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【结 构 式】 
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【分子编号】41688 【品名】2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid 【CA登记号】 |
【 分 子 式 】C22H31N3O5 【 分 子 量 】417.50536 【元素组成】C 63.29% H 7.48% N 10.06% O 19.16% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Synthesis of intermediate (XIV): Protection of 4-piperidone (I) with (Boc)2O in presence of DMAP and Et3N yields (II), which is converted into hydantoin (III) by means of NaCN in presence of (NH4)2CO3. Hydantoin (III) is then fully protected to provide (IV) by treatment with (Boc)2O and DMAP in THF. Alternatively (IV) can be obtained by treatment of 4-piperidone (I) with KCN in presence of (NH4)2CO3 to yield hydantoin (V), which is then protected with (Boc)2O and DMAP in DME. Hydrolysis of (IV) with NaOH affords aminoacid (VI) whose free amine is protected to provide carboxylic acid (VII). Treatment of (VII) with isobutyl chloroformate (IBCF) in DME in presence of NMM, followed by aqueous ammonia, yields amide (VIII), which is converted to (IX) by hydrogenation with H2 over Pd/C. Reductive amination of (IX) with aldehyde (X) affords amino amide (XI), which is treated with triethyl orthoformate to provide spirocycle (XII). Reduction of (XII) with NaBH4 in EtOH gives (XIII), which is alkylated with ethyl bromoacetate (A) followed by hydrolysis with NaOH to yield intermediate (XIV).
| 【1】 Wysong, C.L.; et al.; 4-Aminopiperidine-4-carboxamylic acid: A cyclic alpha,alpha-disubstituted amino acid for preparation of water-soluble highly helical peptides. J Org Chem 1996, 61, 22, 7650-51. |
| 【2】 Amblard, M.; Subra, G.; Bedos, P.; et al.; A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist. J Med Chem 2000, 43, 12, 2387. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (I) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (II) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (III) | 41678 | tert-butyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate | C12H19N3O4 | 详情 | 详情 | |
| (IV) | 41679 | tri(tert-butyl) 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-1,3,8-tricarboxylate | C22H35N3O8 | 详情 | 详情 | |
| (V) | 41680 | 1,3,8-triazaspiro[4.5]decane-2,4-dione | 13625-39-3 | C7H11N3O2 | 详情 | 详情 |
| (VI) | 41681 | 4-amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid | 183673-71-4 | C11H20N2O4 | 详情 | 详情 |
| (VII) | 41682 | 1-(tert-butoxycarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-piperidinecarboxylic acid | C26H30N2O6 | 详情 | 详情 | |
| (VIII) | 41683 | tert-butyl 4-(aminocarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1-piperidinecarboxylate | C26H31N3O5 | 详情 | 详情 | |
| (IX) | 41684 | tert-butyl 4-amino-4-(aminocarbonyl)-1-piperidinecarboxylate | C11H21N3O3 | 详情 | 详情 | |
| (X) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (XI) | 41685 | tert-butyl 4-(aminocarbonyl)-4-(phenethylamino)-1-piperidinecarboxylate | C19H29N3O3 | 详情 | 详情 | |
| (XII) | 41686 | tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-2-ene-8-carboxylate | C20H27N3O3 | 详情 | 详情 | |
| (XIII) | 41687 | tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate | C20H29N3O3 | 详情 | 详情 | |
| (XIV) | 41688 | 2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid | C22H31N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Synthesis of EN 290154: Cleavage of both the Fmoc protecting group and ethyl ester of (XV) by means of HBr in HOAc followed by Boc protection affords (XVI) which is then anchored to a chloromethylated resin to yield (XVII). Deprotection of dihydro-benzothiazepinone (XVII) with TFA in presence of ethanedithiol, followed by coupling with Boc-Ser-OH by means of BOP/DIEA in CH2Cl2, yields derivative (XVIII). Deprotection of (XVIIII) followed by coupling with intermediate (XIV) in the same conditions described for (XVII) affords derivative (XIX). Next steps include sequencial Boc removal and coupling with Boc-Arg(Tos)-OH and then Boc-Lys(Fmoc)-OH. Finally the product is cleaved from the resin by means of HF/anisole.
| 【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185. |
| 【2】 Amblard, M.; Subra, G.; Bedos, P.; et al.; A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist. J Med Chem 2000, 43, 12, 2387. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI),(XVII) | 41690 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C17H24N2O4S | 详情 | 详情 | |
| (XIV) | 41688 | 2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid | C22H31N3O5 | 详情 | 详情 | |
| (XV) | 41689 | ethyl 2-[(3S)-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C29H30N2O4S | 详情 | 详情 | |
| (XVIII) | 41691 | 2-[(3S)-3-([2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]amino)-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C20H29N3O6S | 详情 | 详情 | |
| (XIX) | 41692 | 2-[(3S)-3-[[2-([2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetyl]amino)-3-hydroxypropanoyl]amino]-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C37H50N6O8S | 详情 | 详情 |