Process for the preparation of phosphonamidate compounds

Abstract

This invention relates to methods for preparing phosphonamide ester compounds of, for example, formulas (I) and (II), or their solvates or salts: (I), (I*), wherein: - is a triple bond; or - is a double bond; - is absent when it is a triple bond; or V is H or (C1-C8) alkyl when it is a double bond; X is R when it is a triple bond. 3‑ C; or when it is a double bond, X is R. 4‑ R 5‑ C;R 1 It is an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently (C) 1 -C 8 )alkyl; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8)alkyl; A is a spacer; and PG is a protecting group. The invention also relates to phosphonamide ester compounds of, for example, formula (I) and (I*), or their solvates or salts. (I) (I*) wherein: is a triple bond; or a double bond; V is absent when it is a triple bond; or V is H or (C1-C8)alkyl when it is a double bond; X is present when it is a triple bond; or X is present when it is a double bond.

Description

Cross-reference to related applications

[0001] This application claims priority to European Patent Application No. 23194788.8, filed on 1 September 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0002] This invention relates to methods for preparing phosphonamide ester compounds or their salts or solvates. The invention also relates to phosphonamide ester compounds or their salts and solvates. Furthermore, this invention relates to phosphonamide ester compounds or their salts or solvates that can be obtained, or are being obtained, by the methods of this invention. Background Technology

[0003] Unsaturated phosphonamide esters are important phosphorus (V) compounds that can be used, for example, to prepare bioconjugates with proteins and antibodies, and to prepare bioactive agents such as antibody-drug conjugates; see, for example, WO 2023 / 083900 A1 and WO 2023 / 083919 A1. Phosphamide esters have been synthesized to date via the so-called Staudingerphosphonite reaction; see, for example, WO 2018 / 041985 A1; 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. Ed. 2019, Vol. 58, pp. 11631-11636, https: / / doi.org / 10.1002 / anie.201904193; and 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 schemes depict illustrative examples of the synthesis of phosphonamidate esters via the Staudinger pathway: . In any case, the Staudinger pathway to obtain phosphonamide esters requires the use of alcohols HO-R and azides, i.e., compounds containing the N3 moiety.

[0004] While the Staudinger reaction can deliver phosphonamide esters in a reasonable number of steps, certain drawbacks remain. For example, as can be seen from the above scheme, according to the described mechanism, two equivalents of alcohol are required as starting material in the synthesis. In practice, even larger excesses of up to three equivalents of alcohol are needed to drive the reaction to the desired yield. However, only one equivalent of alcohol is incorporated into the phosphonamide ester product. The other equivalents of alcohol do not contribute to the product but may increase the amount of waste and / or require further separation and / or recycling via additional steps. Furthermore, when the alcohol HO-R is precious, for example, when it is difficult to prepare or expensive, the loss of one equivalent of alcohol during synthesis must be considered. Furthermore, as another example, azides are generally explosive compounds; see, for example, Bräse S., Gil C., Knepper K., Zimmermann V., Organic Azides: An Exploding Diversity of a Unique Class of Compounds, Angewandte Chemie International Edition 2005, Vol. 44, pp. 5188-5240, https: / / doi.org / 10.1002 / anie.200400657. Therefore, the use and handling of azides pose a substantial explosion hazard associated with the synthesis of phosphonamide esters.

[0005] Therefore, there is a need for alternative synthetic routes to obtain phosphonamide esters, particularly synthetic routes that allow for efficient and safe implementation. Summary of the Invention

[0006] The technical problem is solved by the subject matter as defined throughout this specification, and particularly in the appended claims.

[0007] Therefore, the present invention relates to a method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0008] The present invention also relates to a method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0009] The present invention also relates to a method for preparing a compound of formula (I), the method comprising: (ii) To make a compound of formula (VI) or a salt or solvate thereof: (VI), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (V) or their salts or solvates: (V), in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0010] The present invention also relates to a method for preparing a compound of formula (I), the method comprising: (ii) To make a compound of formula (VI) or a salt or solvate thereof: (VI), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (III) or their salts or solvates: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V), in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0011] The present invention also relates to a method for preparing a compound of formula (I), the method comprising: Make the compound of formula (II) or its salt or solvate: (II), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group Reaction with an oxidizing agent yields a compound of formula (I) or a salt or solvate thereof: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0012] The present invention also relates to a method for preparing a compound of formula (I*) or a salt or solvate thereof, the method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is a spacer.

[0013] The present invention also relates to a method for preparing a compound of formula (I*), the method comprising: (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is a spacer.

[0014] The present invention also relates to a compound of formula (I*) or a salt or solvation thereof.

[0015] The present invention also relates to a compound of formula (I*) or a salt or solvation thereof that can be obtained or is being obtained by any of the methods of the present invention.

[0016] The present invention also relates to a compound of formula (I) or a salt or solvate thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0017] The present invention also relates to a compound of formula (I) that can be obtained or is being obtained by any of the methods of the present invention. Attached Figure Description

[0018] The invention will be better understood by referring to the specific embodiments and the accompanying drawings, respectively. The drawings show:

[0019] Figure 1 The HPLC chromatogram of compound P5(PEG24)-COOH synthesized according to Example 2 is shown.

[0020] Figure 2 The HPLC chromatogram of compound P5(PEG12)-COOH synthesized according to Example 3 is shown.

[0021] Figure 3 The HPLC chromatogram of compound P5(PEG12)-COOH, synthesized via the Staudinger pathway according to Comparative Example A, is shown.

[0022] Figure 4 The chromatogram of P5(PEG24)-COOtBu obtained by HPLC / UV analysis is shown. P5(PEG24)-COOtBu was synthesized according to Example 6.

[0023] Figure 5 The mass spectrum of P5(PEG24)-COOtBu synthesized according to Example 6 is shown.

[0024] Figure 6 The compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 is shown. 1 H NMR spectrum.

[0025] Figure 7 The compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 is shown. 31 P NMR spectroscopy.

[0026] Figure 8 The compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 is shown. 13 C NMR spectroscopy.

[0027] Figure 9 The HPLC chromatograms of compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 are shown. Detailed Implementation

[0028] The present invention will be described in detail below, and will also be illustrated by the accompanying embodiments and drawings. definition

[0029] Unless otherwise indicated, the term "alkyl" on its own or as part of another term generally refers to a substituted or unsubstituted straight-chain or branched saturated hydrocarbon having a specified number of carbon atoms; for example, "-(C1-C8)alkyl" or "-(C1-C8)alkyl". 10 "alkyl" means an alkyl group having 1 to 8 or 1 to 10 carbon atoms. When the number of carbon atoms is not specified, an alkyl group may have 1 to 8 carbon atoms. Representative straight-chain (C1-C8) alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, and -n-octyl; branched-chain (C1-C8) alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2-methylbutyl. In some aspects, the alkyl group may be unsubstituted. Optionally, the alkyl group may be substituted, for example, by one or more groups (such as those described herein).

[0030] Unless otherwise indicated, the term "alkylene" on its own or as part of another term generally refers to having the stated number of carbon atoms (preferably 1-10 carbon atoms - (C1-C2)). 10 The alkylene group is a substituted or unsubstituted branched or straight-chain saturated hydrocarbon group centered on two monovalent groups derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. When the number of carbon atoms is not specified, the alkylene group may have 1 to 8 carbon atoms. Typical alkylene groups include, but are not limited to: methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-n-propylene (-CH2CH2CH2-), and 1,4-n-butylene (-CH2CH2CH2CH2-). In some aspects, the alkylene group may be unsubstituted. Optionally, the alkylene group may be substituted, for example, by one or more groups (e.g., those described herein).

[0031] Unless otherwise indicated, the term "alkenyl" on its own or as part of another term generally refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon having a double bond and a specified number of carbon atoms; for example, "-(C2-C8)alkenyl" or "-(C2-C8)alkenyl". 10"Alkenyl" refers to an alkenyl group having 2 to 8 or 2 to 10 carbon atoms, respectively. When the number of carbon atoms is not specified, the alkenyl group may have 2 to 8 carbon atoms. Representative -(C2-C8) alkenyl groups include, but are not limited to, -vinyl, -1-propenyl, -2-propenyl, -1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, and -2,3-dimethyl-2-butenyl. In some aspects, the alkenyl group may be unsubstituted. Optionally, the alkenyl group may be substituted, for example, by one or more groups (such as those described herein).

[0032] Unless otherwise indicated, the term "alkynyl" on its own or as part of another term generally refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon having a triple bond and a specified number of carbon atoms; for example, "-(C2-C8)alkynyl" or "-(C2-C8)alkynyl". 10 "Alynyl" refers to an alkynyl group having 2 to 8 or 2 to 10 carbon atoms. When the number of carbon atoms is not specified, the alkynyl group may have 2 to 8 carbon atoms. Representative -(C2-C8) alkynyl groups include, but are not limited to, -ethynyl, -1-propynyl, -2-propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, and -3-methyl-1-butynyl. In some aspects, the alkynyl group may be unsubstituted. Optionally, the alkynyl group may be substituted, for example, by one or more groups (such as those described herein).

[0033] Unless otherwise indicated, the term "aryl" itself, or as part of another term, generally refers to a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon group having 6 to 20 carbon atoms (preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, and in a very preferred embodiment 6 carbon atoms), derived by removing a hydrogen atom from a single carbon atom of the parent aromatic ring system. Some aryl groups are represented as "Ar" in exemplary structures. Typical aryl groups include, but are not limited to, groups derived from benzene, substituted benzene, naphthalene, anthracene, and biphenyl. An exemplary aryl group is phenyl. In some aspects, the aryl group may be unsubstituted. Optionally, the aryl group may be substituted, for example, by one or more groups (such as those described herein).

[0034] Unless otherwise indicated, the term "arylene" itself, or as part of another term, generally refers to an aryl group as defined above, wherein one hydrogen atom of the aryl group is bond-substituted (i.e., it is divalent), and can be para, meta, or ortho oriented as shown in the following structure, with phenylene as an exemplary group: In selected embodiments, the aryl group is an aryl group as defined above, wherein two or more hydrogen atoms of the aryl group are bond-substituted (i.e., the aryl group may be trivalent). In some aspects, the aryl group may be unsubstituted. Optionally, the aryl group may be substituted, for example, by one or more groups (such as those described herein).

[0035] Unless otherwise indicated, the term "heterocycle" or "ring of heterocycles" itself, or as part of another term, generally refers to a monovalent substituted or unsubstituted aromatic or non-aromatic monocyclic or bicyclic ring system having a specified number of carbon atoms and one to four independent heteroatom ring members selected from N, O, P, or S, and derived by removing a hydrogen atom from a ring atom of the parent ring system (e.g., "(C3-C8) heterocycle" or "(C3-C8) ring"). 10 A "heterocycle" refers to a heterocycle having 3 to 8 or 3 to 10 carbon atoms, respectively. One or more N, C, or S atoms in the heterocycle may be oxidized. The ring including the heteroatom may be aromatic or non-aromatic. Unless otherwise stated, the heterocycle is attached to its side group at any heteroatom or carbon atom, which produces a stable structure. Representative examples of (C3-C8) heterocycles include, but are not limited to, pyrrolidinyl, azacyclic butyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolidinyl, thiophene (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, and isoxazolyl. In some aspects, the heterocyclic group may be unsubstituted. Optionally, the heterocyclic group may be substituted, for example, by one or more groups (such as those described herein).

[0036] Unless otherwise indicated, the term "heterocyclic" or "ring of heterocycles" on its own or as part of another term generally refers to a heterocyclic group as defined above and having a specified number of carbon atoms (e.g., (C3-C8) heterocycle or (C3-C8) ring). 10 A heterocycle is a heterocyclic group in which one hydrogen atom is bonded and substituted (i.e., it is divalent). In selected embodiments, a heterocycle is a heterocyclic group as defined above, wherein two or more hydrogen atoms of the heterocyclic group are bonded and substituted (i.e., the heterocycle may be trivalent). In some aspects, the heterocycle or the ring of a heterocycle may be unsubstituted. Optionally, the heterocycle or the ring of a heterocycle may be substituted, for example, by one or more groups (e.g., those described herein).

[0037] Unless otherwise indicated, the term "carbocyclic" or "ring of carbon rings" itself, or as part of another term, generally refers to a monocyclic or bicyclic aromatic or non-aromatic carbon ring system with a specified number of carbon atoms, derived by removing a hydrogen atom from a ring atom of a parent ring system, whether substituted or unsubstituted (e.g., "(C3-C8) carbon ring" or "(C3-C8) ring"). 10 "Carbon ring" refers to a carbon ring having 3 to 8 or 3 to 10 carbon atoms, respectively. As an illustrative but non-limiting example, the carbon ring can be a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered carbon ring. Representative (C3-C8) carbon rings include, but are not limited to, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptanetrienyl, cyclooctyl, and cyclooctadienyl. In some aspects, the carbon ring may be unsubstituted. Optionally, the carbon ring may be substituted, for example, by one or more groups (such as those described herein).

[0038] Unless otherwise indicated, the term "carbocyclic ring" or "ring of carbon rings" on its own or as part of another term generally refers to a carbocyclic group having a specified number of carbon atoms as defined above (e.g., "(C3-C8)carbocyclic ring" or "(C3-C8)carbocyclic ring"). 10 "Carbocyclic ring" refers to a carbon ring or ring of carbon rings having 3 to 8 or 3 to 10 carbon atoms, respectively, wherein another hydrogen atom of the carbon ring group is bonded and substituted (i.e., it is divalent). In selected embodiments, the carbon ring or ring of carbon rings is a carbon ring group as defined above, wherein two or more hydrogen atoms of the carbon ring group are bonded and substituted (i.e., the carbon ring or ring of carbon rings may be trivalent). In some aspects, the carbon ring or ring of carbon rings may be unsubstituted. Optionally, the heterocyclic ring or ring of heterocyclic rings may be substituted, for example, by one or more groups (e.g., those described herein).

[0039] Unless otherwise defined, the term "halogen" or "halogen group" generally refers to an element in Group 7; preferably fluorine, chlorine, bromine and iodine; more preferably fluorine, chlorine and bromine; and even more preferably chlorine and bromine.

[0040] Unless otherwise indicated, the terms "substituted," "optionally substituted," and "optionally substituted" generally mean that one or more hydrogen atoms can be independently replaced by a substituent. Typical substituents include, but are not limited to, -X, -R, and -O. - -OR, -SR, -S - , -NR2, -NR3, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -NRC(=O)R, -C(=O)R, -C(=O)NR2, -SO3- , -SO3H, -S(=O)2R, -OS(=O)2OR, -S(=O)2NR, -S(=O)R, -OP(=O)(OR)2, -P(=O)(OR)2, -PO4 3- -PO3H2, -C(=O)R, -C(=O)X, -C(=S)R, -CO2R, -CO2, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NR2, -C(=S)NR2 or -C(=NR)NR2, where each X is independently a halogen: -F, -CI, -Br or -I; and each R is independently -H, -(Cl-C 20 )alkyl (e.g., -(C1-C) 10 alkyl or -(C1-C8)alkyl), -(C6-C 20 )Aryl, (e.g. -(C6-C) 10 aryl, or preferably -C6-aryl), -(C3-C 14 Heterocyclic rings (e.g., -(C3-C)) 10 ( ) heterocyclic or -(C3-C8) heterocyclic, protecting group or prodrug moiety. Typical substituents also include (=O).

[0041] As used herein, the term "aliphatic or aromatic residue" generally refers to an aliphatic substituent, such as, but not limited to, alkyl residues; however, it may optionally be substituted with other aliphatic and / or aromatic substituents. As a non-limiting example, an aliphatic residue can be a nucleic acid, enzyme, coenzyme, nucleotide, oligonucleotide, monosaccharide, polysaccharide, polymer, fluorophore, optionally substituted benzene, etc., provided that such a molecule is directly linked to the core structure (in R...). 1 In cases where (e.g., the linkage to an oxygen atom bonded to phosphorus) is aliphatic, the residue may be a substituent. An aromatic residue is a substituent in which the direct linkage to the core structure is part of an aromatic system, such as an optionally substituted phenyl, triazolyl, pyridyl, or nucleotide; as a non-limiting example, if the direct linkage of the nucleotide to the core structure is, for example, via a phenyl residue. As used herein, the term "aromatic residue" also includes heteroaromatic residues.

[0042] As used herein, the term "protecting group" or "protective group" generally refers to a portion that is introduced into a molecule to protect certain functional groups and thus prevent reactions at those functional groups under the synthetic conditions experienced by the molecule in one or more subsequent steps. When protection is no longer needed, for example after one or more reactions have occurred elsewhere at other functional groups in the molecule, the protecting group can be cleaved. Cleavage of the protecting group, or also referred to as "deprotection," results in the restoration of the original functional group that was present before the introduction of the protecting group to protect the functional group. For illustrative purposes only, this is referred to as the protecting group of the carboxylic acid group -COOH. The introduction of a protecting group (which may be abbreviated, for example, as "PG") to protect the carboxylic acid group produces a partial -COOPG. After the cleavage of the protecting group PG, i.e., after deprotection, and optionally after aqueous posttreatment and / or other purification methods known to those skilled in the art, the original carboxylic acid group -COOH is restored. As a precaution, it should be noted, based on the foregoing general definition of a protecting group, that a group used to activate a functional group is not a protecting group within the meaning of the foregoing definition. For example, groups used to activate carboxylic acids to increase reactivity in reactions at the carboxyl group (e.g., acyl chlorides, acid anhydrides, or reactive esters (e.g., N-hydroxysuccinimide (NHS) esters)) are not protecting groups. Such activating groups are not used to protect functional groups and prevent reactions at said functional groups, but rather to impart, provide, or increase the reactivity of said functional groups. Furthermore, reactions at activated functional groups generally do not restore the original functional group but lead to the formation of new functional groups, such as the formation of amides after activating carboxylic acids with, for example, an NHS ester and subsequently reacting with an amine. Various possible protecting groups are known in the art for different functional groups, such as amino, hydroxyl, carbonyl, carboxyl, phosphate, and terminal alkynes, differing in their introduction and / or cleavage conditions. Therefore, suitable protecting groups are known and readily selected by those skilled in the art.

[0043] This disclosure also relates to a “pharmaceutically acceptable salt.” Any pharmaceutically acceptable salt can be used. In particular, the term “pharmaceutically acceptable salt” refers to a salt of the conjugate or compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are of low toxicity and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include, but are not limited to: (1) Acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- Methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucohepanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) a salt formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or a salt formed when an acidic proton present in the parent compound coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. The salt further includes (purely by way of example) sodium, potassium, calcium, magnesium, ammonium, trialkylammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. Counterions or anionic counterions can be used in quaternary ammonium compounds to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F). - Cl - ,Br - I - NO3 - ClO4 - OH - H2PO4 - HSO4 - Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic-5-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0044] As used herein, the term "solvent" can refer to an aggregate comprising one or more molecules of the conjugate or compound described herein and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the conjugates or compounds of this disclosure may exist as hydrates (including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc.) and their corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may contain only external water or a mixture of water and some external solvent. * * * Method for preparing compounds of formula (I)

[0045] This invention relates to a method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (i) Compounds of formula (VIII): (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0046] Without being bound by any theory, it is assumed that the method for preparing the compound of formula (I) can be carried out according to the following proposed reaction scheme: . Therefore, in step (i), compound (VII) (as an illustrative example, compound (VII) could be, for example, a Grignard compound) can react with the compound of formula (VIII) in a substitution reaction at phosphorus to give intermediate (VI), thereby releasing the leaving group LG. In step (ii), intermediate (VI) can react with the compound of formula (V) to give intermediate (IV), thereby releasing HNR. 21 R 22 (or HNR) 23 R 24 In step (iii), intermediate (IV) can react with the alcohol of formula (III) to give intermediate (II), thereby releasing HNR. 23 R 24 (or HNR) 21 R 22 When HNR is in step (ii) 23 R 24 (The phosphorus is released). Then, in step (iv), an oxidant can be used to oxidize intermediate (II) (wherein phosphorus is in oxidized state III) to obtain the phosphonamide ester of formula (I) (wherein phosphorus is in oxidized state V). In a preferred embodiment, as further described below, the method can be carried out as a one-pot process. However, it is also possible to separate one or more intermediates. Also as described herein, the order of introducing the compound of formula (V) and the alcohol of formula (III) can be reversed; that is, it is possible to introduce the alcohol of formula (III) in step (ii) and then introduce the compound of formula (V) in step (iii).

[0047] It has been discovered that the order of substitution reactions at the phosphorus atom can be interchanged; that is, the product obtained in step (i) by reacting the compound of formula (VIII) with the compound of formula (VII) can be reacted with the compound of formula (III) in step (ii), and then the product obtained in step (ii) can be reacted with the compound of formula (V) in step (iii). Therefore, the present invention also relates to a method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (i) Compounds of formula (VIII): (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0048] Compounds of formula (VI) have proven to be quite stable and can therefore be isolated and stored. Therefore, it is also possible to use compounds of formula (VI) as starting materials in methods for preparing compounds of formula (I). Consequently, the present invention also relates to a method for preparing compounds of formula (I) or their salts or solvates, said method comprising: (ii) Compounds of formula (VI): (VI), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (V) or their salts or solvates: (V), in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To facilitate comparison between the foregoing method and methods including steps (i) to (iv), the step numbers are retained, i.e., the foregoing method includes steps (ii) to (iv).

[0049] When a compound of formula (VI) is used as the starting material in step (ii), the order of substitution reactions at the phosphorus atom may also be exchanged; that is, in step (ii), the compound of formula (VI) may react with the compound of formula (III), and then the product obtained in step (ii) may react with the compound of formula (V) in step (iii). Therefore, the present invention also relates to a method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (ii) To make a compound of formula (VI) or a salt or solvate thereof: (VI), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (III) or their salts or solvates: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V), in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

[0050] As an initial advantage, the method of the present invention allows for the preparation of phosphonamide esters without the need for the use of azides; see also Examples 1, 2, 3, 4, 5, 6, and 7 below. Therefore, by using the method of the present invention, phosphonamide esters can be synthesized without the explosion hazards associated with the preparation, use, and storage of azides. Furthermore, it has been found that the method for preparing phosphonamide esters described herein allows for the use of substantially equimolar amounts or about only one molar equivalent of an alcohol of formula (III) based on, for example, formula (VIII) or formula (VI); see also Examples 1, 2, 3, 4, 5, and 6. In contrast, the Staudinger pathway requires at least two molar equivalents of alcohol to prepare phosphonamide esters; see also Comparative Examples A and B. This can be explained by the above reaction scheme showing the reaction sequence with possible intermediates; see, for example, step (iii) in the above reaction scheme, where one molar equivalent of alcohol (III) and one molar equivalent of intermediate (IV) can react with each other to give intermediate (II). Therefore, compared to the Staudinger pathway, the method of the present invention allows for a reduction in the amount of alcohol required to prepare phosphonamide esters. Consequently, the method of the present invention also allows for a reduction in the amount of waste and / or the additional effort required for re-separation, recycling, and / or disposal of excess alcohol. This is particularly advantageous when alcohols are precious, such as when alcohols are difficult to prepare or expensive. As another advantage, the inventors can demonstrate that, compared to the Staudinger pathway, the method of the present invention allows for an increase in the yield of the prepared phosphonamide esters; see Example 3 and Comparative Example A, and Example 4 and Comparative Example B. Furthermore, compared to the Staudinger pathway, the method of the present invention allows for the preparation of phosphonamide esters with significantly shorter reaction times; see the total combined reaction times of Example 1 (the general procedure of Example 1 is applied to Examples 2 and 3), Examples 4, 5, 6, and 7 compared to Comparative Example A and Comparative Example B. As a particular advantage regarding potential industrial applications, the method of the present invention has been found to have good scalability and can be used in an excellent manner for the large-scale synthesis of phosphonamide esters; see Examples 6 and 7. In summary, the method of the present invention allows for the safe and efficient synthesis of phosphonamide esters.

[0051] As described herein, the present invention relates to various methods for preparing compounds of formula (I), differing particularly in the order of the starting materials (e.g., compounds of formula (VIII) or formula (VI)) and the substitution reactions in steps (ii) and (iii). In a preferred embodiment, the present invention relates to a method for preparing compounds of formula (I), the method comprising step (i) wherein a compound of formula (VIII) is used as a starting material, step (ii) is reacting the product obtained in step (i) with a compound of formula (V), step (iii) is reacting the product obtained in step (ii) with a compound of formula (III), and step (iv) is reacting the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I). The inventors have found that the method for preparing compounds of formula (I) using such a starting material and the order of steps (i) to (iv) results in particularly good product yields and purity, as well as excellent scalability of the method. In particular, when the group R 1 When the unit is polyethylene glycol as described herein, this preferred method yields good results.

[0052] In any of the methods described herein that includes step (i), step (i) may be replaced by step (i*), where step (i*) is: (i*) Make compounds of formula (VIII): (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII*): (VII*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ;and Y is a halogen; preferably Y is selected from chlorine (Cl), bromine (Br), and iodine (I); and The reaction is carried out as an electrochemical reaction. The leaving group LG can be any leaving group as described herein; preferably, LG can be selected from chlorine (Cl), bromine (Br), and iodine (I). Without wishing to be bound by any theory, it is assumed that in step (i*), the intermediate (VI) as described herein can be formed by an electrochemical reaction via a mechanism involving a group. The electrochemical reaction can be carried out, for example, by using an electrode (e.g., a metal electrode) immersed in a solution containing a compound of formula (VIII) and a compound of formula (VII*), as is known in the art.

[0053] This disclosure also relates to a salt. There are no particular limitations on the salt. Generally, any salt compatible with the reactants and reaction conditions applied can be used. Those skilled in the art will readily select a suitable salt. In some embodiments, the salt is a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art and can be readily selected by those skilled in the art. As illustrative examples, pharmaceutically acceptable salts that can be used in embodiments of the invention are also described herein.

[0054] Group R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl group. Preferably, R 21 R 22 R 23 and R 24 Each is independently an optionally substituted (C1-C8) alkyl group. More preferably, R 21 R 22 R 23 and R 24 Each is independently a optionally substituted (C1-C6) alkyl group, more preferably a optionally substituted (C1-C4) alkyl group, and even more preferably a optionally substituted (C1-C3) alkyl group. Group R 21 R 22 R23 and R 24 They may be the same or different. Specifically, all substituents on the nitrogen atom in compounds of formula (VIII) can be, for example, methyl, ethyl, or propyl, such as n-propyl or isopropyl. In some embodiments, R... 21 R 22 R 23 and R 24 Each is either n-propyl or isopropyl. Preferably, R 21 R 22 R 23 and R 24 Each is isopropyl. In some implementations, R 21 R 22 R 23 and R 24 Each is a methyl group. In some embodiments, R 21 R 22 R 23 and R 24 Each is an ethyl group.

[0055] Optionally, group R 21 and R 22 In particular, when each is independently an optionally substituted (C1-C8) alkyl group, preferably an optionally substituted (C1-C6) alkyl group, more preferably an optionally substituted (C1-C4) alkyl group, and even more preferably an optionally substituted (C1-C3) alkyl group, they can form a ring together; and / or optionally R 23 and R 24 In particular, when each is independently a optionally substituted (C1-C8) alkyl group, preferably an optionally substituted (C1-C6) alkyl group, more preferably an optionally substituted (C1-C4) alkyl group, and even more preferably an optionally substituted (C1-C3) alkyl group, they can form a ring together; and / or optionally, particularly when each is independently a optionally substituted (C1-C8) alkyl group, preferably an optionally substituted (C1-C6) alkyl group, more preferably an optionally substituted (C1-C4) alkyl group, and even more preferably an optionally substituted (C1-C3) alkyl group, R 21 and R 22 One of them can be with R 23 and R 24 (Especially when each is independently a optionally substituted (C1-C8) alkyl group, preferably an optionally substituted (C1-C6) alkyl group, more preferably an optionally substituted (C1-C4) alkyl group, and even more preferably an optionally substituted (C1-C3) alkyl group) together to form a ring. Preferably, in any of these embodiments, the ring can be a three- to eight-membered ring, more preferably a four- to seven-membered ring, and even more preferably a five- or six-membered ring.

[0056] The leaving group LG is not particularly limited. As used herein, the term "leaving group" generally refers to a portion, such as an atom or group of atoms, that can be separated from the main or residual portion of the substrate during a reaction or a fundamental step of the reaction. In particular, the leaving group can be replaced by another portion, such as an atom or group of atoms, during a substitution reaction (e.g., nucleophilic substitution). With respect to the present invention, any leaving group capable of undergoing a substitution reaction (particularly nucleophilic substitution) at the phosphorus atom can be used. Suitable leaving groups are known to those skilled in the art, and by way of illustrative example, may include halogens, toluenesulfonates, methanesulfonates, or substituted phenols; see, for example, Y. Huang et al., “Asymmetric Snythesis of P-Stereogenic Diarylphosphinites by Palladium-Catalyzed Enantioselective Addition of Diarylphosphines to Benzoquinones”, Journal of the American Chemical Society, 2014, Vol. 136, pp. 4865-4868, DOI: dx.doi.org / 10.1021 / ja501007t; and SH Jun, “Preparation of Phosphine-Amido Hafnium and Zirconium Complexes for Olefin Polymerization”, Organometallics 2013, Vol. 32, pp. 7357-7365, DOI: dx.doi.org / 10.1021 / om400899g. In some embodiments, the leaving group LG is selected from halogens and optionally substituted phenoxy groups. In some embodiments, the leaving group LG is a halogen (e.g., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I)). In some embodiments, the leaving group is selected from fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Preferably, the leaving group LG is chlorine (Cl). In some embodiments, the leaving group LG is optionally substituted phenoxy groups.

[0057] Preferably, It is a triple bond; V does not exist; X is... And R 3 Selected from H (hydrogen), -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group. When R 3 When it is a (C1-C8) alkyl group, R3 Preferably, it is a (C1-C6) alkyl, more preferably a (C1-C4) alkyl, and even more preferably a (C1-C2) alkyl. More preferably, It is a triple bond; V does not exist; X is... And R 3 Is it H or -Si(R) Si )3, where R Si Each is independently a (C1-C8) alkyl group. More preferably, It is a triple bond; V does not exist; X is... And R 3 It is H. Alternatively, It can be a triple bond; V does not exist; X is. And R 3 It is -Si(R) Si 3. Group R Si Each of these, when present, can be independently (C1-C8) alkyl, preferably (C1-C6) alkyl, more preferably (C1-C4) alkyl, and even more preferably (C1-C3) alkyl. Si They may be the same or different. In some implementations, each R... Si It is methyl or ethyl. Preferably, each R Si It is methyl. Therefore, in some embodiments, R 3 It is -Si(CH3)3. It should be noted that when R... 3 It is -Si(R) Si 3. In particular, when -Si(CH3)3 (as is known in the art), R 3 Hydrogen can be converted to H by reacting silyl groups with a suitable reagent (especially fluorides, such as tetra-n-butylammonium fluoride (TBAF) or an acid).

[0058] In some implementation schemes, It is a double bond; V is H or (C1-C8) alkyl; X is And R 4 and R 5 Each is independently H or (C1-C8) alkyl. Preferably, R 4 and R 5 Each is independently an H or (C1-C6) alkyl group, more preferably an H or (C1-C4) alkyl group, and even more preferably an H or (C1-C2) alkyl group. Preferably, R 4 and R 5 They are the same; or even more preferably, R 4 R 5 It is the same as V. More preferably, R 4 and R 5Both are H. Preferably, V is H or a (C1-C6) alkyl, more preferably H or a (C1-C4) alkyl, and even more preferably H or a (C1-C2) alkyl. Even more preferably, V is H. In a preferred embodiment, R 4 R 5 Both V and H are H.

[0059] Regarding the wording used in this article It should be noted that, as is generally known to those skilled in the art, each carbon atom is tetravalent. Therefore, the structure (Where X and V are as defined herein and an asterisk (*) indicates attachment to phosphorus) includes the following structures: and , where R 3 R 4 R 5 V is as defined herein. The tilde indicates that the configuration of the double bond can be E or Z. It is also possible that the compound exists as a mixture of E and Z isomers.

[0060] As described herein with respect to compounds of formula (VII), group M is capable of incorporating groups The metal-containing group of the leaving group LG is transferred to the phosphorus atom of the compound of formula (VIII). Organometallic compounds of formula (VII) capable of such substitution via a substitution reaction at phosphorus are generally known in the art and readily selected by those skilled in the art. Such compounds can also be readily prepared by those skilled in the art if desired or desired; by way of example only, this refers to Grinard's compounds, which can be readily prepared by reacting a suitable halide precursor (particularly suitable chlorine, bromine or iodine compounds) with magnesium to give compounds of formula (VII). As illustrative examples, compounds of formula (VII) may be selected from lithium compounds, wherein M is Li; Grinard's compounds, wherein M is MgY, and Y is a halogen preferably selected from Cl, Br and I; zinc compounds, wherein M may be ZnY, and Y is a halogen preferably selected from Cl, Br and I; and cuprates, wherein M may be CuY, and Y is a halogen preferably selected from Cl, Br and I; see, for example, TA Betley et al., “The Strong-Field Tripodal Phosphine Donor, [PhB(CH2 i Pr2)3] -"Provides Access to Electronically and Coordinatively Unsaturated Transition Metal Complexes", *Inorganic Chemistry*, Vol. 42, No. 17, 2003, pp. 5074-5084, DOI: 10.1021 / ic0343096 (Lithium Compounds); AC Vetter et al., "Long sought synthesis of quaternaryphosphonium salts from phosphine oxides: inverse reactivity approach", *Chemical Communications*, 2018, Vol. 54, pp. 5843-5846, DOI: 10.1039 / c8cc02173b (Grinard's Compounds); F. Langer et al., "A New Efficient Preparation of Polyfunctional Phosphines Using Zinc Organometallics", *Tetrahedron Letters*, Vol. 36, No. 26, pp. 4591-4594, DOI: 10.1016 / 0040-4039(95)00813-r (zinc compounds); and BH Lipshutz et al., “Organocopper Reagents: Substitution, Conjugate Addition, Carbo / Metallocupration, and other Reations”, Organic Ractions, 1992, Vol. 41, edited by Leo A. Paquette et al., pp. 135-631, DOI: 10.1002 / 0471264180.or041.02 (copper compounds). In a preferred embodiment, group M is Li (lithium). More preferably, group M is MgY, wherein Y is a halogen; preferably Y is Cl, Br or I; more preferably, Y is Br.

[0061] Group R bonded to the nitrogen atom of, for example, a compound of formula (V), (I), or (I*) 6 It is H (hydrogen) or (C1-C8) alkyl. When R 6 When it is a (C1-C8) alkyl group, R 6Preferably, it is a (C1-C6) alkyl, more preferably a (C1-C4) alkyl, and even more preferably a (C1-C2) alkyl. In some preferred embodiments, R 6 It is H (hydrogen).

[0062] Group A is a spacer. In compounds of, for example, formula (V), formula (I), or formula (I*), the spacer serves to link a nitrogen atom to a carboxylic acid or protected carboxylic acid group, particularly to the carbonyl carbon atom of the carboxylic acid or protected carboxylic acid group. Spacer A can be any chemical group or part capable of linking a nitrogen atom to a carboxylic acid or ester group (particularly to the carbonyl carbon atom of the carboxylic acid or ester group). Spacer A can be any spacer known to those skilled in the art, such as a part based on a straight-chain or branched hydrocarbon. Spacer A can also contain a cyclic part, such as, but not limited to, an aromatic part. If spacer A is a hydrocarbon-based part, the main chain of spacer A can contain only carbon atoms, but may also contain heteroatoms such as oxygen (O), nitrogen (N), or sulfur (S) atoms, and / or may contain a carbonyl group (C=O). Spacer A can contain or can be, for example, (C1-C 20 A carbon atom chain. In a typical embodiment of the hydrocarbon-based spacer A, the spacer portion comprises between 1 and 150, 1 and 100, 1 and 75, 1 and 50, or 1 and 40, or 1 and 30, or 1 and 20 main chain atoms (including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19 main chain atoms). Those skilled in the art know the appropriate selection of spacer A.

[0063] In some embodiments, spacer A is selected from optionally substituted -(C6-C) 10 ) aryl-, optionally substituted-(C1-C 10 )alkylene-, optionally substituted (C3-C8) carbocyclic-, optionally substituted - (C1-C 10 )alkylene-(C6-C 10 ) aryl-, optionally substituted-(C6-C 10 ) aryl-(C1-C 10 )alkylene-, optionally substituted-(C1-C 10 )alkylene-(C3-C8)carbocyclic-, optionally substituted-(C3-C8)carbocyclic-(C1-C 10 )alkylene-, optionally substituted-(C3-C8)heterocyclic-, optionally substituted-(C1-C 10 )alkylene-(C3-C8)heterocyclic- and optionally substituted-(C3-C8)heterocyclic-(C1-C 10Alkylene-. Preferably, spacer A is selected from optionally substituted -(C6- ... 10 ) aryl-, optionally substituted-(C1-C 10 Alkylene- and optionally substituted (C3-C8) carbocyclic-. In a more preferred embodiment, spacer A is optionally substituted phenylene-.

[0064] The PG is a protecting group. Specifically, PG is a protecting group suitable for protecting the carboxylic acid moiety. For example, in embodiments of the invention, the carboxylic acid moiety can be protected in the form of a carboxylic acid ester. Suitable protecting groups for protecting the carboxylic acid moiety are known and readily selected by those skilled in the art. Illustrative examples that can be used in embodiments of the invention include optionally substituted (C1-C8) alkyl groups, such as (C1-C8) alkyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl, allyl, or benzyl. Preferably, PG is a (C1-C8) alkyl, more preferably (C1-C6) alkyl, and even more preferably (C1-C4) alkyl. PG can be methyl, ethyl, propyl, or butyl. In some preferred embodiments, PG is tert-butyl. By removing the protecting group PG, in other words, by deprotection, PG is replaced by hydrogen, thereby forming the carboxylic acid moiety (COOH). Suitable methods for introducing and removing the carboxylic acid protecting group are known to those skilled in the art. For example, acidic or basic conditions can be used to cleave the carboxylic acid ester to obtain the free carboxylic acid moiety.

[0065] Preferably, in any of the methods described herein, the compound of formula (V) is a compound of formula (Va): (Va), Wherein PG is as defined herein. Therefore, and more preferably, the compound of formula (I) is the compound of formula (Ia): (Ia), in X, V, R 1 And PG as defined in this article. It is worth noting that the expression " "As is common in the art, this indicates that the compound can exist as an ortho, meta, or para isomer. Therefore, the statement ' "Covered by compounds" , and The expression " "Covered by compounds" , and .

[0066] More preferably, in any of the methods described herein, the compound of formula (V) is a compound of formula (Vb): (Vb), Wherein PG is as defined herein. Therefore, and more preferably, the compound of formula (I) is the compound of formula (Ib): (Ib), in X, V, R 1 And PG as defined in this article.

[0067] R 1 It is an optional substituted aliphatic residue or an optional substituted aromatic residue.

[0068] In some implementation schemes, R 1 It can represent an optional substituted (C1-C8) alkyl group.

[0069] R 1 It can represent a (C1-C8) alkyl group optionally substituted with at least one of the following: F, Cl, Br, I, -NO2, -N((C1-C8)alkyl)H, -NH2, -N3, -N((C1-C8)alkyl)2, =O, (C3-C8)cycloalkyl, -SS-((C1-C8)alkyl), (C2-C8)alkenyl or (C2-C8)ynyl.

[0070] R 1 It can represent an optionally substituted phenyl group.

[0071] R 1 It can represent a phenyl group that is optionally and independently substituted with at least one of the following: (C1-C8)alkyl, F, Cl, I, Br, -NO2, -N((C1-C8)alkyl)H, -NH2 or -N((C1-C8)alkyl)2.

[0072] R 1 It can represent an optional substituted 5- or 6-membered heteroaromatic ring, such as pyridyl.

[0073] R 1 It can represent (C1-C8) alkyl, (C1-C8) alkyl substituted with -SS-(C1-C8) alkyl, (C1-C8) alkyl substituted with an optional substituted phenyl; or phenyl; or phenyl substituted with -NO2.

[0074] In some preferred embodiments, R 1 It is a (C1-C8) alkyl group. More preferably, R 1 It is methyl, ethyl, propyl, or butyl. More preferably, R 1 It is methyl or ethyl. Even more preferably, R 1 It is an ethyl group.

[0075] In a particularly preferred embodiment, R 1 It is a polyethylene glycol unit. In some implementations, R 1 It is a polyethylene glycol unit composed of 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and even more preferably 8 to 30 ethylene glycol subunits, each ethylene glycol subunit having the following structure: Throughout this specification, the structure... It is represented as "ethylene glycol subunit".

[0076] Preferably, R 1 It is a polyethylene glycol unit composed of 16 to 30, more preferably 20 to 28, even more preferably 22, 23, 24, 25 or 26, or even more preferably 23, 24 or 25 ethylene glycol subunits, each ethylene glycol subunit having the following structure: In a preferred embodiment, R 1 It is a polyethylene glycol unit containing 24 or about 24 ethylene glycol subunits, each of which has the following structure: It is also possible that R 1 It is a polyethylene glycol unit containing 12 or about 12 ethylene glycol subunits, each ethylene glycol subunit having the following structure: .

[0077] More preferably, R 1 It is a polyethylene glycol unit with the following structure: , in: Indicates the location of O attached to phosphorus; K F It is H (hydrogen) or a capping group as described herein; preferably K. F Selected from -H (hydrogen), protecting groups, -PO3H, -(C1-C 10 )alkyl, -(C1-C 10 )alkyl-SO3H, -(C2-C 10 )alkyl-CO2H, -(C2-C 10 )alkyl-OH, -(C2-C 10 )alkyl-NH2, -(C2-C 10 )alkyl-NH(C1-C3)alkyl and -(C2-C 10 )alkyl-N((C1-C3)alkyl)2; and o is an integer in the range of 1 to 100.

[0078] In some preferred embodiments, K F It is H (hydrogen).

[0079] In some preferred embodiments, K F It is a protecting group. Specifically, when K... F When it is a protecting group, K F This is a suitable protecting group for protecting hydroxyl groups. Suitable protecting groups for protecting hydroxyl groups are known and readily selected by those skilled in the art. Illustrative examples that can be used in embodiments of the invention include tert-butyl, triphenylmethyl, acetyl, and silyl protecting groups. Silyyl protecting groups can be selected from trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), and triisopropyl (TIPS). By removing the protecting group, in other words, by deprotection, K F The hydroxyl protecting group is replaced by hydrogen, thus forming a hydroxyl moiety (OH). Suitable methods for introducing and removing the hydroxyl protecting group are known to those skilled in the art. For example, acidic or basic conditions can be used to cleave ethers or esters to obtain the free hydroxyl moiety. Fluorides (e.g., tetra-n-butylammonium fluoride (TBAF)) can be used to remove the silyl protecting group to obtain the free hydroxyl moiety.

[0080] Integer 'o' represents a repeating unit in a polyethylene glycol cell. The quantity. The integer o can be in the range of 1 to 100. Preferably, o is in the range of 2 to 50. More preferably, o is in the range of 3 to 45. Even more preferably, o is in the range of 4 to 40. Even more preferably, o is in the range of 6 to 35. Even more preferably, o is in the range of 8 to 30. Even more preferably, o is in the range of 16 to 30. Even more preferably, o is in the range of 20 to 28. Even more preferably, o is 22, 23, 24, 25 or 26. Even more preferably, o is 23, 24 or 25. In even more preferred embodiments, o is 24 or about 24. In some preferred embodiments, o is in the range of 8 to 16. More preferably, o is 10, 11, 12, 13 or 14. Even more preferably, o is 11, 12 or 13. Even more preferably, o is 12 or about 12.

[0081] Typically, polydisperse polyethylene glycol (PEG), monodisperse PEG, and discrete PEG can be used in polyethylene glycol units. Polydisperse PEGs are heterogeneous mixtures of sizes and molecular weights, while monodisperse PEGs are typically purified from heterogeneous mixtures and thus provide a single chain length and molecular weight. Preferred PEG units are discrete PEGs, i.e., compounds synthesized in a stepwise manner rather than via polymerization. Discrete PEGs provide single molecules with defined and specified chain lengths.

[0082] The polyethylene glycol unit provided herein comprises one or more polyethylene glycol chains. The polyethylene glycol chains may be linked together, for example, in a linear, branched, or star configuration. Optionally, at least one of the polyethylene glycol chains may be derivatized at one end to covalently attach to an oxygen atom bonded to phosphorus.

[0083] The polyethylene glycol (PEG) unit will attach to the phosphorus-bonded oxygen atom. Another end (or multiple ends) of the PEG unit will be free and untethered, and may take the form of hydrogen, methoxy, carboxylic acid, alcohol, or other suitable functional groups, such as any end-capping group as described herein. The methoxy, carboxylic acid, alcohol, or other suitable functional group acts as a cap for the terminal PEG subunit of the PEG unit. Untethered means that the PEG unit will not attach to another portion at that untethered site. For embodiments in which the PEG unit comprises more than one PEG chain, the multiple PEG chains may be the same or different chemical portions (e.g., PEGs with different molecular weights or numbers of subunits). The multiple PEG chains attach to the phosphorus-bonded oxygen atom at a single attachment site. Those skilled in the art will understand that, in addition to containing repeating polyethylene glycol subunits, polyethylene glycol units may also contain non-polyethylene glycol materials (e.g., to promote coupling of multiple polyethylene glycol chains to each other or to oxygen atoms bonded to phosphorus). Non-polyethylene glycol materials refer to atoms in the polyethylene glycol unit that are not part of the repeating -CH2CH2O- subunit. In the embodiments provided herein, the polyethylene glycol unit may comprise two monomeric polyethylene glycol chains connected to each other via non-polyethylene glycol elements. In other embodiments provided herein, the polyethylene glycol unit may comprise two linear polyethylene glycol chains attached to a central core attached to an oxygen atom bonded to phosphorus (i.e., the polyethylene glycol unit is branched).

[0084] Those skilled in the art can utilize numerous polyethylene glycol (PEG) attachment methods [see, for example, EP 0 401 384 (PEG coupling to G-CSF); U.S. Patent No. 5,757,078 (PEGylation of EPO peptides); U.S. Patent No. 5,672,662 (Polyethylene glycol and related polymers monosubstituted with propionic or butyric acid and their functional derivatives for biotechnological applications); U.S. Patent No. 6,077,939 (PEGylation of the N-terminal α-carbon of peptides); and Veronese (2001) Biomaterials 22:405-417 (a review article on the PEGylation of peptides and proteins)].

[0085] In a preferred embodiment, the polyethylene glycol unit is directly attached to the oxygen atom bonded to phosphorus. In these embodiments, the polyethylene glycol unit does not contain functional groups for attachment to the oxygen atom bonded to phosphorus; that is, the oxygen atom is directly bonded to the carbon atom of the polyethylene glycol unit, preferably to the CH2 atom of the polyethylene glycol unit.

[0086] In one set of embodiments, the polyethylene glycol unit comprises at least one ethylene glycol subunit, preferably at least two ethylene glycol subunits, more preferably at least three ethylene glycol subunits, even more preferably at least four ethylene glycol subunits, even more preferably at least six ethylene glycol subunits, and even more preferably at least eight ethylene glycol subunits. In some such embodiments, the polyethylene glycol unit comprises no more than about 100 ethylene glycol subunits, preferably no more than about 50 ethylene glycol units, more preferably no more than about 45 ethylene glycol subunits, more preferably no more than about 40 ethylene glycol subunits, more preferably no more than about 35 ethylene glycol subunits, and even more preferably no more than about 30 ethylene glycol subunits.

[0087] In one set of embodiments, the polyethylene glycol unit comprises one or more linear polyethylene glycol chains, each linear polyethylene glycol chain having at least one ethylene glycol subunit, preferably at least two ethylene glycol subunits, more preferably at least three ethylene glycol subunits, even more preferably at least four ethylene glycol subunits, even more preferably at least six ethylene glycol subunits, and even more preferably at least eight ethylene glycol subunits. In a preferred embodiment, the polyethylene glycol unit comprises a total of at least one ethylene glycol subunit, preferably at least two ethylene glycol subunits, more preferably at least three, even more preferably at least four, even more preferably at least six, or even more preferably at least eight ethylene glycol subunits. In some such embodiments, the polyethylene glycol unit comprises a total of no more than about 100 ethylene glycol subunits, preferably no more than about 50 ethylene glycol subunits, more preferably no more than about 45 ethylene glycol subunits, even more preferably no more than about 40 ethylene glycol subunits, even more preferably no more than about 35 ethylene glycol subunits, and even more preferably no more than about 30 ethylene glycol subunits.

[0088] In another set of embodiments, the polyethylene glycol unit comprises a total of 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and still more preferably 8 to 30 ethylene glycol subunits. In any of these embodiments, the ethylene glycol subunit can be any ethylene glycol subunit as described herein.

[0089] In another set of embodiments, the polyethylene glycol unit comprises one or more linear polyethylene glycol chains having a total of 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and even more preferably 8 to 30 ethylene glycol subunits.

[0090] In another set of embodiments, the polyethylene glycol unit is a linear monopolyethylene glycol chain having at least one ethylene glycol subunit, preferably at least two ethylene glycol subunits, more preferably at least three ethylene glycol subunits, even more preferably at least six ethylene glycol subunits, and even more preferably at least eight ethylene glycol subunits. Optionally, in any of these embodiments, the linear monoalkylene glycol chain may be derivatized.

[0091] In another set of embodiments, the polyethylene glycol unit is a linear polyethylene glycol chain having 1 to 100, preferably 2 to 50, more preferably 3 to 45, more preferably 4 to 40, more preferably 6 to 35, and more preferably 8 to 30 glycol subunits. Optionally, in any of these embodiments, the linear polyethylene glycol chain can be derivatized.

[0092] In any of the implementations provided herein, it can be used as R 1 An example linear polyethylene glycol unit is as follows: The wavy line indicates the attachment site of the oxygen atom bonded to phosphorus. R 20 It is a PEG attachment unit; preferably, R 20 It does not exist; R 21 It is a PEG end-capping unit (in this paper, R) 21 Also represented as "K" F (”); R 22 It is a PEG coupling unit (i.e., used to couple multiple PEG subunit chains together); n is independently selected from 1 to 100, preferably 2 to 50, more preferably 3 to 45, more preferably 4 to 40, even more preferably 6 to 35, and even more preferably 8 to 30; e is between 2 and 5; Each n' is independently selected from 1 to 100, preferably 2 to 50, more preferably 3 to 45, more preferably 4 to 40, even more preferably 6 to 35, and even more preferably 8 to 30. In a preferred embodiment, at least 1, preferably at least 2, more preferably at least 3, more preferably at least 4, more preferably at least 6, and even more preferably at least 8 ethylene glycol subunits are present in the polyethylene glycol unit. In some embodiments, no more than 100, preferably no more than 50, more preferably no more than 45, more preferably no more than 40, more preferably no more than 35, and even more preferably no more than 30 ethylene glycol subunits are present in the polyethylene glycol unit. When R 20 When not present, the (CH2CH2O) subunit is directly bonded to the oxygen atom, which is attached to phosphorus.

[0093] Preferably, the linear polyethylene glycol unit is , The wavy line indicates the attachment site of the oxygen atom bonded to phosphorus; R 20 R 21 (Also referred to as "K" in this article) F ") and n as defined herein; more preferably R 20 It does not exist. In a preferred embodiment, n is 12 or about 12. In a preferred embodiment, n is 24 or about 24. Preferably, R 21 It is H or a protecting group.

[0094] Polyethylene glycol attachment unit R 20 When present, it is part of the polyethylene glycol (PEG) unit and serves to attach the PEG unit to the phosphorus-bonded oxygen atom. In this respect, the phosphorus-bonded oxygen atom forms a bond with the PEG unit. In an exemplary embodiment, the PEG attachment unit R... 20 When it exists, select from *-(C1-C) 10 )alkyl- # *-Aspartic- # 、*-(C1-C 10 )alkyl-O- # 、*-(C1-C 10 )alkyl-C(O)- # 、*-(C1-C 10 )alkyl-C(O)O- # 、*-(C1-C 10 )alkyl-NH- # 、*-(C1-C 10 )alkyl-S- # 、*-(C1-C 10 )alkyl-C(O)-NH- # 、*-(C1-C 10 )alkyl-NH-C(O)- # And *-CH2-CH2SO2-(C1-C 10 )alkyl- # ; where * represents the attachment point of oxygen bonded to phosphorus, and # represents the attachment point of ethylene glycol unit.

[0095] PEG coupling unit R 22 When present, it is part of a polyethylene glycol unit and serves as a non-PEG material that connects two or more repeating -CH2CH2O- subunit chains. In an exemplary embodiment, the PEG coupling unit R 22 When present, it is independently selected from *-(C1-C) 10)alkyl-C(O)-NH- # 、*-(C1-C 10 )alkyl-NH-C(O)- # 、*-(C2-C 10 )alkyl-NH- # 、*-(C2-C 10 )alkyl-O- # 、*-(C1-C 10 )alkyl-S- # 、or *-(C2-C 10 )alkyl-NH- # ; where * represents the attachment point to the oxygen atom of the ethylene glycol subunit, and # represents the attachment point to the carbon atom of another ethylene glycol subunit.

[0096] Group R 21 Also referred to as "K" in this article F ", in an exemplary embodiment, is H (hydrogen), or may be a capping group, as described herein; preferably, R 21 Independently selected from -H, protecting groups, -PO3H, -(C1-C 10 )alkyl, -(C1-C 10 )alkyl-SO3H, -(C2-C 10 )alkyl-CO2H, -(C2-C 10 )alkyl-OH, -(C2-C 10 )alkyl-NH2, -(C2-C 10 )alkyl-NH(C1-C3)alkyl and -(C2-C 10 )alkyl-N((C1-C3)alkyl)2. In some embodiments, R 21 It can be -(C1-C 10 )alkyl, especially methyl. More preferably, R 21 It is H or a protecting group. Even more preferably, R 21 It is H. In some preferred embodiments, R 21 It is a protecting group. When K F When it is a protecting group, the protecting group can be as described in this article.

[0097] In any of the implementations provided herein, it can be used as R 1 The illustrative linear polyethylene glycol unit is as follows: ; ; ;and ; The wavy lines indicate the attachment sites of oxygen atoms bonded to phosphorus; and each n is 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and even more preferably 8 to 30. In some embodiments, n is about 12. In some embodiments, n is about 24.

[0098] In some embodiments, the polyethylene glycol unit is about 300 Daltons to about 5,000 Daltons; about 300 Daltons to about 4,000 Daltons; about 300 Daltons to about 3,000 Daltons; about 300 Daltons to about 2,000 Daltons; or about 300 Daltons to about 1,000 Daltons. In some such aspects, the polyethylene glycol unit may have at least 6 ethylene glycol subunits or at least 8 ethylene glycol subunits. In some such aspects, the polyethylene glycol unit may have at least 6 ethylene glycol subunits or at least 8 ethylene glycol subunits, but not more than 100 ethylene glycol subunits, preferably not more than 50 ethylene glycol subunits. In some embodiments, the polyethylene glycol unit is about 300 Daltons to about 5,000 Daltons; about 300 Daltons to about 4,000 Daltons; about 300 Daltons to about 3,000 Daltons; about 300 Daltons to about 2,000 Daltons; or about 300 Daltons to about 1,000 Daltons. In some of these aspects, the polyethylene glycol unit may have at least 6 or at least 8 ethylene glycol subunits. In some aspects, the polyethylene glycol unit has at least 6 or at least 8 ethylene glycol subunits, but not more than 100 ethylene glycol subunits, preferably not more than 50 ethylene glycol subunits.

[0099] It should be understood that when referring to ethylene glycol subunits, the number of subunits may represent an average number depending on the context, for example, when referring to a group of conjugate or intermediate compounds and using polydisperse polyethylene glycol.

[0100] In some preferred embodiments of any of the methods described herein, the compound of formula (VIII) is a compound of formula (VIIIc): (VIIIc), The compounds of formula (VII) are the same as those of formula (VIIc): (VIIc), Compounds of formula (V) are compounds of formula (Vc): (Vc), The compounds of formula (III) are the same as those of formula (IIIc): (IIIc), and The compounds of formula (I) are the same as those of formula (Ic): (Ic). In any of these implementation schemes, K F And o as defined herein. Preferably, K F It is H. In some further preferred embodiments, K F It is a protecting group. Preferably, additionally or alternatively, the integer o is 24 or 12. More preferably, o is 24.

[0101] Preferably, as an advantage of the method described herein, compounds of formula (V) and / or formula (III) can be used in substantially equimolar amounts based on the amount of compound of formula (VIII) or compound of formula (VI). As used herein, the term "substantially equimolar amount" can generally refer to a molar ratio of 0.5:1.5 to 1.5:0.5.

[0102] In some preferred embodiments, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (V) is used in substantially equimolar amounts based on the amount of the compound of formula (VIII). Therefore, preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (V) is used in amounts from 0.5 to 1.5 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII). More preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (V) is used in amounts from 0.7 to 1.3 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII). More preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (V) is used in an amount of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII). Even more preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (V) 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). Even more preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (V) is used in an amount of about 1.0 molar equivalent of the compound of formula (VIII). In any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). Alternatively, in any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V).

[0103] In some preferred embodiments, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (V) is used in substantially equimolar amounts based on the amount of the compound of formula (VI). Therefore, preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (V) is used in amounts of 0.5 to 1.5 molar equivalents based on 1.0 molar equivalent of the compound of formula (VI). More preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (V) is used in amounts of 0.7 to 1.3 molar equivalents based on 1.0 molar equivalent of the compound of formula (VI). Even more preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (V) is used in amounts of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalent of the compound of formula (VI). More preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (V) is used in an amount of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI). Even more preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (V) is used in an amount of about 1.0 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI). In any of these embodiments, step (ii) may be reacting the compound of formula (VI) with the compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with the compound of formula (III). It is also possible that in any of these embodiments, step (ii) may be reacting the compound of formula (VI) with the compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with the compound of formula (V).

[0104] In some preferred embodiments, when a compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (III) is used in substantially equimolar amounts based on the amount of the compound of formula (VIII). Therefore, preferably, when a compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (III) is used in amounts from 0.5 to 1.5 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII). More preferably, when a compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (III) is used in amounts from 0.7 to 1.3 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII). More preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (III) is used in an amount of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalent of the compound of formula (VIII). Even more preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, 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). Even more preferably, when the compound of formula (VIII) is used as a starting material in step (i) of any of the methods described herein, the compound of formula (III) is used in an amount of about 1.0 molar equivalent of the compound of formula (VIII). In any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). It is also possible that in any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V). The inventors have found that the method described herein for preparing phosphonamide esters of formula (I) allows the use of alcohols of formula (III) in substantially equimolar amounts based on starting materials of formula (VIII), compared to the Staudinger pathway which requires at least two equivalents of alcohol to prepare phosphonamide esters. Therefore, as an advantage over the Staudinger pathway, the method of the present invention allows for a reduction in the amount of alcohol of formula (III) required to prepare compounds of formula (I). Therefore, the method of the present invention also allows for a reduction in the amount of waste, and / or a reduction in the additional effort required for re-separation, recycling and / or disposal of excess alcohol.In particular, when a precious alcohol is used as a compound of formula (III), it is advantageous to use substantially equimolar amounts of the alcohol. Precious alcohols that can be used in embodiments of the invention include, for example, polyethylene glycol, wherein R is used. 1 yes ,in K F and o as defined in this paper, for example, where K F H is an integer between 1 and 100.

[0105] In some preferred embodiments, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (III) is used in substantially equimolar amounts based on the amount of the compound of formula (VI). Therefore, preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (III) is used in amounts of 0.5 to 1.5 molar equivalents based on 1.0 molar equivalent of the compound of formula (VI). More preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (III) is used in amounts of 0.7 to 1.3 molar equivalents based on 1.0 molar equivalent of the compound of formula (VI). Even more preferably, when the compound of formula (VI) is used as a starting material in step (ii) of any of the methods described herein, the compound of formula (III) is used in amounts of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalent of the compound of formula (VI). More preferably, when the compound of formula (VI) is used as the starting material in step (ii) of any of the methods described herein, the compound of formula (III) is used in an amount of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI). Even more preferably, when the compound of formula (VI) is used as the starting material in step (ii) of any of the methods described herein, the compound of formula (III) is used in an amount of about 1.0 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI). In any of these embodiments, step (ii) may be reacting the compound of formula (VI) with the compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with the compound of formula (III). It is also possible that in any of these embodiments, step (ii) may be reacting the compound of formula (VI) with the compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with the compound of formula (V). Furthermore, it should be noted that the method described herein for preparing phosphonamide esters of formula (I) allows the use of alcohols of formula (III) in substantially equimolar amounts based on starting materials of formula (VI), compared to the Staudinger pathway which requires at least two equivalents of alcohol to prepare phosphonamide esters. Therefore, the amount of alcohol of formula (III) required to prepare compounds of formula (I) can be reduced, and thus the amount of waste and / or the additional effort required for re-separation, recycling, and / or disposal of excess alcohol can be reduced; again, particularly when precious alcohols are used as compounds of formula (III) (e.g., polyethylene glycol), the use of substantially equimolar amounts of alcohol is advantageous.

[0106] Preferably, steps (ii) and / or (iii) of any of the methods described herein are carried out in the presence of an activator. Such an activator is capable of promoting a substitution reaction at the phosphorus atom. Suitable activators are known and will be readily selected by those skilled in the art. In particular, activators used in the oligonucleotide synthesis using the phosphoramidite approach can be used in the methods described herein; see, for example, X. Wei, “Coupling activators for theoligonucleotide synthesis via phosphoramidite approach”, Tetrahedron, Vol. 69 (2013), pp. 3615-3637, DOI: 10.1016 / j.tet.2013.03.001. Suitable activators may include, for example, 1H-tetrazole, 5-ethylthio-1H-tetrazole (ETT), 5-benzylthio-1H-tetrazole (BTT), and 4,5-dicyanimidazole (DCI).

[0107] Preferably, in any of the methods described herein, step (ii) is carried out in the presence of an activator. More preferably, the activator is selected from 1H-tetrazole, 5-ethylthio-1H-tetrazole (ETT), 5-benzylthio-1H-tetrazole (BTT), and 4,5-dicyanimidazolium (DCI). Even more preferably, the activator is 1H-tetrazole. In any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). It is also possible that in any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V). In any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). Alternatively, in any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V).

[0108] Preferably, in any of the methods described herein, step (iii) is carried out in the presence of an activator. More preferably, the activator is selected from 1H-tetrazole, 5-ethylthio-1H-tetrazole (ETT), 5-benzylthio-1H-tetrazole (BTT), and 4,5-dicyanimidazolium (DCI). More preferably, the activator is 1H-tetrazole. In any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). It is also possible that in any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V). In any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). Alternatively, in any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V).

[0109] In step (iv) of any of the methods described herein, an oxidant is used to provide the compound of formula (I). Any oxidant capable of converting a phosphorus (III) compound into a phosphorus (V) compound can be used. Suitable oxidants are known and readily selected by those skilled in the art; see, for example, WO 2019 / 170710 A2. The oxidant may be selected from hydrogen peroxide, m-chloroperoxybenzoic acid (mCPBA), urea-hydrogen peroxide adduct, (camphorsulfonyl)oxazolidinyl propane (CSO), iodine, tert-butyl hydroperoxide (tBuOOH), and air. Preferably, the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid (mCPBA), and urea-hydrogen peroxide adduct. More preferably, the oxidant is hydrogen peroxide. See, for example, Example 4, where good results are demonstrated by using hydrogen peroxide, m-chloroperoxybenzoic acid (mCPBA), or urea-hydrogen peroxide adduct as the oxidant.

[0110] There are no particular limitations on the solvents used in the methods described herein. Solvents for carrying out the steps of the methods described herein (e.g., substitution and oxidation reactions at phosphorus, including the use of organometallic reagents) are known, and those skilled in the art know how to select suitable solvents. Step (i) of any of the methods described herein can be carried out in solvents selected from tetrahydrofuran (THF), diethyl ether, methyltetrahydrofuran, benzene, toluene, xylene, methyl tert-butyl ether (MTBE), diisopropyl ether, dioxane, and any combination thereof. These solvents are inert to organometallic reagents (e.g., Greenard's compounds or organolithium compounds). Preferably, step (i) is carried out in tetrahydrofuran (THF) or diethyl ether. More preferably, step (i) is carried out in tetrahydrofuran (THF). Step (ii) of any of the methods described herein can be carried out in solvents selected from acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, and any combination thereof. These solvents are polar aprotic solvents, which promote substitution reactions at the phosphorus atom, particularly nucleophilic substitution. One or more solvents used in step (i) may also be present in step (ii), for example, when the method is carried out as a one-pot process. Preferably, step (ii) is carried out in acetonitrile (optionally in combination with tetrahydrofuran and / or diethyl ether). Step (iii) of any of the methods described herein can be carried out in solvents selected from: acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, and any combination thereof. These solvents are polar aprotic solvents, which promote substitution reactions at the phosphorus atom, particularly nucleophilic substitution. One or more solvents used in step (i) and / or one or more solvents used in step (ii) may also be present in step (iii), for example, when the method is carried out as a one-pot process. Preferably, step (iii) is carried out in acetonitrile (optionally in combination with tetrahydrofuran and / or diethyl ether). Step (iv) of any of the methods described herein may be carried out in a solvent selected from: acetonitrile, acetone, water, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, and any combination thereof. One or more solvents used in step (i), one or more solvents used in step (ii), and / or one or more solvents used in step (iii) may also be present in step (iv), for example, when the method is carried out as a one-pot process. Preferably, step (iv) is carried out in acetonitrile (optionally in combination with tetrahydrofuran and / or diethyl ether, and optionally further in combination with water). In particular, water may be used when the oxidant is hydrogen peroxide.In any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). Alternatively, in any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V). In any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). Alternatively, in any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V).

[0111] The methods described herein can be carried out on a large scale; for example, compounds of formula (I) can be produced in several 100-gram batches (e.g., in 600-gram batches). Preferably, particularly for large-scale applications, in any of the methods described herein, step (i) is carried out in tetrahydrofuran (THF). Preferably, particularly for large-scale applications, in any of the methods described herein, step (ii) is carried out in a solvent selected from tetrahydrofuran (THF), acetonitrile, and combinations thereof. More preferably, particularly for large-scale applications, in any of the methods described herein, step (ii) is carried out in tetrahydrofuran (THF) (optionally in combination with acetonitrile). Preferably, particularly for large-scale applications, in any of the methods described herein, step (iii) is carried out in a solvent selected from tetrahydrofuran (THF), acetonitrile, and combinations thereof. More preferably, particularly for large-scale applications, in any of the methods described herein, step (iii) is carried out in tetrahydrofuran (THF) (optionally in combination with acetonitrile). Preferably, particularly for large-scale applications, in any of the methods described herein, step (iv) is carried out in a solvent selected from tetrahydrofuran (THF), acetonitrile, and combinations thereof. More preferably, particularly for large-scale applications, in any of the methods described herein, step (iv) is carried out in tetrahydrofuran (THF) (optionally in combination with acetonitrile and / or water). In any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). It is also possible that in any of these embodiments, step (ii) may be reacting the product obtained in step (i) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V). In any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (V), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (III). Alternatively, in any of these embodiments, step (ii) may be reacting a compound of formula (VI) with a compound of formula (III), and step (iii) may be reacting the product obtained in step (ii) with a compound of formula (V).

[0112] There are no particular limitations on the temperature at which the methods described herein are carried out. Those skilled in the art will know that one or more suitable temperatures are selected to perform the steps of the methods described herein. For example, in any of the methods described herein, step (i) using an organometallic reagent can be performed at a temperature of -80ºC to +60ºC. Specifically, in any of the methods described herein, step (i) can be performed at a temperature of -20ºC to +60ºC. Preferably, in any of the methods described herein, step (i) is performed at a temperature of -10ºC to +40ºC. More preferably, in any of the methods described herein, step (i) is performed at a temperature of -5ºC to +35ºC. (The last two sentences are repetitive and can be omitted.) In any of the methods described herein, step (ii) can be performed at a temperature of 0ºC to +60ºC. Preferably, in any of the methods described herein, step (ii) is performed at a temperature of +5ºC to +40ºC. More preferably, in any of the methods described herein, step (ii) is performed at a temperature of +10ºC to +35ºC. In any of the methods described herein, step (iii) can be performed at a temperature of 0ºC to +60ºC. Preferably, in any of the methods described herein, step (iii) is performed at a temperature of +5ºC to +40ºC. More preferably, in any of the methods described herein, step (iii) is performed at a temperature of +10ºC to +35ºC. In any of the methods described herein, step (iv) can be performed at a temperature of 0ºC to +60ºC. Preferably, in any of the methods described herein, step (iv) is performed at a temperature of +5ºC to +40ºC. More preferably, in any of the methods described herein, step (iv) is carried out at a temperature of +10ºC to +35ºC. A suitable reaction time is also readily selected or determined by those skilled in the art. Methods for monitoring the progress of one or more reactions (e.g., chromatography or spectroscopy) are known in the art.

[0113] Preferably, any method described herein for preparing a compound of formula (I) can be carried out as a one-pot process. In particular, any method described herein comprising steps (i) to (iv) for preparing a compound of formula (I) (wherein a compound of formula (VIII) is used as a starting material) can be carried out as a one-pot process. It is also possible to carry out as a one-pot process any method described herein comprising steps (ii) to (iv) for preparing a compound of formula (I), where a compound of formula (VI) is used as a starting material. As used herein, the term "one-pot process" generally refers to a method for preparing a compound of formula (I) in which all steps (i) to (iv), or depending on the appropriate method, are carried out without post-treatment, separation, and / or purification of intermediates. Thus, the term "one-pot process" includes, for example, adding reactants to a reaction mixture, adjusting different temperatures as needed, and / or also filtering the reaction mixture, provided that the reaction mixture does not undergo post-treatment, separation, and / or purification of intermediates between steps. In this regard, the term "one-pot process" also includes the removal and / or exchange of solvent, provided that the non-volatile intermediates, reactants, and / or impurities remain together in the reaction mixture, i.e., the mixture does not undergo post-treatment, separation, and / or purification of the intermediates between steps. Thus, during a one-pot process, the solvent can be removed, for example, by vacuum evaporation. It is also possible that another solvent can be added after solvent removal, provided that the reaction mixture does not undergo post-treatment, separation, and / or purification. In particular, when the solvent is removed and / or exchanged, the reaction mixture containing the intermediates, reactants, and / or impurities can remain in the reaction vessel. All steps (i) through (iv) can be carried out, for example, in the same reaction vessel. Step (v) may also be included in the one-pot process when, as described herein, any of the methods further includes step (v) to provide a compound of formula (I*). Thus, in some embodiments, any method as described herein that includes steps (i) through (v) for the preparation of a compound of formula (I*) (where a compound of formula (VIII) is used as a starting material) can be carried out as a one-pot process. In some embodiments, any method for preparing a compound of formula (I*) including steps (ii) to (v) as described herein (where a compound of formula (VI) is used as a starting material) may be carried out as a one-pot process. However, in contrast to a one-pot process, it is also possible to carry out any of the methods described herein, including steps (i) to (iv), or steps (ii) to (iv), or steps (i) to (v) or steps (ii) to (v) as a series of one or more separate stages, wherein the reaction mixture undergoes post-treatment, separation, and / or purification of one or more intermediates between at least two steps.

[0114] Preferably, in any of the methods described herein, particularly steps (i) to (iv), steps are carried out under an inert gas atmosphere. More preferably, in any of the methods described herein, particularly steps (i) to (iv), steps are carried out under nitrogen or argon. Using an inert gas atmosphere that keeps air and moisture away from one or more reaction mixtures can result in an increase in the yield, purity, and quality of the obtained product.

[0115] An important step in the method described herein is the oxidation in step (iv) to obtain the compound of formula (I). Therefore, the present invention also relates to a method for preparing a compound of formula (I) or a salt or solvation thereof, the method comprising: Make the compound of formula (II) or its salt or solvate: (II), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group Reaction with an oxidizing agent yields a compound of formula (I) or a salt or solvate thereof: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. Any variable (e.g., X, V, R 1 R 3 R Si R 4 R 5 R 6 (A, PG, and oxidizing agent) can be as defined herein. Regarding step (iv) of any of the methods described herein, the method can be further defined as described herein. Optionally, compounds of formula (II) can be prepared according to any method as described herein, including steps (i), (ii), and (iii). Optionally, compounds of formula (II) can also be prepared according to any method as described herein, including steps (ii) and (iii).

[0116] Preferably, the compound of formula (II) is the compound of formula (IIa): (IIa), in X, V, R 1 And PG as defined herein. Therefore, and more preferably, the compound of formula (I) is the compound of formula (Ia): (Ia), in X, V, R 1 And PG as defined in this article. It should be noted that the expression " "As is common in the art, this indicates that the compound can exist as an ortho, meta, or para isomer. Therefore, the statement ' "Covered by compounds" , and The expression " "This has already been explained above."

[0117] More preferably, in any of the methods described herein, the compound of formula (II) is a compound of formula (IIb): (IIb), in X, V, R 1 And PG as defined herein. Therefore, more preferably, compounds of formula (I) are compounds of formula (Ib): (Ib), in X, V, R 1 And PG as defined in this article.

[0118] In some preferred embodiments, the compound of formula (II) is the compound of formula (IIc): (IIc), and The compounds of formula (I) are the same as those of formula (Ic): (Ic). In any of these implementation schemes, K F And o as defined herein. Preferably, K F It is H. In some further preferred embodiments, K F It is a protecting group. Preferably, additionally or alternatively, the integer o is 24 or 12. More preferably, o is 24. Methods for preparing compounds of formula (I*)

[0119] In some embodiments, any method for preparing a compound of formula (I) described herein may further include step (v) of removing the protecting group PG to prepare a compound of formula (I*), comprising: (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R SiEach is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is the spacer. Any variable (e.g., X, V, R 1 R 3 R Si R 4 R 5 R 6 (A and PG) can be as defined herein. In any of these embodiments, step (v) can be as described herein. For example, step (v) can be further described below.

[0120] Optionally, compounds of formula (I) can be prepared according to any of the methods for preparing compounds of formula (I) described herein. The compound of formula (I) can then be used as a starting material for step (v). Therefore, in some embodiments, the invention also relates to a method for preparing compounds of formula (I*), the method comprising steps (i), (ii), (iii), (iv), and (v). In these embodiments, compounds of formula (VIII) are used as starting materials in step (i). In some embodiments, the invention also relates to a method for preparing compounds of formula (I*), the method comprising steps (ii), (iii), (iv), and (v). In these embodiments, compounds of formula (VI) are used as starting materials in step (ii). In any of these embodiments, steps (i), (ii), (iii), (iv), and / or (v) can be as described herein. In some preferred embodiments, the invention relates to a method for preparing compounds of formula (I*) or their salts or solvates, the method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is the spacer. In these implementations, any variable (e.g., R) 21 R 22 R 23 R24 , X, V, M, R 1 R 3 R Si R 4 R 5 R 6 (i), (ii), (iii), (iv), and / or (v) can be as defined herein. In these embodiments, steps (i), (ii), (iii), (iv), and / or (v) can be as described herein. For example, step (v) can be further described below.

[0121] However, removing the protecting group PG is itself an important reaction to provide a free carboxylic acid group in compound (I*), which can then be used for further reactions or functionalization. The inventors have also found that compounds of formula (I) exhibit excellent stability and are therefore well isolated and stored. Therefore, the present invention also relates to a method for preparing compounds of formula (I*) or their salts or solvates, said method comprising: (v) Removing the protecting group PG from the compound of formula (I): (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is the spacer. Any variable (e.g., X, V, R 1 R 3 R Si R 4 R 5 R 6 The protecting groups (A and PG) can be as defined herein. However, the method of removing the protecting group from a compound of formula (I) to obtain a compound of formula (I*) does not require the preparation of the compound of formula (I) using the method of the present invention. Although the method of the present invention allows for the advantageous preparation of compounds of formula (I), the method of removing the protecting group PG from a compound of formula (I) to obtain a compound of formula (I*) is not limited to any preparation including compounds of formula (I).

[0122] The PG is a protecting group. Specifically, PG is a protecting group suitable for protecting the carboxylic acid moiety. Suitable protecting groups for protecting the carboxylic acid moiety are known and readily selected by those skilled in the art. Illustrative examples that can be used in embodiments of the invention include optionally substituted (C1-C8) alkyl groups, such as (C1-C8) alkyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl, allyl, or benzyl. Preferably, PG is (C1-C8) alkyl, more preferably (C1-C6) alkyl, and even more preferably (C1-C4) alkyl. PG can be methyl, ethyl, propyl, or butyl. In some preferred embodiments, PG is tert-butyl. By removing the protecting group PG, in other words, by deprotection, PG is replaced by hydrogen, thereby forming the carboxylic acid moiety (COOH). Suitable methods for introducing and removing the carboxylic acid protecting group are known to those skilled in the art. For example, acidic or basic conditions can be used to cleave the carboxylic acid ester to obtain the free carboxylic acid moiety. In some preferred embodiments, the protecting group PG is tert-butyl, and PG is removed with an acid. More preferably, the protecting group is tert-butyl, and PG is removed with trifluoroacetic acid (TFA). When removing the tert-butyl protecting group with trifluoroacetic acid, the reaction can be carried out under pure conditions, i.e., without using any other solvent besides trifluoroacetic acid. Suitable reaction conditions can be readily determined by those skilled in the art. For example, the removal of the tert-butyl protecting group with trifluoroacetic acid (TFA) can be carried out at temperatures from -20ºC to +60ºC, preferably from -10ºC to +30ºC.

[0123] Preferably, the protecting group PG is removed under an inert gas atmosphere. More preferably, the protecting group is removed under nitrogen or argon. Using an inert gas atmosphere that keeps air and moisture away from the reaction mixture can lead to an increase in the yield, purity, and quality of the obtained product.

[0124] Preferably, the compound of formula (I) is the compound of formula (Ia): (Ia), in X, V, R 1 And PG as defined herein. Therefore, and more preferably, compounds of formula (I*) are compounds of formula (I*a): (I*a), in X, V, R 1 And PG as defined in this article. It should be noted that the expression " "As is common in the art, this indicates that the compound can exist as an ortho, meta, or para isomer. Therefore, the statement ' "Covered by compounds" , and The expression " "This has already been explained above."

[0125] More preferably, the compound of formula (I) is the compound of formula (Ib): (Ib), in X, V, R 1 And PG as defined herein. Therefore, and even more preferably, compounds of formula (I*) are compounds of formula (I*b): (I*b), in X, V, R 1 And PG as defined in this article.

[0126] In some preferred embodiments, the compound of formula (I) is the compound of formula (Ic): (Ic), and Compounds of formula (I*) are compounds of formula (I*c): (I*c). In any of these implementation schemes, K F And o as defined herein. Preferably, K F It is H. In some further preferred embodiments, K F It is a protecting group. Preferably, additionally or alternatively, the integer o is 24 or 12. More preferably, o is 24.

[0127] The present invention also relates to a compound of formula (I*) or a salt or solvate thereof: (I*), in X, V, R 1 R 6 And A as defined herein. Compounds of formula (I*) have been found to have excellent stability and are therefore well isolated and stored.

[0128] The present invention also relates to a compound of formula (I*) or a salt or solvate thereof: (I*), It can be obtained, or is being obtained, through any of the methods of this invention. in X, V, R 1 R 6 And A as defined in this article. Compound of formula (I)

[0129] The inventors have discovered that compounds of formula (I) possess excellent stability and are therefore well separated and stored. Therefore, the present invention also relates to a compound of formula (I) or a salt or solvation thereof: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. Any variable (e.g., X, V, R 1 R 3 R Si R 4 R 5 R 6 (A, PG) can be as defined herein. Optionally, compounds of formula (I) can be prepared according to any of the methods for preparing compounds of formula (I) described herein.

[0130] Preferably, the compound of formula (I) is the compound of formula (Ia): (Ia), in X, V, R1 And PG as defined in this article. The expression " "This has already been explained above."

[0131] More preferably, the compound of formula (I) is the compound of formula (Ib): (Ib), in X, V, R 1 And PG as defined in this article.

[0132] In some preferred embodiments, the compound of formula (I) is the compound of formula (Ic): (Ic). In any of these implementation schemes, K F And o as defined herein. Preferably, K F It is H. In some further preferred embodiments, K F It is a protecting group. Preferably, additionally or alternatively, the integer o is 24 or 12. More preferably, o is 24.

[0133] The present invention also relates to a compound of formula (I) or a salt or solvate thereof: (I), It can be obtained, or is being obtained, through any of the methods of this invention. in X, V, R 1 R 6 A and PG are as defined in this article. The project of this invention

[0134] The invention is further characterized by the following items: 1. A method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. 2. A method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. 3. A method for preparing a compound of formula (I), the method comprising: (ii) To make a compound of formula (VI) or a salt or solvate thereof: (VI), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (V) or their salts or solvates: (V), in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. 4. A method for preparing a compound of formula (I), the method comprising: (ii) To make a compound of formula (VI) or a salt or solvate thereof: (VI), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (III) or their salts or solvates: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V), in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R)Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. 5. The method according to any one of the foregoing items, wherein R 21 R 22 R 23 and R 24 Each is isopropyl. 6. The method according to any one of items 1 to 4, wherein R 21 R 22 R 23 and R 24 Each is a methyl group; or R is a methyl group. 21 R 22 R 23 and R 24 Each is an ethyl group. 7. The method according to any one of items 1, 2, 5 and 6, wherein the leaving group LG is selected from halogens (e.g., F, Cl, Br or I) and optionally substituted phenoxy groups; preferably wherein the leaving group LG is Cl. 8. The method according to any one of the foregoing items, wherein It is a triple bond; V does not exist; X is... And R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently (C1-C8) alkyl; preferably R 3 Is it H or -Si(R) Si )3, where R Si Each is independently (C1-C8) alkyl; more preferably R 3 It's H. 9. The method according to any one of items 1 to 7, wherein It is a double bond; V is H or (C1-C8) alkyl, preferably V is H; X is ;R 4 It is H or (C1-C8) alkyl, preferably R. 4 It is H and R 5 It is H or (C1-C8) alkyl, preferably R.5 It's H. 10. The method according to any one of the preceding items, wherein M is MgY, wherein Y is a halogen, preferably wherein Y is Br. 11. The method according to any one of items 1 to 9, wherein M is Li. 12. The method according to any one of the foregoing items, wherein R 6 It's H. 13. The method according to any one of the foregoing items, wherein the spacer A is selected from optionally substituted -(C6-C) 10 ) aryl-, optionally substituted-(C1-C 10 )alkylene-, optionally substituted (C3-C8) carbocyclic-, optionally substituted - (C1-C 10 )alkylene-(C6-C 10 ) aryl-, optionally substituted-(C6-C 10 ) aryl-(C1-C 10 )alkylene-, optionally substituted-(C1-C 10 )alkylene-(C3-C8)carbocyclic-, optionally substituted-(C3-C8)carbocyclic-(C1-C 10 )alkylene-, optionally substituted-(C3-C8)heterocyclic-, optionally substituted-(C1-C 10 )alkylene-(C3-C8)heterocyclic- and optionally substituted-(C3-C8)heterocyclic-(C1-C 10 )alkylene-; Preferably, the spacer A is selected from optionally substituted -(C6-C) 10 ) aryl-, optionally substituted-(C1-C 10 )alkylene- and optionally substituted -(C3-C8) carbocyclic-; More preferably, the spacer A is optionally substituted -phenylene-. 14. The method according to any one of the preceding items, wherein PG is optionally substituted (C1-C8) alkyl, preferably wherein PG is selected from (C1-C8) alkyl, 9-fluorenylmethyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl, allyl and benzyl, more preferably wherein PG is (C1-C8) alkyl, and even more preferably wherein PG is tert-butyl. 15. The method according to any one of the foregoing items, wherein the compound of formula (V) is And the compound of formula (I) is ,in X, V, R 1 And PG as defined in any of the aforementioned items. 16. The method according to any one of the foregoing items, wherein the compound of formula (V) is And the compound of formula (I) is ,in X, V, R 1 And PG as defined in any of the aforementioned items. 17. The method according to any one of the foregoing items, wherein R 1 It is (C1-C8) alkyl, preferably methyl, ethyl, propyl or butyl, more preferably methyl or ethyl, and even more preferably ethyl. 18. The method according to any one of items 1 to 16, wherein R 1 It is a polyethylene glycol unit. 19. The method of claim 18, wherein the polyethylene glycol unit comprises 1 to 100 subunits having the following structure: ; 20. The method described according to item 18 or 19, wherein R 1 yes: , in: Indicates the position of O; K F Selected from -H, protecting groups, -PO3H, -(C1-C 10 )alkyl, -(C1-C 10 )alkyl-SO3H, -(C2-C 10 )alkyl-CO2H, -(C2-C 10 )alkyl-OH, -(C2-C 10 )alkyl-NH2, -(C2-C 10 )alkyl-NH(C1-C3)alkyl and -(C2-C 10 )alkyl-N((C1-C3)alkyl)2; and o is an integer in the range of 1 to 100. 21. According to the method described in Project 20, where K F It's H. 22. According to the method described in Project 20, where K F It is a protecting group, preferably wherein K F Selected from tert-butyl, triphenylmethyl, acetyl and silyl protecting groups (e.g. trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl (TIPS)). 23. The method according to any one of items 20 to 22, wherein o is in the range of 8 to 30. 24. The method described in Item 23, wherein o is in the range of 20 to 28. 25. The method described according to item 24, where o is 22, 23, 24, 25 or 26. 26. The method described in Item 23, wherein o is in the range of 8 to 16. 27. The method described in Item 26, wherein o is 10, 11, 12, 13 or 14. 28. The method according to any one of the foregoing items, wherein the compound of formula (VIII) is The compound of formula (VII) is The compound of formula (V) is The compound of formula (III) is And the compound of formula (I) is K F and o as defined in any of the aforementioned items; preferably, where K F It is H; and / or preferably, o is 24 or 12. 29. The method according to any one of items 1, 2, and 5 to 28, wherein the compound of formula (V) is used in substantially equimolar amounts based on the amount of the compound of formula (VIII); preferably, wherein the compound of formula (V) is used in amounts of 0.5 to 1.5 molar equivalents based on 1.0 molar equivalents of the compound of formula (VIII); more preferably, wherein the compound of formula (V) is used in amounts of 0.7 to 1.3 molar equivalents based on 1.0 molar equivalents of the compound of formula (VIII); even more preferably, wherein the compound of formula (V) is used in amounts of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalents of the compound of formula (VIII); even more preferably, wherein the compound of formula (V) is used in amounts of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound of formula (VIII); and even more preferably, wherein the compound of formula (V) is used in amounts of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound of formula (VIII). The compound of formula (V) is used in an amount of about 1.0 molar equivalent. 30. The method according to any one of items 3 to 27, wherein the compound of formula (V) is used in substantially equimolar amounts based on the amount of the compound of formula (VI); preferably, the compound of formula (V) is used in amounts of 0.5 to 1.5 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); more preferably, the compound of formula (V) is used in amounts of 0.7 to 1.3 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); even more preferably, the compound of formula (V) is used in amounts of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); even more preferably, the compound of formula (V) is used in amounts of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); and even more preferably, the compound of formula (V) is used in amounts of about 1.0 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI). 31. The method according to any one of items 1, 2, and 5 to 29, wherein the compound of formula (VIII) is used in substantially equimolar amounts based on the amount of the compound; preferably, wherein the compound of formula (VIII) is used in amounts of 0.5 to 1.5 molar equivalents based on 1.0 molar equivalents of the compound; more preferably, wherein the compound of formula (VIII) is used in amounts of 0.7 to 1.3 molar equivalents based on 1.0 molar equivalents of the compound; even more preferably, wherein the compound of formula (VIII) is used in amounts of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalents of the compound; even more preferably, wherein the compound of formula (VIII) is used in amounts of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound; and even more preferably, wherein the compound of formula (VIII) is used in amounts of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound. The compound of formula (III) is used in an amount of about 1.0 molar equivalent. 32. The method according to any one of items 3 to 27 and 30, wherein the compound of formula (III) is used in substantially equimolar amounts based on the amount of the compound of formula (VI); preferably, the compound of formula (III) is used in amounts of 0.5 to 1.5 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); more preferably, the compound of formula (III) is used in amounts of 0.7 to 1.3 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); even more preferably, the compound of formula (III) is used in amounts of 0.8 to 1.2 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); even more preferably, the compound of formula (III) is used in amounts of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI); and even more preferably, the compound of formula (III) is used in amounts of 0.9 to 1.1 molar equivalents based on 1.0 molar equivalents of the compound of formula (VI). The compound of formula (III) is used in an amount of about 1.0 molar equivalent. 33. The method according to any one of the preceding items, wherein step (ii) is carried out in the presence of an activator, preferably wherein the activator is selected from 1H-tetrazole, 5-ethylthio-1H-tetrazole (ETT), 5-benzylthio-1H-tetrazole (BTT) and 4,5-dicyanimidazolium (DCI), more preferably wherein the activator is 1H-tetrazole. 34. The method according to any one of the preceding items, wherein step (iii) is carried out in the presence of an activator, preferably wherein the activator is selected from 1H-tetrazole, 5-ethylthio-1H-tetrazole (ETT), 5-benzylthio-1H-tetrazole (BTT) and 4,5-dicyanimidazolium (DCI), more preferably wherein the activator is 1H-tetrazole. 35. The method according to any one of the preceding items, wherein the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid (mCPBA), urea-hydrogen peroxide adduct, (camphorsulfonyl)oxazolidinyl propane (CSO), iodine, tert-butyl hydrogen peroxide (tBuOOH) and air; preferably wherein the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid (mCPBA) and urea-hydrogen peroxide adduct; more preferably wherein the oxidant is hydrogen peroxide. 36. The method according to any one of the foregoing items, wherein: (a) Step (i) is carried out in a solvent selected from tetrahydrofuran, diethyl ether, methyltetrahydrofuran, benzene, toluene, xylene, methyl tert-butyl ether (MTBE), diisopropyl ether, dioxane, and any combination thereof; preferably wherein step (i) is carried out in tetrahydrofuran; and / or (b) Step (ii) is carried out in a solvent selected from: acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, and any combination thereof; preferably, step (ii) is carried out in acetonitrile (optionally in combination with tetrahydrofuran and / or diethyl ether); and / or (c) Step (iii) is carried out in a solvent selected from: acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, and any combination thereof; preferably, step (iii) is carried out in acetonitrile (optionally in combination with tetrahydrofuran and / or diethyl ether); and / or (d) Step (iv) is carried out in a solvent selected from the following: acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, and any combination thereof; preferably, step (iv) is carried out in acetonitrile (optionally in combination with tetrahydrofuran and / or diethyl ether, and optionally further in combination with water). 37. The method according to any one of items 1 to 35, wherein: (a) Step (i) is carried out in tetrahydrofuran; and / or (b) Step (ii) is carried out in a solvent selected from tetrahydrofuran, acetonitrile, and combinations thereof; preferably, step (ii) is carried out in tetrahydrofuran (optionally in combination with acetonitrile); and / or (c) Step (iii) is carried out in a solvent selected from tetrahydrofuran, acetonitrile, and combinations thereof; preferably, step (iii) is carried out in tetrahydrofuran (optionally in combination with acetonitrile); and / or (d) Step (iv) is carried out in a solvent selected from tetrahydrofuran, acetonitrile, and combinations thereof; preferably, step (iv) is carried out in tetrahydrofuran (optionally in combination with acetonitrile and / or water). 38. The method according to any one of the preceding items, wherein: (a) Step (i) is carried out at a temperature of -20ºC to +60ºC, preferably -10ºC to +40ºC, more preferably -5ºC to +35ºC; and / or (b) Step (ii) is carried out at a temperature of 0ºC to +60ºC, preferably +5ºC to +40ºC, more preferably +10ºC to +35ºC; and / or (c) Step (iii) is carried out at a temperature of 0ºC to +60ºC, preferably +5ºC to +40ºC, more preferably +10ºC to +35ºC; and / or (d) Step (iv) is carried out at a temperature of 0ºC to +60ºC, preferably +5ºC to +40ºC, more preferably +10ºC to +35ºC. 39. The method according to any one of the preceding items, wherein steps (i) to (iv) are performed as a one-pot process. 40. The method according to any one of the preceding items, wherein steps (i) to (iv) are carried out in an inert gas atmosphere, particularly in nitrogen or argon. 41. A method for preparing a compound of formula (I) according to any one of the preceding items, said method comprising: Make the compound of formula (II) or its salt or solvate: (II), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group Reaction with an oxidizing agent yields a compound of formula (I) or a salt or solvate thereof: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. 42. According to the method described in item 41, wherein X, V, R 1 R 3 R Si R 4 R 5 R 6 A, PG and the oxidizing agent are as defined in any of the foregoing items. 43. The method according to item 41 or 42, wherein the compound of formula (II) is And the compound of formula (I) is ,in X, V, R 1 And PG as defined in any of the aforementioned items. 44. The method according to any one of items 41 to 43, wherein the compound of formula (II) is And the compound of formula (I) is ,in X, V, R 1 And PG as defined in any of the aforementioned items. 45. The method according to any one of items 41 to 44, wherein the compound of formula (II) is And the compound of formula (I) is K F and o as defined in any of the aforementioned items; preferably, where K F It is H; and / or preferably, o is 24 or 12. 45a. The method according to any one of the foregoing items, the method further comprising: (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is a spacer. 45b. A method for preparing a compound of formula (I*) or a salt or solvation thereof, said method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof: (V); in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is a spacer. 46. ​​A method for preparing a compound of formula (I*) according to any one of the preceding items, said method comprising: (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is a spacer. 47. The method according to any one of items 45a to 46, wherein X, V, R 1R 3 R Si R 4 R 5 R 6 A and PG are as defined in any of the aforementioned items. 48. The method according to any one of items 45a to 47, wherein the protecting group PG is tert-butyl, and PG is removed with an acid, preferably trifluoroacetic acid. 49. The method according to any one of items 45a to 48, wherein the protecting group PG is removed under an inert gas atmosphere, particularly under nitrogen or argon. 50. The method according to any one of items 45a to 49, wherein the compound of formula (I) is And the compound of formula (I*) is ,in X, V, R 1 And PG as defined in any of the aforementioned items. 51. The method according to any one of items 45a to 50, wherein the compound of formula (I) is And the compound of formula (I*) is ,in X, V, R 1 And PG as defined in any of the aforementioned items. 52. The method according to any one of items 45a to 51, wherein the compound of formula (I) is And the compound of formula (I*) is K F and o as defined in any of the aforementioned items; preferably, where K F It is H; and / or preferably, o is 24 or 12. 52a. A compound of formula (I*) or a salt or solvate thereof: (I*), in X, V, R 1 R 6 And A is as defined in any of the aforementioned items. 52b. A compound of formula (I*) or a salt or solvate thereof: (I*), It can be obtained, or is being obtained, by the method according to any one of the foregoing items. in X, V, R 1 R 6And A is as defined in any of the aforementioned items. 53. A compound of formula (I) or a salt or solvate thereof: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. 54. The compound according to item 53, wherein X, V, R 1 R 3 R Si R 4 R 5 R 6 A and PG are as defined in any of the aforementioned items. 55. The compound according to item 53 or 54, wherein the compound of formula (I) is: , Among them, X, V, R 1 And PG as defined in any of the aforementioned items. 56. The compound according to any one of items 53 to 55, wherein the compound of formula (I) is: , Among them, X, V, R 1 And PG as defined in any of the aforementioned items. 57. The compound according to any one of items 53 to 56, wherein the compound of formula (I) is: , K F and o as defined in any of the aforementioned items; preferably, where K F It is H; and / or preferably, o is 24 or 12. 58. A compound of formula (I) or a salt or solvate thereof: (I), It can be obtained, or is being obtained, by any one of the methods according to items 1 to 45. in X, V, R 1 R 6 A and PG are as defined in any of the aforementioned items. * * *

[0135] It should be noted that, as used herein, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly specifies otherwise. Thus, for example, reference to “a reagent” includes one or more such different reagents, and reference to “the method” includes reference to equivalent steps and methods known to those skilled in the art, which may be modified or substituted for the methods described herein.

[0136] Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to each element in the series. Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the invention described herein using only conventional experimentation. Such equivalents are intended to be covered by this invention.

[0137] The term “and / or” as used anywhere in this document includes the meaning of “and,” “or,” and “all or any other combination of elements connected by the term.”

[0138] The terms “less than” or, consequently, “more than” do not include specific numbers. For example, “less than 20” means less than the indicated number. Similarly, “more than” or “greater than” means more than or greater than the indicated number; for example, “more than 80%” means more than or greater than 80% of the indicated number.

[0139] Throughout this specification and the claims therein, unless the context otherwise requires, the word “comprise” and its variations such as “comprises” or “comprising” shall be understood to imply the inclusion of one or more stated wholes or steps, or groups of wholes or steps, but not excluding any other wholes or steps or groups of wholes or steps. When used herein, the term “comprise” may be replaced by the terms “containing” or “including”, or sometimes by the term “having”. When used herein, “consisting of” does not include any unspecified elements, steps, or components.

[0140] The term "including" means "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0141] As used herein, the terms “about,” “approximately,” or “substantially” mean within 20%, preferably within 15%, more preferably within 10%, and more preferably within 5% of a given value or range. It also includes specific figures, such as “about 20” including the number 20.

[0142] It should be understood that the present invention is not limited to the specific methods, schemes, materials, reagents, and substances described herein, and therefore can be varied. The terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the invention, which is defined only by the claims.

[0143] All publications (including all patents, patent applications, scientific publications, specifications, etc.) cited throughout this specification, whether above or below, are hereby incorporated in their entirety by reference. Nothing in this document should be construed as an admission that the invention is not entitled to any earlier disclosure due to prior invention. In the event that any material incorporated by reference contradicts or is inconsistent with this specification, this specification supersedes any such material.

[0144] All references and patent documents cited in this article are incorporated herein by reference in their entirety. Example

[0145] The invention and its advantages will be even better understood from the following examples, which are provided for illustrative purposes only. The examples are not intended to limit the scope of the invention in any way. Example 1: General method for synthesizing phosphonamide esters via substitution / oxidation pathway

[0146] 100 mg (1.0 equivalent, 0.38 mmol) of bis(diisopropylaminochlorophosphine) was charged into a 25 ml Schlenk tube equipped with a stir bar under a nitrogen atmosphere and cooled to 0ºC with wet ice. 0.9 ml of a solution of acetylenyl magnesium bromide in THF (0.5 M, 1.2 equivalent, 0.45 mmol) was slowly added. After 5 minutes, the cooling bath was removed, and the solution was allowed to stir at rt (rt = room temperature) for 30 minutes. 73 mg of tert-butyl 4-aminobenzoate (1.0 equivalent, 0.38 mmol) was dissolved in 1.0 ml of a solution of 1H-tetrazole in acetonitrile (0.45 M, 1.2 equivalent) and slowly added to the reaction mixture, while stirring at room temperature for 30 minutes. The desired alcohol (1.0 equivalent, 0.38 mmol) was dissolved in 1.0 mL of a solution of 1H-tetrazole in acetonitrile (0.45 M, 1.2 equivalent), and slowly added to the reaction mixture while stirring at room temperature for 30 minutes. A solution of hydrogen peroxide in water (0.2 mL, 30%) was added to the reaction mixture and stirred for five minutes. All volatiles were removed under reduced pressure, and the resulting solid was dissolved in 2 mL of trifluoroacetic acid (TFA) while stirring for 30 minutes. The TFA was removed under a nitrogen stream, and the product was purified by preparative HPLC.

[0147] Preparative HPLC was performed using a VP 250 / 21 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) on a BÜCHI Pure C-850 Flash-Prep system (BÜCHI Labortechnik AG, Switzerland) with the following gradients: Method D: A = H2O + 0.1% TFA (trifluoroacetic acid), B = MeCN (acetonitrile) + 0.1% TFA, flow rate 14 ml / min, 30% B 0-5 min, 30%-70% B 5-35 min, 99% B 35-45 min. Example 2: Synthesis of P5(PEG24)-COOH

[0148] The title compound was synthesized from 50 mg of bis(diisopropylamino)chlorophosphine (187 µmol, 1.00 equivalent), 450 µL of acetylenyl magnesium bromide solution (0.5 M in THF, 225 µmol, 1.20 equivalent), 36 mg of tert-butyl 4-aminobenzoate (187 µmol, 1.00 equivalent), 2 x 500 µL of 1H-tetrazole solution in acetonitrile (0.45 M, 1.2 equivalent), and 201 mg of HO-PEG24-OH (187 µmol, 1.0 equivalent) according to the general method of Example 1. The product was obtained as a colorless oil after preparative HPLC and lyophilization (53.4 mg, 40 µmol, 21%). [The last sentence appears to be incomplete and possibly refers to a specific concentration or value, but without further context, it's unclear what the intended meaning is.] 57 H 106 NO 28 P 2+ HR-MS: [M+2H] 2+ Calculated value: 641.8314, measured value: 641.84318.

[0149] Figure 1 The HPLC chromatogram of compound P5(PEG24)-COOH synthesized according to Example 2 is shown. Example 3: Synthesis of P5(PEG12)-COOH

[0150] The title compound was synthesized from 100 mg bis(diisopropylamino)chlorophosphine (376 µmol, 1.00 equivalent), 900 µL of acetylenyl magnesium bromide solution (0.5 M in THF, 450 µmol, 1.20 equivalent), 72.5 mg tert-butyl 4-aminobenzoate (376 µmol, 1.00 equivalent), 2 x 1 mL of 1H-tetrazole solution in acetonitrile (0.45 M, 450 µmol, 1.20 equivalent), and 189 mg HO-PEG12-OH (376 µmol, 1.0 equivalent) according to the general method of Example 1. The product was obtained as a colorless oil after preparative HPLC and lyophilization (71.93 mg, 95.4 µmol, 25.4%). For C 33 H 57 NO 16 P + HR-MS: [M+H] + Calculated value: 754.3410, measured value: 754.3398.

[0151] Figure 2 The HPLC chromatogram of compound P5(PEG12)-COOH synthesized according to Example 3 is shown. Comparative Example A: Synthesis of P5(PEG12)-COOH via the Staudinger pathway

[0152] 40 mg of bis(diisopropylamino)chlorophosphine (150 µmol, 1.00 equivalent) was added to a 25-mL Schlenk flask under an argon atmosphere, cooled to 0ºC, and 0.36 mL of ethynyl magnesium bromide solution (0.5 M in THF, 180 µmol, 1.2 equivalent) was added dropwise. The yellowish solution was allowed to warm to room temperature and stirred for another 30 minutes. 245 mg of HO-PEG12-OH (450 µmol, 3.0 equivalent) dissolved in 0.83 mL of 1H-tetrazole solution (0.45 M in MeCN, 375 µmol, 2.50 equivalent) was added, and the white suspension was stirred overnight at room temperature. 39 mg of 4-azidobenzoic acid (150 µmol, 1.00 equivalent) dissolved in 0.5 mL of DMF was added, and the suspension was stirred further at room temperature for 24 h. As described in 2.1, the crude reaction mixture was purified using preparative HPLC. After lyophilization, a colorless oily product was obtained (25 mg, 34 µmol, 23%). For C 33 H 57 NO 16 P + HR-MS: [M+H] + Calculated value: 754.3410, measured value: 754.3398.

[0153] Figure 3 The HPLC chromatogram of compound P5(PEG12)-COOH, synthesized via the Staudinger pathway according to Comparative Example A, is shown. explain:

[0154] A comparison of the preparation of P5(PEG12)-COOH according to Example 3 (which was carried out according to the invention) with the preparation of P5(PEG12)-COOH according to Comparative Example A (which was carried out according to the Staudinger pathway) shows that the yield was improved by using the method according to the invention. Example 4: Synthesis of P5(PEG24)-COOH

[0155] 50 mg of bis(diisopropylamino)chlorophosphine (0.188 mmol, 1.00 equivalent) was added to a 25-mL Schlenk flask under an argon atmosphere, cooled to 0ºC, and 420 µl of acetylenyl magnesium bromide solution (0.5 M in THF, 0.207 mmol, 1.10 equivalent) was added dropwise. The yellowish solution was allowed to warm to room temperature and stirred for another 30 minutes. 40 mg of tert-butyl 4-aminobenzoate (1.1 equivalent, 0.207 mmol) was dissolved in 625 µl of 1H-tetrazole in acetonitrile (0.45 M in MeCN, 0.282 mmol, 1.5 equivalent), and slowly added to the reaction mixture while stirring at room temperature for 30 minutes. 202 mg of HO-PEG24-OH (0.188 mmol, 1.0 equivalent) dissolved in 625 µl of 1H-tetrazole solution (0.45 M in MeCN, 0.282 mmol, 1.5 equivalent) was added to the reaction mixture and stirred at room temperature for 30 min. A solution of hydrogen peroxide in water (0.2 mL, 30%) was added to the reaction mixture and stirred for 5 min. All volatiles were removed under reduced pressure, and the resulting solid was dissolved in 2 mL of TFA and stirred for 30 min. The TFA was removed under a nitrogen stream, and the crude reaction mixture was purified by preparative HPLC, yielding 72.0 mg (0.0561 mmol, 29.8%) of the desired compound as a colorless oil after lyophilization. Comparative Example B: Synthesis of P5(PEG24)-COOH via the Staudinger pathway

[0156] 50 mg of bis(diisopropylamino)chlorophosphine (0.188 mmol, 1.00 equivalent) was added to a 25-mL Schlenk flask under an argon atmosphere, cooled to 0ºC, and 420 µL of ethynyl magnesium bromide solution (0.5 M in THF, 0.207 mmol, 1.10 equivalent) was added dropwise. The yellow solution was allowed to warm to room temperature and stirred for another 30 minutes. 606 mg of HO-PEG24-OH (0.564 mmol, 3.0 equivalent) was dissolved in 1.25 mL of 1H-tetrazole solution (0.45 M in MeCN, 0.564 mmol, 3.0 equivalent). 33 mg of 4-azidobenzoic acid (0.188 mmol, 1.00 equivalent) was dissolved in THF and added to the reaction mixture, and the yellow suspension was further stirred at room temperature for 24 h. The crude reaction mixture was purified by preparative HPLC and lyophilized to obtain 36.6 mg (0.0285 mmol, 15.1%) of the desired compound as a colorless oil. explain:

[0157] A head-to-head comparison of the preparation of P5(PEG24)-COOH (conducted according to the invention) in Example 4 with the preparation of P5(PEG24)-COOH (conducted according to the Staudinger pathway) in Comparative Example B (where both preparations begin with the same amount of bis(diisopropylamino)chlorophosphine) clearly demonstrates the advantages of the novel phosphonamide ester synthesis described herein, as a significant increase in yield from 15.1% to 29.8% can be achieved. Example 5: Use of different oxidants

[0158] 100 mg (1.0 equivalent, 0.38 mmol) of bis(diisopropylaminochlorophosphine) was charged into a 25 ml Schlenk tube equipped with a stir bar under a nitrogen atmosphere and cooled to 0ºC with wet ice. 0.9 ml of a solution of ethynylmagnesium bromide in THF (0.5 M, 1.2 equivalent, 0.45 mmol) was slowly added. After 5 minutes, the cooling bath was removed, and the solution was allowed to stir at room temperature for 30 minutes. 80 mg of tert-butyl 4-aminobenzoate (1.1 equivalent, 0.42 mmol) was dissolved in 1.25 ml of a solution of 1H-tetrazole in acetonitrile (0.45 M, 0.57 mmol, 1.5 equivalent) and slowly added to the reaction mixture, while stirring at room temperature for 30 minutes. 458 mg of HO-PEG24-OH (1.1 equivalent, 0.42 mmol) was dissolved in 1.25 ml of a solution of 1H-tetrazole in acetonitrile (0.45 M, 0.57 mmol, 1.5 equivalent), and slowly added to the reaction mixture while stirring at room temperature for 30 minutes.

[0159] As described above, the three reactions were carried out in parallel and processed in the following manner: A) Add 0.2 ml of 30% hydrogen peroxide aqueous solution (CAS: 7722-84-1) B) A solution containing 80 mg mCPBA (CAS: 937-14-4) in THF. C) A solution of 80 mg urea-hydrogen peroxide (CAS: 124-43-6) adduct in DMF. All three reaction mixtures were stirred for 30 minutes. All volatiles were removed under reduced pressure, and the product was purified by preparative HPLC.

[0160] Preparative HPLC was performed using a VP 250 / 21 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) on a BÜCHI Pure C-850 Flash-Prep system (BÜCHI Labortechnik AG, Switzerland) with the following gradients: Method D: A = H₂O + 0.1% TFA (trifluoroacetic acid), B = MeCN (acetonitrile) + 0.1% TFA, flow rate 14 ml / min, 30% B 0-5 min, 30%-70% B 5-35 min, 99% B 35-45 min. The following yields were achieved after lyophilization: A)50.76 mg, 0.037946 mmol, 30.2% B)31.86 mg, 0.023803 mmol, 19.0% C)54.24 mg, 0.040547 mmol, 32.4% Example 6: Large-scale synthesis of P5(PEG24)-COOtBu

[0161] The first four steps (IA-ID) can be performed in a one-pot process. The largest scale evaluated to date is 450 g of chlorophosphine 2, with a yield of 53% after rapid column purification on silica (1200 g of P5(PEG24)-COOtBu). Purity: >80% (HPLC). The procedure is described in the table below. For C 61 H 114 NO 28 P 2+ MS analysis: [M+2H] 2+ Calculated value: 669.9, measured value: 670.5. Characterization methods

[0162] LC / UV-MS analysis was performed on an Agilent 1260 / 6125MS system (using a Waters XBridge C18 column, 4.6 × 150 mm, 3.5 μm, eluting at 1.0 ml / min). The following gradients were used: A: 0.03% TFA in H₂O solution; B: 0.03% TFA in MeCN solution. The gradients were: 20%–30% B 0–5 min, 30%–40% B 5–10 min, 40%–45% B 10–20 min, 45%–95% B 20–25 min, 95% B 25–30 min, 95%–20% B 30–31 min, 20% B 31–35 min. UV wavelength: 264 nm. MS parameters: Ion source: ESI, Mode: Scan, Polarity: Positive, Fragmentor voltage: 135V, Dry gas flow rate: 12.0 L / min, Nebulizer pressure: 50 psig, Dry gas temperature: 350ºC, Capillary voltage: 4000 V Figure 4 The chromatogram of P5(PEG24)-COOtBu obtained by HPLC / UV analysis is shown. P5(PEG24)-COOtBu was synthesized according to Example 6. Figure 5 The mass spectrum of P5(PEG24)-COOtBu synthesized according to Example 6 is shown. Example 7: Large-scale synthesis of P5(PEG24)-COOH

[0163] The tert-butyl group was deprotected by treatment with trifluoroacetic acid (TFA) at 0ºC for 0.5 h. The reaction was then terminated by dilution with acetonitrile / water (ACN / H2O) and storage at a reduced temperature. Termination of the reaction was crucial to avoid at least partial decomposition of the product. The resulting mixture was purified by direct injection into a preparative HPLC. The largest scale tested to date was 600 g of P5(PEG24)-COOtBu. After preparative HPLC and lyophilization, the yield was 55% (317 g) and the purity was >98%.

[0164] The large-scale method for preparing P5(PEG24)-COOH is further described in the table below: The total yield from starting material 2 in the two steps outlined in Examples 6 and 7 was 29.2%. Analytical characterization of compound P5(PEG24)-COOH showed that Figures 6 to 9 middle. Figure 6 The compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 is shown. 1 H NMR spectrum. Figure 7 The compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 is shown. 31 P NMR spectroscopy. Figure 8 The compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 is shown. 13 C NMR spectroscopy. Figure 9 The HPLC chromatograms of compound P5(PEG24)-COOH synthesized according to Examples 6 and 7 are shown.

Claims

1. A method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (V) or a salt or solvate thereof: (V)； in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I)， in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

2. A method for preparing a compound of formula (I) or a salt or solvate thereof, the method comprising: (a) (i) To make a compound of formula (VIII) or a salt or solvate thereof: (VIII), in: R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; and LG is a leaving group Reaction with compounds of formula (VII): (VII), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; and M is capable of converting groups The metal-containing group is transferred to the phosphorus atom to replace the leaving group LG; (ii) React the product obtained in step (i) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V)； in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I)， in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; or (b) (ii) To make a compound of formula (VI) or a salt or solvate thereof: (WE), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (V) or their salts or solvates: (V)， in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; (iii) React the product obtained in step (ii) with a compound of formula (III) or a salt or solvate thereof: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I)， in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; or (c) (ii) To make a compound of formula (VI) or a salt or solvate thereof: (WE), in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 21 R 22 R 23 and R 24 Each is independently H or optionally substituted (C1-C8) alkyl; optionally R 21 and R 22 They can form a ring together; and / or optionally R 23 and R 24 They can form a ring together; and / or optionally R 21 and R 22 One of them can be with R 23 and R 24 One of them together forms a ring; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; and R 5 It is H or (C1-C8) alkyl Reaction with compounds of formula (III) or their salts or solvates: (III), in: R 1 It is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and (iii) React the product obtained in step (ii) with a compound of formula (V) or a salt or solvate thereof: (V)， in: R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group; and (iv) React the product obtained in step (iii) with an oxidizing agent to obtain a compound of formula (I) or a salt or solvation thereof: (I)， in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

3. The method according to claim 1 or 2, wherein: (a) It is a triple bond; V does not exist; X is... And R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently (C1-C8) alkyl; preferably R 3 Is it H or -Si(R) Si )3, where R Si Each is independently (C1-C8) alkyl; more preferably R 3 It is H; or (b) It is a double bond; V is H or (C1-C8) alkyl, preferably V is H; X is ;R 4 It is H or (C1-C8) alkyl, preferably R. 4 It is H and R 5 It is H or (C1-C8) alkyl, preferably R. 5 It's H.

4. The method according to any one of the preceding claims, wherein (a) The leaving group LG is selected from halogens (e.g., F, Cl, Br or I) and optionally substituted phenoxy groups; preferably, the leaving group LG is Cl; and / or (b) M is MgY, where Y is a halogen, preferably where Y is Br; or M is Li; and / or (c) R 6 It's H.

5. The method according to any one of the preceding claims, wherein the spacer A is selected from optionally substituted -(C6-C) 10 ) aryl-, optionally substituted-(C1-C 10 )alkylene-, optionally substituted (C3-C8) carbocyclic-, optionally substituted - (C1-C 10 )alkylene-(C6-C 10 ) aryl-, optionally substituted-(C6-C 10 ) aryl-(C1-C 10 )alkylene-, optionally substituted-(C1-C 10 )alkylene-(C3-C8)carbocyclic-, optionally substituted-(C3-C8)carbocyclic-(C1-C 10 )alkylene-, optionally substituted-(C3-C8)heterocyclic-, optionally substituted-(C1-C 10 )alkylene-(C3-C8)heterocyclic- and optionally substituted-(C3-C8)heterocyclic-(C1-C 10 )alkylene-; Preferably, the spacer A is an optionally substituted -phenylene-.

6. The method according to any one of the preceding claims, wherein PG is optionally a substituted (C1-C8) alkyl group. Preferably, PG is tert-butyl.

7. The method according to any one of the preceding claims, wherein the compound of formula (V) is And the compound of formula (I) is ,in X, V, R 1 and PG as defined in any of the preceding claims; Preferably, the compound of formula (V) is And the compound of formula (I) is ,in X, V, R 1 And PG as defined in any of the preceding claims.

8. The method according to any one of the preceding claims, wherein R 1 yes: ， in: Indicates the position of O; K F Selected from -H, protecting groups, -PO3H, -(C1-C 10 )alkyl, -(C1-C 10 )alkyl-SO3H, -(C2-C 10 )alkyl-CO2H, -(C2-C 10 )alkyl-OH, -(C2-C 10 )alkyl-NH2, -(C2-C 10 )alkyl-NH(C1-C3)alkyl and -(C2-C 10 )alkyl-N((C1-C3)alkyl)2; and o is an integer in the range of 1 to 100; Preferably, where K F It is H; and / or Preferably, o is in the range of 8 to 30, more preferably, o is in the range of 20 to 28.

9. The method according to claim 1, claim 2(a), and any one of claims 3 to 8, wherein the compound of formula (VIII) is The compound of formula (VII) is The compound of formula (V) is The compound of formula (III) is And the compound of formula (I) is K F and o as defined in claim 8; preferably wherein K F It is H; and / or preferably, o is 24 or 12.

10. The method according to claim 1, claim 2(a) and any one of claims 3 to 9, wherein 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 (VIII) is used in an amount of 0.5 to 1.5 molar equivalents, based on a 1.0 molar equivalent of the compound; More preferably, the compound of formula (VIII) is used in an amount of 0.9 to 1.1 molar equivalents, based on a 1.0 molar equivalent of the compound.

11. The method according to any one of the preceding claims, wherein the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid (mCPBA), urea-hydrogen peroxide adduct, (camphorsulfonyl)oxazolidinyl propane (CSO), iodine, tert-butyl hydrogen peroxide (tBuOOH), and air; Preferably, the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid (mCPBA), and urea-hydrogen peroxide adduct; More preferably, the oxidant is hydrogen peroxide.

12. The method according to any one of the preceding claims, wherein steps (i) to (iv) are performed as a one-pot process.

13. The method according to any one of the preceding claims, the method further comprising: (v) Removing the protecting group PG from the compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*)， in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is a spacer.

14. A method for preparing a compound of formula (I*), the method comprising: Removal of the protecting group PG from a compound of formula (I) or its salt or solvate: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group. To obtain a compound of formula (I*) or its salt or solvate: (I*)， in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ;or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; and A is a spacer.

15. A compound of formula (I) or a salt or solvate thereof: (I) in: It is a three-key; or It is a double bond; V It does not exist when it is a triple bond; or V When it is a double bond, it is H or (C1-C8) alkyl; X when When it is a three-key ; or X when When it is a double bond ; R 1 It is either an optional substituted aliphatic residue or an optional substituted aromatic residue; R 3 Selected from H, -Si(R) Si )3 and (C1-C8) alkyl, wherein R Si Each is independently a (C1-C8) alkyl group; R 4 It is H or (C1-C8) alkyl; R 5 It is H or (C1-C8) alkyl; R 6 It is H or (C1-C8) alkyl; A is a spacer; and PG is a protecting group.

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