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【结 构 式】 
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【分子编号】40421 【品名】N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine 【CA登记号】 |
【 分 子 式 】C33H35N5O2S 【 分 子 量 】565.7394 【元素组成】C 70.06% H 6.24% N 12.38% O 5.66% S 5.67% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The reaction of phenylalanine methyl ester (I) with benzaldehyde (II) and TEA in dichloromethane gives the aldimine (III), which is condensed with allyl bromide (IV) by means of n-BuLi in THF yielding the adduct (V). Treatment of (V) with HCl in methanol cleaves the benzylidene protecting group to afford the alpha-allylphenylalanine methyl ester (VI), which is reprotected with Boc2O and NaHCO3 in THF providing the carbamate (VII). The ozonolysis of (VII) with O3 in MeOH/CH2Cl2 gives the aldehyde (VIII), which is cyclized with hydrazine in refluxing THF yielding the tetrahydropyridazinone (IX). Hydrogenation of (IX) with H2 over PtO2 in methanol affords the hexahydropyridazinone (X), which is cyclocondensed with ethyl acrylate (XI) and formaldehyde to furnish the pyrazolopyridazine (XII). Hydrolysis of the ester group of (XII) with LiOH in THF/water gives the acid (XIII), which is finally condensed with the argininol derivative (XIV) by means of EDC, HOBT and DIEA in THF yielding the corresponding amide (XV). Finally, the secondary alcohol of (XV) is oxidized with Dess Martin periodinane (DMP) to afford, after working up, a diastereomeric mixture of amides, from which the target diastereomer is obtained by HPLC chromatography.
| 【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 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) | 40419 | methyl 2-amino-3-phenylpropanoate | 5619-07-8 | C10H13NO2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 40420 | methyl 3-phenyl-2-[[(E)-benzylidene]amino]propanoate | C17H17NO2 | 详情 | 详情 | |
| (IV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (V) | 40416 | methyl 2-benzyl-2-[[(E)-benzylidene]amino]-4-pentenoate | C20H21NO2 | 详情 | 详情 | |
| (VI) | 36771 | methyl 2-amino-2-benzyl-4-pentenoate | C13H17NO2 | 详情 | 详情 | |
| (VII) | 36772 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (VIII) | 36773 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C17H23NO5 | 详情 | 详情 | |
| (IX) | 36774 | tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate | C16H21N3O3 | 详情 | 详情 | |
| (X) | 36775 | tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate | C16H23N3O3 | 详情 | 详情 | |
| (XI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XII) | 40417 | ethyl (1S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate | C22H31N3O5 | 详情 | 详情 | |
| (XIII) | 36779 | (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid | C20H27N3O5 | 详情 | 详情 | |
| (XIV) | 40421 | N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C33H35N5O2S | 详情 | 详情 | |
| (XV) | 40422 | (1S)-7-amino-N-[(1S)-4-[[amino(imino)methyl]amino]-1-[1,3-benzothiazol-2-yl(hydroxy)methyl]butyl]-7-benzyl-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxamide | C28H36N8O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The intermediate argininol derivative (XIV) has been obtained by condensation of N-omega(4-methoxytrityl)-L-argininal (XVI) with benzothiazole (XVII) by means of n-BuLi in ethyl ether.
| 【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 40421 | N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C33H35N5O2S | 详情 | 详情 | |
| (XVI) | 40423 | N-[(4S)-4-amino-5-oxopentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C26H30N4O2 | 详情 | 详情 | |
| (XVII) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The cyclization of N-Boc-L-glutamic acid (I) with paraformaldehyde in refluxing DCE gives the oxazolidinone (II), which is benzylated with benzyl bromide and LiHMDS in THF yielding the benzyl derivative (III). The reaction of (II) with CDI in THF affords the activated acid (IV), which is condensed with the protected glutamic acid (V) by means of LiHMDS in THF to provide the adduct (VI). The decarboxylation of the allyloxycarbonyl group of (VI) by means of a Pd catalyst furnishes the compound (VII), which is deprotected and cyclized by hydrogenation with H2 over Pd/C and PtO2 to give the substituted proline (VIII). The lactam cyclization of (VIII) by means of NaOH in methanol, followed by crystallization yields the bicyclic carboxylic acid (IX), which is condensed with the arginine derivative (X) by means of EDC, HOBT and DIEA in THF affording the adduct (XI). The oxidation of the OH group of (XI) with DMP in dichloromethane gives the precursor (XII), which is finally deprotected by a treatment with TFA and PhS-Me. The intermediate arginine derivative (X) has been obtained as follows: The condensation of the fully protected arginine aldehyde derivative (XIII) with benzothiazole (XIV) by means of n-BuLi in ethyl ether gives the adduct (XV), which is then treated with TFA in order to eliminate the Boc protecting groups and furnish the desired arginine derivative intermediate (X).
| 【1】 Lee, M.S.; Eguchi, M.; Gardner, B.S.; Boatman, P.D.; Kahn, M.; Kim, H.-O.; Nakanishi, H.; Synthesis of dipeptide secondary structure mimetics. Proc. 15th Am. Pep. Symposium, Kluwer Acad. Publ. 1998, 212. |
| 【2】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 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) | 12895 | (2S)-2-[(tert-Butoxycarbonyl)amino]pentanedioic acid | 2419-94-5 | C10H17NO6 | 详情 | 详情 |
| (II) | 41838 | 3-[(4S)-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propionic acid | C11H17NO6 | 详情 | 详情 | |
| (III) | 41839 | 3-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propionic acid | C18H23NO6 | 详情 | 详情 | |
| (IV) | 41840 | tert-butyl (4R)-4-benzyl-4-[3-(1H-imidazol-1-yl)-3-oxopropyl]-5-oxo-1,3-oxazolidine-3-carboxylate | C21H25N3O5 | 详情 | 详情 | |
| (V) | 41841 | 5-allyl 1-benzyl (2S)-2-[[(benzyloxy)carbonyl]amino]pentanedioate | C23H25NO6 | 详情 | 详情 | |
| (VI) | 41842 | 1-allyl 5-benzyl (4S)-2-[3-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propanoyl]-4-[[(benzyloxy)carbonyl]amino]pentanedioate | C41H46N2O11 | 详情 | 详情 | |
| (VII) | 41843 | tert-butyl (4R)-4-benzyl-4-((6S)-7-(benzyloxy)-6-[[(benzyloxy)carbonyl]amino]-3,7-dioxoheptyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C37H42N2O9 | 详情 | 详情 | |
| (VIII) | 41844 | (2S,5R)-5-[2-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]ethyl]-2-pyrrolidinecarboxylic acid | C22H30N2O6 | 详情 | 详情 | |
| (IX) | 41485 | 4-chloro-1-methyl-2-nitrobenzene；4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene | 89-59-8 | C7H6ClNO2 | 详情 | 详情 |
| (X) | 40421 | N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C33H35N5O2S | 详情 | 详情 | |
| (XI) | 41846 | tert-butyl (3S,6R,8aR)-3-[([(1S)-1-[1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxooctahydro-6-indolizinylcarbamate | C54H61N7O6S | 详情 | 详情 | |
| (XII) | 41847 | tert-butyl (3S,6R,8aR)-3-[([(1S)-1-(1,3-benzothiazol-2-ylcarbonyl)-4-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxooctahydro-6-indolizinylcarbamate | C54H59N7O6S | 详情 | 详情 | |
| (XIII) | 41848 | tert-butyl (Z)-([(4S)-4-[(tert-butoxycarbonyl)amino]-5-oxopentyl]amino)[[(4-methoxyphenyl)(diphenyl)methyl]amino]methylidenecarbamate | C36H46N4O6 | 详情 | 详情 | |
| (XIV) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
| (XV) | 41849 | tert-butyl (Z)-([(4S)-5-(1,3-benzothiazol-2-yl)-4-[(tert-butoxycarbonyl)amino]-5-hydroxypentyl]amino)[[(4-methoxyphenyl)(diphenyl)methyl]amino]methylidenecarbamate | C43H51N5O6S | 详情 | 详情 |