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【结 构 式】 
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【分子编号】34552 【品名】trimethylsilyl (2R)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoate 【CA登记号】 |
【 分 子 式 】C10H21F3O3Si2 【 分 子 量 】302.4411496 【元素组成】C 39.71% H 7% F 18.85% O 15.87% Si 18.57% |
合成路线1
该中间体在本合成路线中的序号：(IX)Alkylation of 3-aminothiophenol (II) with methyl 3-(bromomethyl)thiophene-2-carboxylate (I) provides thioether (III). After protection of the amino group of (III) as the corresponding acetamide (IV), its methyl ester group is hydrolyzed under alkaline conditions, to provide the carboxylic acid (V). Activation of acid (V) with trifluoroacetic anhydride, followed by cyclization in the presence of boron trifluoride etherate gives rise to a mixture of regioisomeric thienobenzothiepinones (VI) and (VII), which are separated by column chromatography. Acidic hydrolysis of the desired isomer (VII) provides amine (VIII). Acid chloride (X), prepared by chlorination of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (IX), is then condensed with amine (VIII) to furnish amide (XI). Finally, oxidation of the sulfide group of (XI) to the title sulfone is accomplished by treatment with m-chloroperbenzoic acid
| 【1】 Mimura, T.; Ogasa, T.; Mori, S.; Matsushita, T.; Imai, E. (Kyowa Hakko Kogyo Co., Ltd.); Preparation method of tricyclic cpds.. JP 2002053580 . |
| 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) | 60612 | methyl 3-(bromomethyl)-2-thiophenecarboxylate | C7H7BrO2S | 详情 | 详情 | |
| (II) | 60613 | 3-aminobenzenethiol; 3-aminophenylhydrosulfide | C6H7NS | 详情 | 详情 | |
| (III) | 60614 | methyl 3-{[(3-aminophenyl)sulfanyl]methyl}-2-thiophenecarboxylate | C13H13NO2S2 | 详情 | 详情 | |
| (IV) | 60615 | methyl 3-({[3-(acetylamino)phenyl]sulfanyl}methyl)-2-thiophenecarboxylate | C15H15NO3S2 | 详情 | 详情 | |
| (V) | 60616 | 3-({[3-(acetylamino)phenyl]sulfanyl}methyl)-2-thiophenecarboxylic acid | C14H13NO3S2 | 详情 | 详情 | |
| (VI) | 60617 | N-(10-oxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-7-yl)acetamide | C14H11NO2S2 | 详情 | 详情 | |
| (VII) | 60618 | N-(10-oxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)acetamide | C14H11NO2S2 | 详情 | 详情 | |
| (VIII) | 60619 | 9-aminothieno[3,2-c][1]benzothiepin-10(4H)-one | C12H9NOS2 | 详情 | 详情 | |
| (IX) | 34552 | trimethylsilyl (2R)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoate | C10H21F3O3Si2 | 详情 | 详情 | |
| (X) | 60620 | 3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl chloride | C4H4ClF3O2 | 详情 | 详情 | |
| (XI) | 60621 | 3,3,3-trifluoro-2-hydroxy-2-methyl-N-(10-oxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide | C16H12F3NO3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Alkylation of an equimolecular mixture of trans-2,5-dimethylpiperazine dihydrochloride (I) and the free base (II) with benzyl chloride produced the racemic monobenzyl piperazine, which was resolved using (-)-tartaric acid to yield the required (2R,5S)-isomer (III). (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (IV) was protected as the silyl derivative (V) using bis(trimethylsilyl)urea, and subsequently converted to acid chloride (VI) by means of oxalyl chloride. Coupling of acid chloride (VI) with the chiral piperazine (III) afforded amide (VII), which was desilylated in methanolic HCl yielding (VIII). Hydrogenolysis of the N-benzyl group of (VIII) over Pd/C gave piperazine (IX). Finally, coupling of (IX) with 4-cyanobenzoyl chloride (X) furnished the corresponding bisamide.
| 【1】 Anderson, R.C.; Aicher, T.D.; Bebernitz, G.R.; et al.; (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamides are orally active inhibitors of pyruvate dehydrogenase kinase. J Med Chem 1999, 42, 15, 2741. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I),(II) | 20687 | (2R,5S)-2,5-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (III) | 34550 | (2R,5S)-1-benzyl-2,5-dimethylpiperazine | C13H20N2 | 详情 | 详情 | |
| (IV) | 34551 | (2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid | 114715-77-4 | C4H5F3O3 | 详情 | 详情 |
| (V) | 34552 | trimethylsilyl (2R)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoate | C10H21F3O3Si2 | 详情 | 详情 | |
| (VI) | 34553 | (2S)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoyl chloride | C7H12ClF3O2Si | 详情 | 详情 | |
| (VII) | 34554 | (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]-1-propanone | C20H31F3N2O2Si | 详情 | 详情 | |
| (VIII) | 34555 | (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone | C17H23F3N2O2 | 详情 | 详情 | |
| (IX) | 34556 | (2R)-1-[(2S,5R)-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone | C10H17F3N2O2 | 详情 | 详情 | |
| (X) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |