* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Journal of the American Chemical Society, 2000, vol. 122, # 22, p. 5337 - 5342
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 26, p. 6485 - 6489
The synthesis of a conjugate based on amprenavir proceeded as outlined below. FIG. 6 depicts the overall synthesis. Briefly, a commercially available Phe-derived epoxide is opened with a valine isostere. The resulting compound is coupled to Boc-protected aminobenzenesulfonyl chloride. Deprotection of the Boc groups is followed by coupling to an activated acid derivative of SLF using l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxylsuccinimide (NHS) (10 equivalents EDC to 1 equivalent NHS). The coupling takes place in dimethylformamide (DMF) at room temperature over four hours. Relative nucleophilicity of the two amines is used to direct amide formation; the benzyl amino group is believed to have diffuse electron density and lowered reactivity. We carried out water work-up and flash chromatography on silica gel using 1:1 ethyl acetate: MeOH. Overall yield was very roughly 15%. [00074] The linkers shown in FIG. 5 may be coupled to FK506 or SLF via EDC-mediated amide formation followed by deprotection of the newly installed carboxylate. This acid is then used for conjugation to the amprenavir-based molecule as above. The linker can be <n="17"/>readily altered to enhance solubility or other physical characteristics of the bifunctional compound.[00075] The amprenavir conjugate of this example may also be regarded as a TMCl 14 conjugate, because TMCl 14 shares with amprenavir the structure to the right of the attachment point used in this example.
88%
In dichloromethane;
The synthesis of a conjugate based on amprenavir proceeded as outlined below. FIG. 6 depicts the overall synthesis. Briefly, a commercially available Phe-derived epoxide is opened with a valine isostere. The resulting compound is coupled to Boc-protected aminobenzenesulfonyl chloride. Deprotection of the Boc groups is followed by coupling to an activated acid derivative of SLF using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxylsuccinimide (NHS) (10 equivalents EDC to 1 equivalent NHS). The coupling takes place in dimethylformamide (DMF) at room temperature over four hours. Relative nucleophilicity of the two amines is used to direct amide formation; the benzyl amino group is believed to have diffuse electron density and lowered reactivity. We carried out water work-up and flash chromatography on silica gel using 1:1 ethyl acetate:MeOH. Overall yield was very roughly 15%.
(R)-2-{(R)-2-[3-((2R,3R)-3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-3-methyl-ureido]-4-methyl-pentanoylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-((2R,3R)-3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-3-isopropyl-ureido]-4-methyl-pentanoylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-((2R,3R)-3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-3-isobutyl-ureido]-4-methyl-pentanoylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-propionylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-3-methyl-butyrylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-propionic acid methyl ester[ No CAS ]
(S)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(S)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(S)-2-{(S)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-4-methyl-pentanoic acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-3-phenyl-propionylamino}-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-3-methyl-butyric acid tert-butyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-4-methyl-pentanoic acid tert-butyl ester[ No CAS ]
(R)-2-{(R)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-3-phenyl-propionic acid methyl ester[ No CAS ]
(R)-2-((R)-2-{3-Benzyl-3-[(2R,3R)-3-((R)-2-tert-butoxycarbonylamino-propionylamino)-2-hydroxy-4-phenyl-butyl]-ureido}-4-methyl-pentanoylamino)-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-((R)-2-{3-Benzyl-3-[(2R,3R)-3-((R)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-4-phenyl-butyl]-ureido}-4-methyl-pentanoylamino)-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-((R)-2-{3-Benzyl-3-[(2R,3R)-3-((R)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-2-hydroxy-4-phenyl-butyl]-ureido}-4-methyl-pentanoylamino)-3-methyl-butyric acid methyl ester[ No CAS ]
(R)-2-((R)-2-{3-Benzyl-3-[(2R,3R)-3-((R)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-2-hydroxy-4-phenyl-butyl]-ureido}-4-methyl-pentanoylamino)-3-methyl-butyric acid methyl ester[ No CAS ]
Under a protective gas, a solution of 3.75 g (14.2 mmol) of (2S)-[1'(R)-Boc-amino-2'-phenylethyl]oxirane ?prepared analogously to (2R)-[1'(S)-Boc-amino-2'-phenylethyl]-oxirane (EP-532466-A2, page 42) from (D)-N-Boc-phenylalaninal instead of (L)-N-Boc-phenylalaninal! and 3.24 g (14.2 mmol) of tert-butyl-3-benzyl-carbazate (J. Chem. Soc., Perkin I, 1712 (1975)) in 47 ml of methanol is heated under reflux for 18 h. Concentration of the reaction mixture by evaporation and precipitation with hexane from a concentrated solution in methylene chloride yields the title compound: TLC Rf (T)=0.09; tRet (II)=19.2.