ethyl 4-(9-amino-3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】19341

【品名】ethyl 4-(9-amino-3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate

【CA登记号】

【分子式】C₂₂H₂₃BrClN₃O₂

【分子量】476.80034

【元素组成】C 55.42% H 4.86% Br 16.76% Cl 7.44% N 8.81% O 6.71%

与该中间体有关的原料药合成路线共 4 条

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

该中间体在本合成路线中的序号：(III)

Benzocycloheptapyridine (I) was nitrated with NaNO3 and H2SO4 to afford (II) as the major isomer. Reduction of (III) with iron and CaCl2 gave amine (III), which was brominated to provide (IV). Removal of the amino group of (IV) was accomplished by diazotization, followed by reduction with hypophosphorous acid to give (V). Then, hydrolysis of the carbamate group of (V) in refluxing hydrochloric acid furnished piperidine (VI). Subsequent coupling of (VI) with pyridineacetic acid N-oxide (VII) using EDC and HOBt yielded the corresponding amide. Finally, separation of the target (+)-atropoisomer was achieved by chiral chromatography.

参考文献中间体

合成目标

【1】 (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998, 41, 24, 4890.
【2】 Bishop, W.R.; Girijavallabhan, V.M.; Njoroge, F.G.; Bryant, M.S.; Nomeir, A.A.; Doll, R.J.; Ganguly, A.K.; Kirschmeier, P.; Liu, M.; Vibulbhan, B.; Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity. Bioorg Med Chem 1999, 7, 5, 861.

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)	25664	4-(carboxymethyl)-1-pyridiniumolate	C₇H₇NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Benzocycloheptapyridine (I) was nitrated with NaNO3 and H2SO4 to afford (II) as the major isomer. Reduction of (II) with iron and CaCl2 gave amine (III), which was brominated to provide (IV). Removal of the amino group of (IV) was accomplished by diazotization, followed by reduction with hypophosphorous acid to give (V). Then, hydrolysis of the carbamate group in refluxing hydrochloric acid furnished piperidine (VI). Subsequent coupling of (VI) with N-Boc-piperidineacetic acid (VII) using EDC and HOBt yielded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, piperidine (IX) was condensed with trimethylsilyl isocyanate to produce the corresponding urea. Finally, separation of the target (+)-atropoisomer was achieved by chiral chromatography.

参考文献中间体

合成目标

【1】 (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998, 41, 24, 4890.
【2】 Bishop, W.R.; Girijavallabhan, V.M.; Njoroge, F.G.; Bryant, M.S.; Nomeir, A.A.; Doll, R.J.; Ganguly, A.K.; Kirschmeier, P.; Liu, M.; Vibulbhan, B.; Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity. Bioorg Med Chem 1999, 7, 5, 861.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	19976	isocyanato(trimethyl)silane; trimethylsilyl isocyanate		C₄H₉NOSi	详情	详情
(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)	19346	1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid	157688-46-5	C₁₂H₂₁NO₄	详情	详情
(VIII)	25662	tert-butyl 4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxylate		C₃₁H₃₆Br₂ClN₃O₃	详情	详情
(IX)	25663	1-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone		C₂₆H₂₈Br₂ClN₃O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Introduction of a bromine atom at the 10-position of the benzocycloheptapyridine (I) was achieved by the following sequence. Nitration of (I) using NaNO3-H2SO4 afforded a mixture of nitro compounds (II) and (III), from which the major 9-nitro isomer (III) was separated by silica gel chromatography. Reduction of the nitro group of (III) with iron filings and CaCl2 in refluxing aqueous ethanol gave amine (IV), which was brominated at position 10 with Br2 in AcOH. The brominated aniline (VI) was then deaminated by diazotization, followed by reduction of the resulting diazonium salt with hypophosphorous acid to give trihalo compound (VI). Hydrolysis of carbamate group of (VI) in boiling concentrated HCl afforded piperidine (VII). Subsequent reduction of the C-11 double bond of (VII) was carried out using DIBAL-H in refluxing toluene to afford the corresponding racemic piperidine. Separation of enantiomers was achieved by HPLC on a ChiralPak AD column or by chemical resolution using N-acetyl-L-phenylalanine as the resolving agent. The appropriate R-(+) enantiomer (VIII) was coupled with N-Boc-piperidylacetic acid (IX) in the presence of EDC and HOBt to yield protected amide (X). Hydrolysis of the Boc protecting group was performed with trifluoroacetic acid, and the resulting piperidine (XI) was finally treated with trimethylsilyl isocyanate to give the desired carboxamide (3-5).

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castañer, J.; Lonafarnib. Drugs Fut 2003, 28, 12, 1168.
【2】 Mallams, A.K. (Schering Corp.); Method for preparing substituted 1-piperidinecarboxamide derivatives. WO 9804549 .
【3】 (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998, 41, 24, 4890.
【4】 Doll, R.J.; Kelly, J.M.; Njoroge, F.G.; Mallams, A.K.; Remiszewski, S.W.; Taveras, A.G. (Schering Corp.); Tricyclic amides useful for inhibition of G-protein function and for treatment of proliferative diseases. EP 1019392; EP 1380581; JP 1999501671; WO 9723478 .

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)	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)	19339	ethyl 4-(3-bromo-8-chloro-7-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₁BrClN₃O₄	详情	详情
(III)	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
(IV)	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
(V)	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
(VI)	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
(VII)	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
(VIII)	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
(IX)	19346	1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid	157688-46-5	C₁₂H₂₁NO₄	详情	详情
(X)	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
(XI)	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

合成路线4

该中间体在本合成路线中的序号：(III)

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

合成目标

【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

Extended Information