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【结 构 式】 
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【分子编号】42350 【品名】ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C9H17NO3 【 分 子 量 】187.23892 【元素组成】C 57.73% H 9.15% N 7.48% O 25.63% |
合成路线1
该中间体在本合成路线中的序号：(XV)Treatment of salicyl alcohol (I) with benzyl bromide (II) in DMF in the presence of KOtBu affords benzyloxybenzyl alcohol (III), which is converted into its chloride form (IV) by means of SOCl2 in THF. Reaction of (IV) with PPh3 in refluxing toluene gives triphenyl phosphonium chloride derivative (V), which is then subjected to a Wittig reaction with aldehyde (VI) to yield olefine (VII). Catalytic hydrogenolysis of (VII) over Pd/C provides phenol derivative (VIII), which is then alkylated by reaction with tosylate (XVI) and KOtBu in dimethylacetamide to yield (XVII). Finally, ethoxycarbonyl derivative (XVII) is reduced by means of LiAlH4 in THF and converted into its hydrochloride form by treatment with HCl in dioxane. Intermediate (XVI) can be prepared as follows: Protection of 2(S)-pyrrolidinemethanol (IX) by reaction with ethyl chloroformate in the presence of Et3N in dichloromethane affords carbamate (XI), which is tosylated by means of Ts2O and Et3N in dichloromethane to yield (XII). One carbon elongation of (XII) by reaction with NaCN in DMF provides (XIII), which is then converted into ester (XIV) by means of H2SO4 in EtOH. Reduction of ester (XIV) with LiAlH4 in THF gives alcohol (XV), which is finally tosylated by reaction with Ts2O and Et3N in dichloromethane.
| 【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 . |
| 【2】 Goto, R.; Hayakawa, M.; Ito, R.; Ogawa, T.; Sugidachi, A.; Tanaka, N.; Asai, F.; Fujimoto, K.; [2-(omega-Phenylalkyl)phenoxy]alkylamines II: Synthesis and selective serotonin-2 receptor binding. Chem Pharm Bull 2000, 48, 2, 245. |
| 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) | 42341 | 2-(hydroxymethyl)phenol | 90-01-7 | C7H8O2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 42342 | [2-(benzyloxy)phenyl]methanol | C14H14O2 | 详情 | 详情 | |
| (IV) | 42343 | benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene | C14H13ClO | 详情 | 详情 | |
| (V) | 42344 | [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride | C32H28ClOP | 详情 | 详情 | |
| (VI) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VII) | 42345 | 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether | C22H20O2 | 详情 | 详情 | |
| (VIII) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 | |
| (IX) | 21347 | (2S)pyrrolidinylmethanol | 23356-96-9 | C5H11NO | 详情 | 详情 |
| (X) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (XI) | 42346 | ethyl (2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C8H15NO3 | 详情 | 详情 | |
| (XII) | 42347 | ethyl (2S)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-pyrrolidinecarboxylate | C15H21NO5S | 详情 | 详情 | |
| (XIII) | 42348 | ethyl (2S)-2-(cyanomethyl)-1-pyrrolidinecarboxylate | C9H14N2O2 | 详情 | 详情 | |
| (XIV) | 42349 | ethyl (2S)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate | C11H19NO4 | 详情 | 详情 | |
| (XV) | 42350 | ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C9H17NO3 | 详情 | 详情 | |
| (XVI) | 42351 | ethyl (2S)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate | C16H23NO5S | 详情 | 详情 | |
| (XVII) | 42352 | ethyl (2S)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate | C24H31NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in HOAc, followed by the introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH(XVI), Boc-Hyp-OH(XVIII) and Boc-Pro-OH(XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28946801b).
| 【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.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382. |
| 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),(X) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 | |
| (XI) | 43249 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C16H20N2O5S | 详情 | 详情 | |
| (XII) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (XIII) | 42350 | ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C9H17NO3 | 详情 | 详情 | |
| (XIV) | 43251 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoic acid | C16H21NO4 | 详情 | 详情 | |
| (XV) | 43252 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C37H42N4O8S | 详情 | 详情 | |
| (XVI) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (XVII) | 43253 | 2-[(3S)-3-[[(2R,5R)-2-[(benzyloxy)methyl]-5-(2,3-dihydro-1H-inden-2-yl)-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C39H45N5O9S | 详情 | 详情 | |
| (XVIII) | 19043 | (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (XIX) | 43254 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl]amino)acetyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic aci | C44H52N6O11S | 详情 | 详情 | |
| (XX) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XXI) | 43255 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben | C49H59N7O12S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH (XVI), Boc-Hyp-OH (XVIII) and Boc-Pro-OH (XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28947001b).
| 【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.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382. |
| 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),(X) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 | |
| (XI) | 43249 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C16H20N2O5S | 详情 | 详情 | |
| (XII) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (XIII) | 42350 | ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C9H17NO3 | 详情 | 详情 | |
| (XIV) | 43251 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoic acid | C16H21NO4 | 详情 | 详情 | |
| (XV) | 43252 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C37H42N4O8S | 详情 | 详情 | |
| (XVI) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (XVII) | 43253 | 2-[(3S)-3-[[(2R,5R)-2-[(benzyloxy)methyl]-5-(2,3-dihydro-1H-inden-2-yl)-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C39H45N5O9S | 详情 | 详情 | |
| (XVIII) | 19043 | (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (XIX) | 43254 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl]amino)acetyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic aci | C44H52N6O11S | 详情 | 详情 | |
| (XX) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XXI) | 43255 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben | C49H59N7O12S | 详情 | 详情 |