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
|