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【结 构 式】 
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【分子编号】60593 【品名】p-xylene 【CA登记号】 |
【 分 子 式 】C8H10 【 分 子 量 】106.1674 【元素组成】C 90.51% H 9.49% |
合成路线1
该中间体在本合成路线中的序号：This compound can be obtained in three similar ways: 1) The reaction of N-acetyl-L-methionine (I) with ethyl chloroformate (II) and triethylamine in chloroform gives the corresponding mixed anhydride (III), which is then condensed with 3,4-di(ethoxycarbonyloxy)phenethylamine tosylate (IV) by means of triethylamine in chloroform. 2) The reaction of N-acetyl-L-methionine (I) with N-hydroxysuccinimide (V) by means of dicyclohexylcarbodiimide (DDC) in dioxane gives the corresponding active ester (VI), which is then condensed with the amine (IV) as before. The active ester method can also be carried out in this case using N-hydroxyphthalimide, 1-hydroxybenzothiazole or 4-nitrophenol instead of N-hydroxysuccinimide (V). 3) The reaction of the active ester (VI) with dopamine (VII) by means of triethylamine in DMF gives the corresponding amide (VIII), which is then acylated with ethyl chloroformate (IX) in pyridine.
| 【1】 Kiguchi, T.; Hatashi, K.; Yamaguchi, I. (Tanabe Seiyaku Co., Ltd.); Phenethylamine derivs., process for preparing same and pharmaceutical compositions containing said phenethylamine derivs. EP 0007441; JP 1980007242 . |
| 【2】 Prous, J.; Castaner, J.; DOCARPAMINE. Drugs Fut 1990, 15, 2, 122. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 60593 | p-xylene | C8H10 | 详情 | 详情 | ||
| (II), (IX) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (I) | 11228 | (2S)-2-(Acetamido)-4-(methylsulfanyl)butyric acid | 65-82-7 | C7H13NO3S | 详情 | 详情 |
| (III) | 11230 | N-Acetyl-L-methionine ethoxycarbonyl anhydride | C10H17NO5S | 详情 | 详情 | |
| (IV) | 11231 | 4-(2-aminoethyl)-2-[(ethoxycarbonyl)oxy]phenyl ethyl carbonate | C14H19NO6 | 详情 | 详情 | |
| (V) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (VI) | 11233 | N-[(1S)-1-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-3-(methylsulfanyl)propyl]acetamide | C11H16N2O5S | 详情 | 详情 | |
| (VII) | 11234 | 4-(2-Aminoethyl)-1,2-benzenediol | 51-61-6 | C8H11NO2 | 详情 | 详情 |
| (VIII) | 11235 | (2S)-2-(Acetamido)-N-(3,4-dihydroxyphenethyl)-4-(methylsulfanyl)butanamide | 122570-36-9 | C15H22N2O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：1) The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol and p-toluenesulfonic acid in the usual way, yielding the ethyl ester (III). The selective reduction of (III) with NaBH4 in ethanol affords (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride to the benzoate (V). The selective reduction of (V) with disiamyl borane in THF yields the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane affords the tetrahydrofuryl bromide (VIII), which is then condensed with the adenine (IX), giving 5'-O-benzoyl-2',3'-dideoxyadenosine (X). The deprotection of (X) with NH3 in methanol yields 2',3'-dideoxyadenosine, which is finally deaminated enzymatically with the enzyme adenosine deaminase.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 【2】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 【3】 Taniguchi, M.; Koga, K.; Yamada, S.; Stereoselective synthesis of D-ribose from L-glutamic acid. Tetrahedron 1974, 30, 3547-52. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 60593 | p-xylene | C8H10 | 详情 | 详情 | ||
| (I) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | C5H9NO4 | 详情 | 详情 |
| (II) | 12006 | (R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid | 53558-93-3 | C5H6O4 | 详情 | 详情 |
| (III) | 12007 | ethyl (2S)-5-oxotetrahydro-2-furancarboxylate; (S)-(+)-gamma-Ethoxycarbonyl-gamma-butyrolactone | 55094-96-7 | C7H10O4 | 详情 | 详情 |
| (IV) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (V) | 12009 | [(2S)-5-oxotetrahydro-2-furanyl]methyl benzoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 12010 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl benzoate | C12H14O4 | 详情 | 详情 | |
| (VII) | 12011 | [(2S)-5-(acetoxy)tetrahydro-2-furanyl]methyl benzoate | C14H16O5 | 详情 | 详情 | |
| (VIII) | 12012 | [(2S)-5-bromotetrahydro-2-furanyl]methyl benzoate | C12H13BrO3 | 详情 | 详情 | |
| (IX) | 12013 | N,9-Bis(trimethylsilyl)-9H-purin-6-amine; N-(Trimethylsilyl)-N-[9-(trimethylsilyl)-9H-purin-6-yl]amine | 17995-04-9 | C11H21N5Si2 | 详情 | 详情 |
| (X) | 12014 | [(2S,5R)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H17N5O3 | 详情 | 详情 | |
| (XI) | 12787 | [(2S,5R)-5-(6-Amino-9H-purin-9-yl)tetrahydro-2-furanyl]methanol; Dideoxyadenosine | 4097-22-7 | C10H13N5O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：2) The reaction of uridine (I) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (II), which is acetylated with acetic anhydride at 100 C, yielding the 5'-acetoxy derivative (III). The reaction of (III) with acetic anhydride at temperatures over 120 C affords 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V). Hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to a transdideoxyribosylation with hypoxanthine (VII) by incubation in an appropriate medium with Escherichia coli AJ 2595 resting cells.
| 【1】 Shiragami, H.; Shirae, H.; Irie, Y.; Yokozeki, K.; Yasuda, N.; The synthesis of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine. Nucl Acid Res Symp Ser 1988, 20, 20, 17-18. |
| 【2】 Shirae, H.; Kobayashi, K.; Shiragami, H.; Irie, Y.; Yasuda, N.; Yokozeki, K.; Production of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine from 2',3'-dideoxyuridine and the corresponding purine bases by resting cells of Escherichia coli AJ 2595. Appl Environ Microbiol 1989, 55, 2, 419-24. |
| 【3】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 60593 | p-xylene | C8H10 | 详情 | 详情 | ||
| (I) | 11996 | 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; Uridine | 58-96-8 | C9H12N2O6 | 详情 | 详情 |
| (II) | 11997 | 1-[(3aR,4R,6R,6aR)-6-(Hydroxymethyl)-2-methoxytetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione | C11H14N2O7 | 详情 | 详情 | |
| (III) | 11998 | [(3aR,4R,6R,6aR)-6-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methoxytetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate | C13H16N2O8 | 详情 | 详情 | |
| (IV) | 11999 | [(2S,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl]methyl acetate | C11H12N2O5 | 详情 | 详情 | |
| (V) | 12000 | [(2S,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl acetate | C11H14N2O5 | 详情 | 详情 | |
| (VI) | 12001 | 1-[(2R,5S)-5-(Hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | 5983-09-5 | C9H12N2O4 | 详情 | 详情 |
| (VII) | 12794 | 9H-Purin-6-ol; Hypoxanthine | 68-94-0 | C5H4N4O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Coupling between N-Boc-glycine (I) and 4-aminobenzonitrile (II) via activation with CDI yields amide (III). Subsequent acidic N-Boc group cleavage provides the amino acetanilide (IV). Reductive alkylation of amine (IV) with ethyl 4-oxopiperidine-1-acetate (V) leads to the aminopiperidine (VI). This is reductively alkylated with chloroacetaldehyde in the presence of NaBH3CN, to produce the chloroethyl amine (VII). Cyclization of (VII) by means of NaH in DMF furnishes the piperazinone (VIII). The cyano group of (VIII) is then converted to the corresponding ethyl imidate, which is further displaced with ammonium carbonate producing amidine (IX). Finally, saponification of the ethyl ester group of (IX) with LiOH gives rise to the title amidino acid
| 【1】 Akamatsu, S.; Matsumoto, Y.; Ichihara, M.; Kawasaki, T.; Kaku, S.; Yanagisawa, I. (Yamanouchi Pharmaceutical Co., Ltd.); Novel benzamidine derivs. and medicinal compsn. thereof. EP 0810215; JP 1996333341; JP 1996333342; US 5773442; WO 9624583 . |
| 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) | 60592 | 2-methyl-5-neopentyl-1,5-hexadiene | C12H22 | 详情 | 详情 | |
| (II) | 60593 | p-xylene | C8H10 | 详情 | 详情 | |
| (III) | 60594 | 1-methyl-4-(2-methylene-5-neopentyl-5-hexenyl)benzene | C19H28 | 详情 | 详情 | |
| (IV) | 60595 | 1-(2-ethyl-2-propenyl)-4-methylbenzene | C12H16 | 详情 | 详情 | |
| (V) | 60596 | 1-methylene-4-(2-propyl-2-propenyl)cyclohexane | C13H22 | 详情 | 详情 | |
| (VI) | 60597 | 1-methyl-4-(2-{2-[4-(2-propyl-2-propenyl)cyclohexyl]ethyl}-2-propenyl)benzene | C24H36 | 详情 | 详情 | |
| (VII) | 60598 | 1-methyl-4-(2-{2-[4-(2-propyl-2-propenyl)cyclohexyl]pentyl}-2-propenyl)benzene | C27H42 | 详情 | 详情 | |
| (VIII) | 60599 | C26H38 | 详情 | 详情 | ||
| (IX) | 60600 | ethyl 2-[4-(4-{4-[amino(imino)methyl]phenyl}-3-oxo-1-piperazinyl)-1-piperidinyl]acetate | C20H29N5O3 | 详情 | 详情 |