|
【结 构 式】 
|
【分子编号】19736 【品名】tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C15H28N2O4 【 分 子 量 】300.3984 【元素组成】C 59.98% H 9.39% N 9.33% O 21.3% |
合成路线1
该中间体在本合成路线中的序号：(XI)The reaction of tert-butoxycarbonyl-L-phenylalanine (I) with isobutyl chloroformate in THF gives the expected mixed anhydride which is treated with diazomethane and HCl yielding the corresponding chloromethyl ketone (II). The reduction of (II) with NaBH4 in THF affords the (S)-chlorohydrin (IV), which is treated with KOH in ethanol to obtain the chiral epoxide (V)(1,2). Ring opening of (V) with (±)(cis)-N-tert-butyl-4-(4-pyridylmethoxy)piperidine-2-carboxamide (VI) by a treatment with LiCl in refluxing ethanol gives a mixture of diastereomers that is separated by chromatography giving the pure isomer (VII). The reaction of (VII) with tert-butoxycarbonyl-L-valine (VIII) by treatment first with trifluoroacetic acid (TFA), and condesation by means of BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and NMM (N-methylmorpholine) affords the expected condensation product (IX). Finally, this compound is condensed with quinoline-2-carboxylic acid (X) by means of BOP and NMM as before. 2) The piperidine (VI) has been obtained by condensation of (±)(cis)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (XI) with 4-(chloromethyl)pyridine (XII) by means of NaH in DMS, followed by hydrolysis with HCl.
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 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) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (II) | 19727 | tert-butyl (1S)-1-benzyl-3-diazo-2-oxopropylcarbamate | C15H19N3O3 | 详情 | 详情 | |
| (III) | 19728 | tert-butyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate | C15H20ClNO3 | 详情 | 详情 | |
| (IV) | 19729 | (1S,2S)-[3-chloro-2-hydroxy-1-benzylpropyl]carbamic acid, 1,1-dimethylethyl ether; tert-butyl (1S,2S)-1-benzyl-3-chloro-2-hydroxypropylcarbamate | 165727-45-7 | C15H22ClNO3 | 详情 | 详情 |
| (V) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (VI) | 19731 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C16H25N3O2 | 详情 | 详情 | |
| (VII) | 19732 | tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropylcarbamate | C31H46N4O5 | 详情 | 详情 | |
| (VIII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (IX) | 19734 | tert-butyl (1S)-1-[([(1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropyl]amino)carbonyl]-2-methylpropylcarbamate | C36H55N5O6 | 详情 | 详情 | |
| (X) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XI) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (XII) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The chiral piperidine (2S,4R)(VI) has been obtained as follows: The cyclization of 3-buten-1-ol (XXII) with (S)-1-phenylethylamine (XXIII) and glyoxylic acid (XXIV) by means of tosyl chloride in THF gives a mixture of the (2S,4R) and (2R,4S) lactones (XXV), which is resolved by fractional crystallyzation of their salts with the chiral camphorsulfonic acid (XXVI), followed by elimination of the acid with ammonia to afford (2S,4R)(XXVII). The reaction of lactone (XXVII) with isopropylmagnesium chloride and tert-butylamine in THF gives (2S,4R)-N-tert-butyl-4-hydroxy-1-(1(S)-phenylethyl)piperidine-2-carboxamide (XXVIII), which is debenzylated by hydrogenation and protected with tert-butoxycarbonyl anhydride yielding (2S,4R)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (2S,4R)(XI), which is finally condensed with 4-(chloromethyl)pyridine (XII) as before to obtain the chiral piperidine (2S,4R)(VI), already reported.
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 19731 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C16H25N3O2 | 详情 | 详情 | |
| (XI) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (XII) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XXII) | 19743 | 3-buten-1-ol | 627-27-0 | C4H8O | 详情 | 详情 |
| (XXIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXIV) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXV) | 19746 | 2-[(1S)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one | C14H17NO2 | 详情 | 详情 | |
| (XXVI) | 19747 | (3-bromo-1,7-dimethyl-2-oxobicyclo[2.2.1]hept-7-yl)methanesulfonic acid | C10H15BrO4S | 详情 | 详情 | |
| (XXVII) | 19748 | (1S,5R)-2-[(1S)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one | C14H17NO2 | 详情 | 详情 | |
| (XXVIII) | 19749 | (2S,4R)-N-(tert-butyl)-4-hydroxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxamide | C18H28N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of (2S,4R)-1-(tert-butoxycarbonyl)-N-tert-butyl-4-hydroxypiperidine-2-carboxamide (I) with MsCl and TEA gives the mesylate (II), which is treated with tetrabutylammonium bromide in refluxing THF to yield the corresponding 4-bromo derivative (III). The reaction of (III) with potassium thioacetate, followed by hydrolysis with NaOH affords the sodium thiolate (IV), which is condensed with 4-chloropyridine (V) to provide (2S,4R)-1-(tert-butoxycarbonyl)-N-tert-butyl-4-(4-pyridylsulfanyl)piperidine-2-carboxamide (VI). The deprotection of (VI) with TFA or HCl in dioxane gives intermediate (VII), which is condensed with epoxide (VIII) in refluxing ethanol to obtain the expected addition compound (IX). The deprotection of (IX) with TFA or HCl as before yields the amide (X), which is finally condensed with 2-(2,6-dimethylphenoxy)acetic acid (XI) by means of BOP and DIEA to furnish the target diamide.
| 【1】 Anderson, P.C.; Beaulieu, P.L.; Cameron, D.R.; et al.; 2'6'-Dimethylphenoxyacetyl: A new achiral high affinity P3-P2 ligand for peptidomimetic-based HIV protease inhibitors. J Med Chem 2000, 43, 6, 1094. |
| 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) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (II) | 38756 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-piperidinecarboxylate | C18H34N2O4S | 详情 | 详情 | |
| (III) | 38757 | tert-butyl (2S,4S)-4-bromo-2-[(tert-butylamino)carbonyl]-1-piperidinecarboxylate | C15H27BrN2O3 | 详情 | 详情 | |
| (IV) | 38762 | C15H27N2NaO3S | 详情 | 详情 | ||
| (V) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (VI) | 38758 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylsulfanyl)-1-piperidinecarboxylate | C20H31N3O3S | 详情 | 详情 | |
| (VII) | 38759 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylsulfanyl)-2-piperidinecarboxamide | C15H23N3OS | 详情 | 详情 | |
| (VIII) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (IX) | 38760 | tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylsulfanyl)piperidinyl]-2-hydroxypropylcarbamate | C30H44N4O4S | 详情 | 详情 | |
| (X) | 38761 | (2S,4R)-1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)-4-(4-pyridinylsulfanyl)-2-piperidinecarboxamide | C25H36N4O2S | 详情 | 详情 | |
| (XI) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 |