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【结 构 式】 
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【药物名称】Vitamin K2(20), Menaquinone-4, Menatetrenone, E-0167, MQ-4, MK-4, Ea-0167, Kaytwo(vitamin K deficiency), Glakay(osteoporosis) 【化学名称】(all E)-2-Methyl-3-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)-1,4-naphthoquinone 【CA登记号】863-61-6, 6041-00-5 (undefined isomer), 65061-19-0 (Z,E,E-isomer) 【 分 子 式 】C31H40O2 【 分 子 量 】444.66325 |
【开发单位】Eisai (Originator) 【药理作用】Bone Diseases, Treatment of, Bone Resorption Inhibitors, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Hemostatics, Liver Cancer Therapy, METABOLIC DRUGS, Oncolytic Drugs, Treatment of Osteoporosis, Treatment of Vitamin K Deficiency |
合成路线1
1) The Diels-Alder cyclization of butadiene (I) with 2-methylbenzophenone (II) by means of acetic acid in refluxing toluene followed by oxidation with ceric ammonium nitrate gives 2-methyl-1,4-naphthoquinone (III), which by a new Diels-Alder cyclization with cyclopentadiene (IV) yields 4aalpha-methyl-1,4,4a,5,8,9a-hexahydro-1alpha,4alpha-methanoanthraquinone (V). The alkylation of (V) with 3,7,11,15-tetramethyl-2(E),6(E),10(E),14-hexadecatetraeanyl bromide (VI) by means of potassium tert-butoxide in THF affords the alkylated anthraquinone (VII), which is submitted to a retro Diels-Alder reaction in refluxing toluene containing dichlorodicyanobenzoquinone (DDQ) in order to obtain a simultaneous dehydrogenation. 2) The Diels-Alder cyclization of 1,4-naphthoquinone (VIII) with cyclopentadiene as before gives 1,4,4a,9a-tetrahydro-1,4-methanoanthraquinone (IX), which is alkylated with the alkyl bromide (VI) as before to yield the alkylated anthraquinone (X). The methylation of (X) with methyl iodide and potassium tert-butoxide affords the 9a-methylated anthraquinone (XI), which is finally submitted to a retro Diels-Alder reaction in refluxing toluene.
| 【1】 Graul, A.; Castañer, J.; Menatetrenone. Drugs Fut 1996, 21, 6, 615. |
| 【2】 Hamamura, K.; Iwama, T.; Seki, C.; Konishi, M. (Eisai Co., Ltd.); Preparation process of quinone deriv. and intermediate for the preparation thereof. EP 0613877 . |
| 【3】 Hamamura, K.; Seki, C.; Konishi, M. (Eisai Co., Ltd.); Preparation process of naphthoquinone derivs. and intermediates for the preparation thereof. EP 0636598 . |
| 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) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (II) | 16555 | 2-methyl-2,5-cyclohexadiene-1,4-dione; 2-methylbenzo-1,4-quinone | 553-97-9 | C7H6O2 | 详情 | 详情 |
| (III) | 16556 | 2-methyl-5,8-dihydro-1,4-naphthalenedione | C11H10O2 | 详情 | 详情 | |
| (IV) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (V) | 16558 | (2R)-2-methyltetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4(9),6,13-triene-3,10-dione | C16H16O2 | 详情 | 详情 | |
| (VI) | 16559 | (2E,6E,10E)-1-bromo-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene | C20H33Br | 详情 | 详情 | |
| (VII) | 16560 | (2R,11S)-2-methyl-11-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4(9),6,13-triene-3,10-dione | C36H48O2 | 详情 | 详情 | |
| (VIII) | 16561 | naphthoquinone; 1,4-Naphthoquinone | 130-15-4 | C10H6O2 | 详情 | 详情 |
| (IX) | 16562 | tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-dione | C15H12O2 | 详情 | 详情 | |
| (X) | 16563 | (2S)-2-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-dione | C35H44O2 | 详情 | 详情 | |
| (XI) | 16564 | (2R,11S)-2-methyl-11-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-dione | C36H46O2 | 详情 | 详情 |
合成路线2
3) The condensation of 2-bromo-1,4-dimethoxy-3-methylnaphthalene (XII) with 3,7,11,15-tetramethyl-2(E),6(E),10(E),14-hexadecatetraenal (XIII) by means of butyllithium in ethyl ether gives the corresponding secondary alcohol (XIV), which is selectively reduced (previous silylation) by means of Li in THF to afford the alkylated dimethoxynaphthalene (XV). Finally, this compound is oxidized to the corresponding quinone with ceric ammonium nitrate in acetonitrile/water. 4) By laser beam irradiation (435 nm) of cis-vitamin K2 in diisopropyl ether at 25 C.
| 【1】 Graul, A.; Castañer, J.; Menatetrenone. Drugs Fut 1996, 21, 6, 615. |
| 【2】 Garcías, X.; Ballester, P.; Capó, M.; Saá, J.M.; 2DELTA-Stereocontrolled entry to (E)- or (Z)-prenyl aromatics and quinones. Synthesis of menaquinone-4. J Org Chem 1994, 59, 17, 5093-6. |
| 【3】 Ichino, T.; Nakano, K.; Murakami, K.; Narabe, Y.; Imai, A.; Takahashi, K.; Udagawa, T.; Kusaba, Y.; Muramatsu, T.; Katayama, A. (Eisai Co., Ltd.); Manufacturing method for trans-vitamin K2. JP 1988162649 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 16565 | 2-bromo-4-methoxy-3-methyl-1-naphthyl methyl ether; 2-bromo-1,4-dimethoxy-3-methylnaphthalene | C13H13BrO2 | 详情 | 详情 | |
| (XIII) | 16566 | (2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenal | C20H32O | 详情 | 详情 | |
| (XIV) | 16567 | (2E,6E,10E)-1-(1,4-dimethoxy-3-methyl-2-naphthyl)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol | C33H46O3 | 详情 | 详情 | |
| (XV) | 16568 | (2E,6E,10E)-1-(1,4-dimethoxy-3-methyl-2-naphthyl)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene; 4-methoxy-2-methyl-3-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]-1-naphthyl methyl ether | C33H46O2 | 详情 | 详情 |