|
【结 构 式】 
|
【分子编号】15859 【品名】Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid 【CA登记号】7764-95-6 |
【 分 子 式 】C8H15NO4 【 分 子 量 】189.21144 【元素组成】C 50.78% H 7.99% N 7.4% O 33.82% |
合成路线1
该中间体在本合成路线中的序号：(XV)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：(I)The synthesis of ganirelix was performed using usual solid-state peptide synthesis with a Beckman 990 or a 5.0 L Vega 296 automated solid-phase peptide synthesizer. The synthesis was initiated by condensation of chloromethylated polystyrene/divinylbenzene resin (Merrifieled resin) (II) with Boc-D-alanine (I) by means of cesium carbonate, giving Boc-D-ala-RESIN (III), which was submitted to successive cycles of deprotection with TFA or HCl and addition of a new protected amino acid by means of DCC or HOBt. The following amino acids were added successively: Boc-L-proline (IV), Nalpha-Boc-Nomega,N'omega-diethyl-L-homoarginine (VI), Boc-L-leucine (VIII), Nalpha-Boc-Nomega,N'omega-diethyl-D-homoarginine (X) and Boc-L-tyrosine (XII), yielding successively the peptide resins (V), (VII), (IX), (XI) and (XIII).
| 【1】 Robinson, J.3rd; Morgans, D.J.; Bingenheimer, W.; Arzeno, H.B.; Temporary serine protection in solid phase synthesis of LH-RH analogs. Int J Pept Protein Res 1993, 41, 4, 342. |
| 【2】 Castaner, J.; Leeson, P.; Rabasseda, X.; Ganirelix Acetate. Drugs Fut 1999, 24, 4, 393. |
| 【3】 Nestor, J.J. Jr.; McClure, N.L. (Syntex (USA), Inc.); Temporary minimal protection synthesis of LH-RH analogs. EP 0443532; JP 1992211096; US 5212288 . |
| 【4】 Nestor, J.J. Jr.; Vickery, B.H. (Syntex (USA), Inc.); Nonapeptide and decapeptide analogs of LHRH as LHRH antagonists. EP 0277829; JP 1988201199; US 4801577 . |
| 【5】 Vickery, B.H. (Syntex (USA), Inc.); LHRH antagonist analogs and 19-nor-progestational steroids for therapy. EP 0301850 . |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (IV) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (V) | 23483 | (2R)-2-([[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]amino)propionic acid | C13H22N2O5 | 详情 | 详情 | |
| (VI) | 23484 | (2S)-2-[(tert-butoxycarbonyl)amino]-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoic acid | C16H32N4O4 | 详情 | 详情 | |
| (VII) | 23485 | (2R)-2-([[(2S)-1-((2S)-2-[(tert-butoxycarbonyl)amino]-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoyl)pyrrolidinyl]carbonyl]amino)propionic acid | C24H44N6O6 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 23487 | (2R)-2-([[(2S)-1-((2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl]amino)-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoyl)pyrrolidinyl]carbonyl]amino)propionic acid | C30H55N7O7 | 详情 | 详情 | |
| (X) | 23488 | (2R)-2-[(tert-butoxycarbonyl)amino]-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoic acid | C16H32N4O4 | 详情 | 详情 | |
| (XI) | 23489 | (2R)-2-[([(2S)-1-[(2S,5S,8R,14E)-8-[(tert-butoxycarbonyl)amino]-14-(ethylamino)-2-(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-5-isobutyl-4,7-dioxo-3,6,13,15-tetraaza-14-heptadecen-1-anoyl]pyrrolidinyl]carbonyl)amino]propionic acid | C41H77N11O8 | 详情 | 详情 | |
| (XII) | 23490 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | C14H19NO5 | 详情 | 详情 | |
| (XIII) | 23491 | (2R)-2-[([(2S)-1-[(2S,5S,8R,11S)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-5-isobutyl-15,15-dimethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl]pyrrolidinyl]carbonyl)amino]propionic acid | C50H86N12O10 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The condensation of tert-butoxycarbonyl-D-alanine (I) with ethylenediamine (II) gives the corresponding protected diamide (III), which is deprotected in acidic medium to the diamide (IV). The reduction of (IV) with diborane in THF yields the (R,R)-4,7-diazadecane-2,9-diamine (V), which is finally condensed with 3-nitronaphthalene-1,8-dicarboxylic acid anhydride (VI) in refluxing ethanol and salified with methanesulfonic acid.
| 【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Bisnafide Mesylate. Drugs Fut 1996, 21, 3, 239. |
| 【2】 Sun, J.-H. (DuPont Pharmaceuticals Co.); Bis-naphthalimides containing amino-acid derived linkers as anticancer agents. EP 0506008; EP 0577753; JP 1994506229; US 5206249; WO 9217453 . |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (III) | 15861 | tert-butyl N-[(1R,8R)-1,8,12,12-tetramethyl-2,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-yl]carbamate | C18H34N4O6 | 详情 | 详情 | |
| (IV) | 15862 | (2R)-2-amino-N-(2-[[(2R)-2-aminopropanoyl]amino]ethyl)propanamide | C8H18N4O2 | 详情 | 详情 | |
| (V) | 15863 | (2R)-N(1)-(2-[[(2R)-2-aminopropyl]amino]ethyl)-1,2-propanediamine; N-[(2R)-2-aminopropyl]-N-(2-[[(2R)-2-aminopropyl]amino]ethyl)amine | C8H22N4 | 详情 | 详情 | |
| (VI) | 15864 | 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride | 3027-38-1 | C12H5NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Alternatively, a chiral synthesis of intermediate (V) was developed from enantiopure amino acids. N-Boc-D-alanine (VI) was N-alkylated with allyl bromide in the presence of two equivalents of NaH, and the resulting N-allyl amino acid (VII) was coupled with L-alanine methyl ester (VIII) using 1-dimethylaminopropyl-3-ethylcarbodiimide (DEC) to provide dipeptide (IX). Subsequent acid treatment of (IX) produced both Boc deprotection and cyclization to the diketopiperazine (X), which was finally reduced to piperazine (V) with LiAlH4.
| 【1】 Chang, K.-J.; Bishop, M.J.; Bubacz, D.G.; McNutt, R.W. Jr. (Glaxo Wellcome plc); Piperazine cpds. used in therapy. EP 0711289; JP 1997501156; WO 9504051 . |
| 【2】 Chang, K.; Boswell, G.E.; Bubacz, D.G.; Collins, M.A.; Davis, A.O.; McNutt, R.W. (Delta Pharmaceuticals, Inc.); Opioid diarylmethylpiperazines and piperidines. JP 1995503247; US 5658908; US 5681830; WO 9315062 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 20690 | (2R,5S)-1-allyl-2,5-dimethylpiperazine | C9H18N2 | 详情 | 详情 | |
| (VI) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VII) | 20693 | (2R)-2-[allyl(tert-butoxycarbonyl)amino]propionic acid | C11H19NO4 | 详情 | 详情 | |
| (VIII) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (IX) | 20695 | (2S)-2-([(2R)-2-[allyl(tert-butoxycarbonyl)amino]propanoyl]amino)propionic acid | C14H24N2O5 | 详情 | 详情 | |
| (X) | 20696 | (3S,6R)-1-allyl-3,6-dimethyl-2,5-piperazinedione | C9H14N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)N-Boc-D-Alanine (XI) is converted to the corresponding amide (XII) by reaction with ammonia in the presence of EDC and HOBt. Subsequent treatment of (XII) with Belleau's reagent (2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) furnishes thioamide (XIII). S-Alkylation of thioamide (XIII) with ethyl bromopyruvate (XIV) gives intermediate (XV), which is cyclized to thiazole (XVI) upon treatment with trifluoroacetic anhydride and 2,6-lutidine. After saponification of the ester group of (XVI) with LiOH, the resultant acid (XVII) is coupled with tripeptide (X) to provide precursor (XVIII).
| 【1】 Ley, S.V.; et al.; Total synthesis of the cyclic heptapeptide argyrin B: A new potent inhibitor of T-cell independent antibody formation. Org Lett 2002, 4, 5, 711. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 58834 | methyl 2-{[(2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C26H29N5O5 | 详情 | 详情 | |
| (XI) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (XII) | 46750 | tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate | C8H16N2O3 | 详情 | 详情 | |
| (XIII) | 48364 | tert-butyl (1R)-2-amino-1-methyl-2-thioxoethylcarbamate | C8H16N2O2S | 详情 | 详情 | |
| (XIV) | 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 |
| (XV) | 58835 | ethyl 3-({(2R)-2-[(tert-butoxycarbonyl)amino]propanimidoyl}sulfanyl)-2-oxopropanoate | C13H22N2O5S | 详情 | 详情 | |
| (XVI) | 48366 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C13H20N2O4S | 详情 | 详情 | |
| (XVII) | 58836 | 2-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-1,3-thiazole-4-carboxylic acid | C11H16N2O4S | 详情 | 详情 | |
| (XVIII) | 58837 | methyl 2-{[(2S)-2-{[(2S)-2-{[(2-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-1,3-thiazol-4-yl)carbonyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C37H43N7O8S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)N-Boc-D-alanine (I) was coupled to the resin using diisopropyl carbodiimide and 1-hydroxybenzotriazole to afford resin (II). Subsequent cleavage of the Boc protecting group by means of trifluoroacetic acid provided the D-alanine-bound resin (III). Sequential coupling and deprotection cycles were carried out with the following protected amino acids: N-Boc-L-proline (IV), N-alpha-Boc-N6-isopropyl-N6-carbobenzoxy-L-lysine (VI) and N-Boc-L-leucine (VIII) to afford the respective peptide resins (V), (VII) and (IX). N-alpha-Boc-D-4-(Fmoc-amino)phenylalanine (X) was coupled to (IX), yielding resin (XI). Cleavage of the side-chain Fmoc protecting group with piperidine in DMF gave the aniline derivative (XII). After conversion to the corresponding urea by treatment with tert-butyl isocyanate, the Boc group was cleaved with trifluoroacetic acid to produce resin (XIII).
| 【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453. |
| 【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 . |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 46750 | tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate | C8H16N2O3 | 详情 | 详情 | |
| (III) | 46751 | (2R)-2-aminopropanamide | C3H8N2O | 详情 | 详情 | |
| (IV) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (V) | 46743 | (2S)-N-[(1R)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide | C8H15N3O2 | 详情 | 详情 | |
| (VI) | 46752 | (2S)-6-[[(benzyloxy)carbonyl](isopropyl)amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | 125323-99-1 | C22H34N2O6 | 详情 | 详情 |
| (VII) | 46744 | benzyl (5S)-5-amino-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate | C25H39N5O5 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 46745 | benzyl (5S)-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-5-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-oxohexyl(isopropyl)carbamate | C31H50N6O6 | 详情 | 详情 | |
| (X) | 46746 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]phenyl)propionic acid | 173054-11-0 | C29H30N2O6 | 详情 | 详情 |
| (XI) | 46747 | 9H-fluoren-9-ylmethyl 4-[(2R,5S,8S)-8-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-2-[(tert-butoxycarbonyl)amino]-5-isobutyl-13-isopropyl-3,6,14-trioxo-16-phenyl-15-oxa-4,7,13-triazahexadec-1-yl]phenylcarbamate | C60H78N8O11 | 详情 | 详情 | |
| (XII) | 46748 | benzyl (5S,8S,11R)-11-(4-aminobenzyl)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-8-isobutyl-15,15-dimethyl-7,10,13-trioxo-14-oxa-6,9,12-triazahexadec-1-yl(isopropyl)carbamate | C45H68N8O9 | 详情 | 详情 | |
| (XIII) | 46749 | benzyl (5S)-5-[((2S)-2-[[(2R)-2-amino-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate | C45H69N9O8 | 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 heterocyclic amino acid precursor (VI) was synthesized as follows. Coupling between N-Boc-D-alanine (I) and L-threonine methyl ester (II) in the presence of DCC and HOBt gave dipeptide (III). Cyclization of (III) using Burgess reagent provided the oxazoline (IV) as a mixture of diastereoisomers. Subsequent dehydrogenation of (IV) by means of bromotrichloromethane and DBU afforded the protected oxazole amino acid (V). Basic hydrolysis of the ethyl ester group then yielded the intermediate acid (VI).
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 48360 | methyl (4S,5R)-2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C13H22N2O5 | 详情 | 详情 | |
| (IVb) | 48361 | methyl (4S,5S)-2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C13H22N2O5 | 详情 | 详情 | |
| (I) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 42026 | methyl (2S,3R)-2-amino-3-hydroxybutanoate | C5H11NO3 | 详情 | 详情 | |
| (III) | 48359 | methyl (2S,3R)-2-([(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-3-hydroxybutanoate | C13H24N2O6 | 详情 | 详情 | |
| (V) | 48362 | methyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazole-4-carboxylate | C13H20N2O5 | 详情 | 详情 | |
| (VI) | 48363 | 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazole-4-carboxylic acid | C12H18N2O5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)N-Boc-D-alanine (VII) was converted into amide (VIII) via activation as the corresponding mixed anhydride with isobutyl chloroformate. Treatment of amide (VIII) with Lawesson’s reagent gave thioamide (IX). Coupling of (IX) with ethyl bromopyruvate (X) produced the intermediate hydroxythiazoline (XI), which was further dehydrated using trifluoroacetic anhydride to afford the fully protected thiazole amino acid (XII). Removal of the Boc protecting group of (XII) to give (XIII) was achieved by treatment with either trifluoroacetic acid or acetyl chloride in EtOH.
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VIII) | 46750 | tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate | C8H16N2O3 | 详情 | 详情 | |
| (IX) | 48364 | tert-butyl (1R)-2-amino-1-methyl-2-thioxoethylcarbamate | C8H16N2O2S | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 48365 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-4-hydroxy-4,5-dihydro-1,3-thiazole-4-carboxylate | C13H22N2O5S | 详情 | 详情 | |
| (XII) | 48366 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C13H20N2O4S | 详情 | 详情 | |
| (XIII) | 48367 | ethyl 2-[(1R)-1-aminoethyl]-1,3-thiazole-4-carboxylate | C8H12N2O2S | 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 N-(tert-butoxycarbonyl)-D-alanine (I) with 3,5-dichloroaniline (II) by means of isobutyl chloroformate and NMM gives the corresponding protected amide (III), which is deprotected with TFA to yield alaninamide (IV). The cyclization of (IV) with pivalaldehyde (V) in hot toluene affords the imidazolidinone (VI), which is acylated with TFAA and TEA in THF to provide the trifluoroacetyl derivative (VII). The alkylation of (VII) with 4-bromobenzyl bromide (VIII) and LHMDS in THF gives the benzyl derivative (IX), which is treated first with benzyl trimethylammonium chloride and NaOH and then with 6N HCl (or t-BuOK in THF/water) to yield the propionamide derivative (X). The cyclization of (X) with methyl chloroformate and TEA in THF affords the imidazolidinedione (XI), which is finally methylated with methyl iodide and LHMDS to provide the target compound.
| 【1】 Frutos, R.P.; et al.; An improved synthesis of N-aryl-hydantoin LFA-1 antagonists via the enantiospecific alkylation of a isobutyraldehyde-derived imidazolidinone template. Tetrahedron Asymmetry 2001, 12, 1, 101. |
| 【2】 Yee, N.K.; Self-regeneration of stereocenters: A practical enantiospecific synthesis of LFA-1 antagonist BIRT-377. Org Lett 2000, 2, 18, 2781. |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (III) | 47927 | tert-butyl (1R)-2-(3,5-dichloroanilino)-1-methyl-2-oxoethylcarbamate | C14H18Cl2N2O3 | 详情 | 详情 | |
| (IV) | 47928 | (2R)-2-amino-N-(3,5-dichlorophenyl)propanamide | C9H10Cl2N2O | 详情 | 详情 | |
| (V) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VI) | 47929 | (2S,5R)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-4-imidazolidinone | C14H18Cl2N2O | 详情 | 详情 | |
| (VII) | 47930 | (2R,5R)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-4-imidazolidinone | C16H17Cl2F3N2O2 | 详情 | 详情 | |
| (VIII) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (IX) | 47931 | (2R,5R)-5-(4-bromobenzyl)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-4-imidazolidinone | C23H22BrCl2F3N2O2 | 详情 | 详情 | |
| (X) | 47932 | (2R)-2-amino-3-(4-bromophenyl)-N-(3,5-dichlorophenyl)-2-methylpropanamide | C16H15BrCl2N2O | 详情 | 详情 | |
| (XI) | 47933 | (5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione | C17H13BrCl2N2O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VII)Intramolecular cyclization of p-hydroxy-4-chlorobutyrophenone (I) under alkaline conditions yields cyclopropyl(4-hydroxyphenyl) ketone (II). The phenolic hydroxyl group is then alkylated by 1-bromo-3-chloropropane (III) to furnish the chloropropyl ether (IV). Subsequent condensation of alkyl chloride (IV) with piperazine (V) gives rise to the N-substituted piperazine (VI). This is then coupled with N-Boc-L-alanine (VII) in the presence of EDC/DMAP to afford amide (VIII) (1, 2). After acidic cleavage of the N-Boc protecting group, the resultant monosubstituted piperazine (IX) is acylated by furanoyl chloride (X) to furnish the target furamide derivative
| 【1】 Black, L.A.; Faghih, R.; Liu, H.; et al.; Acyl-D-alanine amides: Selective histamine H3 receptor antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 323. |
| 【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 . |
| 【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 . |
| 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) | 62995 | C10H11ClO2 | 详情 | 详情 | ||
| (II) | 27425 | cyclopropyl(4-hydroxyphenyl)methanone | C10H10O2 | 详情 | 详情 | |
| (III) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (IV) | 62988 | 5-bromo-N-(1H-imidazol-2-yl)-6-quinoxalinamine; N-(5-bromo-6-quinoxalinyl)-N-(1H-imidazol-2-yl)amine | C11H8BrN5 | 详情 | 详情 | |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VI) | 62996 | C17H24N2O2 | 详情 | 详情 | ||
| (VII) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VIII) | 63042 | C28H23ClN2O2 | 详情 | 详情 | ||
| (IX) | 63043 | C17H15ClN2O2 | 详情 | 详情 | ||
| (X) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VII)Cyclization of 4-chloro-4'-hydroxybutyrophenone (I) in the presence of 50% aqueous NaOH produces cyclopropyl (4-hydroxyphenyl) ketone (II). This is then alkylated with 1-bromo-3-chloropropane (III) to afford the chloropropyl ether (IV). Chloride displacement in (IV) with an excess of piperazine (V) in the presence of KI and K2CO3 furnishes the monosubstituted piperazine (VI). Subsequent coupling of piperazine (VI) with N-Boc-L-alanine (VII) leads to amide (VIII). Finally, Boc group cleavage in (VIII) employing trifluoroacetic acid yields the title compound (1-3).
| 【1】 Faghih, R.; Dwight, W.; Black, L.; Liu, H.; Gentles, R.; Phelan, K.; Esbenshade, T.A.; Ireland, L.; Miller, T.R.; Kang, C.-H.; Krueger, K.M.; Fox, G.B.; Hancock; Bennani, Y.L.; Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 2: Binding preference for D-amino acids motifs. Bioorg Med Chem Lett 2002, 12, 15, 2035. |
| 【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 . |
| 【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 . |
| 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) | 62995 | C10H11ClO2 | 详情 | 详情 | ||
| (II) | 27425 | cyclopropyl(4-hydroxyphenyl)methanone | C10H10O2 | 详情 | 详情 | |
| (III) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (IV) | 62998 | [4-(3-chloropropoxy)phenyl](cyclopropyl)methanone | C13H15ClO2 | 详情 | 详情 | |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VI) | 62996 | C17H24N2O2 | 详情 | 详情 | ||
| (VII) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VIII) | 64059 | tert-butyl (1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethylcarbamate | C25H37N3O5 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VIII)Tetrahydropyran-4-carboxylic acid tert-butyl ester (I) is treated with 4-fluorophenyl disulfide (II) in the presence of LDA to produce sulfide (III), which is further oxidized to the corresponding sulfone (IV) utilizing m-chloroperbenzoic acid. Displacement of the aryl fluoride (IV) with the sodium alkoxide of 3-(dibenzylamino)-1-propanol (V) affords the amino ether (VI). Debenzylation of (VI) by hydrogenation in the presence of Pd(OH)2/C gives the primary amine (VII). This is coupled with N-Boc-D-alanine (VIII) employing EDC to provide amide (IX). Cyclization of (IX) in the presence of DMAP, NMM and Boc2O leads to the N-protected hydantoin (X). The N-Boc group of (X) is then selectively removed by HCl in dioxane to furnish (XI).
| 【1】 Becker, D.P.; Villamil, C.; Barta, T.E.; et al.; Design and synthesis of potent and selective 4,4-disubstituted alpha-sulphones hydroxamates as MMP inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 309. |
| 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) | 58908 | tert-butyl tetrahydro-2H-pyran-4-carboxylate | C10H18O3 | 详情 | 详情 | |
| (II) | 52287 | bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene | C12H8F2S2 | 详情 | 详情 | |
| (III) | 58809 | allyl 3-({(tert-butoxycarbonyl)[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate | C33H50N4O8Si | 详情 | 详情 | |
| (IV) | 58910 | tert-butyl 4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate | C16H21FO5S | 详情 | 详情 | |
| (V) | 58911 | 3-(Dibenzylamino)-1-propanol | C17H21NO | 详情 | 详情 | |
| (VI) | 58912 | tert-butyl 4-({4-[3-(dibenzylamino)propoxy]phenyl}sulfonyl)tetrahydro-2H-pyran-4-carboxylate | C33H41NO6S | 详情 | 详情 | |
| (VII) | 58913 | tert-butyl 4-{[4-(3-aminopropoxy)phenyl]sulfonyl}tetrahydro-2H-pyran-4-carboxylate | C19H29NO6S | 详情 | 详情 | |
| (VIII) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (IX) | 58914 | tert-butyl 4-({4-[3-({(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)propoxy]phenyl}sulfonyl)tetrahydro-2H-pyran-4-carboxylate | C27H42N2O9S | 详情 | 详情 | |
| (X) | 58915 | tert-butyl (5R)-3-[3-(4-{[4-(tert-butoxycarbonyl)tetrahydro-2H-pyran-4-yl]sulfonyl}phenoxy)propyl]-5-methyl-2,4-dioxo-1-imidazolidinecarboxylate | C28H40N2O10S | 详情 | 详情 | |
| (XI) | 58916 | tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxoimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate | C23H32N2O8S | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)In an alternative procedure, N-Boc-D-alanine (I) is activated as the mixed anhydride (II) by treatment with isobutyl chloroformate. Coupling of anhydride (II) with N-(4-fluorobenzyl)glycine methyl ester (III) produces dipeptide (IV). Further cleavage of the N-Boc protecting group of (IV) under acidic conditions proceeds with concomitant cyclization to the diketopiperazine (V). This is then reduced by means of LiAlH4 to piperazine (VI). Finally, acylation of piperazine (VI) with (4-chlorophenoxy)acetyl chloride (VII) provides the title compound.
| 【1】 Islam, I.; May, K.; Bauman, J.; et al.; Synthesis and SAR of CCR1-specific non-peptide antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 334. |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 61036 | ®-2-((tert-butoxycarbonyl)amino)propanoic (isobutyl carbonic) anhydride | C13H23NO6 | 详情 | 详情 | |
| (III) | 61037 | methyl 2-[(4-fluorobenzyl)amino]acetate | C10H12FNO2 | 详情 | 详情 | |
| (IV) | 61038 | methyl 2-[{(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl}(4-fluorobenzyl)amino]acetate | C18H25FN2O5 | 详情 | 详情 | |
| (V) | 61039 | (3R)-1-(4-fluorobenzyl)-3-methyl-2,5-piperazinedione | C12H13FN2O2 | 详情 | 详情 | |
| (VI) | 61035 | (3R)-1-(4-fluorobenzyl)-3-methylpiperazine | C12H17FN2 | 详情 | 详情 | |
| (VII) | 24258 | 2-(4-chlorophenoxy)acetyl chloride | 4122-68-3 | C8H6Cl2O2 | 详情 | 详情 |