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【结 构 式】

【分子编号】26200

【品名】ethyl (3S)-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate

【CA登记号】

【 分 子 式 】C12H18N2O2S

【 分 子 量 】254.3532

【元素组成】C 56.67% H 7.13% N 11.01% O 12.58% S 12.61%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

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:(VIII)

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:(VIII)

Alternatively, N-Boc-D-tryptophan (IX) was esterified with benzyl alcohol in the presence of EDC and DMAP to give benzyl ester (XIII). Deprotection of the Boc group of (XIII) with TFA, followed by coupling of the resulting amino ester (XIV) with N-Boc-2-aminoisobutyric acid (XI) provided protected dipeptide (XV). Hydrogenolytic removal of the benzyl ester of (XV) gave carboxylic acid (XVI), which was coupled to the (S)-nipecotate (VIII) to afford the precursor (XII). Finally, removal of the Boc protecting group by treatment with HCl in EtOAc yielded the title compound.

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
(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
(IX) 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
(XIII) 27719 benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate C23H26N2O4 详情 详情
(XIV) 25797 benzyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate C18H18N2O2 详情 详情
(XV) 27720 benzyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoate C27H33N3O5 详情 详情
(XVI) 27721 (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propionic acid C20H27N3O5 详情 详情
Extended Information