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【结 构 式】

【药物名称】Atazanavir sulfate, BMS-232632-05, CGP-73547, BMS-232632(free base), Reyataz

【化学名称】N'-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)-L-tert-leucylamino]-4-phenylbutyl]-Nalpha-(methoxycarbonyl)-N'-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide sulfate salt (1:1)

【CA登记号】229975-97-7, 198904-31-3 (free base)

【 分 子 式 】C38H54N6O11S

【 分 子 量 】802.95168

【开发单位】Bristol-Myers Squibb (Orphan Drug), Novartis (Originator), Bristol-Myers Squibb (Licensee)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1

 

1 Fassler A, Bold G, Capraro H, et aL 1996. Aza-peptide analogs as potent human immunodeficiency virus type-l protease inhibitors with oral bioavailability.JMed Cha;n, 39, 3203一3216
2 Fassler A, Bold G, Capraro H, et aL 1997. lruermediates Ior the prepantion of peptide analogues, W0 9746514
3 Giordano C, Pozzoli C, Benedetti F.2001. Ptocess for the pr帕嘣tion可8ryl-pyritlinyl compounds, W0 012083
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) 22231 4-Bromobenzaldehyde 1122-91-4 C7H5BrO 详情 详情
(II) 23438 (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene C9H11BrO2 详情 详情
(III) 29052 2-Bromopyridine;α-bromopyridine;α-bromoazine 109-04-6 C5H4BrN 详情 详情
(IV) 23440 4-(2-pyridinyl)benzaldehyde C12H9NO 详情 详情
(V) 10893 tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate 870-46-2 C5H12N2O2 详情 详情
(VI) 23442 tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate C17H19N3O2 详情 详情
(VII) 23452 tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate C14H19NO3 详情 详情
(VIII) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(XXI) 66122 (2R,3R)-3-amino-4-phenyl-1-(1-(4-(pyridin-2-yl)benzyl)hydrazinyl)butan-2-ol trihydrochloride   C22H29Cl3N4O 详情 详情
(XXII) 66123 1,1,3,3-tetramethyl-2-(2-oxopiperidin-1-yl)isouronium tetrafluoroborate   C10H20F4N3O2 详情 详情

合成路线2

 

1 Kimsl, Wei CK, Lindrud M, et aL 2005. Process for cxmtrolled crystalluation of pharmaceutical salts with desirable crystal properties W0 2005108380
2 Kim Sj, Lotz BT, Malley MF, et al. 2005. Synthesis of atazanavir bisdfate and preparation and analysis of novel crystalline forms for admuustration for treatment of HIV. W0 2005108349
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIII) 66124 1H-benzo[d][1,2,3]triazol-1-yl 2-((methoxycarbonyl)amino)-3,3-dimethylbutanoate   C14H18N4O4 详情 详情
(XXIV) 28444 (2S,3S)-3-amino-1-[1-([1,1'-biphenyl]-4-ylmethyl)hydrazino]-4-phenyl-2-butanol C23H27N3O 详情 详情

合成路线3

1) The reaction of 4-bromobenzaldehyde (I) with trimethylorthoformate (II) and p-toluenesulfonic acid in methanol gives ketal (III), which is condensed with 2-pyridylmagnesium bromide in THF, yielding 4-(2-pyridyl)benzaldehyde (IV). The reaction of (IV) with tert-butyl carbazate (V) in refluxing ethanol affords hydrazone (VI), which is reduced with H2 over Pd/C in methanol to the hydrazine (VII). The condensation of (VII) with the epoxide (VIII) in hot isopropanol gives the expected addition product (IX), which by treatment with HCl or formic acid results in the fully deprotected intermediate (X). Finally, this compound is condensed with N-(methoxycarbonyl)-L-tert-leucine (XI) by means of O-(2-oxo-1,2-dihydro-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) in dichloromethane or DMF.

1 New aza-dipeptide analogues as potent and orally a. J Med Chem 1998, 41, 18, 3387.
2 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M.; Khanna, S.C. (Novartis AG); Antivirally active heterocyclic azahexane derivs.. EP 0900210; JP 1999511177; US 5849911; WO 9740029 .
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) 22231 4-Bromobenzaldehyde 1122-91-4 C7H5BrO 详情 详情
(II) 23438 (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene C9H11BrO2 详情 详情
(III) 23439 bromo(2-pyridinylmethyl)magnesium C6H6BrMgN 详情 详情
(IV) 23440 4-(2-pyridinyl)benzaldehyde C12H9NO 详情 详情
(V) 10893 tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate 870-46-2 C5H12N2O2 详情 详情
(VI) 23442 tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate C17H19N3O2 详情 详情
(VII) 23443 tert-butyl 2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate C17H21N3O2 详情 详情
(VIII) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(IX) 23445 tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate C32H42N4O5 详情 详情
(X) 23446 (2S,3S)-3-amino-4-phenyl-1-[1-[4-(2-pyridinyl)benzyl]hydrazino]-2-butanol C22H26N4O 详情 详情
(XI) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情

合成路线4

2) Intermediate (IX) can also be obtained as follows: The cyclization of 4-cyanobenzoic acid methyl ester (XII) with acetylene at 15 Atm by means of cobaltocene in toluene at 180 C gives 4-(2-pyridyl)benzoic acid methyl ester (XIII), which is saponified with NaOH in methanol to the corresponding acid (XIV). The activation of (XIV) with isobutyl chloroformate yields the mixed anhydride (XV), which is condensed with N-(tert-butoxycarbonyl)-L-phenylalaninal (XVI) and KCN in dichloromethane, affording (XVII). The reaction of (XVII) with tert-butyl carbazate (V) by means of acetic acid in methanol gives hydrazone (XVIII), which is reduced to hydrazine (XIX) by means of sodium cyanoborohydride in THF. The isomerization of (XIX) by means of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTDE) in hot diglyme yields hydrazide (XX), which is finally reduced to intermediate (IX) with diisobutylaluminum hydride in dichloromethane/THF.

1 Fassler, A.; Steiner, H.; Bold, G.; Capraro, H.-G. (Novartis AG); Process for the preparation of hydrazine derivs. useful as intermediates for the preparation of peptide analogues. WO 9746514 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 23634 acetylene 74-86-2 C2H2 详情 详情
(V) 10893 tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate 870-46-2 C5H12N2O2 详情 详情
(IX) 23445 tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate C32H42N4O5 详情 详情
(XII) 10169 methyl 4-cyanobenzoate;4-Cyanobenzoic acid methyl ester 1129-35-7 C9H7NO2 详情 详情
(XIII) 23449 methyl 4-(2-pyridinyl)benzoate C13H11NO2 详情 详情
(XIV) 23450 4-(2-pyridinyl)benzoic acid C12H9NO2 详情 详情
(XV) 23451 4-(2-Pyridyl)benzoic acid isobutoxycarbonyl anhydride C17H17NO4 详情 详情
(XVI) 14540 tert-butyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate C14H19NO3 详情 详情
(XVII) 23453 (1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-cyano-3-phenylpropyl 4-(2-pyridinyl)benzoate C27H27N3O4 详情 详情
(XVIII) 23454 tert-butyl 2-((E,2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-phenyl-2-[[4-(2-pyridinyl)benzoyl]oxy]butylidene)-1-hydrazinecarboxylate C32H38N4O6 详情 详情
(XIX) 23455 tert-butyl 2-((2S,3S)-3-[(tert-butoxycarbonyl)amino]-4-phenyl-2-[[4-(2-pyridinyl)benzoyl]oxy]butyl)-1-hydrazinecarboxylate C32H40N4O6 详情 详情
(XX) 23457 tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzoyl]-1-hydrazinecarboxylate C32H40N4O6 详情 详情

合成路线5

The intermediate carbazate (VI) has been obtained as follows. The condensation of phenylboronic acid (I) with 2-bromopyridine (II) by means of Pd(PPh3)4 gives 4-(2-pyridyl)benzaldehyde (III), which is condensed with tert-butyl carbazate (IV) in hot toluene/isopropyl alcohol to yield the benzylidenehydrazone (V). Finally, this compound is reduced with sodium formate over Pd/C in ethanol to afford the target intermediate; the carbazate (VI). The selective monosilylation of the primary OH group of diol (VII) with Tbdms-Cl, TEA and DMAP followed by reaction of the secondary OH group with MsCl gives the protected mesylate (VIII), which is desilylated with NH4F and AcOH yielding the primary alcohol (IX). The epoxidation of (IX) with t-BuOK in isopropyl alcohol affords the chiral epoxide (X), which is condensed with the intermediate carbazate (VI) in refluxing isopropanol to provide the adduct (XI). Elimination of the two Boc protecting groups of (XI) with HCl in hot THF gives the diamino compound (XII), which is finally condensed with two moles of N-(methoxycarbonyl)-L-tert-leucine (XIII) by means of WSC, HOBt and DIEA in dichloromethane to provide the target Atazanavir.

1 Xu, Z.; Singh, J.; Schwinden, M.D.; Zheng, B.; Kissick, T.P.; Patel, B.; Humora, M.J.; Quiroz, F.; Dong, L.; Hsieh, D.-M.; Heikes, J.E.; Pudipeddi, M.; Lindrud, M.D.; Srivastava, S.K.; Kronenthal, D.R.; Mueller, R.H.; Process research and development for an efficient synthesis of the HIV protease inhibitor BMS-232632. Org. Proc. Res. & Develop. 2002, 6, 3, 323.
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) 61564 4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid 87199-17-5 C7H7BO3 详情 详情
(II) 29052 2-Bromopyridine;α-bromopyridine;α-bromoazine 109-04-6 C5H4BrN 详情 详情
(III) 23440 4-(2-pyridinyl)benzaldehyde C12H9NO 详情 详情
(IV) 10893 tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate 870-46-2 C5H12N2O2 详情 详情
(V) 23442 tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate C17H19N3O2 详情 详情
(VI) 23443 tert-butyl 2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate C17H21N3O2 详情 详情
(VII) 61565 tert-butyl (1S,2S)-1-benzyl-2,3-dihydroxypropylcarbamate C15H23NO4 详情 详情
(VIII) 61566 (1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenylpropyl methanesulfonate C22H39NO6SSi 详情 详情
(IX) 61567 (1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-(hydroxymethyl)-3-phenylpropyl methanesulfonate C16H25NO6S 详情 详情
(X) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(XI) 23445 tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate C32H42N4O5 详情 详情
(XII) 23446 (2S,3S)-3-amino-4-phenyl-1-[1-[4-(2-pyridinyl)benzyl]hydrazino]-2-butanol C22H26N4O 详情 详情
(XIII) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情
Extended Information