• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】23444

【品名】tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate

【CA登记号】

【 分 子 式 】C15H21NO3

【 分 子 量 】263.33668

【元素组成】C 68.42% H 8.04% N 5.32% O 18.23%

与该中间体有关的原料药合成路线共 7 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

In an alternative procedure, condensation of 4-biphenylcarbaldehyde (X) with tert-butyl carbazate afforded hydrazone (XI), which was reduced to the benzylhydrazine (XII) by hydrogenation over Pd/C. Opening of the Boc-protected epoxide (XIII) with hydrazine (XII) gave hydrazinoalcohol (VI). This was deprotected with HCl and then coupled as above with N-methoxycarbonyl-L-tert-leucine (X) by means of TPTU.

1 New aza-dipeptide analogues as potent and orally a. J Med Chem 1998, 41, 18, 3387.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 28443 tert-butyl 2-([1,1'-biphenyl]-4-ylmethyl)-2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-1-hydrazinecarboxylate C33H43N3O5 详情 详情
(IX) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情
(X) 28446 [1,1'-biphenyl]-4-carbaldehyde 3218-36-8 C13H10O 详情 详情
(XI) 28447 tert-butyl (Z)-2-([1,1'-biphenyl]-4-ylmethyl)-1-diazenecarboxylate C18H20N2O2 详情 详情
(XII) 28448 tert-butyl 2-([1,1'-biphenyl]-4-ylmethyl)-1-hydrazinecarboxylate C18H22N2O2 详情 详情
(XIII) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

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3

该中间体在本合成路线中的序号:(X)

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

合成路线4

该中间体在本合成路线中的序号:(XVIII)

In a variation of this procedure, aryl tetrazole (II) was alkylated with ICH3 to provide methyltetrazole (XV). Condensation of (XV) with tert-butyl carbazate afforded hydrazone (XVI), which was reduced to the benzylhydrazine (XVII) by means of NaBH3CN and p-toluenesulfonic acid. Opening of the Boc-protected epoxide (XVIII) with hydrazine (XVII) gave hydrazinoalcohol (XIX). Acid deprotection of both Boc groups of (XIX) furnished diamino compound (XX), which was finally coupled with N-methoxycarbonyl-L-tert-leucine (X) by means of TPTU.

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
(II) 28449 4-(2H-1,2,3,4-tetraazol-5-yl)benzaldehyde 74815-22-8 C8H6N4O 详情 详情
(X) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情
(XV) 28461 4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzaldehyde C9H8N4O 详情 详情
(XVI) 28462 tert-butyl 2-[(Z)-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)phenyl]methylidene]-1-hydrazinecarboxylate C14H18N6O2 详情 详情
(XVII) 28463 tert-butyl 2-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzyl]-1-hydrazinecarboxylate C14H20N6O2 详情 详情
(XVIII) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(XIX) 28464 tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzyl]-1-hydrazinecarboxylate C29H41N7O5 详情 详情
(XX) 28465 (2S,3S)-3-amino-1-[1-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzyl]hydrazino]-4-phenyl-2-butanol C19H25N7O 详情 详情

合成路线5

该中间体在本合成路线中的序号:(VI)

4-Bromobenzaldehyde dimethyl acetal (I) was converted to the corresponding Grignard reagent and then coupled with 2-bromothiazole (II) in the presence of [1,3-bis(diphenylphosphino)propane]nickel chloride to afford 4-(2-thiazolyl)benzaldehyde dimethylacetal (III). After acid hydrolysis of the acetal group of (II), the resulting aldehyde was condensed with tert-butyl carbazate to give hydrazone (IV), which was further reduced to the benzylhydrazine (V) employing NaBH3CN and p-toluenesulfonic acid. Opening of the Boc-protected epoxide (VI) with hydrazine (V) gave hydrazinoalcohol (VII). Both Boc groups of (VII) were removed by treatment with formic acid to yield diamino compound (VIII). Finally, coupling of (VIII) with N-methoxycarbonyl-L-tert-leucine (IX) by means of O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetra fluoroborate (TPTU) provided the title bisamide.

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) 23438 (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene C9H11BrO2 详情 详情
(II) 23161 2-bromo-1,3-thiazole 3034-53-5 C3H2BrNS 详情 详情
(III) 28434 2-[4-(dimethoxymethyl)phenyl]-1,3-thiazole C12H13NO2S 详情 详情
(IV) 28435 tert-butyl 2-[(Z)-[4-(1,3-thiazol-2-yl)phenyl]methylidene]-1-hydrazinecarboxylate C15H17N3O2S 详情 详情
(V) 28436 tert-butyl 2-[4-(1,3-thiazol-2-yl)benzyl]-1-hydrazinecarboxylate C15H19N3O2S 详情 详情
(VI) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(VII) 28437 tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(1,3-thiazol-2-yl)benzyl]-1-hydrazinecarboxylate C30H40N4O5S 详情 详情
(VIII) 28438 (2S,3S)-3-amino-4-phenyl-1-[1-[4-(1,3-thiazol-2-yl)benzyl]hydrazino]-2-butanol C20H24N4OS 详情 详情
(IX) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情

合成路线6

该中间体在本合成路线中的序号:(I)

Coupling between epoxide (I) and amine (II) affords amino alcohol (III). The amino group of (III) is then protected with benzyl chloroformate to provide carbamate (IV). Removal of the N-Boc group of (IV) with trifluoroacetic acid yields amine (V), which is subsequently coupled with N-Boc-L-valine (VI) by means of TBTU to furnish amide (VII). After acidic Boc group cleavage in (VII), the resultant amine (VIII) is acylated by picolinic acid (IX) producing amide (X).

1 Noteberg, D.; et al.; New antimalarials: Design and synthesis of protease inhibitors with effect in cultured parasite-infected human erythrocytes. Drugs Fut 2002, 27, Suppl. A.
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) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(II) 58402 (2S)-2-amino-3-(4-bromophenyl)propanamide C9H11BrN2O 详情 详情
(III) 58396 tert-butyl (1S,2S)-3-{[(1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl]amino}-1-benzyl-2-hydroxypropylcarbamate C24H32BrN3O4 详情 详情
(IV) 58397 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}carbamate C32H38BrN3O6 详情 详情
(V) 58398 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]carbamate C27H30BrN3O4 详情 详情
(VI) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VII) 58399 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-3-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}amino)-2-hydroxy-4-phenylbutyl]carbamate C37H47BrN4O7 详情 详情
(VIII) 58400 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl((2S,3S)-3-{[(2S)-2-amino-3-methylbutanoyl]amino}-2-hydroxy-4-phenylbutyl)carbamate C32H39BrN4O5 详情 详情
(IX) 59950 (chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane C6H15ClOSi 详情 详情
(X) 58401 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-2-hydroxy-3-({(2S)-3-methyl-2-[(2-pyridinylcarbonyl)amino]butanoyl}amino)-4-phenylbutyl]carbamate C38H42BrN5O6 详情 详情

合成路线7

该中间体在本合成路线中的序号:(VIII)

 

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
Extended Information