-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】3-[4-[2-[4-[3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl]piperidin-1-yl]-2-oxoethyl]-1-piperidinyl]-3-oxopropionamide

【CA登记号】210646-43-8

【分子式】C₂₉H₃₃Br₂ClN₄O₃

【分子量】680.87236

【开发单位】Schering-Plough (Originator)

【药理作用】ONCOLYTIC DRUGS, Farnesyl Transferase Inhibitors

合成路线1 合成路线2

合成路线1

Compound (I) is nitrated employing KNO3 in cold H2SO4 to produce (II). Subsequent nitro group reduction in (II) to afford amine (III) is carried out by means of iron powder in the presence of CaCl2. Bromination of (III) in AcOH then gives (IV). The amino group of (IV) is removed via diazotization with t-butyl nitrite in hot DMF to furnish (V). Further acidic hydrolysis of the ethyl carbamate group of (V) leads to amine (VI). Double bond reduction in (VI) by means of DIBAL in toluene, followed by resolution of the resultant racemic mixture by chiral preparative HPLC provides intermediate (VII) (1,2).

参考文献中间体

【1】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. US 6030982 .
【2】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. WO 9830558 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	19338	ethyl 4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	C₂₂H₂₂BrClN₂O₂	详情	详情
(II)	19340	ethyl 4-(3-bromo-8-chloro-9-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	C₂₂H₂₁BrClN₃O₄	详情	详情
(III)	19341	ethyl 4-(9-amino-3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	C₂₂H₂₃BrClN₃O₂	详情	详情
(IV)	19342	ethyl 4-(9-amino-3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	C₂₂H₂₂Br₂ClN₃O₂	详情	详情
(V)	19343	ethyl 4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	C₂₂H₂₁Br₂ClN₂O₂	详情	详情
(VI)	19344	3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₉H₁₇Br₂ClN₂	详情	详情
(VII)	19345	(11R)-3,10-dibromo-8-chloro-11-(4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₉H₁₉Br₂ClN₂	详情	详情

合成路线2

Amine (VII) is coupled to N-Boc-4-piperidineacetic acid (VIII) by means of EDC/HOBt to afford amide (IX). Subsequent acidic cleavage of the N-Boc group of (IX) leads to amine (X) (1,2). Piperidine (X) is finally coupled with malonic acid mono-amide (XI) to furnish the title compound (1,2). In a related method, piperidine (X) is coupled to mono-methyl malonate (XII), yielding the amide ester (XIII). Basic hydrolysis of the methyl ester group of (XIII) then leads to the sodium carboxylate salt (XIV), which is finally reacted with ammonium chloride in the presence of EDC/HOBt to produce the target amide (3).

参考文献中间体

【1】 Njoroge, F.G.; Vibulbhan, B.; Pinto, P.; Strickland, C.L.; Bishop, W.R.; Kirschmeir, P.; Girijavallabhan, V.; Ganguly, A.K.; Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase. Bioorg Med Chem 2003, 11, 1, 139.
【2】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. US 6030982 .
【3】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. WO 9830558 .

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)	19345	(11R)-3,10-dibromo-8-chloro-11-(4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₉H₁₉Br₂ClN₂	详情	详情
(VIII)	19346	1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid	157688-46-5	C₁₂H₂₁NO₄	详情	详情
(IX)	19347	tert-butyl 4-(2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-oxoethyl)-1-piperidinecarboxylate		C₃₁H₃₈Br₂ClN₃O₃	详情	详情
(X)	19348	1-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone		C₂₆H₃₀Br₂ClN₃O	详情	详情
(XI)	63973	3-oxo-beta-alanine		C₃H₅NO₃	详情	详情
(XII)	16198	3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester	16695-14-0	C₄H₆O₄	详情	详情
(XIII)	63971	methyl 3-[4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl}-2-oxoethyl)-1-piperidinyl]-3-oxopropanoate		C₃₀H₃₄Br₂ClN₃O₄	详情	详情
(XIV)	63972	sodium 3-[4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl}-2-oxoethyl)-1-piperidinyl]-3-oxopropanoate		C₂₉H₃₁Br₂ClN₃NaO₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)