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【结 构 式】

【药物名称】TMC-95B

【化学名称】(10S,11R,12S,15S,18S)-15-(Carbamoylmethyl)-10,11,23-trihydroxy-18-[3(R)-methyl-2-oxopentanamido]-9,14,17-trioxo-N-[1(Z)-propenyl]-8,13,16-triazatetracyclo[18.3.1.0(2,7).0(6,10)]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide
　　　　　　(3S,7S,15S,18S,21S,22R)-2,3-Dihydro-3,13,22-trihydroxy-15-[3(R)-methyl-1,2-dioxopentylamino]-2,16,19-trioxo-21-[1(Z)-propenylaminocarbonyl]-,7,3-([1,3]benzenopropaniminoethaniminoethano)-1H-indole-18-acetamide

【CA登记号】262854-05-7

【 分 子 式 】C33H38N6O10

【 分 子 量 】678.70501

【开发单位】Tanabe Seiyaku (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Proteasome Inhibitor

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

The borinated tyrosine intermediate (VII) has been obtained as follows: The esterification of L-tyrosine (I) with SOCl2 and methanol gives the methyl ester (II), which is N-protected with Cbz-Cl and K2CO3 to yield the carbamate (III). The O-protection of (III) with benzyl bromide and Cs2CO3 affords the benzyl ether (IV), which is iodinated with I2 and Ag2SO4 to provide the 3-iodotyrosine derivative (V). Finally, the borylation of (V) by means of pinacolatodiborane (VI) catalyzed by PdCl2[bis(diphenylphosphanyl)ferrocene] (PdCl2(dppf)) gives rise to the target tyrosine intermediate (VII).

参考文献 中间体
【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.
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) 48794 (S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine 60-18-4 C9H11NO3 详情 详情
(II) 21431 methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate 1080-06-4 C10H13NO3 详情 详情
(III) 53339 methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoate n/a C18H19NO5 详情 详情
(IV) 53340 methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)phenyl]propanoate n/a C25H25NO5 详情 详情
(V) 53341 methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-iodophenyl]propanoate n/a C25H24INO5 详情 详情
(VI) 53342 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester 73183-34-3 C12H24B2O4 详情 详情
(VII) 53343 methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate n/a C31H36BNO7 详情 详情

合成路线2

The crossed aldol condensation of 7-iodo-2,3-dihydro-1H-indol-2-one (VIII) with the chiral oxazolidine-carbaldehyde (IX) by means of LDA in THF gives a mixture of (Z)-(X) and (E)-(XI) isomers, which is isomerized to the desired (E)-(XI) compound by treatment with I2 . The condensation of (XI) with the borinated tyrosine intermediate (VII) catalyzed with PdCl2(dppf)2 yields the diaryl compound (XII), whose ester group is hydrolyzed with LiOH in THF/water to afford the carboxylic acid (XIII). The condensation of (XIII) with L-asparagine tert-butyl ester (XIV) by means of EDC and 1-hydroxy-7-azabenzotriazole (HOAt) in THF provides adduct (XV), which is oxidized with OsO4, NMO and 1,4-bis(9-O-dihydroquinidinine)phthalazine ((DHOD)2PHAL) in tert-butanol/water to give the glycol (XVI). The cleavage of the oxazolidine ring of (XVI) by means of pyridinium p-toluenesulfonate (PPTS) yields the trihydroxy compound (XVII).

参考文献 中间体
【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.
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) 53343 methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate n/a C31H36BNO7 详情 详情
(VIII) 53344 7-iodo-1,3-dihydro-2H-indol-2-one n/a C8H6INO 详情 详情
(IX) 53345 tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate n/a C11H19NO4 详情 详情
(X) 53346 tert-butyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate n/a C19H23IN2O4 详情 详情
(XI) 53348 tert-butyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate n/a C19H23IN2O4 详情 详情
(XII) 53347 tert-butyl (4S)-4-({7-[2-(benzyloxy)-5-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropyl)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate n/a C44H47N3O9 详情 详情
(XIII) 53349 (2S)-3-[4-(benzyloxy)-3-(3-{(E)-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]methylidene}-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoic acid n/a C43H45N3O9 详情 详情
(XIV) 53350 tert-butyl (2S)-2,4-diamino-4-oxobutanoate 63094-81-5（盐酸盐） C8H16N2O3 详情 详情
(XV) 53351 tert-butyl (4S)-4-({7-[5-((2S)-3-{[(1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl]amino}-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl)-2-(benzyloxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate n/a C51H59N5O11 详情 详情
(XVI) 53352 tert-butyl (4R)-4-[(R)-{(3S)-7-[5-((2S)-3-{[(1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl]amino}-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl)-2-(benzyloxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazolid n/a C51H61N5O13 详情 详情
(XVII) 53353 tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate n/a C48H57N5O13 详情 详情

合成路线3

The selective protection of the primary OH group of (XVII) with Tips-Cl and imidazole yields the silyl ether (XVIII), which is treated with TFA in dichloromethane to afford the carboxylic acid (XIX). The macrolactamization of (XIX) by means of EDC, HOAt and DIEA in DMF/dichloromethane provides the macrolactam (XX), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to furnish the aminophenol (XXI). The condensation of (XXI) with racemic 3-methyl-2-oxopentanoic acid (XXII) by means of EDC and HOAt in DMF/dichloromethane gives the amide (XXIII) as a diastereomeric mixture. The desilylation of (XXIII) by means of HF and pyridine gives the tetrahydroxy compound (XXIV), which is fully resilylated with Tes-OTf and lutidine in dichloromethane to yield the tetra-silyl ether (XXV).

参考文献 中间体
【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 53353 tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate n/a C48H57N5O13 详情 详情
(XVIII) 53354 tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate n/a C57H77N5O13Si 详情 详情
(XIX) 53355 (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoic acid n/a C53H69N5O13Si 详情 详情
(XX) 53356 benzyl (10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-23-(benzyloxy)-10,11-dihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-ylcarbamate n/a C48H59N5O10Si 详情 详情
(XXI) 53357 2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide n/a C33H47N5O8Si 详情 详情
(XXII) 46950 3-methyl-2-oxopentanoic acid C6H10O3 详情 详情
(XXIII) 53358 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C39H55N5O10Si 详情 详情
(XXIV) 53359 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C30H35N5O10 详情 详情
(XXV) 53360 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C54H91N5O10Si4 详情 详情

合成路线4

The oxidation of the primary silyl ether of (XXV) with the Jones reagent gives a mixture of the carboxylic acid derivatives (XXVI) and (XXVII). This mixture is condensed with the silylated amine (XXVIII) by means of EDC and HOAt in DMF/dichloromethane to yield a mixture of the corresponding amides (XXIX) and (XXX). The rearrangement of the mixture (XXIX) + (XXX) in refluxing o-xylene affords provided a mixture of the (E)-propenylamides (XXXI) and (XXXII), which is desilylated by means of HF and pyridine in THF to give compound (XXXIII) as a diastereomeric mixture that is separated by RP-HPLC to afford the target TMC-95B.

参考文献 中间体
【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 53360 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C54H91N5O10Si4 详情 详情
(XXVI) 53361 (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11-bis[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid n/a C42H61N5O11Si2 详情 详情
(XXVII) 53362 (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid n/a C48H75N5O11Si3 详情 详情
(XXVIII) 53368 1-(triethylsilyl)-2-propen-1-amine; 1-(triethylsilyl)-2-propenylamine n/a C9H21NSi 详情 详情
(XXIX) 53363 (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11-bis[(triethylsilyl)oxy]-N-[1-(triethylsilyl)-2-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid n/a C51H80N6O10Si3 详情 详情
(XXX) 53364 (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-N-[1-(triethylsilyl)-2-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid n/a C57H94N6O10Si4 详情 详情
(XXXI) 53365 (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-10,11-bis[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxilic acid n/a C45H66N6O10Si2 详情 详情
(XXXII) 53366 (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-10,11,23-tris[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide n/a C51H80N6O10Si3 详情 详情
(XXXIII) 53367 (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide n/a C33H38N6O10 详情 详情
Extended Information