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【结 构 式】

【药物名称】

【化学名称】4-[2,2-Dimethyl-4-(4-methylphenyl)-2H-naphtho[2,3-b]thiopyran-7-yl]benzoic acid

【CA登记号】204449-02-5

【 分 子 式 】C29H24O2S

【 分 子 量 】436.57743

【开发单位】Allergan (Originator)

【药理作用】DERMATOLOGIC DRUGS, Specific Antidotes, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Retinoid RAR Antagonists

合成路线1

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
Extended Information