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KR-20260065883-A - Method for preparing phosphonamidate compounds

KR20260065883AKR 20260065883 AKR20260065883 AKR 20260065883AKR-20260065883-A

Abstract

The present invention relates, for example, to a method for preparing phosphonamidate compounds of formulas (I) and (II) or solvates or salts thereof: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector). The present invention also relates to phosphonamidate compounds of formulas (I) and (I*), or solvates or salts thereof, for example.

Inventors

  • 카스퍼, 마르크-안드레
  • 마르크, 올리비에르
  • 마쿠이, 파울
  • 슈마커, 도미니크
  • 헬마-스메츠, 요나스
  • 게를라흐, 마르쿠스

Assignees

  • 투불리스 게엠베하

Dates

Publication Date
20260511
Application Date
20240830
Priority Date
20230901

Claims (15)

  1. A method for preparing a compound of formula (I) or a salt or solvate thereof, comprising the following steps: (i) A compound of formula (VIII) or a salt or solvate thereof: (In the above formula, R21 , R22 , R23 , and R24 are each independently H or optionally substituted ( C1 - C8 )alkyl; optionally, R21 and R22 can form a ring together and/or; optionally, R23 and R24 can form a ring together and/or; optionally, one of R21 and R22 can form a ring together with one of R23 and R24 ; LG is in a withdrawal phase) Step of reacting with the compound of chemical formula (VII): (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; M is a nuclear reactor designed to replace the leaving phase LG. It is a metal containr capable of delivering (ii) a step of reacting the product obtained in step (i) with a compound of formula (V) or its salt or solvate: (In the above formula, R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector); (iii) A step of reacting the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (In the above formula, R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue); and (iv) A step of reacting the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvate thereof: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector).
  2. A method for preparing a compound of formula (I) or a salt or solvate thereof, comprising the following steps: (a) (i) A compound of formula (VIII) or a salt or solvate thereof: (In the above formula, R21 , R22 , R23 , and R24 are each independently H or optionally substituted ( C1 - C8 )alkyl; optionally, R21 and R22 can form a ring together and/or; optionally, R23 and R24 can form a ring together and/or; optionally, one of R21 and R22 can form a ring together with one of R23 and R24 ; LG is in a withdrawal phase) Step of reacting with the compound of chemical formula (VII): (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; M is a nuclear reactor designed to replace the leaving phase LG. It is a metal containr capable of delivering (ii) A step of reacting the product obtained in step (i) with a compound of formula (III) or a salt or solvate thereof: (In the above formula, R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue); (iii) A step of reacting the product obtained in step (ii) with a compound of formula (V) or its salt or solvate: (In the above formula, R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector); and (iv) A step of reacting the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvate thereof: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector); or (b) (ii) a compound of formula (VI) or its salt or solvate: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R21 , R22 , R23 , and R24 are each independently H or optionally substituted ( C1 - C8 )alkyl; optionally, R21 and R22 can form a ring together and/or; optionally, R23 and R24 can form a ring together and/or; optionally, one of R21 and R22 can form a ring together with one of R23 and R24 ; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl) Step of reacting with a compound of formula (V) or its salt or solvate: (In the above formula, R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector); (iii) A step of reacting the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (In the above formula, R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue); and (iv) A step of reacting the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvate thereof: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector); or (c) (ii) a compound of formula (VI) or its salt or solvate: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R21 , R22 , R23 , and R24 are each independently H or optionally substituted ( C1 - C8 )alkyl; optionally, R21 and R22 can form a ring together and/or; optionally, R23 and R24 can form a ring together and/or; optionally, one of R21 and R22 can form a ring together with one of R23 and R24 ; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl) Step of reacting with a compound of formula (III) or its salt or solvate: (In the above formula, R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue); and (iii) A step of reacting the product obtained in step (ii) with a compound of formula (V) or its salt or solvate: (In the above formula, R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector); and (iv) A step of reacting the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvate thereof: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector).
  3. In paragraph 1 or 2, (a) is a triple bond; V is absent; and X is and; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, wherein RSi is each independently ( C1 - C8 )alkyl; preferably R3 is H or -Si( RSi ) 3 , wherein RSi is each independently ( C1 - C8 )alkyl; more preferably R3 is H or; or (b) is a double bond; V is H or ( C1 - C8 )alkyl, preferably V is H; and X is A method in which R4 is H or ( C1 - C8 )alkyl, preferably R4 is H, and R5 is H or ( C1 - C8 )alkyl, preferably R5 is H.
  4. In any one of paragraphs 1 through 3, (a) The leaving group LG is selected from the group consisting of a halogen (e.g., F, Cl, Br, or I) and an optionally substituted phenoxy, preferably the leaving group LG is Cl and/or; (b) M is MgY, where Y is a halogen, preferably Y is Br; or M is Li and/or; (c) R 6 is H, method.
  5. In any one of claims 1 to 4, spacer A is optionally substituted -( C6 - C10 )arylene-, optionally substituted -( C1 - C10 )alkylene-, optionally substituted -( C3 - C8 )carbocyclo-, optionally substituted -( C1 - C10 )alkylene-( C6 - C10 )arylene-, optionally substituted -( C6 -C10)arylene-(C1- C10 )alkylene-, optionally substituted -( C1 - C10 )alkylene-( C3 - C8 )carbocyclo-, optionally substituted -( C3 - C8 )carbocyclo-( C1 - C10 ) alkylene-, optionally substituted -( C3 - C8 )heterocyclo-, optionally substituted -( C1 -C Selected from the group consisting of 10 )alkylene-( C3 - C8 )heterocyclo- and optionally substituted -( C3 - C8 )heterocyclo-( C1 - C10 )alkylene-; Preferably, spacer A is optionally substituted -phenylene-, method.
  6. In any one of claims 1 to 5, PG is optionally substituted ( C1 - C8 )alkyl, and Preferably, PG is tert-butyl, method.
  7. In any one of claims 1 to 6, the compound of formula (V) and the compound of chemical formula (I) and, here , X, V, R 1 and PG are as defined in any one of paragraphs 1 through 6; Preferably, the compound of formula (V) and the compound of chemical formula (I) and, here , X, V, R 1 and PG are methods as defined in any one of paragraphs 1 through 6.
  8. In any one of paragraphs 1 through 7, R 1 is the following method. , In the above formula, indicates the position of O; K F is selected from the group consisting of -H, a protecting group, -PO₃H , -( C₁ - C₆ )alkyl, -( C₁ - C₆ )alkyl- SO₃H , -( C₂ - C₆ )alkyl- CO₂H , -( C₂ - C₆ )alkyl-OH, -( C₂ - C₆ )alkyl- NH₂ , -( C₂ - C₆ )alkyl-NH( C₁ - C₃ )alkyl, and -( C₂ - C₆ )alkyl-N(( C₁ - C₃ )alkyl) ₂ ; o is an integer in the range of 1 to 100; Preferably K F is H and/or; Preferably, o is an integer in the range of 8 to 30, and more preferably, o is an integer in the range of 20 to 28.
  9. In any one of paragraphs 1, 2 and 3 through 8, the compound of formula (VIII) and the compound of chemical formula (VII) is and the compound of chemical formula (V) is and the compound of chemical formula (III) is and the compound of chemical formula (I) is A method in which, where K F and o are as defined in paragraph 8; preferably K F is H and/or; preferably o is 24 or 12.
  10. In any one of claims 1, 2 and 3 through 9, the compound of formula (III) is used in substantially equimolar amounts based on the amount of the compound of formula (VIII); Preferably, the compound of formula (III) is used in an amount of 0.5 to 1.5 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII); More preferably, the compound of formula (III) is used in an amount of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII), in a method.
  11. In any one of claims 1 to 10, the oxidizing agent is selected from the group consisting of hydrogen peroxide, meta-chloroperoxybenzoic acid (mCPBA), urea-hydrogen peroxide adduct, (campersulfonyl)oxaziridine (CSO), iodine, tert-butylhydroperoxide (tBuOOH), and air; Preferably, the oxidizing agent is selected from the group consisting of hydrogen peroxide, meta-chloroperoxybenzoic acid (mCPBA), and urea-hydrogen peroxide adducts; More preferably, the oxidizing agent is hydrogen peroxide.
  12. A method according to any one of claims 1 to 11, wherein steps (i) to (iv) are performed as a one-pot process.
  13. A method according to any one of paragraphs 1 through 12, further comprising the following steps: (v) By removing the protecting group PG from a compound of formula (I) or its salt or solvate: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector) Step to obtain a compound of chemical formula (I*) or its salt or solvate: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer).
  14. A method for preparing a compound of formula (I*) comprising the following steps: By removing the protecting group PG from a compound of formula (I) or its salt or solvate: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector) Step to obtain a compound of chemical formula (I*) or its salt or solvate: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer).
  15. Compound of formula (I) or its salt or solvate: (In the above formula, is a triple bond; or is a double bond; V is If it is a triple bond, it is absent; or V is If it is a double bond, it is H or ( C1 - C8 )alkyl; X is In the case where it is a triple bond or X is If it is a double bond And; R1 is an arbitrarily substituted aliphatic residue or an arbitrarily substituted aromatic residue; R3 is selected from the group consisting of H, -Si( RSi ) 3 and ( C1 - C8 )alkyl, where RSi is independently ( C1 - C8 )alkyl; R4 is H or ( C1 - C8 )alkyl; R5 is H or ( C1 - C8 )alkyl; R6 is H or ( C1 - C8 )alkyl; A is a spacer; PG is a protector).

Description

Method for preparing phosphonamidate compounds Cross-reference of related applications This application claims priority to European patent application No. 23194788.8 filed on September 1, 2023, the entire contents of which are incorporated herein for all purposes. Technology field The present invention relates to a method for preparing a phosphonamidate compound or a salt or solvate thereof. The present invention also relates to a phosphonamidate compound or a salt and solvate thereof. Furthermore, the present invention relates to a phosphonamidate compound or a salt or solvate thereof that can be obtained or is obtained by the method of the present invention. Unsaturated phosphonamidates are important phosphorus (V) compounds that can be used, for example, in the preparation of bioconjugates with proteins and antibodies, as well as in the preparation of biologically active agents such as antibody-drug conjugates; see, for example, WO 2023/083900 A1 and WO 2023/083919 A1. To date, phosphonamidates have been synthesized via the so-called Staudinger phosphonite reaction; for example, WO 2018/041985 A1; literature [M.-A. Kasper, A. Stengl, P. Ochtrop, M. Gerlach, T. Stoschek, D. Schumacher, J. Helma, M. Penkert, E. Krause, H. Leonhardt, CPR Hackenberger, “Ethynylphosphonamidates for the Rapid and Cysteine-Selective Generation of Efficacious Antibody-Drug Conjugates” , Angew. Chem. Int. See Ed. 2019, vol. 58, pp. 11631-11636, https://doi.org/10.1002/anie.201904193]; and the literature [M.-A. Kasper, M. Glanz, A. Stengl, M. Penkert, S. Klenk, T. Sauer, D. Schumacher, J. Helma, E. Krause, MC Cardoso, H. Leonhardt, CPR Hackenberger, “Cysteine-Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations” , Angew. Chem Int. Ed. 2019, vol. 58, pp. 11625-11630, https://doi.org/10.1002/anie.201814715]. The following diagram shows an example of phosphonamidate synthesis via the Staudinger path: In any case, the Staudinger pathway for synthesizing phosphonamidate requires the use of an alcohol HO-R and an azide, i.e., a compound containing an N3 moiety. The Staudinger reaction can produce phosphonamidate within a reasonable number of steps, but several drawbacks still remain. For example, as shown in the diagram above, depending on the mechanism, two equivalents of alcohol must be used as the starting material for the synthesis. In practice, to proceed with the reaction in a satisfactory yield, an excess of up to three equivalents of alcohol must be added. However, the phosphonamidate product contains only one equivalent of alcohol. While the other equivalents of alcohol do not contribute to product production, they may increase waste volume or require re-separation and/or recycling through additional processes. Furthermore, if the alcohol HO-R is rare—for example, if it is difficult to manufacture or expensive—the loss of one equivalent of alcohol during the synthesis process must be taken into account. As another example, azides are generally explosive compounds; for instance, [Brδse S., Gil C., Knepper K., Zimmermann V., Organic Azides: An Exploding Diversity of a Unique Class of Compounds, Angewandte Chemie International Edition 2005, vol. See 44, pp. 5188-5240, https://doi.org/10.1002/anie.200400657. Therefore, the use and handling of azide entail a significant explosion risk associated with the phosphonamidate synthesis process. Accordingly, additional phosphonamidate synthesis pathways are needed, particularly those capable of efficient and safe synthesis. The present invention will be better understood when considering the non-limiting embodiments and the accompanying drawings together with the detailed description. The drawings represent the following:Figure 1 shows the HPLC chromatogram of compound P5(PEG24)-COOH synthesized according to Example 2 . Figure 2 shows the HPLC chromatogram of compound P5(PEG12)-COOH synthesized according to Example 3 . Figure 3 shows the HPLC chromatogram of compound P5(PEG12)-COOH synthesized according to Comparative Example A via the Staudinger route. Figure 4 shows the chromatogram of P5(PEG24)-COOtBu obtained by HPLC/UV analysis. P5(PEG24)-COOtBu was synthesized according to Example 6 . Figure 5 shows the mass spectrum of P5(PEG24)-COOtBu synthesized according to Example 6 . Figure 6 shows the 1H NMR spectrum of the compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 . Figure 7 shows the 31 P NMR spectrum of the compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 . Figure 8 shows the 13 C NMR spectrum of the compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 . Figure 9 shows the HPLC chromatogram of compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 . The present invention is described in detail below and further explained through the attached embodiments and drawings. definition Unless otherwise indicated, the term “alkyl” means a substituted or unsubstituted straight-chain or branched saturated hydrocarb