Navitoclax, ABT-263, -Drug Synthesis Database

【结构式】

【药物名称】Navitoclax, ABT-263

【化学名称】N-[4-[4-[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexenylmethyl]piperazin-1-yl]benzoyl]-4-[3-(4-morpholinyl)-(1R)-(phenylsulfanylmethyl) propylamino]-3-(trifluoromethylsulfonyl)benzenesulfonamide

【CA登记号】923564-51-6

【分子式】C₄₇H₅₅ClF₃N₅O₆S₃

【分子量】974.613

【开发单位】Abbott Laboratories; developed in collaboration with Genentech

【药理作用】Bcl-2 Inhibitor, Apoptosis Inducer, Oncolytic

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

Ring opening of 3(R)-(benzyloxycarbonylamino)-γ-butyrolactone (I) with morpholine (II) in dioxane at 65 °C provides the morpholide (III), which is condensed with diphenyl disulfide in the presence of Bu3P in hot toluene, yielding the phenyl thioether (IV). Then, the benzyloxycarbonyl protecting group is removed with 30% HBr in AcOH, and the resulting deprotected amino-amide (V) is reduced to diamine (VI) using a solution of borane in tetrahydrofuran (1). Subsequent coupling of diamine (VI) with 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (VII) in the presence of DIEA in THF or DMSO gives the sulfanilamide (VIII) (1-3), which is finally acylated with the piperazinylbenzoic acid derivative (IX) by means of EDC and DMAP in CH2Cl 2 (1-4). Scheme 1.

参考文献中间体

【1】 Bruncko, M., Ding, H., Elmore, S.W. et al. (Abbott Laboratories Inc.). Apoptosis promoters. EP 1888550, US 2007027135, US 7390799, WO 2007040650.
【2】 Ding, H., Park, C.-M., Bruncko, M. et al. ABT-263, an orally bioavailable inhibitor of Bcl-2 family proteins. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 110.
【3】 Zhang, H., Zhou, J., Ha, C., Pei, D., Ding, K. An efficient synthesis of ABT-263, a novel inhibitor of antiapoptotic Bcl-2 proteins. Synthesis 2008, (15): 2398-404.
【4】 Song, X., Bruncko, M., Ding, H. et al. P2 site SAR development toward ABT-263, an orally bioavailable inhibitor of Bcl-2 family proteins. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 78.

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)	65752	3(R )-(benzyloxycarbonylamino)-γ-butyrolactone; Benzyl (R)-5-oxotetrahydrofuran-3-ylcarbamate; N-[(3R)-Tetrahydro-5-oxo-3-furanyl]carbamic acid phenylmethyl ester	118399-28-3	C₁₂H₁₃NO₄	详情	详情
(II)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(III)	65753			C₁₆H₂₂N₂O₅	详情	详情
(IV)	65754			C₂₂H₂₆N₂O₄S	详情	详情
(V)	65755			C₁₄H₂₀N₂O₂S	详情	详情
(VI)	65756			C₁₄H₂₂N₂OS	详情	详情
(VII)	65757	4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide	1027345-08-9	C₇H₅F₄NO₄S₂	详情	详情
(VIII)	65758			C₂₁H₂₆F₃N₃O₅S₃	详情	详情
(IX)	65759			C₂₆H₃₁ClN₂O₂	详情	详情

合成路线2

The building block (IX) can be obtained by several related methods:
Reaction of 4,4-dimethylcyclohexanone (XVII) with DMF and PBr3 under Vilsmeier formylation conditions provides the carbaldehyde (XVIII), which is subjected to reductive amination with 4-piperazinobenzoic acid ethyl ester (XIX) and NaBH3CN resulting in the cyclohexenylmethyl piperazine (XX). Subsequent Suzuki coupling of compound (XX) with 4-chlorophenylboronic acid (XXI) followed by ethyl ester hydrolysis of the resultant adduct (XXII) leads to the target intermediate (IX) (1). Scheme 3.
In a related procedure, 2-hydroxy-5,5-dimethyl-1-cyclohexenecarboxylic acid methyl ester (XXIII) is converted to the corresponding triflate (XXIV), which undergoes Suzuki coupling with boronic acid (XXI) to yield the 2-arylcyclohexenecarboxylate derivative (XXV). After reduction of ester (XXV) with LiBH4, the resulting primary alcohol (XXVI) is converted to the corresponding mesylate (XXVII) with methanesulfonyl chloride, and then condensed with the piperazine derivative (XIX) followed by ethyl ester hydrolysis to yield the key precursor (IX) (4). Scheme 3.

参考文献中间体

【1】 Bruncko, M., Ding, H., Elmore, S.W. et al. (Abbott Laboratories Inc.). Apoptosis promoters. EP 1888550, US 2007027135, US 7390799, WO 2007040650.
【4】 Song, X., Bruncko, M., Ding, H. et al. P2 site SAR development toward ABT-263, an orally bioavailable inhibitor of Bcl-2 family proteins. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 78.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	65759			C₂₆H₃₁ClN₂O₂	详情	详情
(XVII)	65767	4,4-Dimethylcyclohexanone; 4,4-Dimethyl-1-cyclohexanone	4255-62-3	C₈H₁₄O	详情	详情
(XVIII)	65768			C₉H₁₃BrO	详情	详情
(XIX)	65769	Ethyl 4-(1-piperazinyl)benzoate	80518-57-6	C₁₃H₁₈N₂O₂	详情	详情
(XX)	65770			C₂₂H₃₁BrN₂O₂	详情	详情
(XXI)	17575	4-chlorophenylboronic acid	1679-18-1	C₆H₆BClO₂	详情	详情
(XXII)	65771			C₂₈H₃₅ClN₂O₂	详情	详情
(XXIII)	65772			C₁₀H₁₆O₃	详情	详情
(XXIV)	65773			C₁₁H₁₆F₃O₅S	详情	详情
(XXV)	65774			C₁₆H₂₀ClO₂	详情	详情
(XXVI)	65775			C₁₅H₁₉ClO	详情	详情
(XXVII)	65776			C₁₆H₂₁ClO₃S	详情	详情

合成路线3

In a further method, Mannich reaction of 4,4-dimethylcyclohexanone (XVII) with tert-butyl 4-piperazinobenzoate (XXVIII) and paraformaldehyde by means of HCl in tert-butanol affords the piperazinylmethyl-cyclohexanone (XXIX), which is further condensed with 4-chlorophenylmagnesium bromide (XXX), yielding carbinol (XXXI). Simultaneous dehydration of alcohol (XXXI) and cleavage of the tert-butyl ester in refluxing 6 M HCl gives carboxylic acid (IX) (3). Scheme 4.

参考文献中间体

【3】 Zhang, H., Zhou, J., Ha, C., Pei, D., Ding, K. An efficient synthesis of ABT-263, a novel inhibitor of antiapoptotic Bcl-2 proteins. Synthesis 2008, (15): 2398-404.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	65759			C₂₆H₃₁ClN₂O₂	详情	详情
(XVII)	65767	4,4-Dimethylcyclohexanone; 4,4-Dimethyl-1-cyclohexanone	4255-62-3	C₈H₁₄O	详情	详情
(XXVIII)	65777	2-Methyl-2-Propanyl 4-(1-Piperazinyl)Benzoate; tert-butyl 4-(1-Piperazinyl)Benzoate	187669-28-9	C₁₅H₂₂N₂O₂	详情	详情
(XXIX)	65778			C₂₄H₃₅N₂O₃	详情	详情
(XXX)	25127	bromo(4-chlorophenyl)magnesium	873-77-8	C₆H₄BrClMg	详情	详情
(XXXI)	65779			C₃₀H₄₀ClN₂O₃	详情	详情

合成路线4

The precursor 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (VII) can be prepared by the following methods:
Condensation of 2-fluorobenzenethiol (X) with iodotriluoromethane in the presence of triethylamine and methyl viologen (1,1’-dimethyl-4,4’-bipyridinium dichloide) yields the trifluoromethyl sulfide (XI), which is oxidized to sulfone (XII) by means of NaIO4 and catalytic RuCl3 (1, 2). Subsequent chlorosulfonation of (XII) with ClSO3H affords the acid chloride (XIII), which is finally converted to the target sulfonamide (VII) upon quenching with ammonium hydroxide in cold isopropanol (1-3). Scheme 2.
In an improved method, treatment of bis(o-nitro-phenyl)disulfide (XIV) with potassium trifluoroacetate in sulfolane at 180-230 °C provides the trifluoromethyl sulide (XV), which is oxidized to the corresponding sulfone derivative (XVI) using periodic acid and a catalytic amount of CrO3. Finally, compound (XIV) is submitted to nitro group displacement with dried potassium fluoride and tetraphenylphosphonium bromide in hot DMSO (3). Scheme 2.

参考文献中间体

【1】 Bruncko, M., Ding, H., Elmore, S.W. et al. (Abbott Laboratories Inc.). Apoptosis promoters. EP 1888550, US 2007027135, US 7390799, WO 2007040650.
【2】 Ding, H., Park, C.-M., Bruncko, M. et al. ABT-263, an orally bioavailable inhibitor of Bcl-2 family proteins. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 110.
【3】 Zhang, H., Zhou, J., Ha, C., Pei, D., Ding, K. An efficient synthesis of ABT-263, a novel inhibitor of antiapoptotic Bcl-2 proteins. Synthesis 2008, (15): 2398-404.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	65757	4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide	1027345-08-9	C₇H₅F₄NO₄S₂	详情	详情
(X)	65760	2-Fluorothiophenol; 2-Fluorobenzenethiol	2557-78-0	C₆H₅FS	详情	详情
(XI)	65761	1-Fluoro-2-[(Trifluoromethyl)Thio]Benzene; 1-Fluoro-2-(Trifluoromethylthio)Benzene; 2-Fluorophenyl Trifluoromethyl Sulphide	1978-16-1	C₇H₄F₄S	详情	详情
(XII)	65762	2-Fluorophenyl trifluoromethyl sulfone; 1-Fluoro-2-(trifluoromethylsulfonyl)benzene	2358-41-0	C₇H₄F₄O₂S	详情	详情
(XIII)	65763	4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonyl Chloride	1027345-07-8	C₇H₃ClF₄O₄S₂	详情	详情
(XIV)	65764	Bis(2-nitrophenyl) disulfide; 2-Nitrophenyl disulfide; 2,2'-Dinitrodiphenyl disulfide	1155-00-6	C₁₂H₈N₂O₄S₂	详情	详情
(XV)	65765	2-(trifluoromethylthio)nitrobenzene; 1-nitro-2-[(trifluoromethyl)thio]Benzene	1644-87-7	C₇H₄F₃NO₂S	详情	详情
(XVI)	65766	1-Nitro-2-(trifluoromethylsulfonyl)benzene	384-37-2	C₇H₄F₃NO₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)