|
【结 构 式】 
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【分子编号】13952 【品名】(S)-(-)-Phenylalanine; L-Phenylalanine 【CA登记号】63-91-2 |
【 分 子 式 】C9H11NO2 【 分 子 量 】165.19188 【元素组成】C 65.44% H 6.71% N 8.48% O 19.37% |
合成路线1
该中间体在本合成路线中的序号：(II)By reductocondensation of 4-chlorobenzaldehyde (I) with L-phenylalanine (II) by means of cyanoborohydride in methanol.
| 【1】 Ferres, H. (SmithKline Beecham plc); N-Substituted alpha-aminoacids, processes for making them and pharmaceutical compositions containing them. EP 0031653; ES 497907; JP 56092843 . |
| 【2】 Castaner, J.; Serradell, M.N.; Thorpe, P.; BRL-26314. Drugs Fut 1985, 10, 1, 12. |
合成路线2
该中间体在本合成路线中的序号：(I)The synthesis of Ro-31-8959/003 (X) was carried out as follows: Condensation of L-phenylalanine (I) with formaldehyde in concentrated hydrochloric acid gave the tetrahydroisoquinoline (II), which was hydrogenated in 90% acetic acid over rhodium on carbon to yield the decahydroisoquinoline (III) as a mixture of diastereoisomers. Treatment of (III) with benzyl chloroformate in aqueous sodium hydroxide solution gave a mixture of N-protected amino acids which was separated by fractional crystallization of the cyclohexylamine salts to give the (S,S,S)-isomer. Reaction with dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethoxyethane, followed by treatment of the activated ester with tert-butylamine in dichloromethane and subsequent hydrogenolysis of the benzyloxycarbonyl protecting group gave the decahydroisoquinoline (IV). In the other branch of the synthesis L-phenylalanine was treated with benzyl chloroformate in aqueous sodium hydroxide solution to give the N-protected amino acid. This was converted to the corresponding mixed anhydride with isobutyl chloroformate and N-ethylmorpholine in tetrahydrofuran and immediately reacted with diazomethane in diethyl ether to give the diazomethyl ketone (V). Treatment of (V) with ethereal hydrogen chloride gave the chloromethyl ketone (VI), which on reduction with sodium borohydride in aqueous tetrahydrofuran gave a mixture of diastereoisomeric chlorohydrins. Solvent extraction with boiling n-hexane followed by recrystallization of the less soluble isomer from isopropanol gave pure chlorohydrin (VII), which on treatment with ethanolic potassium hydroxide gave the epoxide (VIII). Condensation of (VIII) with (IV) in ethanol gave the hydroxyethylamine (IX). Hydrogenolysis of (IX) was followed by condensation with N-benzyloxycarbonyl-L-asparagine in tetrahydrofuran in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Hydrogenolysis in ethanol over palladium on charcoal, followed by condensation with quinoline-2-carboxylic acid in tetrahydrofuran in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, gave the free base, Ro-31-8959/000. Treatment with methanesulfonic acid in aqueous ethanol then afforded the mesylate salt (X), Ro-31-8959/003.
| 【1】 Martin, J.A.; Ro-31-8959/003. Drugs Fut 1991, 16, 3, 210. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 13953 | (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid | 74163-81-8 | C10H11NO2 | 详情 | 详情 |
| (III) | 13954 | (3S)Decahydro-3-isoquinolinecarboxylic acid | C10H17NO2 | 详情 | 详情 | |
| (IV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (V) | 13956 | (3S)-1-Imino-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone | C18H18N2O3 | 详情 | 详情 | |
| (VI) | 13957 | (3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone | C18H18ClNO3 | 详情 | 详情 | |
| (VII) | 13958 | (2S,3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanol | C18H20ClNO3 | 详情 | 详情 | |
| (VIII) | 13959 | N-[(1S)-1-[(2S)Oxiranyl]-2-phenylethyl]-N-[(2-phenylacetyl)oxy]amine; (1S)-1-[(2S)Oxiranyl]-2-phenyl-N-[(2-phenylacetyl)oxy]-1-ethanamine | C18H19NO3 | 详情 | 详情 | |
| (IX) | 13960 | (3S,4aS,8aS)-N-(tert-Butyl)-2-((2R,3S)-2-hydroxy-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]butyl)decahydro-3-isoquinolinecarboxamide | C32H45N3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)An alternative procedure for the preparation of the intermediate urea (IX) has been reported. Alkylation of L-phenylalanine (XIV) with benzyl bromide provided the N,N-dibenzyl amine (XV), which was reduced to amino alcohol (XVI) using DIBAL in cold toluene. In an improved large-scale process, amino alcohol (XVI) was prepared by benzylation of L-phenylalaninol (XVII). Swern oxidation of the alcohol function of (XVI) afforded aldehyde (XVIII). Subsequent reaction of (XVIII) with chloromethyllithium at low temperature furnished the desired epoxide (XX) along with minor amounts of its diastereoisomer (XIX). Opening of this mixture with isobutyl amine (V) gave diamino alcohol (XXIa-b). After coupling of (XXIa-b) with tert-butyl isocyanate (VII) to produce the corresponding ureas (XXIIa-b) [the required isomer (XXIIb) was isolated by recrystallization]. Removal of the benzyl protecting groups of (XXIIb) then yielded the target intermediate (IX).
| 【1】 Talley, J.J.; Getman, D.P.; DeCrescenzo, G.A.; Lin, K.-O.; Vazquez, M.L.; Mueller, R.A.; Reed, K.L.; Heintz, R.M.; Clare, M.; Freskos, J.N.; Sun, E.T. (Pharmacia Corp.); Urea-containing hydroxyethylamine cpds. as retroviral protease inhibitors. JP 1995508041; WO 9323368 . |
| 【2】 Liu, C.; et al.; Development of large-scale process for an HIV protease inhibitor. Org Process Res Dev 1997, 1, 1, 45. |
| 【3】 Getman, D.P.; et al.; Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem 1993, 36, 2, 288. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (XXIa) | 37939 | (2S,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (XXIb) | 37940 | (2R,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (XXIIa) | 37941 | N'-(tert-butyl)-N-[(2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea | C33H45N3O2 | 详情 | 详情 | |
| (XXIIb) | 37942 | N'-(tert-butyl)-N-[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea | C33H45N3O2 | 详情 | 详情 | |
| (V) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (IX) | 37931 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N'-(tert-butyl)-N-isobutylurea | C19H33N3O2 | 详情 | 详情 | |
| (XIV) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XV) | 37935 | (2S)-2-(dibenzylamino)-3-phenylpropionic acid | C23H23NO2 | 详情 | 详情 | |
| (XVI) | 30457 | (2S)-2-(dibenzylamino)-3-phenyl-1-propanol | 111060-52-7 | C23H25NO | 详情 | 详情 |
| (XVII) | 28523 | (2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol | 5267-64-1 | C9H13NO | 详情 | 详情 |
| (XVIII) | 37936 | (2S)-2-(dibenzylamino)-3-phenylpropanal | C23H23NO | 详情 | 详情 | |
| (XIX) | 37937 | N,N-dibenzyl-N-[(1S)-1-[(2R)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2R)oxiranyl]-2-phenyl-1-ethanamine | C24H25NO | 详情 | 详情 | |
| (XX) | 37938 | N,N-dibenzyl-N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2S)oxiranyl]-2-phenyl-1-ethanamine | C24H25NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Reaction of 3,4-dihydro-2H-pyran (I) with potassium cyanide, HCl/HOAc and KOH in H2O, followed by treatment with ammonium carbonate in H2O provides hydantoin (II). Hydrolysis of compound (II) with LiOH in H2O at 135 C gives the racemic lithium salt (III), which by treatment with methyl trifluoroacetate and Li2CO3 in a refluxing mixture of BuOH/MeOH followed by enzymatic resolution with acylase I leads to the optically pure (S)-enantiomer (IV). Compound (IV) is converted into its corresponding methyl ester (V) using trimethyl orthoformate and HCl in refluxing MeOH. The ester (V) is then coupled with N-phthaloyl-L-phenylalanine acid chloride (VI) by means of NMM in DMF/CH2Cl2 to provide the alpha-amino-omega-hydroxyhexanoic acid derivative (VII). Compound (VI) is prepared separately from L-phenylalanine (VIII) by reaction with phthalic anhydride (IX) in refluxing toluene or DMF to yield compound (X), which is treated with oxalyl chloride in refluxing toluene in the presence of DMF or in DMF/CH2Cl2. Oxidation of (VII) under Swern conditions [(COCl)2, DMSO and Et3N] followed by treatment with Oxone (potassium peroxymonosulfate) provides aldehyde (XI), which is then subjected to cyclization by means of TFA in CH2Cl2 to furnish the tetrahydropyridine derivative (XII).
| 【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458. |
| 【2】 Flynn, G.A.; Warshawsky, A.M.; Mehdi, S.; Bey, P.; Beight, D.W.; Giroux, E.L.; Burkholder, T.P. (Merrell Pharmaceuticals, Inc.); Novel mercaptoacetylamide derivs. useful as inhibitors of enkephalinase and ACE. EP 0481522; JP 1992282382; US 5430145 . |
| 【3】 Horgan, S.W.; Burkhouse, D.W.; Cregge, R.J.; et al.; Process development in the synthesis of the ACE intermediate MDL 28,726. Org Process Res Dev 1999, 3, 4, 241. |
| 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) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (II) | 50628 | 5-(4-hydroxybutyl)-2,4-imidazolidinedione | C7H12N2O3 | 详情 | 详情 | |
| (III) | 53406 | lithium 2-amino-6-hydroxyhexanoate | n/a | C6H12LiNO3 | 详情 | 详情 |
| (IV) | 53407 | lithium (2S)-2-amino-6-hydroxyhexanoate | n/a | C6H12LiNO3 | 详情 | 详情 |
| (V) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (VI) | 52756 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride | C17H12ClNO3 | 详情 | 详情 | |
| (VII) | 37294 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-hydroxyhexanoate | C24H26N2O6 | 详情 | 详情 | |
| (VIII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (IX) | 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 |
| (X) | 37293 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropionic acid | 5123-55-7 | C17H13NO4 | 详情 | 详情 |
| (XI) | 37295 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-oxohexanoate | C24H24N2O6 | 详情 | 详情 | |
| (XII) | 37296 | methyl (2S)-1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate | C24H22N2O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXIX)A new method for the preparation of a key diaminoalcohol intermediate in the synthesis of ritonavir has been described: The reaction of L-phenylalanine (XXIX) with benzyl chloride by means of K2CO3 and KOH in hot water gives N,N-dibenzyl-L-phenylalanine benzyl ester (XXX), which is condensed first with acetonitrile by means of NaNH2 and then with benzylmagnesium chloride, both reactions in methyl tert-butyl ether, yielding 5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one (XXXI). The reduction of (XXXI) with NaBH4 with an accurate control of the solvent and acidity, results in an enhanced enantioselectivity towards the desired (S,S,S)-enantiomer of 5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol (XXXII). Finally, this compound is deprotected by hydrogenation with ammonium formate over Pd/C in methanol/water to provide the target chiral diaminoalcohol (VIII).
| 【1】 Allen, M.S.; Stuk, T.L.; Haight, A.R.; et al.; Reduction of an enaminone: Synthesis of the diamino alcohol core of ritonavir. Org Process Res Dev 1999, 3, 2, 94. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 16592 | (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hexanol | C18H24N2O | 详情 | 详情 | |
| (XXIX) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XXX) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (XXXI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (XXXII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 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 reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot ethanol/water gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII). The protection of the amino group of (VII) with Boc2O and K2CO3 in methyl tert-butyl ether yields the carbamate (VIII), which is debenzylated with ammonium formate over Pd/C in methanol affording the amino compound (IX). The condensation of (IX) with 2-(2,6-dimethylphenoxy)acetic acid (X) by means of EDAC in DMF provides the corresponding amide (XI), which is deprotected at the carbamate group with TFA in dichloromethane to give (XII) with a free amino group. Finally, this compound is condensed with 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid (XIII) by means of EDAC in DMF or SOCl2 and imidazole to furnish the target compound. The intermediate 2-(2,6-dimethylphenoxy)acetic acid (X) has been obtained by condensation of 2,6-dimethylphenol (XIV) with ethyl 2-bromoacetate (XV) by means of Cs2CO3 in refluxing dioxane to give the acetate ester (XVI), which is hydrolyzed with LiOH ethanol/water to afford the target intermediate (X).
| 【1】 Stoner, E.J.; et al.; Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling. Org Process Res Dev 1999, 3, 2, 145. |
| 【2】 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 . |
| 【3】 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IV) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (V) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (VI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (VII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (VIII) | 38542 | tert-butyl (1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentylcarbamate | C37H44N2O3 | 详情 | 详情 | |
| (IX) | 38543 | tert-butyl (1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate | C23H32N2O3 | 详情 | 详情 | |
| (X) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 | |
| (XI) | 38545 | tert-butyl (1S,3S,4S)-1-benzyl-4-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenylpentylcarbamate | C33H42N2O5 | 详情 | 详情 | |
| (XII) | 38546 | N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide | C28H34N2O3 | 详情 | 详情 | |
| (XIII) | 38264 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid | C9H16N2O3 | 详情 | 详情 | |
| (XIV) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (XV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XVI) | 38544 | ethyl 2-(2,6-dimethylphenoxy)acetate | C12H16O3 | 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 reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot EtOH/H2O gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII) (slightly impurified (~10%) with other diastereomers that are not eliminated at this stage). The condensation of (VII) with acid chloride (VIII) (obtained by reaction of acid (IX) with SOCl2) in the presence of imidazole yields the amide (X), which is debenzylated with ammonium formate over Pd/C in methanol affording the amine (XI). At this stage the purification (elimination of the diastereomers) has been performed by crystallization of its salt with L-pyroglutamic acid (XII) in EtOH/DMF, pure salt (XIII) being obtained. Finally, this compound is condensed with the acid chloride (XIV) (obtained by reaction of acid (XV) with SOCl2) by means of NaHCO3 in ethyl acetate/water. The intermediates, the acids (IX) and (XV), have been obtained as indicated in schemes 24659001a and 24659001b (intermediates (XIII) and (X) of these schemes, respectively).
| 【1】 Stoner, E.J.; et al.; Synthesis of HIV protease inhibitor ABT-378 (lopinavir). Org Process Res Dev 2000, 4, 4, 264. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IV) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (V) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (VI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (VII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (VIII) | 38265 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl chloride | C9H15ClN2O2 | 详情 | 详情 | |
| (IX) | 38264 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid | C9H16N2O3 | 详情 | 详情 | |
| (X) | 38266 | (2S)-N-[(1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide | C41H50N4O3 | 详情 | 详情 | |
| (XI) | 38267 | (2S)-N-[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide | C27H38N4O3 | 详情 | 详情 | |
| (XII) | 32406 | (2S)-5-oxo-2-pyrrolidinecarboxylic acid | 98-79-3 | C5H7NO3 | 详情 | 详情 |
| (XIII) | 38268 | (2S,3S,5S)-3-hydroxy-5-([(2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl]amino)-1,6-diphenyl-2-hexanaminium (2S)-5-oxo-2-pyrrolidinecarboxylate | C32H45N5O6 | 详情 | 详情 | |
| (XIV) | 38269 | 2-(2,6-dimethylphenoxy)acetyl chloride | C10H11ClO2 | 详情 | 详情 | |
| (XV) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXII)In an alternative procedure, initial anchoring of N-Fmoc-L-phenylalanine (IX) to the chlorotrityl resin afforded resin (XXI), which was deprotected with piperidine in DMF to provide the phenylalanine-resin (XXII). Sequential coupling and deprotection cycles with N-Fmoc-L-tryptophan (XI), N-Fmoc-L-aspartic acid beta-t-butyl ester (XIII), and N-Fmoc-N’-(tetraacetyl-beta-D-glycosyl)asparragine (XXV) yielded the peptide resins (XXIII), (XXIV) and (XXVI), respectively.
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX),(XXI) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (XI) | 56129 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(1H-indol-3-yl)propanoic acid | C26H22N2O4 | 详情 | 详情 | |
| (XIII) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XXII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XXIII) | 56133 | (2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid | C20H21N3O3 | 详情 | 详情 | |
| (XXIV) | 56134 | (2S)-2-{[(2S)-2-{[(2S)-2-amino-4-(tert-butoxy)-4-oxobutanoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid | C28H34N4O6 | 详情 | 详情 | |
| (XXV) | 56135 | (2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxobutanoic acid | C33H37N3O13 | 详情 | 详情 | |
| (XXVI) | 56136 | (2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-amino-4-oxobutanoyl]amino}-4-(tert-butoxy)-4-oxobutanoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid | C46H59N7O16 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)The reaction of L-phenylalanine (I) with benzyl chloride and K2CO3 gives the tribenzylated compound (II), which is condensed with acetonitrile by means of NaNH2 yielding 4(S)-(dibenzylamino)-3-oxo-4-phenylbutyronitrile (III). The reaction of (III) with benzylmagnesium chloride in THF affords the unsaturated, partially protected diaminohexenone (IV), which is reduced with NaBH4 and NaBH3(OTf) to provide a mixture of diastereomeric diaminohexanones, from which the desired diastereomer (V) is isolated by crystallization. The acylation of the free amino group of (V) with acylated anthranilic acid (VI) by means of HOBT gives the expected amide (VII), which is debenzylated by treatment with Pd/C and ammonium formate yielding intermediate (VIII). Finally this compound is acylated with the activated N-succinylcarbamate (IX) to afford the desired target compound.
| 【1】 Stuk, T.L.; et al.; An efficient stereocontrolled strategy for the synthesis of hydroxyethylene dipeptide isosteres. J Org Chem 1994, 59, 15, 4040. |
| 【2】 Randad, R.S.; Lubkowska, L.; Eissenstat, M.A.; Gulnik, S.V.; Yu, B.; Bhat, T.N.; Clanton, D.J.; House, T.; Stinson, S.F.; Erickson, J.W.; Unsymmetric nonpeptidic HIV protease inhibitors containing anthranilamide as a P2' ligand. Bioorg Med Chem Lett 1998, 8, 24, 3537. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (IV) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (V) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (V) | 41850 | 2-[[(2-pyridinylmethoxy)carbonyl]amino]benzoic acid | C14H12N2O4 | 详情 | 详情 | |
| (VI) | 41851 | 2-pyridinylmethyl 2-([[(1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentyl]amino]carbonyl)phenylcarbamate | C46H46N4O4 | 详情 | 详情 | |
| (VII) | 41852 | 2-pyridinylmethyl 2-([[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]amino]carbonyl)phenylcarbamate | C32H34N4O4 | 详情 | 详情 | |
| (VIII) | 41853 | 1,3-thiazol-5-ylmethyl 2,5-dioxo-1-pyrrolidinecarboxylate | C9H8N2O4S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). Reduction of the ester function of (X) with Ca(BH4)2 gave alcohol (XI), which was finally oxidized under Swern conditions to the target aldehyde.
| 【1】 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (III) | 24385 | sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate | C14H18NNaO2 | 详情 | 详情 | |
| (IV) | 24386 | benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C22H25NO4 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 24388 | benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C25H29NO4 | 详情 | 详情 | |
| (VII) | 24389 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate | C24H27NO5 | 详情 | 详情 | |
| (VIII) | 24390 | methyl (2S)-2-amino-4-phenylbutanoate | C11H15NO2 | 详情 | 详情 | |
| (IX) | 24391 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C35H42N2O6 | 详情 | 详情 | |
| (X) | 24392 | methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate | C30H32N2O5 | 详情 | 详情 | |
| (XI) | 24393 | benzyl (3R)-3-benzyl-1-[(1S)-1-(hydroxymethyl)-3-phenylpropyl]-2-oxopyrrolidinylcarbamate | C29H32N2O4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). The carbobenzoxy group of (X) was then removed by hydrogenolysis over Pd/C, and the resulting amine was acylated with benzenesulfonyl chloride to produce sulfonamide (XI). Finally, the target aldehyde was obtained by the sequence of ester reduction of (XI) with Ca(BH4)2, followed by Swern oxidation of the resulting alcohol.
| 【1】 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (III) | 24385 | sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate | C14H18NNaO2 | 详情 | 详情 | |
| (IV) | 24386 | benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C22H25NO4 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 24388 | benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C25H29NO4 | 详情 | 详情 | |
| (VII) | 24389 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate | C24H27NO5 | 详情 | 详情 | |
| (VIII) | 24390 | methyl (2S)-2-amino-4-phenylbutanoate | C11H15NO2 | 详情 | 详情 | |
| (IX) | 24391 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C35H42N2O6 | 详情 | 详情 | |
| (X) | 24392 | methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate | C30H32N2O5 | 详情 | 详情 | |
| (XI) | 24394 | methyl (2S)-2-[(3R)-3-benzyl-2-oxo-3-[(phenylsulfonyl)amino]pyrrolidinyl]-4-phenylbutanoate | C28H30N2O5S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XIII)Preparation of the title compound was carried out by solid-phase peptide synthesis, starting from Wang resin bounded to N-Fmoc-phenylalanine (XII). Removal of the Fmoc group of (XII) with piperidine in DMF provided phenylalanine-resin (XIII), which was subsequently coupled with N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) in the presence of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt). Cleavage of the Fmoc group from the resulting protected dipeptide-resin furnished (XV). Sequential coupling-deprotection cycles with N-Fmoc-alanine (XVI), intermediate (XI) and Nalpha-Fmoc-Nbeta-trityl-asparagine (XIX) furnished the peptide resins (XVII), (XVIII) and (XX), respectively. (Scheme 28685901b).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 | |
| (XII) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (XIII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XIV) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (XV) | 40634 | (2S)-2-[[(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid | C18H26N2O5 | 详情 | 详情 | |
| (XVI) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
| (XVII) | 40635 | (2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid | C21H31N3O6 | 详情 | 详情 | |
| (XVIII) | 40636 | (5S,7R,10S,13S,16S)-5-[(1S)-1-amino-3-methylbutyl]-16-benzyl-13-[3-(tert-butoxy)-3-oxopropyl]-2,2,3,3,7,10-hexamethyl-8,11,14-trioxo-4-oxa-9,12,15-triaza-3-silaheptadecan-17-oic acid | C37H64N4O8Si | 详情 | 详情 | |
| (XIX) | 40637 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxo-4-(tritylamino)butyric acid | C38H32N2O5 | 详情 | 详情 | |
| (XX) | 40638 | (5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid | C60H84N6O10Si | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XIII)Preparation of the title compound was carried out by solid-phase peptide synthesis, starting from Wang resin bounded to N-Fmoc-phenylalanine (XII). Removal of the Fmoc group of (XII) with piperidine in DMF provided phenylalanine-resin (XIII), which was subsequently coupled with N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) in the presence of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt). Cleavage of the Fmoc group from the resulting protected dipeptide-resin furnished (XV). Sequential coupling-deprotection cycles with N-Fmoc-alanine (XVI), intermediate (XI) and Nalpha-Fmoc-Nbeta-trityl-asparagine (XIX) furnished the peptide resins (XVII), (XVIII), (XX), (XXII) and (XXIII), respectively. (Scheme 28686001b).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 | |
| (XII) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (XIII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XIV) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (XV) | 40634 | (2S)-2-[[(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid | C18H26N2O5 | 详情 | 详情 | |
| (XVI) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
| (XVII) | 40635 | (2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid | C21H31N3O6 | 详情 | 详情 | |
| (XVIII) | 40636 | (5S,7R,10S,13S,16S)-5-[(1S)-1-amino-3-methylbutyl]-16-benzyl-13-[3-(tert-butoxy)-3-oxopropyl]-2,2,3,3,7,10-hexamethyl-8,11,14-trioxo-4-oxa-9,12,15-triaza-3-silaheptadecan-17-oic acid | C37H64N4O8Si | 详情 | 详情 | |
| (XIX) | 40637 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxo-4-(tritylamino)butyric acid | C38H32N2O5 | 详情 | 详情 | |
| (XX) | 40638 | (5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid | C60H84N6O10Si | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(I)In an alternative method, L-phenylalanine (I) is esterified employing SOCl2 in MeOH. The resultant phenylalanine methyl ester (II) is then acylated with the sulfonyl proline derivative (III) by means of PyBOP to furnish the sulfonyl dipeptide (IV). Finally, saponification of the methyl ester group of (IV) with LiOH leads to the title compound
| 【1】 Kopka, I.E.; Young, D.N.; Lin, L.S.; et al.; Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists. Bioorg Med Chem Lett 2002, 12, 4, 637. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (III) | 60842 | (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methyl-2-pyrrolidinecarboxylic acid | C12H13Cl2NO4S | 详情 | 详情 | |
| (IV) | 60843 | methyl (2S)-2-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methylpyrrolidinyl}carbonyl)amino]-3-phenylpropanoate | C22H24Cl2N2O5S | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(II)The title compound is prepared by solid-phase peptide synthesis starting from N-Fmoc-L-phenylalanine attached to Wang resin (I). Deprotection of (I) with piperidine in NMP removes the N-Fmoc group, yielding the phenylalanine resin (II). Coupling of (II) with N-trityl glycine (III) in the presence of PyBOP and HOBt, followed by acidic cleavage of the N-trityl group furnishes the dipeptide derivative (IV). To this is assembled N-Fmoc-S-trityl-D-penicillamine (V), followed by deprotection with piperidine in NMP, to produce resin (VI). Subsequent coupling of (VI) with N-Cbz-O-benzyl-L-tyrosine (VII) leads to the protected tetrapeptide (VIII). Removal of the S-trityl protecting group of (VIII) employing trifluoroacetic acid provides thiol (IX).
| 【1】 Rew, Y.; Malkmus, S.; Svensson, C.; Yaksh, T.L.; Chung, N.N.; Schiller, P.W.; Cassel, J.A.; DeHaven, R.; Goodman, M.; Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-Opioid receptor selective ligands. J Med Chem 2002, 45, 17, 3746. |
| 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) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (II) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (III) | 63269 | 2-(tritylamino)acetic acid | C21H19NO2 | 详情 | 详情 | |
| (IV) | 63270 | (2S)-2-[(2-aminoacetyl)amino]-3-phenylpropanoic acid | C11H14N2O3 | 详情 | 详情 | |
| (V) | 63271 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methyl-3-(tritylsulfanyl)butanoic acid | C39H35NO4S | 详情 | 详情 | |
| (VI) | 63272 | (2S)-2-[(2-{[(2S)-2-amino-3-methyl-3-(tritylsulfanyl)butanoyl]amino}acetyl)amino]-3-phenylpropanoic acid | C35H37N3O4S | 详情 | 详情 | |
| (VII) | 27842 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(benzyloxy)phenyl]propionic acid | C24H23NO5 | 详情 | 详情 | |
| (VIII) | 63273 | (5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-[1-methyl-1-(tritylsulfanyl)ethyl]-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid | C59H58N4O8S | 详情 | 详情 | |
| (IX) | 63274 | (5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-(1-methyl-1-sulfanylethyl)-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid | C40H44N4O8S | 详情 | 详情 |