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【结 构 式】 
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【分子编号】26186 【品名】1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate 【CA登记号】 |
【 分 子 式 】C13H23NO4 【 分 子 量 】257.32996 【元素组成】C 60.68% H 9.01% N 5.44% O 24.87% |
合成路线1
该中间体在本合成路线中的序号：(II)Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 4-(bromomethyl)thiazole (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.
| 【1】 Schleim, K.D.; Leung, K.; Cheng, K.; Patchent, A.A.; Morriello, G.; Smith, R.; Jacks, T.; Yang, L.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogues. Bioorg Med Chem Lett 1999, 9, 13, 1761. |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 26196 | 4-(bromomethyl)-1,3-thiazole | C4H4BrNS | 详情 | 详情 | |
| (IV) | 26197 | 1-(tert-butyl) 3-ethyl 3-(1,3-thiazol-4-ylmethyl)-1,3-piperidinedicarboxylate | C17H26N2O4S | 详情 | 详情 | |
| (V) | 26198 | ethyl 3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (VI) | 26190 | (2R)-2-(acetoxy)-2-phenylethanoic acid | C10H10O4 | 详情 | 详情 | |
| (VII) | 26199 | ethyl (3S)-1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C22H26N2O5S | 详情 | 详情 | |
| (VIII) | 26200 | ethyl (3S)-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26201 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C28H36N4O5S | 详情 | 详情 | |
| (XI) | 26202 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C23H28N4O3S | 详情 | 详情 | |
| (XII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIII) | 26203 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C32H43N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The synthesis of the precursor (XII) has been reported by two related procedures. Ethyl nipecotate (I) was protected as the N-Boc derivative (II) using di-tert-butyl dicarbonate. Benzylic bromination of 4-methylthiazole (III) with NBS and AIBN provided bromide (IV). Then, alkylation of protected nipecotate (II) with bromide (IV) in the presence of potassium hexamethyldisilazide gave the thiazolylmethyl derivative (V). Subsequent acid deprotection of the Boc group of (V) yielded racemic piperidine (VI). Resolution was achieved by coupling with (R)-O-acetylmandelic acid, followed by chromatographic separation of the diastereomeric amides (VII), and hydrolytic removal of the chiral auxiliary. The required (S)-nipecotate (VIII) was condensed with N-Boc-D-tryptophan (IX) to provide amide (X). Deprotection of the Boc group and further coupling of (X) with N-Boc-2-aminoisobutyric acid (XI) then furnished intermediate (XII).
| 【1】 Cheng, K.; Yang, L.; Morriello, G.; Smith, R.; Patchett, A.A.; Scheim, k.D.; Jacks, T.; Leung, K.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogue L-165,666. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 074. |
| 【2】 Morriello, G.J.; Patchett, A.A.; Yang, L.; Chen, M.H.; Nargund, R. (Merck & Co., Inc.); Piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone. EP 0739204; US 5492916; US 5492920; US 5494919; WO 9513069 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 27718 | 4-methyl-1,3-thiazole | 693-95-8 | C4H5NS | 详情 | 详情 |
| (IV) | 26196 | 4-(bromomethyl)-1,3-thiazole | C4H4BrNS | 详情 | 详情 | |
| (V) | 27723 | 1-(tert-butyl) 3-ethyl 3-(1,3-thiazol-4-ylmethyl)-1,3-piperidinedicarboxylate | C17H26N2O4S | 详情 | 详情 | |
| (VI) | 27722 | ethyl 3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VII) | 27724 | ethyl 1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C22H26N2O5S | 详情 | 详情 | |
| (VIII) | 26200 | ethyl (3S)-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26201 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C28H36N4O5S | 详情 | 详情 | |
| (XI) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XII) | 26203 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C32H43N5O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 2-(chloromethyl)pyridine chloride (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.
| 【1】 Schleim, K.D.; Leung, K.; Cheng, K.; Patchent, A.A.; Morriello, G.; Smith, R.; Jacks, T.; Yang, L.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogues. Bioorg Med Chem Lett 1999, 9, 13, 1761. |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 26187 | 2-(Chloromethyl)pyridine | 4377-33-7 | C6H6ClN | 详情 | 详情 |
| (IV) | 26188 | 1-(tert-butyl) 3-ethyl 3-(2-pyridinylmethyl)-1,3-piperidinedicarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (V) | 26189 | ethyl 3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VI) | 26190 | (2R)-2-(acetoxy)-2-phenylethanoic acid | C10H10O4 | 详情 | 详情 | |
| (VII) | 26191 | ethyl (3S)-1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C24H28N2O5 | 详情 | 详情 | |
| (VIII) | 26192 | ethyl (3S)-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26193 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C30H38N4O5 | 详情 | 详情 | |
| (XI) | 26194 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C25H30N4O3 | 详情 | 详情 | |
| (XII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIII) | 26195 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C34H45N5O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Ethyl nipecotate (I) was protected as the N-Boc derivative (II) and subsequently reduced to alcohol (III) by means of LiAlH4. Conversion of alcohol (III) into iodide (IV) was achieved by treatment with iodine and triphenylphosphine. The dianion of the chiral azetidinecarboxylic acid (V) was alkylated with iodide (IV) to furnish adduct (VI) as a diastereomeric mixture that was desilylated to (VII) using tetrabutylammonium fluoride. Benzyl ester (VIII) was then obtained by reaction of carboxylic acid (VII) with benzyl bromide and NaHCO3.
| 【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 51124 | tert-butyl 3-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 51120 | tert-butyl 3-(iodomethyl)-1-piperidinecarboxylate | C11H20INO2 | 详情 | 详情 | |
| (V) | 51121 | (2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C21H38N2O5Si | 详情 | 详情 | |
| (VI) | 49426 | (2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (VII) | 51122 | (2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-4-oxo-2-azetidinecarboxylic acid | C15H24N2O5 | 详情 | 详情 | |
| (VIII) | 51123 | tert-butyl 3-([(2S,3R)-2-[(benzyloxy)carbonyl]-4-oxoazetidinyl]methyl)-1-piperidinecarboxylate | C22H30N2O5 | 详情 | 详情 |