SB-357114
Chemical Name: N-[3-Methyl-1(S)-[N-[3-oxo-1-(pyridin-2-ylsulfonyl)perhydroazepin-4(S)-yl]carbamoyl]butyl]-1-benzofuran-2-carboxamide
CAS No. 281217-45-6, 281216-44-2 (Deuterium labeled), 281218-50-6 (Deuterium labeled), 281215-30-3 (diastereomeric mixture), 281214-75-3 (stereoisomer)
项目整合开发状态: Preclinical
项目研究机构: GlaxoSmithKline (Originator)
合成路线:N-Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) by means of NaH in DMF provides olefin metathesis substrate (III),which is then converted into azepine (IV) by means of catalytic bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride (Grubbs catalyst) in refluxing CH2Cl2.Epoxidation of (IV) with m-CPBA in CH2Cl2 affords oxirane (V),which is then treated with NaN3 and NH4Cl in H2O/MeOH to provide a mixture of regioisomers from which (VI) is chromatographically isolated.Reduction of azide (VI) with 1,3-propanedithiol and Et3N in MeOH furnishes amino alcohol derivative (VII),which is then acylated with Boc-Leu-OH by means of EDC and HOBt to provide protected derivative (IX).Removal of the Z protecting group by hydrogenolysis over Pd/C in MeOH gives amine (X),which is then condensed with 2-pyridylsulfonyl chloride (XI) by means of Et3N in CH2Cl2 to yield compound (XII).Boc removal from (XII) by treatment with HCl in MeOH/AcOEt affords amine (XIII),which is then acylated with benzofuran-2-carboxylic acid (XIV) by means of EDC and HOBt to give derivative (XV).Finally,the desired product is obtained by oxidation of (XV) with pyridine sulfur trioxide complex and Et3N in DMSO followed by diastereomer separation by HPLC.
合成路线:Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) in the presence of NaH provides the aza diene derivative (III).Cyclization of (III) under olefin metathesis conditions,employing a ruthenium catalyst,gives rise to the tetrahydroazepine (IV).Oxidation of (IV) with m-chloroperbenzoic acid yields epoxide (V),which is subsequently converted into the trans azido alcohol (VI) upon ring opening with NaN3 and NH4Cl.Azide (VI) is reduced to the corresponding amine (VII) by using 1,3-propanedithiol.Acylation of the racemic trans amino alcohol (VII) by N-Boc-L-leucine (VIII) produces a diastereomeric mixture of amides,which are separated by column chromatography.The desired isomer (IX) is then subjected to catalytic hydrogenolysis of the N-carbobenzoxy group to afford azepine (X).Then,acylation of (X) with 3-(2-pyridyl)phenylacetic acid (XI) furnishes amide (XII).
合成路线:Acidic cleavage of the Boc protecting group of (XII) affords amine (XIII).This is coupled with 5-[2-(morpholin-4-yl)ethoxy]benzofuran-2-carboxylic acid (XIV) using EDC to furnish amide (XV).The azepine 3-hydroxyl group of (XV) is finally oxidized to the target ketone using DMSO in the presence of sulfur trioxide-pyridine complex.
📌 参考资料/链接：
参考文献标题:Protease inhibitors
文献作者:Cummings,M.D.; Veber,D.F.; Yamashita,D.; Ru,Y.; Marquis,R.W.Jr.; Thompson,S.K.(SmithKline Beecham Corp.)
参考来源:EP 1158986; WO 0038687
📄 详细内容
合成路线:N-Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) by means of NaH in DMF provides olefin metathesis substrate (III),which is then converted into azepine (IV) by means of catalytic bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride (Grubbs catalyst) in refluxing CH2Cl2.Epoxidation of (IV) with m-CPBA in CH2Cl2 affords oxirane (V),which is then treated with NaN3 and NH4Cl in H2O/MeOH to provide a mixture of regioisomers from which (VI) is chromatographically isolated.Reduction of azide (VI) with 1,3-propanedithiol and Et3N in MeOH furnishes amino alcohol derivative (VII),which is then acylated with Boc-Leu-OH by means of EDC and HOBt to provide protected derivative (IX).Removal of the Z protecting group by hydrogenolysis over Pd/C in MeOH gives amine (X),which is then condensed with 2-pyridylsulfonyl chloride (XI) by means of Et3N in CH2Cl2 to yield compound (XII).Boc removal from (XII) by treatment with HCl in MeOH/AcOEt affords amine (XIII),which is then acylated with benzofuran-2-carboxylic acid (XIV) by means of EDC and HOBt to give derivative (XV).Finally,the desired product is obtained by oxidation of (XV) with pyridine sulfur trioxide complex and Et3N in DMSO followed by diastereomer separation by HPLC.
参考文献标题:Methods of treatment
文献作者:Veber,D.F.; Marquis,R.W.Jr.; Thompson,S.K.; Yamashita,D.S.; Ru,Y.; Cummings,M.D.(GlaxoSmithKline Inc.)
参考来源:WO 0178734
合成路线:N-Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) by means of NaH in DMF provides olefin metathesis substrate (III),which is then converted into azepine (IV) by means of catalytic bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride (Grubbs catalyst) in refluxing CH2Cl2.Epoxidation of (IV) with m-CPBA in CH2Cl2 affords oxirane (V),which is then treated with NaN3 and NH4Cl in H2O/MeOH to provide a mixture of regioisomers from which (VI) is chromatographically isolated.Reduction of azide (VI) with 1,3-propanedithiol and Et3N in MeOH furnishes amino alcohol derivative (VII),which is then acylated with Boc-Leu-OH by means of EDC and HOBt to provide protected derivative (IX).Removal of the Z protecting group by hydrogenolysis over Pd/C in MeOH gives amine (X),which is then condensed with 2-pyridylsulfonyl chloride (XI) by means of Et3N in CH2Cl2 to yield compound (XII).Boc removal from (XII) by treatment with HCl in MeOH/AcOEt affords amine (XIII),which is then acylated with benzofuran-2-carboxylic acid (XIV) by means of EDC and HOBt to give derivative (XV).Finally,the desired product is obtained by oxidation of (XV) with pyridine sulfur trioxide complex and Et3N in DMSO followed by diastereomer separation by HPLC.
参考文献标题:Protease inhibitors
文献作者:Veber,D.F.; Marquis,R.W.Jr.; Thompson,S.K.; Ru,Y.; Cummings,M.D.; Yamashita,D.(GlaxoSmithKline Inc.)
参考来源:WO 0195911
合成路线:N-Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) by means of NaH in DMF provides olefin metathesis substrate (III),which is then converted into azepine (IV) by means of catalytic bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride (Grubbs catalyst) in refluxing CH2Cl2.Epoxidation of (IV) with m-CPBA in CH2Cl2 affords oxirane (V),which is then treated with NaN3 and NH4Cl in H2O/MeOH to provide a mixture of regioisomers from which (VI) is chromatographically isolated.Reduction of azide (VI) with 1,3-propanedithiol and Et3N in MeOH furnishes amino alcohol derivative (VII),which is then acylated with Boc-Leu-OH by means of EDC and HOBt to provide protected derivative (IX).Removal of the Z protecting group by hydrogenolysis over Pd/C in MeOH gives amine (X),which is then condensed with 2-pyridylsulfonyl chloride (XI) by means of Et3N in CH2Cl2 to yield compound (XII).Boc removal from (XII) by treatment with HCl in MeOH/AcOEt affords amine (XIII),which is then acylated with benzofuran-2-carboxylic acid (XIV) by means of EDC and HOBt to give derivative (XV).Finally,the desired product is obtained by oxidation of (XV) with pyridine sulfur trioxide complex and Et3N in DMSO followed by diastereomer separation by HPLC.
参考文献标题:Azepanone-based inhibitors of human and rat cathepsin K
文献作者:Marquis,R.W.; Ru,Y.; LoCastro,S.M.; Zeng,J.; Yamashita,D.S.; Oh,H.J.; Erhard,K.F.; Davis,L.D.; Tomaszek,T.A.; Tew,D.; Salyers,K.L.; Proksch,J.; Ward,K.; Smith,B.R.; Levy,M.A.; Cummings,M.D.; Haltiwanger,R.C.; Trescher,G.; et al.
参考来源:J Med Chem 2001,44(9),1380