ChemicalBook CAS DataBase List Trabectedin

Trabectedin synthesis

14synthesis methods

Product Name:Trabectedin
CAS Number:114899-77-3
Molecular formula:C39H43N3O11S
Molecular Weight:761.84

While the challenging total synthesis of trabectedin has been accomplished by a few research groups, the commercial preparation begins from readily available cyanosafracin B in 21 steps. Following the Boc and MOM protection of the amine and phenol functionalities, respectively, the methoxy-pquinone was hydrolyzed with sodium hydroxide in methanol. The resulting quinine was reduced (hydrogen over Pd/C) to give an unstable hydroquinone that was subsequently alkylated with bromochloromethane and allyl bromide. The MOM and Boc groups were then removed followed by cleavage of the amide by Edman degradation (through formation of the thiourea with phenyl isothiocyanate and treatment with HCl in 1,4-dioxane). At this point, the amine was protected as the TROC carbamate before reprotecting the phenol as the MOM ether and then liberating the amine with zinc in acetic acid. The amine was converted to an alcohol moiety with sodium nitrite in acetic acid, and this handle was acylated with (S)-N-[(trichloroethoxy)carbonyl]-S-(9-fluorenylmethyl)cysteine. Removal of the allyl-protecting group followed by oxidation provided an 492 Shridhar Hegde and Michelle Schmidt alpha-hydroxy ketone intermediate. Dehydration and deprotection of the cysteine established the Michael addition of the thiol to the o-quinone methide with concomitant trapping with acetic anhydride. The remaining steps involved removal of protecting groups, installation of the tetrahydroisoquinoline ring via a Pictet Spengler reaction, and conversion of the cyano to the alcohol of the carbinolamine with silver nitrate in acetonitrile and water.

114899-80-8 Synthesis

114899-80-8
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114899-77-3
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Yield:114899-77-3 95%

Reaction Conditions:

with silver nitrate in water;acetonitrile at 20; for 24 h;Inert atmosphere;

Steps:

19 Example 19, Synthesis of Et-743

Compound 29 (7.7 mg, 0.01 mmol) was dissolved in 1 mL of acetonitrile in proportion, under argon.AgNO3 (32.3 mg, 0.19 mmol) was added to the mixed solvent of water, and the reaction was stirred at room temperature for 24 h.Add 1 mL of saturated sodium chloride and saturated sodium bicarbonate solution for 10 min.It was extracted with ethyl acetate three times, and the organic phases were combined, dried over anhydrous sodium sulfate and filtered.The solvent was removed by distillation under reduced pressure, flash column chromatography (DCM / MeOH = 20: 1), to give the compound 31 7.2mg (Et-743).The yield was 95%.

References:

CN109912629,2019,A Location in patent:Paragraph 0301-0305