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【结 构 式】 
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【分子编号】58791 【品名】tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate 【CA登记号】 |
【 分 子 式 】C29H31N3O4S 【 分 子 量 】517.64896 【元素组成】C 67.29% H 6.04% N 8.12% O 12.36% S 6.19% |
合成路线1
该中间体在本合成路线中的序号：(XII)Condensation between (S)-alpha-methylbenzylamine (I) and ethyl glyoxylate (II) afforded imine (III), which was subjected to hetero-Diels-Alder cycloaddition with 2-(trimethylsilyloxy)-1,3-butadiene (IV) producing piperidinecarboxylate (V) as the major diastereoisomer. Ketalization of (V) with triethyl orthoformate gave the corresponding the diethyl acetal (VI). The ester group of (VI) was then reduced to alcohol (VII) employing LiAlH4. Mitsunobu condensation of alcohol (VII) with phthalimide (VIII) gave (IX) which, followed by acidic ketal hydrolysis, furnished (X). Condensation of piperidinone (X) with t-butyl cyanoacetate (XI) in the presence of sulfur and morpholine gave rise to two regioisomeric thienopyridine derivatives (XII) and (XIII), which were separated by column chromatography.
| 【1】 Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 . |
| 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) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (II) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (III) | 58785 | ethyl 2-{[(1S)-1-phenylethyl]imino}acetate | C12H15NO2 | 详情 | 详情 | |
| (IV) | 18557 | 1-methylene-2-propenyl trimethylsilyl ether; trimethyl[(1-methylene-2-propenyl)oxy]silane | 38053-91-7 | C7H14OSi | 详情 | 详情 |
| (V) | 58786 | ethyl (2R)-4-oxo-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (VI) | 58787 | ethyl (2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate | C20H31NO4 | 详情 | 详情 | |
| (VII) | 58788 | {(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methanol | C18H29NO3 | 详情 | 详情 | |
| (VIII) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (IX) | 58789 | 2-({(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione | C26H32N2O4 | 详情 | 详情 | |
| (X) | 58790 | 2-({(2R)-4-oxo-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione | C22H22N2O3 | 详情 | 详情 | |
| (XI) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (XII) | 58791 | tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C29H31N3O4S | 详情 | 详情 | |
| (XIII) | 58792 | tert-butyl (5R)-2-amino-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C29H31N3O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The desired minor isomer (XII) was subjected to hydrazinolysis to provide amine (XIV). Selective acylation at the aliphatic amino group of (XIV) with 5-hydroxyindole-2-carboxylic acid (XV) in the presence of EDC as the coupling reagent furnished amide (XVI). The remaining primary amino group of (XVI) was subsequently acylated by the oxalyl imidazolide (XVII) producing oxalamide (XVIII). The chiral auxiliary alpha-methylbenzyl group of (XVIII) was then removed by transfer hydrogenolysis with formic acid and Pd/C, producing the secondary amine (XIX). Finally, tert-butyl esters cleavage in (XIX) was accomplished by treatment with trifluoroacetic acid to yield the corresponding dicarboxylic acid.
| 【1】 Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 . |
| 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) | 58791 | tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C29H31N3O4S | 详情 | 详情 | |
| (XIV) | 58793 | tert-butyl (7S)-2-amino-7-(aminomethyl)-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C21H29N3O2S | 详情 | 详情 | |
| (XV) | 58796 | 5-Hydroxy-2-indolecarboxylic acid; 5-Hydroxyindole-2-carboxylic acid | 21598-06-1 | C9H7NO3 | 详情 | 详情 |
| (XVI) | 58794 | tert-butyl (7S)-2-amino-7-({[(5-hydroxy-1H-indol-2-yl)carbonyl]amino}methyl)-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C30H34N4O4S | 详情 | 详情 | |
| (XVII) | 58795 | tert-butyl 2-(1H-imidazol-1-yl)-2-oxoacetate | C9H12N2O3 | 详情 | 详情 | |
| (XVIII) | 58797 | tert-butyl (7S)-2-{[2-(tert-butoxy)-2-oxoacetyl]amino}-7-({[(5-hydroxy-1H-indol-2-yl)carbonyl]amino}methyl)-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C36H42N4O7S | 详情 | 详情 | |
| (XIX) | 58798 | tert-butyl (7S)-2-{[2-(tert-butoxy)-2-oxoacetyl]amino}-7-({[(5-hydroxy-1H-indol-2-yl)carbonyl]amino}methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C28H34N4O7S | 详情 | 详情 |