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CN-121986103-A - Synthetic method for producing ecteinascidin compounds

CN121986103ACN 121986103 ACN121986103 ACN 121986103ACN-121986103-A

Abstract

The present invention relates to a process for converting a compound of formula (I) into a compound of formula (II), and to a compound of formula (I).

Inventors

  • M. J. Martin Lopez
  • G. Tarazonaramos
  • M. D.C. Kovasmachent

Assignees

  • 法马马有限公司

Dates

Publication Date
20260505
Application Date
20231009

Claims (20)

  1. 1. A process for the synthesis of ecteinascidin compounds, the process comprising the step of oxidising a reaction mixture comprising a compound of formula I to give a compound of formula II: Wherein: r 1 is OH or CN; r 2 is hydrogen or Prot NH , and R 3 is hydrogen or Prot OH , Wherein Prot NH is a protecting group for an amino group and Prot OH is a protecting group for OH.
  2. 2. The method of claim 1, wherein R 1 is OH.
  3. 3. The method of claim 1, wherein R 1 is CN.
  4. 4. A process according to any one of claims 1 to 3, wherein R 2 is hydrogen.
  5. 5. A method according to any one of claims 1 to 3, wherein R 2 is Prot NH .
  6. 6. The process according to claim 5, wherein Prot NH is selected from allyl carbamate (Alloc), 2-trichloroethyl carbamate (Troc), benzyl carbamate (Cbz), 9-fluorenylmethyl-carbamate (Fmoc), CONHPh, CSNHPh and tert-butyl carbamate (Boc), preferably tert-butyl carbamate (Boc).
  7. 7. The method of any one of claims 1 to 6, wherein R 3 is hydrogen.
  8. 8. The method according to any one of claims 1 to 7, wherein oxidation is performed using an oxidizing agent, biochemical oxidation or electrochemical oxidation.
  9. 9. The method of claim 8, wherein the oxidizing agent is selected from the group consisting of metal oxidizing agents such as Cr (VI) compounds, mn (IV) compounds, mn (VII) compounds, fe (III) compounds, cu (II) compounds, ag (I) compounds, pb (IV) compounds, ce (IV) compounds, mn (III) compounds, mn (IV) compounds, mn (VII) compounds, halogen compounds such as I 2 and HIO 3 , quinones such as tetrachlorobenzoquinone, molecular oxygen, hydrogen peroxide, hypochlorites such as NaOCl and Ca (OCl) 2 , chlorites, 1, 4-benzoquinone and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, or combinations thereof.
  10. 10. The method of claim 9, wherein the oxidizing agent is selected from the group consisting of molecular oxygen, hydrogen peroxide, 1, 4-benzoquinone, and metal oxidizing agents, or a combination thereof.
  11. 11. The method of claim 9 or claim 10, wherein the metal oxidant is a transition metal oxidant.
  12. 12. The method of claim 11, wherein the transition metal is Fe, cu, or Mn.
  13. 13. The method of claim 11, wherein the transition metal oxidant is selected from Fe (III) compounds (e.g., feCl 3 or K 3 [Fe(CN) 6 ), cu (II) compounds (e.g., cuSO 4 ), mn (III) compounds (e.g., mn (OAc) 3 ), mn (IV) compounds (e.g., mnO 2 ), and Mn (VII) compounds (e.g., KMnO 4 ).
  14. 14. The method of claim 13, wherein the Fe (III) compound is FeCl 3 .
  15. 15. The method of claim 9, wherein the oxidizing agent is a halogen compound (such as I 2 and HIO 3 ).
  16. 16. The method of claim 9, wherein the oxidizing agent is a quinone (such as tetrachlorobenzoquinone).
  17. 17. The process according to any one of claims 8 to 16, wherein the number of equivalents of the oxidizing agent relative to the compounds of formula I in the reaction mixture is from about 1.0 equivalent to about 15.0 equivalents, preferably from about 1.2 equivalent to about 10.0 equivalents, more preferably from about 1.5 equivalent to about 8.0 equivalents, even more preferably from about 2.0 equivalents to about 5.0 equivalents.
  18. 18. The method of any one of claims 8 to 10, wherein the oxidizing agent is molecular oxygen.
  19. 19. The method of claim 18, wherein the molecular oxygen is provided by exposing the reaction mixture to a reactive atmosphere comprising molecular oxygen.
  20. 20. The method of claim 18 or claim 19, wherein during the step of oxidizing the reaction mixture comprising the compound of formula I to obtain the compound of formula II, a stream comprising molecular oxygen is bubbled through the reaction mixture.

Description

Synthetic method for producing ecteinascidin compounds Technical Field The present invention relates to synthetic methods and in particular to synthetic methods for the manufacture of ecteinascidin compounds. Background Ecteinascidins are a group of naturally occurring marine compounds and synthetic analogs thereof, which are well characterized and structurally characterized, and which are disclosed as having antibacterial and cytotoxic properties. See, for example, european patent 309.477, WO 03/66638, WO 03/08423, WO 01/77115, WO 03/014127, WO 2018/197663, R.Sakai et al, 1992, proc. Natl. Acad. Sci. USA 89, pages 11456-11460, R.Menchaca et al, 2003, J.org.chem.68 (23), pages 8859-8866, and I. Manzanares et al, 2001, curr. Med. Chem. Anti-CANCER AGENTS, pages 257-276, and references therein. Examples of ecteinascidins are provided by ET-743、ET-729、ET-745、ET-759A、ET-759B、ET-759C、ET-770、ET-815、ET-731、ET-745B、ET-722、ET-736、ET-738、ET-808、ET-752、ET-594、ET-552、ET-637、ET-652、ET-583、ET-597、ET-596、ET-639、ET-641 and synthetic analogs thereof (such as acetylated forms, formylated forms, methylated forms, and oxide forms). However, there remains a need to develop more efficient methods (particularly semi-synthetic routes) to manufacture ecteinascidin compounds and related compounds. The present invention addresses this need. Disclosure of Invention According to an aspect of the present invention there is provided a process for the synthesis of ecteinascidin compounds, the process comprising the step of oxidising a reaction mixture comprising a compound of formula I to give a compound of formula II: Wherein: r 1 is OH or CN; r 2 is hydrogen or Prot NH, and R 3 is hydrogen or Prot OH, Wherein Prot NH is a protecting group for an amino group and Prot OH is a protecting group for OH. The present inventors have identified that compound HQ-3 is highly insoluble in both organic and aqueous media, thereby forming a precipitate and allowing a reduction in overall process yield. By reducing the amount of compound HQ-3 produced as a downstream intermediate, in particular by oxidizing the compound of formula I to the compound of formula II at an early stage of ecteinascidin compound synthesis, a reduction in the amount of precipitate produced during the course of the reaction can be achieved. This therefore results in a more efficient and productive process, especially on a plant scale. In a preferred aspect, R 1 is OH. In a preferred aspect, R 1 is CN. In a preferred aspect, R 2 is hydrogen. In a preferred aspect, R 2 is Prot NH. In a preferred aspect Prot NH is selected from allyl carbamate (Alloc), 2-trichloroethyl carbamate (Troc), benzyl carbamate (Cbz), 9-fluorenylmethyl-carbamate (Fmoc), CONHPh, CSNHPh and tert-butyl carbamate (Boc), preferably tert-butyl carbamate (Boc). In an alternative aspect, prot NH does not include CONHPh. In alternative aspects Prot NH is selected from allyl carbamate (Alloc), 2-trichloroethyl carbamate (Troc), benzyl carbamate (Cbz), 9-fluorenylmethyl-carbamate (Fmoc), CSNHPh and tert-butyl carbamate (Boc), preferably tert-butyl carbamate (Boc). In a preferred aspect, R 3 is hydrogen. In a preferred aspect, the oxidation is carried out using an oxidizing agent, biochemical oxidation or electrochemical oxidation. In a preferred aspect, the oxidizing agent is selected from the group consisting of metal oxidizing agents such as Cr (VI) compounds, mn (IV) compounds, mn (VII) compounds, fe (III) compounds, cu (II) compounds, ag (I) compounds, pb (IV) compounds, ce (IV) compounds, molecular oxygen, hydrogen peroxide, hypochlorites such as NaOCl and Ca (OCl) 2, chlorite, 1, 4-benzoquinone, and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, or combinations thereof. In a preferred aspect, the oxidizing agent is selected from the group consisting of molecular oxygen, hydrogen peroxide, 1, 4-benzoquinone, and metal oxidizing agents, or combinations thereof. In a preferred aspect, the metal oxidant is a transition metal oxidant. In a preferred aspect, the transition metal is Fe, cu or Mn. In a preferred aspect, the transition metal oxidizing agent is selected from the group consisting of Fe (III) compounds (e.g., feCl 3 or K 3[Fe(CN)6), cu (II) compounds (e.g., cuSO 4), mn (III) compounds (e.g., mn (OAc) 3), mn (IV) compounds (e.g., mnO 2), and Mn (VII) compounds (e.g., KMnO 4). In a preferred aspect, the Fe (III) compound is FeCl 3. In a preferred aspect, the oxidizing agent may be a halogen-based oxidizing agent. Halogen may be iodine (e.g., I 2 and HIO 3). In a preferred aspect, the oxidizing agent may be a quinone (e.g., tetrachlorobenzoquinone). In a preferred aspect, the number of equivalents of oxidizing agent relative to the number of equivalents of compound of formula I in the reaction mixture is from about 1.0 equivalent to about 15.0 equivalents, preferably from about 1.2 equivalents to about 10.0 equivalents, more preferably from about 1.5 equivalents to about 8.0 equivalents, even more preferably