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【结 构 式】

【药物名称】

【化学名称】(2R,6S,13aR,14aR,16aS)-2-[2-(2-Acetamidothiazol-4-yl)-7-methoxyquinolin-4-yloxy]-6-(tert-butoxycarboxamido)-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylic acid

【CA登记号】300832-31-9

【 分 子 式 】C38H48N6O9S

【 分 子 量 】764.90506

【开发单位】Boehringer Ingelheim (Originator)

【药理作用】Anti-Hepatitis C Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, HCV NS3 Protease Inhibitors

合成路线1合成路线2合成路线3合成路线4

合成路线1

The aminoacid building block (VIII) can be prepared by two different ways. The oxidative cleavage of 7-octene-1,2-diol (I) by means of NaIO4 yields aldehyde (II). Partial hydrolysis of diethyl 2-acetamidomalonate (III) provides monoacid (IV), which is subjected to Knoevenagel-type condensation with 6-heptenal (II) in the presence of Ac2O and pyridine to afford enamide (V). Enantioselective hydrogenation of the enamide double bond to the (S)-amidoester (VI) is then achieved by using the Burk's method. In order to replace the N-acetyl protecting group of (VI), the acetamide nitrogen is protected with Boc2O, and the resulting imide (VII) is further hydrolyzed to the target N-Boc aminoacid (VIII) under standard basic conditions.

参考文献 中间体
【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 .
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) 58933 7-Octene-1,2-diol C8H16O2 详情 详情
(II) 27179 6-heptenal C7H12O 详情 详情
(III) 16170 1,2-dichloroethane 107-06-2 C2H4Cl2 详情 详情
(IV) 58934 Ethyl 2-acetamidomalonate C7H11NO5 详情 详情
(V) 58935 ethyl (2Z)-2-(acetylamino)-2,8-nonadienoate C13H21NO3 详情 详情
(VI) 58936 ethyl (2S)-2-(acetylamino)-8-nonenoate C13H23NO3 详情 详情
(VII) 58937 (2S)-2-[acetyl(tert-butoxycarbonyl)amino]-8-nonenoic acid C16H27NO5 详情 详情
(VIII) 58938 (2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid C14H25NO4 详情 详情

合成路线2

Alternatively, 8-bromo-1-octene (IX) is converted into the corresponding Grignard reagent (X) which is further carboxylated by solid carbon dioxide in cold THF to produce acid (XI). Coupling of acid (XI) with the lithium derivative of (S)-4-benzyl-2-oxazolidinone (XII), via activation with pivalic anhydride, leads to the chiral N-acyl oxazolidinone (XIII). Stereoselective alpha-azidation of the potassium enolate of (XIII) with trizylazide forms the (S)-azide (XIV). Subsequent reduction of azide (XIV) employing SnCl2 leads to amine (XV), which is further protected as the N-Boc derivative (XVI) with Boc2O in the presence of NaHCO3. Then, hydrolysis of the chiral auxiliary of (XVI) by means of lithium hydroperoxide gives rise to the desired N-Boc aminoacid (VIII).

参考文献 中间体
【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 58938 (2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid C14H25NO4 详情 详情
(IX) 58939 8-Bromo-1-octene C8H15Br 详情 详情
(X) 58940 bromo(7-octenyl)magnesium C8H15BrMg 详情 详情
(XI) 58941 8-nonenoic acid C9H16O2 详情 详情
(XII) 58942 　 C10H10LiNO2 详情 详情
(XIII) 58943 (4S)-4-benzyl-3-(8-nonenoyl)-1,3-oxazolidin-2-one C19H25NO3 详情 详情
(XIV) 58944 (4S)-3-[(2S)-2-azido-8-nonenoyl]-4-benzyl-1,3-oxazolidin-2-one C19H24N4O3 详情 详情
(XV) 58945 (4S)-3-[(2S)-2-amino-8-nonenoyl]-4-benzyl-1,3-oxazolidin-2-one C19H26N2O3 详情 详情
(XVI) 58946 tert-butyl (1S)-1-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-7-octenylcarbamate C24H34N2O5 详情 详情

合成路线3

Coupling between the Boc-aminoacid (VIII) and dipeptide ester (XV) affords the linear tripeptide (XVI). Macrocyclization of (XVI) to produce (XVII) is accomplished by intramolecular olefin metathesis in the presence of Hoveyda's catalyst. Subsequent catalytic hydrogenation of (XVII) leads to a mixture of the desired saturated macrocycle (XIX) and compound (XVIII), produced by hydrogenolysis of the cyclopropane ring. Mitsunobu coupling of (XIX) with methyl 4-hydroxy-7-methoxyquinoline-2-carboxylate (XX) gives rise to quinolinyl ether (XXI). The quinoline carboxylate group of (XXI) is then selectively hydrolyzed by NaOH to furnish the sodium carboxylate salt (XXII).

参考文献 中间体
【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 58938 (2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid C14H25NO4 详情 详情
(XV) 58947 methyl (1R,2S)-1-({[(2S,4R)-4-hydroxypyrrolidinyl]carbonyl}amino)-2-vinylcyclopropanecarboxylate C12H18N2O4 详情 详情
(XVI) 58948 methyl (1R,2S)-1-{[((2S,4R)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]-8-nonenoyl}-4-hydroxypyrrolidinyl)carbonyl]amino}-2-vinylcyclopropanecarboxylate C26H41N3O7 详情 详情
(XVII) 58949 methyl (2R,6S,13aS,16aS)-6-[(tert-butoxycarbonyl)amino]-2-hydroxy-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate C24H37N3O7 详情 详情
(XVIII) 58950 methyl (13S,17R,18aS)-13-[(tert-butoxycarbonyl)amino]-17-hydroxy-1,14-dioxooctadecahydropyrrolo[1,2-a][1,4]diazacyclohexadecine-3-carboxylate C24H41N3O7 详情 详情
(XIX) 58951 methyl (2R,6S,13aR,16aS)-6-[(tert-butoxycarbonyl)amino]-2-hydroxy-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate C24H39N3O7 详情 详情
(XX) 58952 methyl 4-hydroxy-7-methoxy-2-quinolinecarboxylate C12H11NO4 详情 详情
(XXI) 58953 methyl (2R,6S,13aR,16aS)-6-[(tert-butoxycarbonyl)amino]-2-{[7-methoxy-2-(methoxycarbonyl)-4-quinolinyl]oxy}-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate C36H48N4O10 详情 详情
(XXII) 58954 sodium 4-{[(2R,6S,13aR,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-(methoxycarbonyl)-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl]oxy}-7-methoxy-2-quinolinecarboxylate C35H45N4NaO10 详情 详情

合成路线4

The sodium carboxylate (XXII) is activated as the mixed anhydride (XXIII) by treatment with isobutyl chloroformate and triethylamine. Subsequent addition of diazomethane to the mixed anhydride (XXIII) leads to diazo ketone (XXIV), which is further transformed into bromo ketone (XXV) upon treatment with HBr. Cyclization of bromo ketone (XXV) with N-acetyl thiourea (XXVI) produces the thiazole derivative (XXVII). The methyl ester group of (XXVII) is finally hydrolyzed by means of LiOH to the target carboxylic acid.

参考文献 中间体
【1】 Halmos, T.; Llinas-Brunet, M.; Faucher, A.-M.; Ghiro, E.; Goudreau, N.; Tsantrizos, Y.S.; Cameron, D.R. (Boehringer Ingelheim (Canada) Ltd.); Macrocyclic peptides active against the hepatitis C virus. EP 1169339; JP 2002542160; WO 0059929 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 58954 sodium 4-{[(2R,6S,13aR,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-(methoxycarbonyl)-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl]oxy}-7-methoxy-2-quinolinecarboxylate C35H45N4NaO10 详情 详情
(XXIII) 58955 　 C40H54N4O12 详情 详情
(XXIV) 58956 　 C36H46N6O9 详情 详情
(XXV) 58957 methyl (2R,6S,13aR,16aS)-2-{[2-(2-bromoacetyl)-7-methoxy-4-quinolinyl]oxy}-6-[(tert-butoxycarbonyl)amino]-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate C36H47BrN4O9 详情 详情
(XXVI) 58958 1-Acetyl-2-thiourea; N-Acetylthiourea 591-08-2 C3H6N2OS 详情 详情
(XXVII) 58959 methyl (2R,6S,13aR,16aS)-2-({2-[2-(acetylamino)-1,3-thiazol-4-yl]-7-methoxy-4-quinolinyl}oxy)-6-[(tert-butoxycarbonyl)amino]-5,16-dioxohexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate C39H50N6O9S 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)