Exatecan mesilate, DX-8951f, DX-8951(free base), -Drug Synthesis Database

【结构式】

【药物名称】Exatecan mesilate, DX-8951f, DX-8951(free base)

【化学名称】(1S,9S)-1-Amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione mesylate

【CA登记号】169869-90-3, 171335-80-1 (free base), 197720-53-9 (hydrate), 144008-87-7 (monohydrochloride)

【分子式】C₂₅H₂₆FN₃O₇S

【分子量】531.56427

【开发单位】Daiichi Pharmaceutical (Originator), Yakult Honsha (Originator), EORTC (Not Determined)

【药理作用】Breast Cancer Therapy, Leukemia Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Prostate Cancer Therapy, Camptothecins, DNA Topoisomerase I Inhibitors

合成路线1 合成路线2

合成路线1

Friedel-Crafts acylation of 2-fluorotoluene (I) with succinic anhydride (II) in the presence of AlCl3 afforded 4-(4-fluoro-3-methylphenyl)-4-oxobutanoic acid (III). Ketone (III) reduction by hydrogenation over Pd/C furnished the arylbutyric acid (IV), which was esterified to (V) by means of SOCl2 in MeOH. Subsequent aromatic ring nitration of (V) yielded (VI). After basic hydrolysis of the methyl ester of (VI), the arylbutyric acid (VII) was subjected to intramolecular cyclization in hot polyphosphoric acid producing tetralone (VIII). Reduction of the keto group of (VIII) with NaBH4, followed by dehydration of the resultant alcohol (IX) under acidic conditions, gave rise to the dihydronaphthalene (X). Hydrogenation of the olefin double bond of (X) and simultaneous nitro group reduction in the presence of PtO2 produced the amino tetralin (XI). The amino group of (XI) was further protected as the acetamide (XII) employing Ac2O and Et3N. Regioselective benzylic oxidation of (XII) with KMnO4 gave tetralone (XIII). Functionalization of the alpha position of (XIII) to ketone was achieved employing n-butyl nitrite and potassium tert-butoxide. The resulting keto oxime (XIV) was then reduced with zinc in the presence of Ac2O, yielding acetamide (XV). Both amide functions of (XV) were hydrolyzed under acidic conditions to give diamine (XVI). The aliphatic amine of (XVI) was then selectively acylated with ethyl trifluoroacetate to produce the trifluoroacetamide (XVII).

参考文献中间体

【1】 Chilman-Blair, K.; Mealy, N.E.; Castaner, J.; Bayes, M.; Exatecan Mesilate. Drugs Fut 2004, 29, 1, 9.
【2】 Terasawa, H.; Ejima, A.; Ohsuki, S.; Uoto, K. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Hexacyclic cpd.. EP 0495432; JP 1993059061; US 5834476; US 6407115 .
【3】 Terasawa, H.; Sato, K.; Mitsui, I. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Antitumor agents. JP 1994087746 .

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)	52759	2-Fluorotoluene; o-Fluorotoluene	95-52-3	C₇H₇F	详情	详情
(II)	11291	Dihydro-2,5-furandione; Succinic anhydride	108-30-5	C₄H₄O₃	详情	详情
(III)	52760	4-(4-fluoro-3-methylphenyl)-4-oxobutanoic acid		C₁₁H₁₁FO₃	详情	详情
(IV)	52761	4-(4-fluoro-3-methylphenyl)butanoic acid		C₁₁H₁₃FO₂	详情	详情
(V)	52762	methyl 4-(4-fluoro-3-methylphenyl)butanoate		C₁₂H₁₅FO₂	详情	详情
(VI)	52763	methyl 4-(4-fluoro-5-methyl-2-nitrophenyl)butanoate		C₁₂H₁₄FNO₄	详情	详情
(VII)	52764	4-(4-fluoro-5-methyl-2-nitrophenyl)butanoic acid		C₁₁H₁₂FNO₄	详情	详情
(VIII)	52765	7-fluoro-8-methyl-5-nitro-3,4-dihydro-1(2H)-naphthalenone		C₁₁H₁₀FNO₃	详情	详情
(IX)	52766	7-fluoro-8-methyl-5-nitro-1,2,3,4-tetrahydro-1-naphthalenol		C₁₁H₁₂FNO₃	详情	详情
(X)	52767	6-fluoro-5-methyl-8-nitro-1,2-dihydronaphthalene		C₁₁H₁₀FNO₂	详情	详情
(XI)	52768	3-fluoro-4-methyl-5,6,7,8-tetrahydro-1-naphthalenylamine; 3-fluoro-4-methyl-5,6,7,8-tetrahydro-1-naphthalenamine		C₁₁H₁₄FN	详情	详情
(XII)	52769	N-(3-fluoro-4-methyl-5,6,7,8-tetrahydro-1-naphthalenyl)acetamide		C₁₃H₁₆FNO	详情	详情
(XIII)	52770	N-(3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)acetamide		C₁₃H₁₄FNO₂	详情	详情
(XIV)	52771	N-[3-fluoro-7-(hydroxyimino)-4-methyl-8-oxo-5,8-dihydro-1(6H)-naphthalenyl]acetamide		C₁₃H₁₃FN₂O₃	详情	详情
(XV)	52772	N-[7-(acetylamino)-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydro-1-naphthalenyl]acetamide		C₁₅H₁₇FN₂O₃	详情	详情
(XVI)	52773	2,8-diamino-6-fluoro-5-methyl-3,4-dihydro-1(2H)-naphthalenone		C₁₁H₁₃FN₂O	详情	详情
(XVII)	52774	N-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)-2,2,2-trifluoroacetamide		C₁₃H₁₂F₄N₂O₂	详情	详情

合成路线2

The pyranoindolizine acetal (XVIII) was hydrolyzed to the trione (XIX) in 90% trifluoroacetic acid. Condensation of (XIX) with amino ketone (XVII) in refluxing toluene produced the hexacyclic compound (XX) as a diastereomeric mixture. The title compound was then obtained by acidic hydrolysis of the trifluoroacetamido group, followed by isolation of the desired isomer by preparative HPLC. The synthesis of the title compound was also reported by condensation of trione (XIX) with the acetamido tetralone (XXI). The resultant hexacyclic acetamide (XXII) was subsequently hydrolyzed with methanesulfonic acid, and the diastereomeric mixture of mesylate salts was finally separated by fractional crystallization.

参考文献中间体

【1】 Chilman-Blair, K.; Mealy, N.E.; Castaner, J.; Bayes, M.; Exatecan Mesilate. Drugs Fut 2004, 29, 1, 9.
【2】 Terasawa, H.; Ejima, A.; Ohsuki, S.; Uoto, K. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Hexacyclic cpd.. EP 0495432; JP 1993059061; US 5834476; US 6407115 .
【3】 Kamihara, S.; Kanai, K.; Noguchi, S.; Terasawa, H.; Kitaoka, H. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Campthothecin deriv. with antitumour activity. CA 2173671; EP 0737686; JP 1996337584 .
【4】 Terasawa, H.; Sato, K.; Mitsui, I. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Antitumor agents. JP 1994087746 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVII)	52774	N-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)-2,2,2-trifluoroacetamide	C₁₃H₁₂F₄N₂O₂	详情	详情
(XVIII)	52775		C₁₅H₁₇NO₆	详情	详情
(XIX)	10841	(4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione	C₁₃H₁₃NO₅	详情	详情
(XX)	52777	N-[(9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]-2,2,2-trifluoroacetamide	C₂₆H₂₁F₄N₃O₅	详情	详情
(XXI)	52776	N-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide	C₁₃H₁₅FN₂O₂	详情	详情
(XXII)	52778	N-[(9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]acetamide	C₂₆H₂₄FN₃O₅	详情	详情

Extended Information