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【结 构 式】 
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【分子编号】53626 【品名】(4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone 【CA登记号】n/a |
【 分 子 式 】C19H27N3O3 【 分 子 量 】345.4418 【元素组成】C 66.06% H 7.88% N 12.16% O 13.89% |
合成路线1
该中间体在本合成路线中的序号：(IX)In a different procedure, displacement of the propionate group of azetidinone (IV) by benzyl 4-hydroxybenzoate (V) in the presence of Cs2CO3 afforded the racemic adduct (VI). Subsequent transfer hydrogenolysis of (VI) with cyclohexene and Pd/C provided the carboxylic acid (VII), which was resolved employing (S)-alpha-methylbenzylamine. Alternatively, a kinetic enzymatic resolution of the benzyl ester (VI) was developed. Treatment of ester (VI) with lipase PS-800 provided the desired (S)-acid (VIII), while leaving the unchanged (R)-benzyl ester. Coupling of acid (VIII) with N-methylpiperazine (III) in the presence of DCC and HOBt furnished the corresponding amide (IX).
| 【1】 Cvetovich, R.J.; et al.; An asymmetric synthesis of L-694,458, a human leukocyte elastase inhibitor, via novel enzyme resolution of beta-lactam esters. J Org Chem 1996, 61, 19, 6575. |
| 【2】 Li, H.-Y.; Fortunak, J.M.; Storace, L.; Sheeran, P.J.; Anzalone, L. (DuPont Pharmaceuticals Co.); An efficient process for the preparation of a human leukocyte elastase inhibitor. WO 0012474 . |
| 【3】 Amato, J.S.; Cvetovich, R.; Hartner, F.W. (Merck & Co., Inc.); Process for preparing substd. azetidinones. WO 9716448 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (IV) | 53621 | 3,3-diethyl-4-oxo-2-azetidinyl propionate | n/a | C10H17NO3 | 详情 | 详情 |
| (V) | 53622 | 4-Hydroxybenzoic acid benzyl ester; Benzyl 4-hydroxybenzoate; Benzyl-p-Hydroxybenzoate; Benzylparaben | 94-18-8 | C14H12O3 | 详情 | 详情 |
| (VI) | 53623 | benzyl 4-[(3,3-diethyl-4-oxo-2-azetidinyl)oxy]benzoate | n/a | C21H23NO4 | 详情 | 详情 |
| (VII) | 53624 | 4-[(3,3-diethyl-4-oxo-2-azetidinyl)oxy]benzoic acid | n/a | C14H17NO4 | 详情 | 详情 |
| (VIII) | 53625 | 4-{[(2S)-3,3-diethyl-4-oxoazetidinyl]oxy}benzoic acid | n/a | C14H17NO4 | 详情 | 详情 |
| (IX) | 53626 | (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The required (S)-alpha-propylpiperonyl alcohol (XV) was prepared by two alternative routes. Asymmetric addition of di-n-propyl zinc to piperonal (X) in the presence of titanium isopropoxide and the chiral bis-triflamide (XI) yielded the (S)-alcohol (XV) in high enantiomeric excess. Alternatively, ketone (XIII) was reduced with the oxazaborolidine-borane complex (XIV) to give (XV). Treatment of the (S)-alcohol (XV) with DPPA in the presence of DBU produced the (R)-azide (XVI). This was then reduced with LiAlH4 to yield amine (XVII) with some loss of optical purity. Optical enrichment was achieved by crystallization as the D-pyroglutamic acid salt. The (R)-amine (XVII) was converted to isocyanate (XVIII) by treatment with phosgene. Finally, coupling between isocyanate (XVIII) and azetidinone (IX) in the presence of DBU in acetonitrile led to the title compound.
| 【1】 Cvetovich, R.J.; et al.; An asymmetric synthesis of L-694,458, a human leukocyte elastase inhibitor, via novel enzyme resolution of beta-lactam esters. J Org Chem 1996, 61, 19, 6575. |
| 【2】 Amato, J.S.; Cvetovich, R.; Hartner, F.W. (Merck & Co., Inc.); Process for preparing substd. azetidinones. WO 9716448 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 53626 | (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
| (X) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (XI) | 53627 | trifluoro-N-((1R,2R)-2-{[(trifluoromethyl)sulfonyl]amino}cyclohexyl)methanesulfonamide | n/a | C8H12F6N2O4S2 | 详情 | 详情 |
| (XIII) | 53629 | 1-(1,3-benzodioxol-5-yl)-1-butanone | 63740-97-6 | C11H12O3 | 详情 | 详情 |
| (XIV) | 20631 | (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-83-0 | C18H20BNO | 详情 | 详情 |
| (XV) | 53628 | (1S)-1-(1,3-benzodioxol-5-yl)-1-butanol | n/a | C11H14O3 | 详情 | 详情 |
| (XVI) | 53630 | (1R)-1-(1,3-benzodioxol-5-yl)butyl azide; 5-[(1R)-1-azidobutyl]-1,3-benzodioxole | n/a | C11H13N3O2 | 详情 | 详情 |
| (XVII) | 53631 | (1R)-1-(1,3-benzodioxol-5-yl)-1-butanamine; (1R)-1-(1,3-benzodioxol-5-yl)butylamine | n/a | C11H15NO2 | 详情 | 详情 |
| (XVIII) | 53632 | 5-[(1R)-1-isocyanatobutyl]-1,3-benzodioxole; (1R)-1-(1,3-benzodioxol-5-yl)butyl isocyanate | n/a | C12H13NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)In a further procedure, 4-hydroxybenzoic acid (XIX) was converted to amide (XXII) via formation of the mixed anhydride-ester (XX) with pivaloyl chloride, followed by coupling with N-methylpiperazine (III) and alcoholysis of the resultant amide-ester (XXI) or, alternatively, by direct coupling of acid (XIX) with piperazine (III) in the presence of DCC. The propionate group of azetidinone (IV) was then displaced by the 4-hydroxybenzamide (XXII) to give the racemic adduct (XXIII). Resolution of (XXIII) by means of (-)-diisopropylidene ketogulonic acid (DAG) provided the desired enantiomer (IX), which was finally converted into the title compound by condensation with isocyanate (XVIII) in the presence of DBU in acetonitrile.
| 【1】 Storace, L.; et al.; An efficient large-scale process for the human leukocyte elastase inhibitor, DMP 777. Org Process Res Dev 2002, 6, 1, 54. |
| 【2】 Li, H.-Y.; Fortunak, J.M.; Storace, L.; Sheeran, P.J.; Anzalone, L. (DuPont Pharmaceuticals Co.); An efficient process for the preparation of a human leukocyte elastase inhibitor. WO 0012474 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (IV) | 53621 | 3,3-diethyl-4-oxo-2-azetidinyl propionate | n/a | C10H17NO3 | 详情 | 详情 |
| (IX) | 53626 | (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
| (XVIII) | 53632 | 5-[(1R)-1-isocyanatobutyl]-1,3-benzodioxole; (1R)-1-(1,3-benzodioxol-5-yl)butyl isocyanate | n/a | C12H13NO3 | 详情 | 详情 |
| (XIX) | 28205 | 4-hydroxybenzoic acid | 99-96-7 | C7H6O3 | 详情 | 详情 |
| (XX) | 53634 | 1,1-dimethylpropanoic 4-[(2,2-dimethylpropanoyl)oxy]-1-benzenecarboxylic anhydride | n/a | C17H22O5 | 详情 | 详情 |
| (XXI) | 53635 | 4-[(4-methyl-1-piperazinyl)carbonyl]phenyl pivalate | n/a | C17H24N2O3 | 详情 | 详情 |
| (XXII) | 53633 | (4-hydroxyphenyl)(4-methyl-1-piperazinyl)methanone | n/a | C12H16N2O2 | 详情 | 详情 |
| (XXIII) | 53636 | 3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXVII)The silylation of the acetonide (XVIII) with Tms-Cl and LDA in THF gives dienolate (XIX), which is enantioselectively condensed with acrolein (XX) by means of Carreira's Ti catalyst in ethyl ether to yield the chiral allyl alcohol (XXI). The reaction of (XXI), N,O-dimethylhydroxylamine (XXII) and Me2AlCl affords the amide (XXIII), which is selectively reduced with Me4NBH(OAc)3 in HOAc/acetonitrile to provide the dihydroxyamide (XXIV). The silylation of the OH groups of (XXIV) with Tbdms-Cl and imidazole gives the disilylated compound (XXV), which is submitted to a Grignard reaction with vinylmagnesium bromide (XXVI) in THF to yield the vinyl ketone (XXVII). The Michael addition reaction with Ph2P(O)-Li and simultaneous triflation with (XXVIII) in THF affords the enol triflate (XXIX), which is cyclized by means of Pd(OAc)2, PPh3 and TEA in THF to provide the phosphorane (XXXa-b) as an inseparable mixture of the (Z)- and (E)-isomers. Finally, this mixture is submitted to photochemical isomerization with a medium-pressure UV mercury lamp in the presence of 9-fluorenone, furnishing the target intermediate, the (Z)-isomer (X) with a 95 % yield.
| 【1】 Anné, S.; et al.; Enantioselective syntheses of key A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Synlett 1999, 9, 1435. |
| 【2】 Hiyamizu, H.; et al.; A concise enantioselective synthesis of a key A-ring synthon for 1alpha-hydroxyvitamin D3 compounds. Org Lett 2001, 3, 3, 473. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXa),(X) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (XXXb) | 53658 | (E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide; (E)-[2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane | n/a | C33H51O3PSi2 | 详情 | 详情 |
| (XVIII) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (XIX) | 53651 | [(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether | n/a | C10H18O3Si | 详情 | 详情 |
| (XX) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (XXI) | 53652 | 6-[(2S)-2-hydroxy-3-butenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one | n/a | C10H14O4 | 详情 | 详情 |
| (XXII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XXIII) | 53653 | (5S)-5-hydroxy-N-methoxy-N-methyl-3-oxo-6-heptenamide | n/a | C9H15NO4 | 详情 | 详情 |
| (XXIV) | 53654 | (3S,5S)-3,5-dihydroxy-N-methoxy-N-methyl-6-heptenamide | n/a | C9H17NO4 | 详情 | 详情 |
| (XXV) | 53655 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methyl-6-heptenamide | n/a | C21H45NO4Si2 | 详情 | 详情 |
| (XXVI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XXVII) | 53626 | (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
| (XXVIII) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (XXIX) | 53657 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-2-(diphenylphosphoryl)ethylidene]-6-heptenyl trifluoromethanesulfonate | n/a | C34H52F3O6PSSi2 | 详情 | 详情 |