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【结 构 式】 
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【分子编号】16302 【品名】(2R)-2-methoxy-2-phenylethanoyl chloride 【CA登记号】 |
【 分 子 式 】C9H9ClO2 【 分 子 量 】184.62196 【元素组成】C 58.55% H 4.91% Cl 19.2% O 17.33% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 1) The reaction of 4-(benzoyloxy)-2-azetidinone (IV) with 2 equivalents of 1-lithio-2-(trimethylsilyl)acetylene (V) gives azetidinone (VI), which is opened with anhydrous HCl in ethanol, yielding racemic 3-amino-5-(trimethylsilyl)-4-pentynoic acid ethyl ester (VII). Resolution of (VII) by means of diastereomeric amide formation with (R)-O-methyl mandelic acid chloride (VIII) and chromatographic separation of the diastereoisomers (MPLC, ether/hexane) affords the amide (IX), which is then N-protected with Boc2O in acetonitrile to give (X). Treatment of (X) with tetramethylguanidine in methanol gives methyl ester (XI), which is finally treated first with TFA and then with HCl in ethanol to afford ethyl ester (III).
| 【1】 Zablocki, J.A.; Rico, J.G.; Garland, R.B.; et al.; Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists. J Med Chem 1995, 38, 13, 2378-94. |
| 【2】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17739 | N,N,N',N'-tetramethylguanidine; 1,1,3,3-Tetramethylguanidine | 80-70-6 | C5H13N3 | 详情 | 详情 | |
| (III) | 16297 | ethyl (3S)-3-amino-4-pentynoate | C7H11NO2 | 详情 | 详情 | |
| (IV) | 16298 | 4-oxo-2-azetanyl benzoate; 4-Benzoyloxy-2-azetidinone | 28562-58-5 | C10H9NO3 | 详情 | 详情 |
| (V) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (VI) | 16300 | 4-[2-(trimethylsilyl)ethynyl]-2-azetanone | C8H13NOSi | 详情 | 详情 | |
| (VII) | 16301 | 3-amino-5-(trimethylsilyl)-4-pentynoic acid | C8H15NO2Si | 详情 | 详情 | |
| (VIII) | 16302 | (2R)-2-methoxy-2-phenylethanoyl chloride | C9H9ClO2 | 详情 | 详情 | |
| (IX) | 16303 | (3S)-3-[[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoic acid | C17H23NO4Si | 详情 | 详情 | |
| (X) | 16304 | ethyl (3S)-3-[(tert-butoxycarbonyl)[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoate | C24H35NO6Si | 详情 | 详情 | |
| (XI) | 17740 | ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-pentynoate | C12H19NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Alkylation of 4,5,6,7-tetrahydro-1,2-benzisoxazol-3-ol (I) with ethyl bromide in the presence of K2CO3 afforded the ethoxy derivative (II). Subsequent oxidation of (II) with sodium dichromate and H2SO4 provided the desired ketone (III) along with minor amounts of the isomeric 7-oxo compound (IV) that were separated by column chromatography. Conversion of (III) to the corresponding oxime (V), followed by reduction with aluminum amalgam yielded amine (VI). Resolution was achieved via formation of the diastereomeric amides with (R)-alpha-methoxyphenylacetyl chloride (VII) and isolation of the desired isomer (VIII) by preparative HPLC. Cleavage of amide and ether groups of (VIII) by means of HBr furnished (R)-4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (IX). Protection as the corresponding tert-butyl carbamate, followed by N-methylation with CH3I and NaH provided intermediate (X). An alternative procedure for the preparation of intermediate (X) consisted in the reductive amination of ketone (III) with methylamine and NaBH3CN, followed by condensation of the resulting amine (XI) with the chiral acid chloride (VII) and chromatographic isolation of the desired diastereoisomer (XII). The alpha-methoxyphenylacetyl group of (XII) was then removed by an alternative method consisting in the treatment with lithium triethylborohydride to give the chiral amine (XIII). Cleavage of the ethyl ether group of (XIII) was effected by means of HBr in AcOH, and the resulting compound (XIV) was condensed with di-tert-butyl dicarbonate to produce carbamate (X). Subsequent reaction of (X) with pivaloyloxymethyl iodide (XV) in the presence of potassium tert-butoxide yielded the target O-alkylated compound (XVI) along with some N-alkylated regioisomer. The Boc protecting group of (XVI) was finally removed by treatment with trifluoroacetic acid.
| 【1】 Frolund, B.; Falch, E.; Perregaard, J.; et al.; Selective inhibitors of glial GABA uptake: Synthesis, absolute stereochemistry, and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and analogues. J Med Chem 1999, 42, 26, 5402. |
| 【2】 Falch, E.; Moltzen, L.S.; Schousboe, A.; Frolund, B.; Perregaard, J.K.; Krogsgaard-Larsen, P. (H. Lundbeck A/S); 4-Aminotetrahydrobenzisoxazole or -isothiazole cpds.. WO 9626929 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (I) | 37236 | 4,5,6,7-tetrahydro-1,2-benzisoxazol-3-ol | C7H9NO2 | 详情 | 详情 | |
| (II) | 37237 | ethyl 4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl ether; 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole | C9H13NO2 | 详情 | 详情 | |
| (III) | 37238 | 3-ethoxy-6,7-dihydro-1,2-benzisoxazol-4(5H)-one | C9H11NO3 | 详情 | 详情 | |
| (IV) | 37239 | 3-ethoxy-5,6-dihydro-1,2-benzisoxazol-7(4H)-one | C9H11NO3 | 详情 | 详情 | |
| (V) | 37240 | 3-ethoxy-6,7-dihydro-1,2-benzisoxazol-4(5H)-one oxime | C9H12N2O3 | 详情 | 详情 | |
| (VI) | 37241 | 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-amine; 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-ylamine | C9H14N2O2 | 详情 | 详情 | |
| (VII) | 16302 | (2R)-2-methoxy-2-phenylethanoyl chloride | C9H9ClO2 | 详情 | 详情 | |
| (VIII) | 37242 | (2R)-N-[(4R)-3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-yl]-2-methoxy-2-phenylethanamide | C18H22N2O4 | 详情 | 详情 | |
| (IX) | 37243 | (4R)-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazol-3-ol | C7H10N2O2 | 详情 | 详情 | |
| (X) | 34244 | methyl 2-[(1R,2R,3R)-2-[(benzyloxy)methyl]-5-[(Z)-2-methoxy-2-oxoethylidene]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C25H34O7 | 详情 | 详情 | |
| (XI) | 37245 | N-(3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-yl)-N-methylamine; 3-ethoxy-N-methyl-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-amine | C10H16N2O2 | 详情 | 详情 | |
| (XII) | 37246 | (2R)-N-[(4R)-3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-yl]-2-methoxy-N-methyl-2-phenylethanamide | C19H24N2O4 | 详情 | 详情 | |
| (XIII) | 37247 | (4R)-3-ethoxy-N-methyl-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-amine; N-[(4R)-3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-yl]-N-methylamine | C10H16N2O2 | 详情 | 详情 | |
| (XIV) | 37248 | (4R)-4-(methylamino)-4,5,6,7-tetrahydro-1,2-benzisoxazol-3-ol | C8H12N2O2 | 详情 | 详情 | |
| (XV) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 | |
| (XVI) | 37249 | ([(4R)-4-[(tert-butoxycarbonyl)(methyl)amino]-4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl]oxy)methyl pivalate | C19H30N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Protection of 3-amino-5-Boc-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (I) by treatment with ethyl chloroformate and DIEA gives the 1-ethoxycarbonyl derivative (II). After conversion of 4-(4-methylpiperazinyl)benzoic acid (III) to the corresponding acid chloride by means of oxalyl chloride and DMF, coupling with the amino heterocycle (II) furnishes the amide (IV). The N-Boc group of (IV) is then selectively deprotected under acidic conditions to give (V). Activation of (R)-α-methoxyphenylacetic acid (VI) with oxalyl choride and DMF gives the acid chloride (VII), which is coupled with the deprotected pyrrolopyrazole (V) to yield amide (VIII). Finally, the ethoxycarbonyl group of (VIII) is removed by treatment with Et3N in MeOH to provide the title compound (1, 2). Scheme 1.
| 【1】 Fancelli, D., Forte, B., Moll, J., Varasi, M., Vianello, P. (Pfizer Italia Srl). Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors. EP 1644376, US 2005032839, WO 2005005427. |
| 【2】 Fancelli, D., Moll, J., Varasi, M. et al. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: Identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem 2006, 49(24): 7247-51. |
| 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) | 65715 | tert-Butyl 3-amino-4,6-dihydropyrrolo[3,4-C]pyrozole-5-carboxylate; 5-Boc-3-amino-4,6-dihydropyrrolo[3,4-c]pyrozole | 398491-59-3 | C10H16N4O2 | 详情 | 详情 |
| (II) | 65716 | Ethyl 5-(tert-butoxycarbonyl)-3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-1-carboxylate; 3-Amino-5-((tert-butoxy)carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester; 3-Amino-5-tert-butyloxycarbonyl-1-ethoxycarbonyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole | 398495-65-3 | C13H20N4O4 | 详情 | 详情 |
| (III) | 65717 | 4-(4-Methylpiperazino)benzoic acid; 4-(4-Methylpiperazin-1-yl)benzoic acid | 86620-62-4 | C12H16N2O2 | 详情 | 详情 |
| (IV) | 65718 | 1-Ethyl 5-(2-methyl-2-propanyl) 3-{[4-(4-methyl-1-piperazinyl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate | 761443-69-0 | C25H34N6O5 | 详情 | 详情 |
| (V) | 65719 | Ethyl 3-{[4-(4-methyl-1-piperazinyl)benzoyl]amino}-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate | 761443-50-9 | C20H26N6O3 | 详情 | 详情 |
| (VI) | 50060 | (2R)-2-methoxy-2-phenylethanoic acid | 3966-32-3 | C9H10O3 | 详情 | 详情 |
| (VII) | 16302 | (2R)-2-methoxy-2-phenylethanoyl chloride | C9H9ClO2 | 详情 | 详情 | |
| (VIII) | 65720 | C29H34N6O5 | 详情 | 详情 |