Lonafarnib, Sch-66336, Sarasar, -Drug Synthesis Database

【结构式】

【药物名称】Lonafarnib, Sch-66336, Sarasar

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

【CA登记号】193275-84-2, 193275-85-3 ((-)-enantiomer)

【分子式】C₂₇H₃₁Br₂ClN₄O₂

【分子量】638.83472

【开发单位】Schering-Plough (Originator), EORTC (Not Determined)

【药理作用】Breast Cancer Therapy, Head and Neck Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, Apoptosis Inducers, Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways

合成路线1 合成路线2 合成路线3

合成路线1

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

【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2

The starting product is the benzocyclohetapyridine (VII), already reported as intermediate (VII) in the synthesis of 25468001a. Compound (VII) is resolved into its atropaisomers by digestion with Toyobo LIP-300 enzyme in the presence of trifluroethyl isobutyrate (XII) to give a mixture of unreacted (-)-(XIII) and acylated compound (+)-(XIV) that are separated by acid extraction. The undesired atropaisomer (-)-(XIII) can be recovered by thermal razemization in diethyleneglycol dibutyl ether at 210 C and new enzymatic separation. The acid hydrolysis of the separated amide (+)-(XIV) produces the desired atropaisomer (+)-(XIII), which is reduced to the (R)-(+)-(VIII), intermediate already reported with no. (VIII) in the synthesis of 25468001a. (6,7)

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Lonafarnib. Drugs Fut 2003, 28, 12, 1168.
【2】 Morgan, B.; Zaks, A.; Dodds, D.R.; Liu, J.; Jain, R.; Megati, S.; Njoroge, F.G.; Girijavallabhan, V.M.; Enzymatic kinetic resolution of piperidine atropisomers: Synthesis of a key intermediate of the farnesyl protein transferase inhibitor, SCH66336. J Org Chem 2000, 65, 18, 5451.
【3】 Njoroge, F.G.; Vibulbhan, B.; Girijavallabhan, V.M. (Schering Corp.); Process for producing (8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidine. EP 1091954; JP 2002519419; WO 0001689 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(-)-(XIII)	41836	(-)-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
(+)-(XIII)	41837	(+)-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)	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
(XII)	41835	2,2,2-trifluoroethyl 2-methylpropanoate	C₆H₉F₃O₂	详情	详情
(XIV)	41834	1-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-methyl-1-propanone	C₂₃H₂₃Br₂ClN₂O	详情	详情

合成路线3

The nitration of loratadine (I) (1) by means of tetrabutylammonium nitrate and trifluoroacetic anhydride (TFAA) in dichloromethane gives the 3-nitro derivative (II), which is reduced with iron filings and CaCl2 in refluxing ethanol/water to yield the 3-amino derivative (III). Treatment of compound (III) with NaNO2, HBr and Br2 provides 4-(3-bromo-8-chloro-5,6-dihydro-1H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylic acid ethyl ester (IV) (see scheme 25468001a, intermediate (I).(2)

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Lonafarnib. Drugs Fut 2003, 28, 12, 1168.
【2】 Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4-(8-chloro-5, 6-dihydro-11H-benzo[5,6]cyclohepta[1, 2-b]pyridin-11-ylidene)piperidine inhibitors of farnesyl-protein transferase: Design and synthesis of in vivo active antitumor compou. J Med Chem 1997, 40, 26, 4290.
【3】 Prous, J.; Castañer, J.; Loratadine. Drugs Fut 1987, 12, 6, 544.

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)	17877	ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	79794-75-5	C₂₂H₂₃ClN₂O₂	详情	详情
(II)	63294	ethyl 4-(8-chloro-3-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₂ClN₃O₄	详情	详情
(III)	63295	ethyl 4-(3-amino-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₄ClN₃O₂	详情	详情
(IV)	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

Extended Information

Drug NewChemical Entity Original Patent(1)