|
【结 构 式】 
|
【分子编号】17639 【品名】beta-Alanine, ethyl ester; ethyl 3-aminopropanoate 【CA登记号】924-73-2 |
【 分 子 式 】C5H11NO2 【 分 子 量 】117.14788 【元素组成】C 51.26% H 9.46% N 11.96% O 27.31% |
合成路线1
该中间体在本合成路线中的序号：(VII)1) Hydrogenation of 5-nitroisatoic anhydride (I) over Pd/C provided amine (II), which was acylated to amide (IV) with 4-cyanobenzoyl chloride (III). Subsequent reaction of (IV) with beta-alanine ethyl ester (V) yielded diamide (VI). The amino group of (VI) was then protected by alkylation with benzhydryl bromide (VII) yielding (VIII). Further condensation of (VIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide in the presence of Cs2CO3 afforded benzodiazepinedione (X). The benzhydryl protecting group of (X) was cleaved by treatment with HF in the presence of ethyl methyl sulfide and anisole to yield (XI). The tetrazole ring of (XII) was then constructed by treatment of (XI) with trimethylsilylazide under Mitsunobu conditions. Subsequent conversion of the cyano group of (XII) into amidine was effected by the sequence of H2S addition, followed by S-methylation with CH3I to give (XIII), and then substitution of the methylthio group of (XIII) for an amino group. Finally, basic hydrolysis with LiOH provided the target carboxylic acid.
| 【1】 Robarge, K.D.; Dina, M.S.; Somers, T.C.; Lee, A.; Rawson, T.E.; Olivero, A.G.; Tischler, M.H.; Webb, R.R. II; Weese, K.J.; Aliagas, I.; Blackburn, B.K.; Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists. Bioorg Med Chem 1998, 6, 12, 2345. |
| 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) | 22347 | 5-Nitroisatoic anhydride; 6-nitro-2H-3,1-benzoxazine-2,4(1H)-dione | 4693-02-1 | C8H4N2O5 | 详情 | 详情 |
| (II) | 22348 | 6-amino-2H-3,1-benzoxazine-2,4(1H)-dione | C8H6N2O3 | 详情 | 详情 | |
| (IV) | 22350 | 4-cyano-N-(2,4-dioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzamide | C16H9N3O4 | 详情 | 详情 | |
| (VI) | 22351 | ethyl 3-([2-amino-5-[(4-cyanobenzoyl)amino]benzoyl]amino)propanoate | C20H20N4O4 | 详情 | 详情 | |
| (VII) | 17639 | beta-Alanine, ethyl ester; ethyl 3-aminopropanoate | 924-73-2 | C5H11NO2 | 详情 | 详情 |
| (VIII) | 22353 | ethyl 3-([2-(benzhydrylamino)-5-[(4-cyanobenzoyl)amino]benzoyl]amino)propanoate | C33H30N4O4 | 详情 | 详情 | |
| (X) | 22355 | ethyl 3-[1-benzhydryl-7-[(4-cyanobenzoyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate | C35H30N4O5 | 详情 | 详情 | |
| (XI) | 22356 | ethyl 3-[7-[(4-cyanobenzoyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate | C22H20N4O5 | 详情 | 详情 | |
| (XII) | 22357 | ethyl 3-[8-[(4-cyanobenzoyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C22H19N7O4 | 详情 | 详情 | |
| (XIII) | 22358 | ethyl 3-[8-([4-[imino(methylsulfanyl)methyl]benzoyl]amino)-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C23H23N7O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)2) An improved procedure consisted of condensation of 5-nitroisatoic anhydride (I) with beta-alanine ethyl ester (V) to give amide (XIV). The amino group of (XIV) was protected with benzhydryl bromide (VII) yielding (XV), and then the nitro group of (XV) was reduced to aniline (XVI) by catalytic transfer hydrogenation. Protection of the amine of (XVI) as the tert-butyl carbamate (XVIII) was effected using 2-(tert-butoxycarbonyloxymino)-2-phenylacetonitrile (XVII). The sequence of condensation of (XVIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide with DBU provided the benzodiazepinedione (XIX). Hydrogenolysis of the N-benzhydryl group of (XIX) in the presence of Pearlman's catalyst, followed by treatment with trimethylsilyl azide furnished the tetrazole (XX). The Boc group of (XX) was deprotected with trifluoroacetic acid, and subsequent coupling with 4-cyanobenzoyl chloride (III) gave amide (XXI). The cyano group was of (XXI) then converted to hydroxyamidine (XXII) with hydroxylamine. Catalytic hydrogenation of (XXII) in the presence of Ac2O and AcOH produced the corresponding amidine. Finally, the ester group was hydrolyzed with LiOH.
| 【1】 Robarge, K.D.; Dina, M.S.; Somers, T.C.; Lee, A.; Rawson, T.E.; Olivero, A.G.; Tischler, M.H.; Webb, R.R. II; Weese, K.J.; Aliagas, I.; Blackburn, B.K.; Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists. Bioorg Med Chem 1998, 6, 12, 2345. |
| 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) | 22347 | 5-Nitroisatoic anhydride; 6-nitro-2H-3,1-benzoxazine-2,4(1H)-dione | 4693-02-1 | C8H4N2O5 | 详情 | 详情 |
| (III) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (VII) | 17639 | beta-Alanine, ethyl ester; ethyl 3-aminopropanoate | 924-73-2 | C5H11NO2 | 详情 | 详情 |
| (IX) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIV) | 22360 | ethyl 3-[(2-amino-5-nitrobenzoyl)amino]propanoate | C12H15N3O5 | 详情 | 详情 | |
| (XV) | 22361 | ethyl 3-[[2-(benzhydrylamino)-5-nitrobenzoyl]amino]propanoate | C25H25N3O5 | 详情 | 详情 | |
| (XVI) | 22362 | ethyl 3-[[5-amino-2-(benzhydrylamino)benzoyl]amino]propanoate | C25H27N3O3 | 详情 | 详情 | |
| (XVII) | 22363 | 2-[[(tert-butoxycarbonyl)oxy]imino]-2-phenylacetonitrile | 58632-95-4 | C13H14N2O3 | 详情 | 详情 |
| (XVIII) | 22364 | ethyl 3-([2-(benzhydrylamino)-5-[(tert-butoxycarbonyl)amino]benzoyl]amino)propanoate | C30H35N3O5 | 详情 | 详情 | |
| (XIX) | 22365 | ethyl 3-[1-benzhydryl-7-[(tert-butoxycarbonyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate | C32H35N3O6 | 详情 | 详情 | |
| (XX) | 22366 | ethyl 3-[8-[(tert-butoxycarbonyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C19H24N6O5 | 详情 | 详情 | |
| (XXI) | 22357 | ethyl 3-[8-[(4-cyanobenzoyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C22H19N7O4 | 详情 | 详情 | |
| (XXII) | 22368 | ethyl 3-[8-([4-[amino(hydroxyimino)methyl]benzoyl]amino)-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C22H22N8O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The condensation of 4-aminobenzamide (I) with N-(tert-butoxycarbonyl)-L-methionine (II) by means of 2-chloro-1-methylpyridinium iodide (CMPI) and N-methylmorpholine (NMM) in DMF gives the corresponding methioninamide (III), which is cyclized by means of trimethylsulfonium iodide and K2CO3 in hot DMSO yielding the pyrrolidinone (IV). The dehydration of (IV) with trifluoroacetic anhydride in THF affords the corresponding nitrile (V), which is deprotected with dry HCl in ethyl acetate giving the amine (VI). The condensation of (VI) with beta-alanine ethyl ester (VII) and carbonyl diimidazole (CDI) in pyridine yields the substituted urea (VIII), which is treated with hydroxylamine hydrochloride and triethylamine in ethyl acetate to afford the N-hydroxybenzamidine (IX). Finally, this compound is hydrogenated with H2 over Pd/C in acetic acid.
| 【1】 Castañer, J.; Merlos, M.; Leeson, P.A.; Orbofiban Acetate. Drugs Fut 1998, 23, 11, 1190-1198. |
| 【2】 Abood, N.A.; Flynn, D.L.; Laneman, S.A.; Nosal, R.; Schretzman, L.A. (Pharmacia Corp.); Process for the preparation of amidino phenyl pyrrolidine betal-alanine urea analogs. US 5484946 . |
| 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) | 16778 | 4-aminobenzamide; p-aminobenzamide | 2835-68-9 | C7H8N2O | 详情 | 详情 |
| (II) | 17634 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine | 2488-15-5 | C10H19NO4S | 详情 | 详情 |
| (III) | 17635 | tert-butyl (1S)-1-[[4-(aminocarbonyl)anilino]carbonyl]-3-(methylsulfanyl)propylcarbamate | C17H25N3O4S | 详情 | 详情 | |
| (IV) | 17636 | tert-butyl (3S)-1-[4-(aminocarbonyl)phenyl]-2-oxopyrrolidinylcarbamate | C16H21N3O4 | 详情 | 详情 | |
| (V) | 17637 | tert-butyl (3S)-1-(4-cyanophenyl)-2-oxopyrrolidinylcarbamate | C16H19N3O3 | 详情 | 详情 | |
| (VI) | 17638 | 4-[(3S)-3-amino-2-oxopyrrolidinyl]benzonitrile | C11H11N3O | 详情 | 详情 | |
| (VII) | 17639 | beta-Alanine, ethyl ester; ethyl 3-aminopropanoate | 924-73-2 | C5H11NO2 | 详情 | 详情 |
| (VIII) | 17640 | ethyl 3-[([[(3S)-1-(4-cyanophenyl)-2-oxopyrrolidinyl]amino]carbonyl)amino]propanoate | C17H20N4O4 | 详情 | 详情 | |
| (IX) | 17641 | ethyl 3-([[((3S)-1-[4-[amino(hydroxyimino)methyl]phenyl]-2-oxopyrrolidinyl)amino]carbonyl]amino)propanoate | C17H23N5O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Coupling between ethyl 3-aminopropionate (I) and N-Boc-glycine (II) by means of EDC and HOBt affords the protected dipeptide (III). After acidic Boc group cleavage in (III), the N-deprotected dipeptide (IV) is acylated by 3,3,3-triphenylpropionic acid (V) to produce amide (VI). Saponification of the ethyl ester group of (VI) yields acid (VII). This is coupled with (R)-1-Boc-3-(aminomethyl)piperidine (VIII) to afford amide (IX), which is further subjected to acidic N-Boc group cleavage. The resultant piperidine derivative (X) is then reductively condensed with cyclohexanecarboxaldehyde (XI) in the presence of NaBH(OAc)3 to furnish the title compound.
| 【1】 Kimura, T.; Noguchi, K.; Otake, N.; Uchiyama, M.; Naya, A.; Sagara, Y.; Numazawa, T.; Fujikawa, T. (Banyu Pharmaceutical Co., Ltd.); Novel amide derivs.. EP 1213281; WO 0107406 . |
| 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) | 17639 | beta-Alanine, ethyl ester; ethyl 3-aminopropanoate | 924-73-2 | C5H11NO2 | 详情 | 详情 |
| (II) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (III) | 57638 | ethyl 3-({2-[(tert-butoxycarbonyl)amino]acetyl}amino)propanoate | C12H22N2O5 | 详情 | 详情 | |
| (IV) | 57639 | ethyl 3-[(2-aminoacetyl)amino]propanoate | C7H14N2O3 | 详情 | 详情 | |
| (V) | 57640 | 3,3,3-Triphenylpropionic acid; Tritylacetic acid | 900-91-4 | C21H18O2 | 详情 | 详情 |
| (VI) | 57641 | ethyl 3-({2-[(3,3,3-triphenylpropanoyl)amino]acetyl}amino)propanoate | C28H30N2O4 | 详情 | 详情 | |
| (VII) | 57642 | N-{2-[(3,3,3-triphenylpropanoyl)amino]acetyl}-beta-alanine | C26H26N2O4 | 详情 | 详情 | |
| (VIII) | 57643 | tert-butyl (3R)-3-(aminomethyl)-1-piperidinecarboxylate | C11H22N2O2 | 详情 | 详情 | |
| (IX) | 57644 | tert-butyl (3R)-3-({[3-({2-[(3,3,3-triphenylpropanoyl)amino]acetyl}amino)propanoyl]amino}methyl)-1-piperidinecarboxylate | C37H46N4O5 | 详情 | 详情 | |
| (X) | 57645 | N-{2-oxo-2-[(3-oxo-3-{[(3S)piperidinylmethyl]amino}propyl)amino]ethyl}-3,3,3-triphenylpropanamide | C32H38N4O3 | 详情 | 详情 | |
| (XI) | 33694 | cyclohexanecarbaldehyde | 2043-61-0 | C7H12O | 详情 | 详情 |