情 | 详情 | |
| (VIII) | 23032 | 3-methyl-1-butanol | 123-51-3 | C5H12O | 详情 | 详情 |
| (IX) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (IX) | 44607 | 2-hydroxy-2-oxoacetic acid | C2H2O4 | 详情 | 详情 | |
| (X) | 23034 | isopentyl 2-(isopentyloxy)-2-oxoacetate | C12H22O4 | 详情 | 详情 | |
| (X) | 44608 | isopentyl 2-(isopentyloxy)-2-oxoacetate | C12H22O4 | 详情 | 详情 | |
| (XI) | 23035 | isopentyl 4-(4-hydroxy-7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)-2,4-dioxobutanoate | C20H23NO6 | 详情 | 详情 | |
| (XI) | 44609 | isopentyl 4-(4-hydroxy-7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)-2,4-dioxobutanoate | C20H23NO6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(C)18-Methyl-4-oestrene-3,17-dione (I) is hydroxylated by fermentation with Penicillium raistrickii giving the 15alpha-hydroxy compound (II), which is ketalized with 2,2-dimethylpropanediol (A), triethyl orthoformate and p-toluenesulfonic acid in CH2Cl2 giving a mixture of the DELTA(5-6) and DELTA(5-10)-ketals (IIIa-b). These ketals are mesylated witn methanesulfonyl chloride in pyridine yielding the mesyl ester (IVa-b), which is treated with sodium acetate in DMF to afford the oestradiene ketal (Va-b). Finally, this compound is treated with ethynylmagnesium bromide (B) and refluxed with oxalic acid (C) in methanol.
| 【1】 Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.; Steinbeck, H.; Steroids and pharmaceutical compositions thereof. BE 0847090; FR 2326927; GB 1569135; JP 52046060; US 4081537 . |
| 【2】 Castaner, J.; Blancafort, P.; Gestodene. Drugs Fut 1977, 2, 12, 805. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (B) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
| (IIIa) | 33952 | C24H36O4 | 详情 | 详情 | ||
| (IIIb) | 33953 | C24H36O4 | 详情 | 详情 | ||
| (IVa) | 33954 | C27H42O4S | 详情 | 详情 | ||
| (IVb) | 33955 | C27H42O4S | 详情 | 详情 | ||
| (Va) | 33956 | C24H34O3 | 详情 | 详情 | ||
| (Vb) | 33957 | C24H34O3 | 详情 | 详情 | ||
| (I) | 33950 | (8R,9S,10R,13S,14S)-13-ethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H26O2 | 详情 | 详情 | |
| (II) | 33951 | (8R,9S,10R,13S,14S,15S)-13-ethyl-15-hydroxy-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H26O3 | 详情 | 详情 | |
| (C) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(C)Ketals (IIIa-b) can also be treated with trimethylsilyl chloride in pyridine to give the trimethylsilyl derivative (VIa-b), which is then treated with ethynylmagnesium bromide (B) and oxalic acid (C) in methanol.
| 【1】 Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.; Steinbeck, H.; Steroids and pharmaceutical compositions thereof. BE 0847090; FR 2326927; GB 1569135; JP 52046060; US 4081537 . |
| 【2】 Castaner, J.; Blancafort, P.; Gestodene. Drugs Fut 1977, 2, 12, 805. |
合成路线5
该中间体在本合成路线中的序号：(C)Ketals (IIIa-b) can also be acetylated with acetic anhydride in pyridine to the acetate (VIIa-b), which is then treated with ethynylmagnesium bromide (B) and oxalic acid (C) in methanol.
| 【1】 Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.; Steinbeck, H.; Steroids and pharmaceutical compositions thereof. BE 0847090; FR 2326927; GB 1569135; JP 52046060; US 4081537 . |
| 【2】 Castaner, J.; Blancafort, P.; Gestodene. Drugs Fut 1977, 2, 12, 805. |
合成路线6
该中间体在本合成路线中的序号：(V)The condensation of 5-chloro-2-nitroaniline (I) with imidazole (II) by means of KOH in DMSO gives 5-(1-imidazolyl)-2-nitroaniline (III). Hydrogenation of (III) over Pd/C in 1N HCl gives the diamine (IV), which is condensed with oxalic acid (V) in 4N HCl yielding 6-(1-imidazolyl)quinoxaline-2,3(1H,4H)-dione hydrochloride (VI). Finally, this compound is nitrated with HNO3/H2SO4.
| 【1】 Ngo, J.; Rabasseda, X.; Castaner, J.; YM-900. Drugs Fut 1997, 22, 3, 256. |
| 【2】 Sakamoto, S.; Ohmori, J.; Shimizu-Sasamata, M.; et al.; Imidazolylquinoxaline-2,3-diones: Novel and potent antagonists of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) excitatory amino acid receptor. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-022.A.. |
| 【3】 Ohmori, J.; Sakamoto, S.; Kubota, H.; Shimizu-Sasamata, M.; Okada, M.; Kawasaki, S.; Hidaka, K.; Togami, J.; Furuya, T.; Murase, K.; 6-(1H-Imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds: Structure-activity relationships for the AMPA-type non-NMDA receptor. J Med Chem 1994, 37, 4, 467-75. |
| 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) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (II) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (III) | 15711 | 5-(1H-imidazol-1-yl)-2-nitroaniline; 5-(1H-imidazol-1-yl)-2-nitrophenylamine | C9H8N4O2 | 详情 | 详情 | |
| (IV) | 15712 | 4-(1H-imidazol-1-yl)-1,2-benzenediamine; 2-amino-4-(1H-imidazol-1-yl)phenylamine | C9H10N4 | 详情 | 详情 | |
| (V) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (VI) | 15714 | 6-(1H-imidazol-1-yl)-1,4-dihydro-2,3-quinoxalinedione hydrochloride | C11H9ClN4O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：The reaction of (XXVIII) with Pd and CO in MeOH gives the methyl ester (XXIX), which is treated with PhI(OCOCF3)2 and MeOH to afford the gem-dimethoxy compound (XXX). The reduction of the ester group of (XXX) with DIBAL in toluene gives the carbinol (XXXI), which is treated with tert-butyl hydroperoxide and Et2Al-CN in toluene to yield the dihydroxycarbonitrile (XXXII). The sulfonation of the primary OH group of (XXXII) with MsCl affords the mesylate (XXXIII), which is treated with K2CO3 in MeOH providing the intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid in EtOH/H2O affords the maleic anhydride derivative (XXXV).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669. |
| 【2】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (XXVIII) | 35696 | C49H75F3O7S3Si | 详情 | 详情 | ||
| (XXIX) | 35697 | C50H78O6S2Si | 详情 | 详情 | ||
| (XXX) | 35698 | C49H78O8Si | 详情 | 详情 | ||
| (XXXI) | 35699 | C48H78O7Si | 详情 | 详情 | ||
| (XXXII) | 35700 | C49H79NO8Si | 详情 | 详情 | ||
| (XXXIII) | 40299 | C51H83NO8SSi | 详情 | 详情 | ||
| (XXXIV) | 35702 | C49H77NO7Si | 详情 | 详情 | ||
| (XXXV) | 35703 | C49H74O9Si | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XI)A short-step synthesis of CS-834 has been described: The condensation of azetidinone (I) with pyrrolidinone (II) by means of CDI gives the thioester (III), which is desilylated with BF3/Et2O to the alcohol (IV). In order to have a more labile protecting group, alcohol (IV) is resilylated with TMS-Cl (or TES-Cl) and triethylamine affording the silyl ether (V), which is protected again at the pyrrolidine nitrogen with TES-Cl, affording the disilylated azetidinone (VI). The condensation of (VI) with the oxalyl chloride (VII) by means of triethylamine in dichloromethane gives the expected oxalylazetidinone (VIII), which is treated with diethyl ethylphosphonite in toluene yielding the ylide (IX). This compound, without isolation, is cyclized in refluxing mesitylene to afford the protected carbapenem intermediate (X), which is finally desilylated with HCl in acetonitrile. The cyclization of azetidinone (VIII) to carbapenem (X) can also be performed with triethyl phosphite instead of diethyl ethylphosphonite. The oxalyl chloride (VII) is obtained by monoesterification of oxalic acid (XI) with pivaloyloxymethyl iodide (XII) by means of triethylamine yielding monoester (XIII), which is finally converted to intermediate (VII) by treatment with oxalyl chloride in dichloromethane.
| 【1】 Oida, S.; Mori, M.; A short-step synthesis of orally active carbapenem antibiotic CS-834. Chem Pharm Bull 2000, 48, 1, 126. |
| 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) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (II) | 17192 | (4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one | 157429-42-0 | C4H7NOS | 详情 | 详情 |
| (III) | 33402 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanethioate | C18H32N2O4SSi | 详情 | 详情 | |
| (IV) | 33403 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]propanethioate | C12H18N2O4S | 详情 | 详情 | |
| (V) | 33404 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate | C15H26N2O4SSi | 详情 | 详情 | |
| (VI) | 33405 | S-[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate | C21H40N2O4SSi2 | 详情 | 详情 | |
| (VII) | 17199 | [(2-chloro-2-oxoacetyl)oxy]methyl pivalate | C8H11ClO5 | 详情 | 详情 | |
| (VIII) | 33406 | [[2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)-2-oxoacetyl]oxy]methyl pivalate | C29H50N2O9SSi2 | 详情 | 详情 | |
| (IX) | 33407 | [[2-[diethoxy(ethyl)phosphoranylidene]-2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)acetyl]oxy]methyl pivalate | C35H65N2O10PSSi2 | 详情 | 详情 | |
| (X) | 33408 | [(2,2-dimethylpropanoyl)oxy]methyl (4R,5S,6S)-4-methyl-7-oxo-3-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C29H50N2O7SSi2 | 详情 | 详情 | |
| (XI) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (XII) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 | |
| (XIII) | 33409 | 2-[[(2,2-dimethylpropanoyl)oxy]methoxy]-2-oxoacetic acid | C8H12O6 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：The reaction of (XXVIII) with Pd and CO in MeOH gives the methyl ester (XXIX), which is treated with PhI(OCOCF3)2 and MeOH to afford the gem-dimethoxy compound (XXX). The reduction of the ester group of (XXX) with DIBAL in toluene gives the carbinol (XXXI), which is treated with tert-butyl hydroperoxide and Et2Al(CN) in toluene to yield the dihydroxycarbonitrile (XXXII). The sulfonation of the primary OH group of (XXXII) with MsCl affords mesylate (XXXIII), which is treated with K2CO3 in MeOH providing intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid affords the maleic anhydride derivative (XXXV).
| 【1】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829. |
| 【2】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (XXVIII) | 35696 | C49H75F3O7S3Si | 详情 | 详情 | ||
| (XXIX) | 35697 | C50H78O6S2Si | 详情 | 详情 | ||
| (XXX) | 35698 | C49H78O8Si | 详情 | 详情 | ||
| (XXXI) | 35699 | C48H78O7Si | 详情 | 详情 | ||
| (XXXII) | 35700 | C49H79NO8Si | 详情 | 详情 | ||
| (XXXIII) | 40299 | C51H83NO8SSi | 详情 | 详情 | ||
| (XXXIV) | 35702 | C49H77NO7Si | 详情 | 详情 | ||
| (XXXV) | 35703 | C49H74O9Si | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：Condensation of 4,5-dichloro-1,2-phenylenediamine (I) with 1-phenyl-1,2-propanedione (II) in boiling AcOH provided quinoxaline (III). Subsequent reaction of (III) with ethyl bromopyruvate (IV) led to the pyrroloquinoxaline (V). After reduction of the ester group of (V) to alcohol (VI) with LiAlH4, further oxidation with MnO2 produced aldehyde (VII). This was condensed with boiling 3-(dimethylamino)propylamine (VIII), and the resulting imine (IX) was finally reduced to the target amine with NaBH4 in MeOH. The title compound was finally converted to the dioxalate salt upon treatment with oxalic acid in isopropanol.
| 【1】 Guillon, J.; Rault, S.; Kervran, A.; Renard, P.; Manechez, D.; Pfeiffer, B.; Dallemagne, P.; Synthesis of new pyrrolo[1,2-a]quinoxalines: Potential non-peptide glucagon receptor antagonists. Eur J Med Chem 1998, 33, 4, 293. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (I) | 18003 | 4,5-dichloro-1,2-benzenediamine; 4,5-Dichloro-o-phenylenediamine; 2-amino-4,5-dichlorophenylamine | 5348-42-5 | C6H6Cl2N2 | 详情 | 详情 |
| (II) | 31481 | 1-phenyl-1,2-propanedione | 579-07-7 | C9H8O2 | 详情 | 详情 |
| (III) | 31482 | 6,7-dichloro-2-methyl-3-phenylquinoxaline | C15H10Cl2N2 | 详情 | 详情 | |
| (IV) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (V) | 31483 | ethyl 7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxaline-2-carboxylate | C20H14Cl2N2O2 | 详情 | 详情 | |
| (VI) | 31484 | (7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methanol | C18H12Cl2N2O | 详情 | 详情 | |
| (VII) | 31486 | 7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxaline-2-carbaldehyde | C18H10Cl2N2O | 详情 | 详情 | |
| (VIII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (IX) | 31485 | N(1)-[(E)-(7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methylidene]-N(3),N(3)-dimethyl-1,3-propanediamine; N-[(E)-(7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methylidene]-N-[3-(dimethylamino)propyl]amine | C23H22Cl2N4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：The N-arylpyrrole (III) was prepared by the Clauson-Kaas reaction of 2-nitroaniline (I) with 2,5-dimethoxytetrahydrofuran (II) in AcOH under microwave irradiation. Subsequent reduction of the nitro group of (III) using BiCl3 and NaBH4 provided aniline (IV), which was condensed with cinnamoyl chloride (V) in the presence of pyridine to give the corresponding amide (VI). Cyclization of (VI) using POCl3 and pyridine produced the pyrroloquinoxaline (VII), and further Vilsmeier-Haack formylation gave aldehyde (VIII). This was condensed with boiling 3-(dimethylamino)propylamine (IX), and the resulting imine (X) was finally reduced to the target amine with NaBH4 in MeOH. The title compound was finally converted to the trioxalate salt upon treatment with oxalic acid in isopropanol.
| 【1】 Guillon, J.; Rault, S.; Kervran, A.; Renard, P.; Manechez, D.; Pfeiffer, B.; Dallemagne, P.; Synthesis of new pyrrolo[1,2-a]quinoxalines: Potential non-peptide glucagon receptor antagonists. Eur J Med Chem 1998, 33, 4, 293. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (I) | 11608 | o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine | 88-74-4 | C6H6N2O2 | 详情 | 详情 |
| (II) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (III) | 31487 | 1-(2-nitrophenyl)-1H-pyrrole | 33265-60-0 | C10H8N2O2 | 详情 | 详情 |
| (IV) | 31488 | 2-(1H-pyrrol-1-yl)aniline; 2-(1H-pyrrol-1-yl)phenylamine | 6025-60-1 | C10H10N2 | 详情 | 详情 |
| (V) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (VI) | 31489 | (E)-3-phenyl-N-[2-(1H-pyrrol-1-yl)phenyl]-2-propenamide | C19H16N2O | 详情 | 详情 | |
| (VII) | 31490 | 4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxaline | C19H14N2 | 详情 | 详情 | |
| (VIII) | 31491 | 4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxaline-1-carbaldehyde | C20H14N2O | 详情 | 详情 | |
| (IX) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (X) | 31492 | N-[3-(dimethylamino)propyl]-N-((E)-[4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxalin-1-yl]methylidene)amine; N(1),N(1)-dimethyl-N(3)-((E)-[4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxalin-1-yl]methylidene)-1,3-propanediamine | C25H26N4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)Treatment of diamino compound (I) with oxalic acid (II) in refluxing HCl provides tetrahydroquinoxalindione derivative (III), which is then converted into dichloro compound (IV) by reaction with refluxing POCl3. Treatment of (IV) with Na in refluxing MeOH affords dimethoxy quinoxaline (V), which is then brominated by reaction with NBS and AIBN in refluxing CCl4 to give bromomethyl derivative (VI). Nitration of (VI) by reaction with isopropyl nitrate in H2SO4 yields nitro derivative (VII), which is then converted into protected amino methyl derivative (IX) by reaction with di-tert-butyl-iminocarboxylate (VIII) and cesium carbonate in DMF. Removal of the Boc groups of (IX) by means of TFA gives aminomethyl derivative (X), which is then converted into phosphonic dimethyl ester (XII) by first treatment with formaline in EtOH followed by reaction with dimethyl phosphonate (XI), Et3N and trimethylsilyl chloride (TMSCl) in CHCl3. Finally, treatment of (XII) with trimethylsilyl bromide (TMSBr) in CH2Cl2 obtains the desired product.
| 【1】 Acklin, P.; Allgeier, H.; Auberson, Y.; Ofner, S.; Veenstra, S.J. (Novartis AG); Substd. aminoalkane phosphonic acids. EP 0934326; US 6117873; WO 9817672 . |
| 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) | 48441 | 2,3-Diaminotoluene; o-Tolylenediamine | 2687-25-4 | C7H10N2 | 详情 | 详情 |
| (II) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (III) | 48442 | 5-methyl-1,4-dihydro-2,3-quinoxalinedione | C9H8N2O2 | 详情 | 详情 | |
| (IV) | 48443 | 2,3-dichloro-5-methylquinoxaline | C9H6Cl2N2 | 详情 | 详情 | |
| (V) | 48444 | 2,3-dimethoxy-5-methylquinoxaline; 3-methoxy-5-methyl-2-quinoxalinyl methyl ether | C11H12N2O2 | 详情 | 详情 | |
| (VI) | 48445 | 5-(bromomethyl)-3-methoxy-2-quinoxalinyl methyl ether; 5-(bromomethyl)-2,3-dimethoxyquinoxaline | C11H11BrN2O2 | 详情 | 详情 | |
| (VII) | 48446 | 5-(bromomethyl)-3-methoxy-7-nitro-2-quinoxalinyl methyl ether; 5-(bromomethyl)-2,3-dimethoxy-7-nitroquinoxaline | C11H10BrN3O4 | 详情 | 详情 | |
| (VIII) | 48447 | Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester | 51779-32-9 | C10H19NO4 | 详情 | 详情 |
| (IX) | 48448 | 5-[[bis(tert-butoxycarbonyl)amino]methyl]-2,3-dimethoxy-7-nitroquinoxaline | C21H28N4O8 | 详情 | 详情 | |
| (X) | 48449 | (2,3-dimethoxy-7-nitro-5-quinoxalinyl)methanamine; (2,3-dimethoxy-7-nitro-5-quinoxalinyl)methylamine | C11H12N4O4 | 详情 | 详情 | |
| (XI) | 32359 | dimethyl phosphonate | 868-85-9 | C2H7O3P | 详情 | 详情 |
| (XII) | 48450 | dimethyl [[(2,3-dimethoxy-7-nitro-5-quinoxalinyl)methyl]amino]methylphosphonate | C14H19N4O7P | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：Dihydroartemisinin (II) was prepared by NaBH4 reduction of artemisinin (I). Condensation of (II) with 2-bromoethanol (A) in the presence of boron trifluoride etherate yielded the 10beta-bromoethyl acetal (III). Finally, reaction of (III) with dimethylamine in DMF provided the desired amine, which was finally converted to the oxalate salt.
| 【1】 Pan, J.-P.; Jiang, H.-J.; Wu, J.-M.; Zhu, Y.-M.; Wu, G.-S.; Li, Y.; Synthesis and antimalarial activity of artemisinin derivatives containing an amino group. J Med Chem 2000, 43, 9, 1635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (A) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (I) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 40705 | (1R,4S,5R,8S,9R,10S,12R,13R)-10-(2-bromoethoxy)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane; 2-bromoethyl (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadec-10-yl ether | C17H27BrO5 | 详情 | 详情 |