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【结 构 式】

【药物名称】CGH-1484A

【化学名称】N-[1(S)-(Benzothiazol-2-ylmethyl)-2-[4-(2-fluoroethyl)piperidin-1-yl]-2-oxoethyl]-3,3-dimethyl-6-[3-[4-[2-(4-morpholinyl)-2-oxoethyl]piperazin-1-yl]-3-oxopropyl]-1,2,3,4-tetrahydroquinoline-8-sulfonamide hydrochloride
　　　　　　(S)-4-[2-[4-[3-[8-[1-(2-Benzothiazolylmethyl)-2-[4-(2-fluoroethyl)-1-piperidinyl]-2-oxoethylaminosulfonyl]-1,2,3,4-tetrahydro-3,3-dimethyl-6-quinolinyl]-1-oxopropyl]-1-piperazinyl]acetyl]morpholine hydrochloride

【CA登记号】202468-90-4 (free base)

【 分 子 式 】C41H57ClFN7O6S2

【 分 子 量 】862.53414

【开发单位】Novartis (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin 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5合成路线6

合成路线1

Alcohol (I) was converted to fluoride (II) by treatment with either diethylaminosulfur trifluoride or the Ishikawa reagent. Subsequent acid cleavage of the Boc protecting group of (III) provided piperidine (VI). Alternatively, alcohol (III) was converted to mesylate (IV), which was displaced with tetrabutylammonium fluoride to afford fluoride (V). The benzamido group of (V) was then hydrolyzed with HCl in aqueous MeOH.

参考文献 中间体
【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .
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) 43453 tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate C12H23NO3 详情 详情
(II) 43454 tert-butyl 4-(2-fluoroethyl)-1-piperidinecarboxylate C12H22FNO2 详情 详情
(III) 43455 [4-(2-hydroxyethyl)-1-piperidinyl](phenyl)methanone C14H19NO2 详情 详情
(IV) 43456 2-(1-benzoyl-4-piperidinyl)ethyl methanesulfonate C15H21NO4S 详情 详情
(V) 43457 [4-(2-fluoroethyl)-1-piperidinyl](phenyl)methanone C14H18FNO 详情 详情
(VI) 28517 4-(2-fluoroethyl)piperidine C7H14FN 详情 详情

合成路线2

Amine intermediate (XIV) has been obtained as follows: N-(Carbobenzoxy)-L-aspartic acid alpha-benzyl ester (VII) was converted to acid chloride (VIII) and then coupled to 2-aminophenyl disulfide (IX) to afford the bis-amide (X). Reductive cleavage of the disulfide group of (X), followed by basic cyclization, produced the benzothiazole (XI) (2). Hydrolysis of the benzyl ester group of (XI) and subsequent coupling of the resulting carboxylic acid (XII) with piperidine (VI) gave amide (XIII). The carbobenzoxy group of (XII) was then cleaved with HBr in HOAc, yielding intermediate amine (XIV).

参考文献 中间体
【1】 Baettig, U.; et al.; The design and synthesis of thrombin inhibitors: Analogues of MD805 containing non-polar surrogates for arginine at the P1 position. Bioorg Med Chem Lett 2000, 10, 14, 1563.
【2】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 28517 4-(2-fluoroethyl)piperidine C7H14FN 详情 详情
(VII) 43458 (3S)-4-(benzyloxy)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid 4779-31-1 C19H19NO6 详情 详情
(VIII) 43459 benzyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-chloro-4-oxobutanoate C19H18ClNO5 详情 详情
(IX) 43460 2-[(2-aminophenyl)disulfanyl]aniline; 2-[(2-aminophenyl)disulfanyl]phenylamine 1141-88-4 C12H12N2S2 详情 详情
(X) 43461 benzyl (2S)-4-[2-([2-[((3S)-4-(benzyloxy)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoyl)amino]phenyl]disulfanyl)anilino]-2-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate C50H46N4O10S2 详情 详情
(XI) 43462 benzyl (2S)-3-(1,3-benzothiazol-2-yl)-2-[[(benzyloxy)carbonyl]amino]propanoate C25H22N2O4S 详情 详情
(XII) 43463 (2S)-3-(1,3-benzothiazol-2-yl)-2-[[(benzyloxy)carbonyl]amino]propionic acid C18H16N2O4S 详情 详情
(XIII) 43464 benzyl (1S)-1-(1,3-benzothiazol-2-ylmethyl)-2-[4-(2-fluoroethyl)-1-piperidinyl]-2-oxoethylcarbamate C25H28FN3O3S 详情 详情
(XIV) 43465 (2S)-2-amino-3-(1,3-benzothiazol-2-yl)-1-[4-(2-fluoroethyl)-1-piperidinyl]-1-propanone C17H22FN3OS 详情 详情

合成路线3

2-Aminobenzonitrile (XV) was acylated with 2-bromoisobutyryl bromide (XVI) to afford the cyano amide (XVII). Halogen-metal exchange with ethylmagnesium bromide followed by intramolecular addition to the cyano group of (XVII) gave rise to the quinoline dione (XVIII). This was reduced to the tetrahydroquinoline (XIX) by means of LiAlH4 and AlCl3. Iodination of (XIX) with benzyltrimethylammonium iodine dichloride furnished (XX), which was coupled with ethyl acrylate (XXI) in the presence of palladium acetate, yielding the unsaturated ester (XXII). After catalytic hydrogenation of the olefin (XXII) to propionyl ester (XXIII), sulfonation and treatment with POCl3, intermediate sulfonyl chloride (XXIV) was obtained.

参考文献 中间体
【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 19493 2-aminobenzonitrile 1885-29-6 C7H6N2 详情 详情
(XVI) 19367 2-bromo-2-methylpropanoyl bromide 20769-85-1 C4H6Br2O 详情 详情
(XVII) 43466 2-bromo-N-(2-cyanophenyl)-2-methylpropanamide C11H11BrN2O 详情 详情
(XVIII) 43467 3,3-dimethyl-2,4(1H,3H)-quinolinedione C11H11NO2 详情 详情
(XIX) 43468 3,3-dimethyl-1,2,3,4-tetrahydroquinoline C11H15N 详情 详情
(XX) 43469 6-iodo-3,3-dimethyl-1,2,3,4-tetrahydroquinoline C11H14IN 详情 详情
(XXI) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(XXII) 43470 ethyl (E)-3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-propenoate C16H21NO2 详情 详情
(XXIII) 43471 ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)propanoate C16H23NO2 详情 详情
(XXIV) 43472 ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate C16H22ClNO4S 详情 详情

合成路线4

An alternative procedure for the preparation of tetrahydroquinoline (XXIII) consisted in the acylation of ethyl 4-aminocinnamate (XXV) with the in situ prepared dimethylmalonyl chloride (to give (XXVI)), followed by cyclization to the quinoline dione (XXVII) by means of phosphorus pentoxide and methanesulfonic acid. The hydrogenation of the double bond of (XXVII) and simultaneous reduction of the keto group produced quinolinone (XXVIII). Further reduction of the lactam carbonyl group of (XXVIII) to provide (XXIII) was carried out via conversion to thiolactam (XXIX), which was alkylated with iodomethane to the S-methyl thioimidate (XXX) and then reduced with NaBH3CN.

参考文献 中间体
【1】 Hayler, J.; LeGrand, D.; Kane, P.D.; et al.; The design and synthesis of thrombin inhibitors: The introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors. Bioorg Med Chem Lett 2000, 10, 14, 1567.
【2】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIX) 43477 ethyl 3-(3,3-dimethyl-2-thioxo-1,2,3,4-tetrahydro-6-quinolinyl)propanoate C16H21NO2S 详情 详情
(XXIII) 43471 ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)propanoate C16H23NO2 详情 详情
(XXV) 43473 ethyl (E)-3-(4-aminophenyl)-2-propenoate 5048-82-8 C11H13NO2 详情 详情
(XXVI) 43474 3-[4-[(E)-3-ethoxy-3-oxo-1-propenyl]anilino]-2,2-dimethyl-3-oxopropionic acid C16H19NO5 详情 详情
(XXVII) 43475 ethyl (E)-3-(3,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-propenoate C16H17NO4 详情 详情
(XXVIII) 43476 ethyl 3-(3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)propanoate C16H21NO3 详情 详情
(XXX) 43478 ethyl 3-[3,3-dimethyl-2-(methylsulfanyl)-3,4-dihydro-6-quinolinyl]propanoate C17H23NO2S 详情 详情

合成路线5

Quinolinone (XXVIII) was also obtained by reduction of quinoline dione (XXXI) to alcohol (XXXII), followed by esterification to acetate (XXXIII) and hydrogenolysis of the acetoxy group in the presence of palladium oxide.

参考文献 中间体
【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVIII) 43476 ethyl 3-(3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)propanoate C16H21NO3 详情 详情
(XXXI) 43479 ethyl 3-(3,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-6-quinolinyl)propanoate C16H19NO4 详情 详情
(XXXII) 43480 ethyl 3-(4-hydroxy-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)propanoate C16H21NO4 详情 详情
(XXXIII) 43481 ethyl 3-[4-(acetoxy)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl]propanoate C18H23NO5 详情 详情

合成路线6

Coupling between sulfonyl chloride (XXIV) and amine (XIV) provided sulfonamide (XXXIV). The ethyl ester group of (XXXIV) was then hydrolyzed to carboxylic acid (XXXV), which was finally coupled with N-(2-morpholin-4-yl-2-oxoethyl)piperazine (XXXVI) to furnish the title amide.

参考文献 中间体
【1】 Hayler, J.; LeGrand, D.; Kane, P.D.; et al.; The design and synthesis of thrombin inhibitors: The introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors. Bioorg Med Chem Lett 2000, 10, 14, 1567.
【2】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 43465 (2S)-2-amino-3-(1,3-benzothiazol-2-yl)-1-[4-(2-fluoroethyl)-1-piperidinyl]-1-propanone C17H22FN3OS 详情 详情
(XXIV) 43472 ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate C16H22ClNO4S 详情 详情
(XXXIV) 43482 ethyl 3-[8-[([(1S)-1-(1,3-benzothiazol-2-ylmethyl)-2-[4-(2-fluoroethyl)-1-piperidinyl]-2-oxoethyl]amino)sulfonyl]-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate C33H43FN4O5S2 详情 详情
(XXXV) 43483 3-[8-[([(1S)-1-(1,3-benzothiazol-2-ylmethyl)-2-[4-(2-fluoroethyl)-1-piperidinyl]-2-oxoethyl]amino)sulfonyl]-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propionic acid C31H39FN4O5S2 详情 详情
(XXXVI) 43484 1-(4-morpholinyl)-2-(1-piperazinyl)-1-ethanone C10H19N3O2 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)