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【结 构 式】 
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【分子编号】10293 【品名】methyl (2R)-2-amino-3-(2-chloro-4-quinolinyl)propanoate 【CA登记号】 |
【 分 子 式 】C13H13ClN2O2 【 分 子 量 】264.7112 【元素组成】C 58.99% H 4.95% Cl 13.39% N 10.58% O 12.09% |
合成路线1
该中间体在本合成路线中的序号：(VIR)The synthesis of (R)- and (S)-isomers of OPC-12759 has been described: These optical isomers can be obtained in three different ways: 1) The reaction of 4-(bromomethyl)quinolin-2(1H)-one (I) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), which, without separation, is condensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) by means of butyllithium in hexane, yielding (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl affords 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). Finally, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3 in acetone, affording (R)-OPC-12759.
| 【1】 Morita, S.; Yamasaki, K.; Shimizu, T.; Uchida, M.; Otsubo, K.; Kanbe, T.; Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide). Chem Pharm Bull 1991, 39, 11, 2906. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVS) | 10291 | (S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (2S)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine; (3S)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether | 78342-42-4 | C9H16N2O2 | 详情 | 详情 |
| (VR) | 10292 | (3R,6S)-3-[(2-Chloro-4-quinolinyl)methyl]-6-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; 2-Chloro-4-[[(2R,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]quinoline | C19H22ClN3O2 | 详情 | 详情 | |
| (VIR) | 10293 | methyl (2R)-2-amino-3-(2-chloro-4-quinolinyl)propanoate | C13H13ClN2O2 | 详情 | 详情 | |
| (VIIR) | 10294 | (2R)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid | C12H12N2O3 | 详情 | 详情 | |
| (I) | 10288 | 4-(Bromomethyl)-2(1H)-quinolinone | C10H8BrNO | 详情 | 详情 | |
| (II) | 10289 | 4-(Bromomethyl)-2-chloroquinoline | C10H7BrClN | 详情 | 详情 | |
| (III) | 10290 | 2-Chloro-4-(chloromethyl)quinoline | C10H7Cl2N | 详情 | 详情 | |
| (VIII) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)4-Aminobutyraldehyde diethyl acetal (I) was treated with N-(ethoxycarbonyl)phthalimide (II) in THF to produce the phthalimido acetal (III), which was hydrolyzed to aldehyde (IV) with HCl in aqueous THF. Subsequent reductive alkylation of 7-methoxy-1,2,3,4-tetrahydroisoquinoline (V) with (IV) in the presence of sodium triacetoxyborohydride provided (VI). After conversion to the hydrochloride salt, the methyl ether of (VI) was cleaved using BBr3 in CH2Cl2 to give the phenol (VII), which was treated with trifluoromethanesulfonic anhydride in pyridine to afford triflate (VIII). The phthalimido group of (VIII) was then removed with ethanolic hydrazine and the resulting primary amine (IX) was finally coupled with 3-(3-indolyl)acrylic acid (X) in the presence of EDC and HOBt to yield the target amide.
| 【1】 Nash, D.J.; Stemp, G. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. and their pharmaceutical use. EP 0922035; WO 9806699 . |
| 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) | 23323 | 4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine | 6346-09-4 | C8H19NO2 | 详情 | 详情 |
| (II) | 10293 | methyl (2R)-2-amino-3-(2-chloro-4-quinolinyl)propanoate | C13H13ClN2O2 | 详情 | 详情 | |
| (III) | 23325 | 2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione | C16H21NO4 | 详情 | 详情 | |
| (IV) | 21620 | 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butanal | C12H11NO3 | 详情 | 详情 | |
| (V) | 21619 | 7-methoxy-1,2,3,4-tetrahydroisoquinoline; methyl 1,2,3,4-tetrahydro-7-isoquinolinyl ether | C10H13NO | 详情 | 详情 | |
| (VI) | 21621 | 2-[4-[7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione | C22H24N2O3 | 详情 | 详情 | |
| (VII) | 21622 | 2-[4-[7-hydroxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione | C21H22N2O3 | 详情 | 详情 | |
| (VIII) | 21623 | 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate | C22H21F3N2O5S | 详情 | 详情 | |
| (IX) | 21624 | 2-(4-aminobutyl)-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate | C14H19F3N2O3S | 详情 | 详情 | |
| (X) | 21625 | trans-3-(3-Indolyl)-2-propenoic acid; trans-Indole-3-acrylic acid; trans-beta-Indoleacrylic acid; Indole-3-acrylic acid; 3-(3-Indolyl)acrylic acid; (E)-3-(1H-indol-3-yl)-2-propenoic acid | 29953-71-7 | C11H9NO2 | 详情 | 详情 |