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【结 构 式】 
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【分子编号】12005 【品名】L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid 【CA登记号】56-86-0 |
【 分 子 式 】C5H9NO4 【 分 子 量 】147.1308 【元素组成】C 40.82% H 6.17% N 9.52% O 43.5% |
合成路线1
该中间体在本合成路线中的序号：(XVI)The lactyl dipeptide (X) is obtained as follows: The condensation of tert-butoxycarbonylalanine (XV) with glutamic acid (XVI) gives tert-butoxycarbonylalanylglutamic acid (XVII), which is esterified partially with benzyl bromide (F) yielding the mono ester (XVIII). Elimination of the tert-butoxycarbonyl group of (XVIII) with trifluoroacetic acid affords alanylglutamic acid monobenzyl ester (XIX), which is finally condensed with 2-acetoxypropionyl chloride (XX) to afford (X).
| 【1】 Hemmi, K.; Nakaguchi, O.; Hashimoto, M.; Taleno, H.; Kitaura, Y.; Okada, S.; An efficient method for selective amino acid protection of meso-2,2'-diaminocarboxylic acid: An improved synthesis of FK-156. Tetrahedron Lett 1982, 23, 6, 693-696. |
| 【2】 Imanaka, H.; Nakahaa, K.; Gotoh, T.; Aoki, H.; Iwami, M.; Studies on a new immunoactive peptide, FK-156. I. Taxonomy of the producing strains. J Antibiot 1982, 35, 10, 1280-85. |
| 【3】 Gotoh, T.; Imoraka, H.; Nakahara, K.; Tanaka, H.; Uchida, I.; Kawai, Y.; Studies on a new immunoactive peptide, FK-156. III. Structure elucidation. J Antibiot 1982, 35, 10, 1293-99. |
| 【4】 Okada, S.; Hemmi, K.; Takano, H.; Hashimoto, M.; Nakaguchi, O.; Kitaura, Y.; Aratani, M.; Miyazaki, Y.; Studies of a new immunoactive peptide, FK-156. IV. Synthesis od FK-156 and its geometric isomer. J Antibiot 1982, 35, 10, 1300-11. |
| 【5】 Okahara, M.; Nakahara, K.; Gotoh, T.; Hashimoto, M..; Kino, T.; Aoki, H.; Imanaka, H.; Kohsaka, M.; Nishiura, T.; Kuroda, Y.; Studies on a new immunoactive peptide, FK-156. II. Fermentation, extraction and chemical and biological charaterization. J Antibiot 1982, 35, 10, 1286-92. |
| 【6】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K.; Aratani, M.; Takeno, H.; Okada, S.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New peptides, processes for their preparation and pharmaceutical compsns. containing them. EP 0027260 . |
| 【7】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 . |
| 【8】 Arya, V.P.; Blancafort, P.; Castaner, J.; Serradell, M.N.; FK-156. Drugs Fut 1983, 8, 8, 667. |
| 【9】 Hemmi, K.; Takeno, H.; Okada, S.; Nakaguchi, O.; Kitaura, Y.; Hashimoto, M.; Total synthesis of FK-156 isolated from a Streptomyces as an immunostimulating peptide: Application of a novel copper chelate amino protection. J Am Chem Soc 1981, 103, 7026. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (F) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (X) | 36102 | (4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid | C20H26N2O8 | 详情 | 详情 | |
| (XV) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (XVI) | 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 |
| (XVII) | 36118 | (2R)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)pentanedioic acid | C13H22N2O7 | 详情 | 详情 | |
| (XVIII) | 36119 | (4R)-5-(benzyloxy)-4-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-5-oxopentanoic acid | C20H28N2O7 | 详情 | 详情 | |
| (XIX) | 36120 | (4R)-4-[[(2S)-2-aminopropanoyl]amino]-5-(benzyloxy)-5-oxopentanoic acid | C15H20N2O5 | 详情 | 详情 | |
| (XX) | 36121 | 2-chloro-1-methyl-2-oxoethyl acetate | 36394-75-9 | C5H7ClO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The dihydropyridine-4-carboxylic acid derivative (I) was activated as the pentafluorophenyl ester (II) using pentafluorophenol and DCC. Coupling of the active ester (II) with glutamic acid (III) furnished the N-acyl glutamic acid (IV). Alternatively, (IV) was obtained by coupling of glutamic acid (III) with the pyridine acid (I) via activation with DCC/HOBt. Diacid (IV) was finally treated with NaOH to produce the corresponding disodium salt.
| 【1】 Biseniex, E.A.; Uldrikis, Y.R.; Dubur, G.Y.; Veveris, M.M.; Kimenis, A.A.; Ivanov, E.V. (Latvian Institute of Organic Synthesis); 2-(2,6-Dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamide) glutaric acid its disodium salt and method of their preparation. US 4485239 . |
| 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) | 55616 | 3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydro-4-pyridinecarboxylic acid | C14H19NO6 | 详情 | 详情 | |
| (II) | 55612 | ethyl (4R)-3-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]-1,3-thiazolidine-4-carboxylate | C17H21NO3S | 详情 | 详情 | |
| (III) | 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 |
| (IV) | 55618 | (2S)-2-({[3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydro-4-pyridinyl]carbonyl}amino)pentanedioic acid | C19H26N2O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)In a related method for the preparation of (IV), acid (I) was activated as the mixed anhydride (V) using isobutyl chloroformate. Coupling of anhydride (V) with the silyl ester (VI), prepared from glutamic acid (III) and hexamethyldisilazane, provided amide (IV).
| 【1】 Biseniex, E.A.; Uldrikis, Y.R.; Dubur, G.Y.; Veveris, M.M.; Kimenis, A.A.; Ivanov, E.V. (Latvian Institute of Organic Synthesis); 2-(2,6-Dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamide) glutaric acid its disodium salt and method of their preparation. US 4485239 . |
| 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) | 55616 | 3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydro-4-pyridinecarboxylic acid | C14H19NO6 | 详情 | 详情 | |
| (III) | 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 |
| (IV) | 55618 | (2S)-2-({[3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydro-4-pyridinyl]carbonyl}amino)pentanedioic acid | C19H26N2O9 | 详情 | 详情 | |
| (V) | 55619 | C19H27NO8 | 详情 | 详情 | ||
| (VI) | 55620 | bis(trimethylsilyl) (2S)-2-aminopentanedioate | C11H25NO4Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)A new synthesis of 2',3'-dideoxyadenosine has been described: 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 - p-toluenesulfonic acid to the ester (III). The selective reduction of (III) with NaBH4 in ethanol yields (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride as usual, affording the benzoate (V). The selective reduction of (V) with disiamyl borane in THF gives the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane yields the tetrahydrofuryl bromide (VIII), which is condensed with the silylated adenine (IX) to afford 5'-O-benzoyl-2',3'-dideoxyadenosine (X). Finally, this compound is deprotected with NH3 in methanol.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 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) | 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 |
合成路线5
该中间体在本合成路线中的序号：(I)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6
该中间体在本合成路线中的序号：(I)The synthesis of pidotimod has been carried out using N-tert-butoxycarbonyl-L-pyroglutamic acid as starting material, in order to avoid the formation of diketopiperazine derivatives. L-Glutamic acid (I) was condensed with di-tert-butyl dicarbonate by means of triethylamine in DMF to give N-(tert-butoxycarbonyl)-L-glutamic acid (II), which is dissolved in THF and treated with dicyclohexylcarbodiimide (DCC) to obtain N-(tert-butoxycarbonyl)-L-glutamic anhydride (III). The treatment of anhydride (III) with dicyclohexylamine in THF-ethyl ether affords the dicyclohexylamine salt of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (IV), which by acidification with aqueous citric acid yields the corresponding free acid (V). The condensation of equimolecular amounts of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (V) with L-thiazolidine-4-carboxylic acid ethyl ester (VIII) by means of DCC in methylene chloride gives the coupled ester (IX), which is hydrolyzed with aqueous NaOH, and the corresponding sodium salt acidified to yield the N-tert-butoxycarbonyl derivative (X). Finally, this compound is deprotected with trifluoroacetic acid to obtain crystalline pidotimod (XI). The intermediate thiazolidine (VIII) has been obtained as follows: Esterification of L-thiazolidine-4-carboxylic acid (VI) with ethanol by means of SOCl2 gives the corresponding ethyl ester hydrochloride (VII), which by treatment with K2CO3 in water yields the free ester (VIII).
| 【1】 Klieger, E.; Schroder, E.; Synthesis and reactions of N-substituted-L-glutamic acid derivatives. Liebigs Ann Chem 1964, 673. |
| 【2】 Mailland, F.; Coppi, G.; Signorelli, G.; Pidotimod. Drugs Fut 1991, 16, 12, 1096. |
| 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) | 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) | 12895 | (2S)-2-[(tert-Butoxycarbonyl)amino]pentanedioic acid | 2419-94-5 | C10H17NO6 | 详情 | 详情 |
| (III) | 12896 | tert-butyl (3S)-2,6-dioxotetrahydro-2H-pyran-3-ylcarbamate | C10H15NO5 | 详情 | 详情 | |
| (IV) | 12897 | (2S)-1-(tert-Butoxycarbonyl)-5-oxo-2-pyrrolidinecarboxylic acid | C10H15NO5 | 详情 | 详情 | |
| (V) | 12897 | (2S)-1-(tert-Butoxycarbonyl)-5-oxo-2-pyrrolidinecarboxylic acid | C10H15NO5 | 详情 | 详情 | |
| (VI) | 12899 | L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid | 34592-47-7 | C4H7NO2S | 详情 | 详情 |
| (VII) | 12900 | ethyl (4R)-1,3-Thiazolidine-4-carboxylate hydrochloride | C6H12ClNO2S | 详情 | 详情 | |
| (VIII) | 12901 | ethyl (4R)-1,3-thiazolidine-4-carboxylate | C6H11NO2S | 详情 | 详情 | |
| (IX) | 12902 | ethyl (4R)-3-[[(2S)-1-(tert-butoxycarbonyl)-5-oxopyrrolidinyl]carbonyl]-1,3-thiazolidine-4-carboxylate | C16H24N2O6S | 详情 | 详情 | |
| (X) | 12903 | (4R)-3-[[(2S)-1-(tert-Butoxycarbonyl)-5-oxopyrrolidinyl]carbonyl]-1,3-thiazolidine-4-carboxylic acid | C14H20N2O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The cyclization of (S)-glutamic acid (I) by means of H2SO4 and NaNO2 gives the gamma lactone (II), which is treated with hot SOCl2 to yield the corresponding acyl chloride (III). The reaction of (III) with 4-methoxybenzylamine (IV) affords the expected amide (V), which is submitted to rearrangement in the presence of t-BuOK in THF to provide piperidinedione (VI). The reaction of (VI) with Tbdps-Cl and imidazole gives the silyl ether (VII), which is reduced with NaBH4 in methanol to yield a mixture of regioisomers (VIII). The phenyl migration in (VIII) was easily promoted by reaction with BF3/Et2O through the nonisolated intermediate cis-(IX) to yield (X). The reduction of (X) by means of LiAlH4 in THF affords the N-protected hydroxypiperidine (XI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol to provide the free hydroxypiperidine (XII). The reprotection of (XII) with Boc2O gives the carbamate-protected piperidine (XIII), which is oxidized by means of DMSO, (COCl)2 and DIEA in dichloromethane to yield piperidone (XIV). The reaction of (XIV) with NH2OH and K2CO3 affords the corresponding oxime (XV), which is treated with Ac2O in THF to provide the O-acetyloxime (XVI). The reduction of (XVI) with BH3/Me2S in hot THF gives the expected amine (XVII), which is condensed with 2-methoxybenzaldehyde (XVIII) in THF to yield the imine (XIX). The reduction of (XIX) with NaBH4 in methanol affords the protected benzylamine (XX), which is finally deprotected by means of HCl in methanol to provide CP-99,994.
| 【1】 Wei, B.-G.; Huang, P.-Q.; Liu, L.-X.; Ruan, Y.-P.; Asymmetric synthesis of (+)-L-733, 060 and (+)-CP-99, 994 based on a new chiral 3-piperidinol synthon. Org Lett 2003, 5, 11, 1927. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| cis-(IX) | 64777 | (5S,6S)-5-{[tert-butyl(fluoro)phenylsilyl]oxy}-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone | C29H34FNO3Si | 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) | 64772 | (2S)-5-oxotetrahydro-2-furancarbonyl chloride | C5H5ClO3 | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 64773 | (2S)-N-(4-methoxybenzyl)-5-oxotetrahydro-2-furancarboxamide | C13H15NO4 | 详情 | 详情 | |
| (VI) | 64774 | (3S)-3-hydroxy-1-(4-methoxybenzyl)-2,6-piperidinedione | C13H15NO4 | 详情 | 详情 | |
| (VII) | 64775 | (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-(4-methoxybenzyl)-2,6-piperidinedione | C29H33NO4Si | 详情 | 详情 | |
| (VIII) | 64776 | (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-hydroxy-1-(4-methoxybenzyl)-2-piperidinone | C29H35NO4Si | 详情 | 详情 | |
| (X) | 64778 | (5S,6S)-5-hydroxy-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone | C19H21NO3 | 详情 | 详情 | |
| (XI) | 64779 | (2S,3S)-1-(4-methoxybenzyl)-2-phenyl-3-piperidinol | C19H23NO2 | 详情 | 详情 | |
| (XII) | 64498 | (2S,3S)-2-phenyl-3-piperidinol | C11H15NO | 详情 | 详情 | |
| (XIII) | 64499 | tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (XIV) | 62266 | tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (XV) | 64780 | tert-butyl (2S)-3-(hydroxyimino)-2-phenyl-1-piperidinecarboxylate | C16H22N2O3 | 详情 | 详情 | |
| (XVI) | 64781 | tert-butyl (2S)-3-[(acetyloxy)imino]-2-phenyl-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (XVII) | 31756 | tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 | |
| (XVIII) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (XIX) | 64782 | tert-butyl (2S,3S)-3-{[(E)-(2-methoxyphenyl)methylidene]amino}-2-phenyl-1-piperidinecarboxylate | C24H30N2O3 | 详情 | 详情 | |
| (XX) | 31757 | tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate | C24H32N2O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Protection of L-glutamic acid (I) with allyl alcohol and chlorotrimethylsilane produced the gamma-allyl ester (II). Subsequent treatment of (II) with fluorenylmethoxycarbonyl chloride afforded the N-Fmoc derivative (III). This was coupled to Wang resin using EDC and DMAP to provide the glutamate-coupled resin (IV). Removal of the Fmoc protecting group by means of piperidine gave (V), which was then condensed with decanoyl chloride (VI) yielding amide (VII). The allyl ester was then cleaved by treatment with Pd(PPh3)4 and the resulting carboxylic acid (VIII) was coupled with monoprotected diamine (IX) to furnish diamide (X). Deprotection of the allyl carbamate of (X) provided amine (XI).
| 【1】 Wipf, P.; et al.; Combinatorial synthesis and biological evaluation of library of small-molecule Ser/Thr-protein phosphatase inhibitors. Bioorg Med Chem 1997, 5, 1, 165. |
| 【2】 Lazo, J.S.; Rice, R.L.; Cunningham, A.; Wipf, P. (University of Pittsburgh); Phosphatase inhibitors and methods of use thereof. EP 0959884; US 5700821; WO 9804257 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II), (V) | 28269 | (2S)-5-(allyloxy)-2-amino-5-oxopentanoic acid | C8H13NO4 | 详情 | 详情 | |
| (III), (IV) | 28270 | (2S)-5-(allyloxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | C23H23NO6 | 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 |
| (V) | 28269 | (2S)-5-(allyloxy)-2-amino-5-oxopentanoic acid | C8H13NO4 | 详情 | 详情 | |
| (VI) | 28271 | decanoyl chloride | 112-13-0 | C10H19ClO | 详情 | 详情 |
| (VII) | 28272 | (2S)-5-(allyloxy)-2-(decanoylamino)-5-oxopentanoic acid | C18H31NO5 | 详情 | 详情 | |
| (VIII) | 28273 | (2S)-2-(decanoylamino)pentanedioic acid | C15H27NO5 | 详情 | 详情 | |
| (IX) | 28274 | allyl 2-(benzylamino)ethylcarbamate | C13H18N2O2 | 详情 | 详情 | |
| (X) | 28275 | (2S)-5-[(2-[[(allyloxy)carbonyl]amino]ethyl)(benzyl)amino]-2-(decanoylamino)-5-oxopentanoic acid | C28H43N3O6 | 详情 | 详情 | |
| (XI) | 28276 | (2S)-5-[(2-aminoethyl)(benzyl)amino]-2-(decanoylamino)-5-oxopentanoic acid | C24H39N3O4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)加拿大Alberta大学Knaus研究小组将谷氨酸选择性保护为单酯（II），并将氨基保护后，游离羧酸被还原为一级醇（IV）.Swern氧化将IV转化为醛（V），后者立即进行Witting反应，产生烯烃（VI）.最后，用TMSI脱除氨基保护基，并用3mol/L盐酸水解酯，即得到（S）-Vi-gabatrin （VII）.
| 【1】 Wei ZY, Knaus EE. 1993.A short efficient synthesis of (S)-4-amino-5-hexenoic acid[(8-Vigabatrin)].J Org Chem, 58: 1586-1588. |
| 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) | 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) | 69497 | C7H15NO8S | 详情 | 详情 | ||
| (III) | 69498 | (R)-5-ethoxy-2-((methoxycarbonyl)amino)-5-oxopentanoic acid | C9H15NO6 | 详情 | 详情 | |
| (IV) | 69499 | (R)-ethyl 5-hydroxy-4-((methoxycarbonyl)amino)pentanoate | C9H17NO5 | 详情 | 详情 | |
| (V) | 69500 | (R)-ethyl 4-((methoxycarbonyl)amino)-5-oxopentanoate | C9H15NO5 | 详情 | 详情 | |
| (VI) | 69501 | (R)-ethyl 4-((methoxycarbonyl)amino)hex-5-enoate | C10H17NO4 | 详情 | 详情 |