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【结 构 式】 
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【分子编号】25047 【品名】butyric anhydride 【CA登记号】106-31-0 |
【 分 子 式 】C8H14O3 【 分 子 量 】158.19736 【元素组成】C 60.74% H 8.92% O 30.34% |
合成路线1
该中间体在本合成路线中的序号：(A)Electrophilic bromination of ethyl p-methoxycinnamate (I) by means of N-bromosuccinimide in moist acetone gave rise to the racemic erythro bromohydrin (II), which was esterified with butyric anhydride to produce the racemic bromoester (III). Kinetic resolution of (III) employing Candida cylindracea lipase caused the enantioselective hydrolysis of the (S,S)-enantiomer, yielding the chiral bromohydrin (V). Cyclization of (V) in the presence of NaOMe furnished epoxide (VI). The target thiazepinone (VIII) was then obtained by condensation between the glycidic ester (VI) and 2-aminobenzenethiol (VII)
| 【1】 McCague, R.; Wang, S.; Taylor, S.J.C. (Celltech Group plc); Chiral arylpropionates and their use. WO 9413828 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
| (I) | 62431 | ethyl (E)-3-(4-methoxyphenyl)-2-propenoate | C12H14O3 | 详情 | 详情 | |
| (II) | 62432 | ethyl (2S,3S)-2-bromo-3-hydroxy-3-(4-methoxyphenyl)propanoate | C12H15BrO4 | 详情 | 详情 | |
| (III) | 62433 | (1S,2S)-2-bromo-3-ethoxy-1-(4-methoxyphenyl)-3-oxopropyl butyrate | C16H21BrO5 | 详情 | 详情 | |
| (IV) | 62434 | (1R,2R)-2-bromo-3-ethoxy-1-(4-methoxyphenyl)-3-oxopropyl butyrate | C16H21BrO5 | 详情 | 详情 | |
| (V) | 62432 | ethyl (2S,3S)-2-bromo-3-hydroxy-3-(4-methoxyphenyl)propanoate | C12H15BrO4 | 详情 | 详情 | |
| (VI) | 62435 | ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C12H14O4 | 详情 | 详情 | |
| (VII) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (VIII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Treatment of (1E,3S)-1-iodo-3-(tert-butyldimethylsilyloxy)-1-octene (I) with BuLi in ethyl ether, followed by reaction with 7-[3(R)-(tert-butyldimethylsilyloxy)-5-oxo-1-cyclopenten-1-yl] heptanoic acid butyl ester (II) by means of tributylphosphine-copper(I) iodide complex and tributylphosphine in ethyl ether provides the protected nonisolated intermediate (III), which is treated with butyric anhydride (IV) to afford derivative (V). Finally, this compound is converted into the desired product by removal of the TBDMS groups by means HF in acetonitrile/H2O (1). Alternatively, the synthesis can be performed by following a different protection strategy: Esterification of carboxylic acid (VI) with butyl iodide in DMSO by means of diisopropylamine provides derivative (VII), which is then protected by reaction with 3,4-dihydro-2H-pyran (VIII) to furnish compound (IX). Next, coupling of (IX) with iodo derivative (I) by means of tert-BuLi, tributylphosphine - copper (I) iodide complex and tributylphosphine in ethyl ether gives the adduct (X), which by reaction with butyric anhydride (IV) affords derivative (XI). Finally, this compound is converted into the desired product by following this deprotection protocol: 1) Bu4NF in THF; 2) Ac2O, DMAP in CH2Cl2 in the presence of pyridine; and finally 3) pyridinium p-toluenesulfonate (PPTS) in EtOH.
| 【1】 Makino, M.; et al.; Synthesis of novel prostaglandin E1 prodrugs as inhibitors of platelet aggregation. Reports Res Lab Asahi Glass Co Ltd 1997, 47, 95. |
| 【2】 Mizushima, Y.; Inomata, T.; Yasuda, A. (Asahi Glass Co., Ltd.; Seikagaku Corp.); Emulsion of lipid containing a prostaglandin analogue. EP 0423697; EP 0624574 . |
| 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) | 50846 | tert-butyl(dimethyl)silyl (1S,2E)-3-iodo-1-pentyl-2-propenyl ether; tert-butyl[[(1S,2E)-3-iodo-1-pentyl-2-propenyl]oxy]dimethylsilane | C14H29IOSi | 详情 | 详情 | |
| (II) | 50847 | butyl 7-((3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-oxo-1-cyclopenten-1-yl)heptanoate | C22H40O4Si | 详情 | 详情 | |
| (III) | 50848 | butyl 7-[(4R,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-hydroxy-1-cyclopenten-1-yl]heptanoate | C36H70O5Si2 | 详情 | 详情 | |
| (IV) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
| (V) | 50849 | butyl 7-[(4R,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(butyryloxy)-1-cyclopenten-1-yl]heptanoate | C40H76O6Si2 | 详情 | 详情 | |
| (VI) | 50850 | 7-[(3R)-3-hydroxy-5-oxo-1-cyclopenten-1-yl]heptanoic acid | C12H18O4 | 详情 | 详情 | |
| (VII) | 50851 | butyl 7-[(3R)-3-hydroxy-5-oxo-1-cyclopenten-1-yl]heptanoate | C16H26O4 | 详情 | 详情 | |
| (VIII) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (IX) | 50852 | butyl 7-[(3R)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)-1-cyclopenten-1-yl]heptanoate | C21H34O5 | 详情 | 详情 | |
| (X) | 50853 | butyl 7-[(2R,3R)-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]heptanoate | C35H64O6Si | 详情 | 详情 | |
| (XI) | 50854 | butyl 7-[(4R,5R)-5-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(butyryloxy)-4-(tetrahydro-2H-pyran-2-yloxy)-1-cyclopenten-1-yl]heptanoate | C39H70O7Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The synthetic scheme of tritiated MX-68 ia also presented in Scheme 22540503a. Treatment of compound (I) with triphenylphosphine, followed by Wittig reaction with 4-ethylbenzoic aldehyde (II) yields an olefin (III). To improve the solubility of (III) in routine organic solvents, the amino group of compound (III) is acylated with anhydride (IV) to give a lipophilic olefin (V). The olefin moiety is next oxidized by treatment of ozone to give an aldehyde (VI). Reduction of compound (VI) with NaBT4 is performed in isopropanol to give the corresponding tritiated alcohol (VII). The alohol (VII) is deacylated to yield acyl-free pteridine (VIII). The conversion of compound (VIII) to HBr salt, followed by bromination of alcohol with dibromotriphenylphosphorane, amination with compound (IX) and alkali hydrolysis produces [9-3H]-MX-68.
| 【1】 Matsuoka, H.; et al.; Synthesis of tritiated N-[4-(2, 4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1, 4-benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68). J Label Compd Radiopharm 1997, 39, 5, 363. |
| 【2】 Mihara, M.; Matsuoka, H.; The synthesis and biological evaluation of new methotrexate derivatives in rheumatoid arthritis. Drugs Fut 1998, 23, 9, 1015. |
| 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) | 11006 | 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine | 52853-40-4 | C7H7BrN6 | 详情 | 详情 |
| (II) | 25045 | 4-ethylbenzaldehyde | 4748-78-1 | C9H10O | 详情 | 详情 |
| (III) | 25046 | 6-(4-ethylstyryl)-2,4-pteridinediamine | C16H16N6 | 详情 | 详情 | |
| (IV) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
| (V) | 25048 | N-[2-(butyrylamino)-6-(4-ethylstyryl)-4-pteridinyl]butanamide | C24H28N6O2 | 详情 | 详情 | |
| (VI) | 25049 | N-[2-(butyrylamino)-6-formyl-4-pteridinyl]butanamide | C15H18N6O3 | 详情 | 详情 | |
| (VII) | 25050 | N-[2-(butyrylamino)-6-(hydroxymethyl)-4-pteridinyl]butanamide | C15H20N6O3 | 详情 | 详情 | |
| (VIII) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
| (IX) | 19823 | dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate | C17H22N2O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The acylation of (S,S)-pseudoephedrine (I) with butyric anhydride (II) gave the corresponding butyramide (III), which was asymmetrically alkylated with m-methoxybenzyl bromide (IV) in the presence of LDA and LiCl in THF at low temperature to produce the (S,S,R) isomer (V). Amide hydrolysis of (V) to provide the (R)-carboxylic acid (VI) was effected according to a described procedure by treatment with methanesulfonic acid in boiling THF, and then with lithium borohydride and tetrabutylammonium hydroxide. Further treatment of (VI) with ethereal diazomethane afforded the methyl ester (VII). This was submitted to acyloin condensation using Na metal and trimethylsilyl chloride to form the corresponding acyloin as the bis(silyl) ether (VIII). Double cyclization of (VIII) using TiCl4 at low temperature yielded the required tetrahydrochrysene system with minimal epimerization. The major cis isomer (IX) was then isolated by flash chromatography. Finally, deprotection of the methyl ethers of (IX) with BBr3 furnished the title bis-phenolic compound.
| 【1】 Meyers, M.J.; et al.; Estrogen receptor subtype-selective ligands: Asymmetric synthesis and biological evaluation of cis- and trans-5,11-dialkyl-5,6,11,12-tetrahydrochrysenes. J Med Chem 1999, 42, 13, 2456. |
| 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) | 34409 | (1S,2S)-2-(methylamino)-1-phenyl-1-propanol | 90-82-4 | C10H15NO | 详情 | 详情 |
| (II) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
| (III) | 34402 | N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbutanamide | C14H21NO2 | 详情 | 详情 | |
| (IV) | 34403 | 1-(bromomethyl)-3-methoxybenzene; 3-(bromomethyl)phenyl methyl ether | C8H9BrO | 详情 | 详情 | |
| (V) | 34404 | (2R)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-(3-methoxybenzyl)-N-methylbutanamide | C22H29NO3 | 详情 | 详情 | |
| (VI) | 34405 | (2R)-2-(3-methoxybenzyl)butyric acid | C12H16O3 | 详情 | 详情 | |
| (VII) | 34406 | methyl (2R)-2-(3-methoxybenzyl)butanoate | C13H18O3 | 详情 | 详情 | |
| (VIII) | 34407 | 3-[(2R,3E,5R)-2-ethyl-5-(3-methoxybenzyl)-3,4-bis[(trimethylsilyl)oxy]-3-heptenyl]phenyl methyl ether; (E)-4,5-bis[(1R)-1-(3-methoxybenzyl)propyl]-2,2,7,7-tetramethyl-3,6-dioxa-2,7-disila-4-octene | C30H48O4Si2 | 详情 | 详情 | |
| (IX) | 34408 | (5R,11R)-5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro-2-chrysenyl methyl ether; (5R,11R)-5,11-diethyl-2,8-dimethoxy-5,6,11,12-tetrahydrochrysene | C24H28O2 | 详情 | 详情 |