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【结 构 式】 
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【分子编号】18471 【品名】N-(tert-butoxycarbonyl)-2-methylalanine 【CA登记号】30992-29-1 |
【 分 子 式 】C9H17NO4 【 分 子 量 】203.23832 【元素组成】C 53.19% H 8.43% N 6.89% O 31.49% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The reaction of (X) with N-(tert-butoxycarbonyl)-D-tryptophan (XI) by means of DCC and HOBT in ethyl acetate affords the expected condensation product (XII), which is deprotected with HCl in hot ethanol giving compound (XIII) with its amino group free. The reaction of (XIII) with 2-(tert-butoxycarbonylamino)isobutyric acid (XIV) by means of DCC and HOBT as before yields the expected condensation product (XV), which is finally deprotected with HCl in methanol as before to give the target compound.
| 【1】 Maligres, P.E.; et al.; Preparation of (S)-3-carbethoxy-3-benzylpiperidine and the growth hormone secretagogue L-163,540. J Org Chem 1998, 63, 25, 9548. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 20217 | ethyl (3S)-3-benzyl-3-piperidinecarboxylate | C15H21NO2 | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 20220 | ethyl (3S)-3-benzyl-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-piperidinecarboxylate | C31H39N3O5 | 详情 | 详情 | |
| (XIII) | 20221 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-benzyl-3-piperidinecarboxylate | C26H31N3O3 | 详情 | 详情 | |
| (XIV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XV) | 20223 | ethyl (3S)-3-benzyl-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-piperidinecarboxylate | C35H46N4O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)N-Boc-D-(3-phenylpropyl)glycine (I) was esterified to benzyl ester (II), and then, tert-butoxycarbonyl group was cleaved by acidic treatment to give amine (III). This was coupled with N-Boc-2-aminoisobutyric acid (IV) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to afford dipeptide ester (V), from which the benzyl ester group was removed by hydrogenolysis in the presence of Pd/C. The resulting acid (VI) was condensed with 1-(2-nitrophenyl)piperazine (VII) in the presence of EDC and HOBt to produce piperazide (VIII). Subsequent reduction of the nitro group by hydrogenation in the presence of Raney-Ni gave aniline (IX), which was treated with 2-propanesulfonyl chloride (X) to yield sulfonamide (XI). Finally, the tert-butoxycarbonyl protecting group was removed by treatment either with HCl in EtOAc or with trifluoroacetic acid to afford the target compound as the hydrochloride or the trifluoroacetate salt, respectively.
| 【1】 Barakat, K.J.; Cheng, K.; Chan, W.W.; Butler, B.S.; Jacks, T.M.; Schleim, K.D.; Hora, D.F. Jr.; Hickey, G.J.; Smith, R.G.; Patchett, A.A.; Nargund, R.P.; Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues. Bioorg Med Chem Lett 1998, 8, 11, 1431. |
| 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) | 18468 | (2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoic acid | C16H23NO4 | 详情 | 详情 | |
| (II) | 18469 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoate | C23H29NO4 | 详情 | 详情 | |
| (III) | 18470 | benzyl (2R)-2-amino-5-phenylpentanoate | C18H21NO2 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 18472 | benzyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C27H36N2O5 | 详情 | 详情 | |
| (VI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (VII) | 18474 | 1-(2-nitrophenyl)piperazine | C10H13N3O2 | 详情 | 详情 | |
| (VIII) | 18475 | tert-butyl 1,1-dimethyl-2-[((1R)-1-[[4-(2-nitrophenyl)-1-piperazinyl]carbonyl]-4-phenylbutyl)amino]-2-oxoethylcarbamate | C30H41N5O6 | 详情 | 详情 | |
| (IX) | 18476 | tert-butyl 2-[((1R)-1-[[4-(2-aminophenyl)-1-piperazinyl]carbonyl]-4-phenylbutyl)amino]-1,1-dimethyl-2-oxoethylcarbamate | C30H43N5O4 | 详情 | 详情 | |
| (X) | 18477 | 2-propanesulfonyl chloride | 10147-37-2 | C3H7ClO2S | 详情 | 详情 |
| (XI) | 18478 | tert-butyl 2-([(1R)-1-[(4-[2-[(isopropylsulfonyl)amino]phenyl]-1-piperazinyl)carbonyl]-4-phenylbutyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C33H49N5O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The intermediate dipeptide (VI) was prepared by two similar ways. Treatment of N-Boc-O-benzyl-D-serine (I) with MeI and K2CO3 produced the methyl ester (II). Subsequent deprotection of the Boc group of (II) with trifluoroacetic acid gave aminoester (III), which was coupled with N-Boc-alpha-methylalanine (IV) using EDC and HOBt yielding (V). Hydrolysis of the resulting dipeptide ester (V) then provided intermediate (VI). In an alternative procedure, N-Boc-alpha-methyl alanine (IV) was activated as the N-hydroxysuccinimidyl ester (VII), which was condensed with O-benzyl-D-serine (VIII) to produce dipeptide (VI).
| 【1】 Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.; Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 276. |
| 【2】 Carpino, P.A.; Jardine, D.P.A.; Lefker, B.A.; Ragan, J.A. (Pfizer Inc.); Growth-hormone secretagogues. EP 0869968; JP 1999501945; WO 9724369 . |
| 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) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (II) | 28100 | methyl (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoate | C16H23NO5 | 详情 | 详情 | |
| (III) | 28101 | methyl (2R)-2-amino-3-(benzyloxy)propanoate | C11H15NO3 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 28102 | methyl (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoate | C20H30N2O6 | 详情 | 详情 | |
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (VII) | 28104 | tert-butyl 2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1,1-dimethyl-2-oxoethylcarbamate | C13H20N2O6 | 详情 | 详情 | |
| (VIII) | 28105 | (2R)-2-amino-3-(benzyloxy)propionic acid | C10H13NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)The successive condensations of fluorenylmethoxycarbonyl-Rink amide resin (I) with Nalpha-FMOC-Nepsilon-Boc-L-lysine (II), FMOC-D-phenylalanine (IV), FMOC-D-2-naphthylalanine (VI), FMOC-Npi-trityl-L-histidine (VIII), and finally 2-(tert-butoxycarbonylamino)isobutyric acid (X), using the solid phase peptide technique synthesis yielded resins (III), (V), (VII), (IX) and finally (XI). This last resin was then treated with trifluoroacetic acid in order to eliminate the Boc protecting groups and the solid phase resin and isolate the target compound.
| 【1】 Muller, L.; et al.; C-14-labelling of ipamorelin, a growth hormone secretagogue. J Label Compd Radiopharm 1998, 41, 12, 1093. |
| 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) | 18854 | (2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | C26H32N2O6 | 详情 | 详情 | |
| (II) | 28722 | 9H-fluoren-9-ylmethyl carbamate | 84418-43-9 | C15H13NO2 | 详情 | 详情 |
| (III) | 28723 | 9H-fluoren-9-ylmethyl (1S)-1-(aminocarbonyl)-5-[(tert-butoxycarbonyl)amino]pentylcarbamate | C26H33N3O5 | 详情 | 详情 | |
| (IV) | 28730 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid | C24H21NO4 | 详情 | 详情 | |
| (V) | 28724 | 9H-fluoren-9-ylmethyl (1R)-2-([(1S)-1-(aminocarbonyl)-5-[(tert-butoxycarbonyl)amino]pentyl]amino)-1-benzyl-2-oxoethylcarbamate | C35H42N4O6 | 详情 | 详情 | |
| (VI) | 28725 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-naphthyl)propionic acid | C28H23NO4 | 详情 | 详情 | |
| (VII) | 28726 | 9H-fluoren-9-ylmethyl (1R,4R,7S)-7-(aminocarbonyl)-4-benzyl-15,15-dimethyl-1-(2-naphthylmethyl)-2,5,13-trioxo-14-oxa-3,6,12-triazahexadec-1-ylcarbamate | C48H53N5O7 | 详情 | 详情 | |
| (VIII) | 28727 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-5-yl)propionic acid | C40H33N3O4 | 详情 | 详情 | |
| (IX) | 28728 | 9H-fluoren-9-ylmethyl (1S,4R,7R,10S)-10-(aminocarbonyl)-7-benzyl-18,18-dimethyl-4-(2-naphthylmethyl)-2,5,8,16-tetraoxo-1-[(1-trityl-1H-imidazol-5-yl)methyl]-17-oxa-3,6,9,15-tetraazanonadec-1-ylcarbamate | C73H74N8O8 | 详情 | 详情 | |
| (X) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XI) | 28729 | tert-butyl (4S,7R,10R,13S)-13-(aminocarbonyl)-10-benzyl-1,1,21,21-tetramethyl-7-(2-naphthylmethyl)-2,5,8,11,19-pentaoxo-4-[(1-trityl-1H-imidazol-5-yl)methyl]-20-oxa-3,6,9,12,18-pentaazadocos-1-ylcarbamate | C67H79N9O9 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)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6
该中间体在本合成路线中的序号：(XI)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7
该中间体在本合成路线中的序号：(IX)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 |
合成路线8
该中间体在本合成路线中的序号：(XII)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9
该中间体在本合成路线中的序号：(IV)Treatment of N-Boc-D-serine benzyl ether (I) with methyl iodide and NaHCO3 provided methyl ester (II). Subsequent acid cleavage of the Boc group of (II) gave aminoester (III), which was coupled with N-Boc-alpha-aminoisobutyric acid (IV) to afford dipeptide (V). The methyl ester group of (V) was then hydrolyzed to acid (VI) using LiOH.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 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) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (II) | 28100 | methyl (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoate | C16H23NO5 | 详情 | 详情 | |
| (III) | 28101 | methyl (2R)-2-amino-3-(benzyloxy)propanoate | C11H15NO3 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 28102 | methyl (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoate | C20H30N2O6 | 详情 | 详情 | |
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)The alkylation of diethyl acetamidomalonate (II) with 1-bromo-3-phenylpropane (I) by means of NaOEt provided the substituted malonate (III), which upon hydrolysis and further decarboxylation gave rise to racemic 2-(acetylamino)-5-phenylpentanoic acid (IVa-b). Kinetic resolution employing Acylase I in the presence of CoCl2 produced a mixture of the (S)-amino acid (V) and the unaltered (R)-amide (VI), which were separated by differential solubility. The desired (R)-amide (VI) was hydrolyzed with aqueous HCl and then treated with EtOH to produce aminoester (VII). Subsequent coupling of (VII) with N-Boc-alpha-aminoisobutyric acid (VIII) employing 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) yielded the protected dipeptide (IX). Basic hydrolysis of the ethyl ester of (IX) afforded the intermediate (X).
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa),(VI) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (IVb) | 35775 | (2S)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (I) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (V) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (X) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VIII)Alkylation of diethyl acetamidomalonate (I) with 1-bromo-3-phenylpropane (II) in the presence of NaOEt afforded phenylpropyl malonate (III). Hydrolysis and subsequent decarboxylation of malonate ester (III) yielded racemic 2-(acetylamino)-5-phenylpentanoic acid (IV). Kinetic resolution was achieved by enantioselective hydrolysis of the (S)-acetamide to give amino acid (VI). The desired (R)-enantiomer (V) was then hydrolyzed with HCl and further esterified with HCl-EtOH to provide amino ester (VII). Coupling with N-Boc-alpha-aminoisobutyric acid (VIII) via activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine (IX) furnished dipeptide (X). The ethyl ester group of (X) was then hydrolyzed to acid (XI) using LiOH.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 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) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (II) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (IV) | 38799 | N-acetyl-5-phenylnorvaline | C13H17NO3 | 详情 | 详情 | |
| (V) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (VI) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 38798 | 2-chloro-4,6-dimethoxy-1,3,5-triazine; 4-chloro-6-methoxy-1,3,5-triazin-2-yl methyl ether | 3140-73-6 | C5H6ClN3O2 | 详情 | 详情 |
| (X) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (XI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XVI)Alkaline hydrolysis of ethyl ester (XII) affords acid (XIII), which is further coupled to ethylamine, producing amide (XIV). Then, removal of the N-Boc group of (XIV) with HCl in EtOAc gives amine (XV). This is coupled to N-Boc-alpha-methylalanine (XVI) to furnish the dipeptide derivative (XVII). Finally, acidic Boc-group cleavage in (XVII) leads to the title compound.
| 【1】 Brinkmann, V.; Hesise, C.E.; Davis, M.D.; et al.; FTY720, a novel therapeutic for transplantation and autoimmunity, targets G-protein-coupled receptors for sphingosine-1-phosphate. 19th Int Congr Transplant Soc (Aug 25 2002, Miami) 2002, Abst 0116. |
| 【2】 Patchett, A.A.; Tata, J.R.; Lu, Z. (Merck & Co., Inc.); Bridged piperidines promote release of growth hormone. US 5731317 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 58372 | ethyl 2-((1R,5S)-8-{(2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoyl}-8-azabicyclo[3.2.1]oct-3-yl)benzoate | C32H42N2O5 | 详情 | 详情 | |
| (XIII) | 58373 | 2-((1R,5S)-8-{(2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoyl}-8-azabicyclo[3.2.1]oct-3-yl)benzoic acid | C30H38N2O5 | 详情 | 详情 | |
| (XIV) | 58374 | tert-butyl (1R)-1-[((1R,5S)-3-{2-[(ethylamino)carbonyl]phenyl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-4-phenylbutylcarbamate | C32H43N3O4 | 详情 | 详情 | |
| (XV) | 58375 | 2-{(1R,5S)-8-[(2R)-2-amino-5-phenylpentanoyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-ethylbenzamide | C27H35N3O2 | 详情 | 详情 | |
| (XVI) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XVII) | 58376 | tert-butyl 2-({(1R)-1-[((1R,5S)-3-{2-[(ethylamino)carbonyl]phenyl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-4-phenylbutyl}amino)-1,1-dimethyl-2-oxoethylcarbamate | C36H50N4O5 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XIII)Coupling of the amine (XII) with N-Boc-2-aminoisobutyric acid (XIII) leads to the dipeptide amide (XIV). Alkaline hydrolysis of the ethyl ester group of (XIV) gives the benzoic acid (XV), which is then coupled to ethylamine to produce the amide (XVI). Finally, the N-Boc protecting group of (XVI) is cleaved by means of HCl in dioxane to furnish the target compound.
| 【1】 Lu, Z.; Tata, J.R.; Cheng, K.; Wei, L.; Chan, W.W.-S.; Butler, B.; Schleim, K.D.; Jacks, T.M.; Hickey, G.; Patchett, A.A.; Substituted bridged phenyl piperidines: Orally active growth hormone secretagogues. Bioorg Med Chem Lett 2003, 13, 10, 1817. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 64728 | ethyl 2-[8-(2-amino-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoate | C26H32N2O3 | 详情 | 详情 | |
| (XIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIV) | 64729 | ethyl 2-[8-(2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropanoyl]amino}-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoate | C35H47N3O6 | 详情 | 详情 | |
| (XV) | 64730 | 2-[8-(2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropanoyl]amino}-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoic acid | C33H43N3O6 | 详情 | 详情 | |
| (XVI) | 64731 | 1,1-dimethylethyl 2-({1-[(3-{2-[(ethylamino)carbonyl]phenyl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-3-phenylpropyl}amino)-1,1-dimethyl-2-oxoethylcarbamate | C35H48N4O5 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)N-Protection of 2-methylalanine with Boc2O, optionally in the presence of NaHCO3, in THF/H2O yields N-Boc-2-methylalanine (II) , which is then methylated with Me3SiCHN2 in MeOH/THF or with MeI using KHCO3 in DMF to give the methyl ester (III) . Reduction of the ester (III) by means of LiBH4 in THF /EtOH affords the primary alcohol (IV) , which can also be prepared from 2-amino-2-methyl-1-propanol (V) by N-protection with Boc2O in CH2Cl2 . After conversion of alcohol (IV) to the corresponding mesylate (VI) with MsCl and Et3N in CH2Cl2, N-deprotection with HCl in dioxane provides amine (VII), which by reaction with Na2SO3 in H2O yields the aminosulfonic acid (VIII) . Finally, compound (VIII) is N-chlorinated using trichloroisocyanuric acid , Cl2 , HOCl or NaOCl/HCl .
The aminosulfonic acid (VIII) can also be prepared by the following two strategies: Condensation of acetone (IX) with t-BuSONH2 by means of Ti(OEt)4 gives the N-sulfinylimine (X), which is then coupled with ethyl methanesulfonate (XI) in the presence of BuLi and HMPA in THF to produce the propanesulfonate derivative (XII). Finally, hydrolysis of the sulfonate ester (XII) with LiOH in THF/MeOH/H2O, followed by removal of the sulfinyl protecting group with HCl in MeOH furnishes aminosulfonic acid (VIII) .
Reduction of 2-hydroxy-2-methylpropanenitrile (XIII) by means of LiAlH4 yields 1-amino-2-methylpropan-2-ol (XIV), which is then Nprotected with Boc2O to give N-Boc-1-amino-2-methylpropan-2-ol (XV). Mesylation of the alcohol (XV) with MsCl using Et3N in CH2Cl2 and subsequent N-deprotection of the resulting mesylate (XVI) with HCl in dioxane affords the amino mesylate (XVII). Finally, substitution of the tertiary mesylate (XVII) with Na2SO3 occurs with rearrangement of the primary amino group generating aminosulfonic acid (VIII) .
| 【1】 Shiau, T.P., Houchin, A., Nair, S., Xu, P., Low, E., Najafi, R., Jain, R. Stieglitz rearrangement of N,N-dichloro-beta,beta-disubstituted taurines under mild aqueous conditions. Bioorg Med Chem Lett 2009, 19(4): 1110-4. |
| 【2】 Braghiroli, D., DiBella, M. New methods for the preparation of 2-amino-2-methylpropanesulfonic acid. Tetrahedron Lett 1996, 37(40): 7319-. |
| 【3】 Ilson, B.E. et al. Effect of a new synthetic hexapetide to selectively stimulate growth hormone release in healthy human subjects. J Clin Endocrinol Metab 1989, 69(1): 212. |
| 【4】 Wang, L., Khosrovi, B., Najafi, R. N-Chloro-2,2-dimethyltaurines: A new class of remarkably stable N-chlorotaurines. Tetrahedron Lett 2008, 49(14): 2193-5. |
| 【5】 Debabov, D. NVC-422, a novel n-chlorotaurine derivative as topical antimicrobial. Drug Discov Chem 2010, Abst. |
| 【6】 Najafi, R., Wang, L., Bassiri, M., Yang, J. (NovaBay Pharmaceuticals, Inc.). N,N-Dihalogenated amino acids and derivatives. CA 2535926, EP 1656095, JP 2007502826, US 2005065115, US 7462361, WO 2005020896. |
| 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) | 31173 | 2-methylalanine；2-Aminoisobutyric acid;2-Amino-2-methylpropionic acid;alpha-Aminoisobutyric acid | 62-57-7 | C4H9NO2 | 详情 | 详情 |
| (II) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (III) | 68833 | methyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate | C10H19NO4 | 详情 | 详情 | |
| (IV) | 68834 | tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate;tert-ButylN-(2-hydroxy-1,1-dimethylethyl)carbamate;tert-Butyl(2-hydroxy-1,1-dimethylethyl)carbamate;1,1-Dimethylethyl(2-hydroxy-1,1-dimethylethyl)carbamate;(2-Hydroxy-1,1-dimethylethyl)carbamicacid tert-butyl ester | 102520-97-8 | C9H19NO3 | 详情 | 详情 |
| (V) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (VI) | 68835 | 2-((tert-butoxycarbonyl)amino)-2-methylpropyl methanesulfonate | C10H21NO5S | 详情 | 详情 | |
| (VII) | 68836 | 2-amino-2-methylpropyl methanesulfonate hydrochloride | C5H13NO3S.HCl | 详情 | 详情 | |
| (VIII) | 68837 | 2-amino-2-methylpropyl hydrogen sulfate | C4H11NO4S | 详情 | 详情 | |
| (IX) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (X) | 68838 | 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide | C7H15NOS | 详情 | 详情 | |
| (XI) | 48097 | ethyl methanesulfonate；ethylmesylate;ethyl methanesulphonate；O-ethylmethylsulfonate | 62-50-0 | C3H8O3S | 详情 | 详情 |
| (XII) | 68839 | ethyl 2-(1,1-dimethylethylsulfinamido)-2-methylpropane-1-sulfonate | C10H23NO4S2 | 详情 | 详情 | |
| (XIII) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (XIV) | 25008 | 1-amino-2-methylpropan-2-ol;1-amino-2-methyl-2-propanol;1,1-Dimethylethanolamine;2-Amino-a,a-dimethylethanol;2-Hydroxy-2-methyl-1-propylamine;2-Hydroxyisobutylamine;2-Methyl-2-hydroxypropylamine;3-Amino-2-methyl-2-propanol | 2854-16-2 | C4H11NO | 详情 | 详情 |
| (XV) | 68840 | tert-butyl (2-hydroxy-2-methylpropyl)carbamate;(2-hydroxy-2-methylpropyl)-1,1-dimethylethyl ester Carbamicacid;N-(2-hydroxy-2-methylpropyl)-1,1-dimethylethyl ester Carbamic acid | 183059-24-7 | C9H19NO3 | 详情 | 详情 |
| (XVI) | 68841 | 1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl methanesulfonate | C10H21NO5S | 详情 | 详情 | |
| (XVII) | 68842 | 1-amino-2-methylpropan-2-yl methanesulfonate hydrochloride | C5H13NO3S.HCl | 详情 | 详情 |