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【结 构 式】 
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【分子编号】34677 【品名】3-methyl-2-butenoic acid 【CA登记号】541-47-9 |
【 分 子 式 】C5H8O2 【 分 子 量 】100.11732 【元素组成】C 59.98% H 8.05% O 31.96% |
合成路线1
该中间体在本合成路线中的序号：Condensation of 4-bromothiophenol (I) with 3,3-dimethylacrylic acid in the presence of piperidine gave acid (II), which was converted to the corresponding acid chloride with (COCl)2 and then cyclized by treatment with SnCl4 to the thiochromanone (III). Addition of 4-tolyllithium (IV) to ketone (III) and further dehydration of the resulting tertiary alcohol (V) upon treatment with p-toluenesulfonic acid produced the benzothiochromene (VI). After lithiation by means of BuLi, quenching with DMF produced aldehyde (VII). Subsequent Horner-Emmons condensation of (VII) with phosphonate (VIII) in the presence of BuLi yielded a mixture of E and Z olefins from which the required isomer (IX) was isolated by chromatography. Cyclization of ketal (IX) by means of SnCl4 produced the naphthothiopyran (X). The ethyl ester group of (X) was finally hydrolyzed with LiOH to yield the title carboxylic acid.
| 【1】 Escobar, M.; Vuligonda, V.; Standeven, A.M.; Chandraratna, R.A.S.; A new class of potent RAR antagonists: Dihydroanthracenyl, benzochromenyl and benzothiochromenyl retinoids. Bioorg Med Chem Lett 1999, 9, 5, 743. |
| 【2】 Johnson, A.T.; Chandraratna, R.A.; Vuligonda, V. (Allergan, Inc.); Benzo[1,2-g]-chrom-3-ene and benzo[1,2-g]-thiochrom-3-ene derivatives. EP 0948478; WO 9825875 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 | |
| (I) | 29626 | 4-bromophenylhydrosulfide; 4-bromobenzenethiol | 106-53-6 | C6H5BrS | 详情 | 详情 |
| (II) | 29627 | 3-[(4-bromophenyl)sulfanyl]-3-methylbutyric acid | C11H13BrO2S | 详情 | 详情 | |
| (III) | 29628 | 6-bromo-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C11H11BrOS | 详情 | 详情 | |
| (IV) | 29629 | (4-methylphenyl)lithium | C7H7Li | 详情 | 详情 | |
| (V) | 29630 | 6-bromo-2,2-dimethyl-4-(4-methylphenyl)-4-thiochromanol | C18H19BrOS | 详情 | 详情 | |
| (VI) | 29631 | 6-bromo-2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromene | C18H17BrS | 详情 | 详情 | |
| (VII) | 29632 | 2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromene-6-carbaldehyde | C19H18OS | 详情 | 详情 | |
| (VIII) | 29633 | ethyl 4-[1-(diethoxyphosphoryl)-3,3-dimethoxypropyl]benzoate | C18H29O7P | 详情 | 详情 | |
| (IX) | 29634 | ethyl 4-[(E)-1-(2,2-dimethoxyethyl)-2-[2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromen-6-yl]ethenyl]benzoate | C33H36O4S | 详情 | 详情 | |
| (X) | 29635 | ethyl 4-[2,2-dimethyl-4-(4-methylphenyl)-2H-benzo[g]thiochromen-7-yl]benzoate | C31H28O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Addition of 3-methyl-2-butenoic acid (II) to 4-methoxythiophenol (I) in the presence of piperidine at 105 C afforded adduct (III). After conversion of (III) to the corresponding acid chloride (IV) with oxalyl chloride, Friedel-Crafts cyclization using SnCl4 produced thiochromanone (V). Cleavage of the methyl ether of (V) by means of BBr3 gave phenol (VI), which was converted to triflate (VII) with trifluoromethanesulfonic anhydride in pyridine. Coupling of (VII) with trimethylsilyl acetylene (VIII) using a palladium catalyst provided (IX). Subsequent desilylation of (IX) with K2CO3 in MeOH, followed by palladium-catalyzed coupling of the resulting alkyne with ethyl 4-iodobenzoate (X) afforded the diaryl acetylene (XI). Introduction of the 4-aryl group in (XI) was achieved by conversion of (XI) to vinyl triflate (XIII) upon treatment of the sodium enolate with the bis-triflimide reagent (XII), and further condensation with 4-ethyl-phenylzinc chloride (XIV) yielding (XV). Finally, basic hydrolysis of the ethyl ester (XV) furnished the target carboxylic acid.
| 【1】 Standeven, A.M.; Escobar, M.; Wang, L.; Johnson, A.T.; Chandraratna, R.A.S.; Synthesis and biological activity of high-affinity retinoic acid receptor antagonists. Bioorg Med Chem 1999, 7, 1321. |
| 【2】 Klein, E.S.; Chandraratna, R.A.; Teng, M.; Duong, T.T.; Gillett, S.J.; Beard, R.L.; Vuligonda, V.; Johnson, A.T.; Standeven, A.M.; Nagpal, S. (Allergan, Inc.); Benzopyran and benzothiopyran derivs. having retinoid antagonist-like activity. WO 9933821 . |
| 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) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (II) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (III) | 34678 | 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutyric acid | C12H16O3S | 详情 | 详情 | |
| (IV) | 34679 | 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutanoyl chloride | C12H15ClO2S | 详情 | 详情 | |
| (V) | 34680 | 6-methoxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C12H14O2S | 详情 | 详情 | |
| (VI) | 34681 | 6-hydroxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C11H12O2S | 详情 | 详情 | |
| (VII) | 34682 | 2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl trifluoromethanesulfonate | C12H11F3O4S2 | 详情 | 详情 | |
| (VIII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (IX) | 34683 | 2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-4H-thiochromen-4-one | C16H20OSSi | 详情 | 详情 | |
| (X) | 23796 | ethyl 4-iodobenzoate | 51934-41-9 | C9H9IO2 | 详情 | 详情 |
| (XI) | 34684 | ethyl 4-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl)ethynyl]benzoate | C22H20O3S | 详情 | 详情 | |
| (XII) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (XIII) | 34686 | ethyl 4-[2-(2,2-dimethyl-4-[[(trifluoromethyl)sulfonyl]oxy]-2H-thiochromen-6-yl)ethynyl]benzoate | C23H19F3O5S2 | 详情 | 详情 | |
| (XIV) | 34687 | chloro(4-ethylphenyl)zinc | C8H9ClZn | 详情 | 详情 | |
| (XV) | 34688 | ethyl 4-[2-[4-(4-ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]ethynyl]benzoate | C30H28O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Friedel Crafts' condensation of phloroglucinol (I) with 3,3-dimethylacrylic acid (II) in the presence of boron trifluoride etherate gave the dihydroxy chromanone (III). Selective alkylation of the 7-hydroxyl group of (III) with iodomethane in the presence of K2CO3 furnished the methyl ether (IV). The carbonyl group of (IV) was subsequently reduced with NaBH4 in refluxing THF under basic conditions to produce chroman (V). The lactone ring of (VII) was then formed by a Pechmann reaction of (V) using ethyl acetoacetate (VI) and boron trifluoride to afford the tricyclic compound (VII). Dehydrogenation of (VII) employing DDQ in refluxing dioxan gave (VIII). The target 3'R,4'R-dihydroxylated derivative (IX) was obtained by Sharpless asymmetric dihydroxylation of (VIII) with hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2-PYR) as the chiral catalyst. Diol (IX) was finally esterified with (-)-S-camphanoyl chloride (X) to afford the title diester.
| 【1】 Takeuchi, Y.; McPhail, A.T.; Cosentino, L.M.; Lee, K.-H.; Xie, L.; Anti-AIDS agents.42. Synthesis and anti-HIV activity of disubstituted (3'R, 4'R)-3',4'-Di-O-(S)-camphanoyl-(+)-cis-khellactone analogues. J Med Chem 2001, 44, 5, 664. |
| 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) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (II) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (III) | 22422 | 5,7-dihydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C11H12O4 | 详情 | 详情 | |
| (IV) | 47784 | 5-hydroxy-7-methoxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C12H14O4 | 详情 | 详情 | |
| (V) | 47785 | 7-methoxy-2,2-dimethyl-5-chromanol | C12H16O3 | 详情 | 详情 | |
| (VI) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (VII) | 47786 | 5-methoxy-4,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C16H18O4 | 详情 | 详情 | |
| (VIII) | 47787 | 5-methoxy-4,8,8-trimethyl-2H,8H-pyrano[2,3-f]chromen-2-one | C16H16O4 | 详情 | 详情 | |
| (IX) | 47788 | (9R,10R)-9,10-dihydroxy-5-methoxy-4,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C16H18O6 | 详情 | 详情 | |
| (X) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The amino acid building block (XI) was prepared as follows. Friedel-Crafts condensation of dimethylacrylic acid (I) with benzene in the presence of AlCl3 afforded 3-methyl-3-phenylbutanoic acid (II). After activation of acid (II) as the mixed anhydride (IV) by treatment with pivaloyl chloride (III) and Et3N, coupling with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (V) furnished the chiral N-acyl oxazolidinone (VI). Diastereoselective introduction of an azido group into the lithium enolate of (VI) by means of 2,4,6-triisopropylbenzenesulfonyl azide led to the (S,S)-azido compound (VII). Catalytic hydrogenation of azide (VII) in the presence of Boc2O provided the Boc-protected amine (VIII). The chiral auxiliary of (VIII) was removed by hydrolysis with lithium hydroperoxide, and the resultant carboxylic acid was further converted to the methyl ester (IX) upon treatment with an ethereal solution of diazomethane. The N-methyl derivative (X) was then prepared by alkylation of the tert-butyl carbamate (IX) with iodomethane in the presence of NaH. Basic hydrolysis of ester (X) provided the target N-Boc amino acid (XI).
| 【1】 Roberge, M.; Andersen, R.; Piers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509 . |
| 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) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (II) | 38637 | 3-methyl-3-phenylbutyric acid | C11H14O2 | 详情 | 详情 | |
| (III) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (IV) | 55112 | 1,1-dimethylpropanoic 2-methyl-2-phenylbutanoic anhydride | C16H22O3 | 详情 | 详情 | |
| (V) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (VI) | 55113 | (4S)-4-isopropyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one | C17H23NO3 | 详情 | 详情 | |
| (VII) | 55114 | (4S)-3-[(2S)-2-azido-3-methyl-3-phenylbutanoyl]-4-isopropyl-1,3-oxazolidin-2-one | C17H22N4O3 | 详情 | 详情 | |
| (VIII) | 55115 | tert-butyl (1S)-1-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2-methyl-2-phenylpropylcarbamate | C22H32N2O5 | 详情 | 详情 | |
| (IX) | 55116 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methyl-3-phenylbutanoate | C17H25NO4 | 详情 | 详情 | |
| (X) | 55117 | methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoate | C18H27NO4 | 详情 | 详情 | |
| (XI) | 55118 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid | C17H25NO4 | 详情 | 详情 |