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EP-4317165-B1 - BORONIC ACID COMPOUND AND METHOD FOR PRODUCING SAME

EP4317165B1EP 4317165 B1EP4317165 B1EP 4317165B1EP-4317165-B1

Inventors

  • SHIRAKAMI, YOSHIFUMI
  • KANEDA, KAZUKO
  • KADONAGA, Yuichiro
  • WATABE, Tadashi
  • TOYOSHIMA, ATSUSHI
  • FUKASE, KOICHI
  • SHINOHARA, ATSUSHI
  • YAMANAKA, TOSHIO
  • KONDOH, YUTAKA

Dates

Publication Date
20260506
Application Date
20220324

Claims (12)

  1. A method for producing a compound represented by Formula (5) or a salt thereof, comprising the following Steps 1 to 4; wherein R 1 is a methyl group; P 1 is an ether-type hydroxy-protecting group; P 2 is an amino-protecting group; P 3 is a carboxy-protecting group; m is 0, 1 or 2; X is a halogen atom; and Y is a boryl group (-B(OH) 2 ) or its ester group, Step 1: a step of halogenating a compound represented by Formula (1) or a salt thereof to obtain a compound represented by Formula (2) or a salt thereof; Step 2: a step of protecting the amino group and carboxy group of the compound represented by Formula (2) or a salt thereof and protecting the hydroxy group of the compound or salt with an ether-type protecting group to obtain a compound represented by Formula (3); Step 3: a step of reacting the compound represented by Formula (3) with a reagent for introducing boronic acid in the presence of a palladium catalyst and a base to obtain a compound represented by Formula (4); and Step 4: a step of removing the protecting groups for the carboxy group, amino group and hydroxy group of the compound represented by Formula (4) to obtain the compound represented by Formula (5) or a salt thereof.
  2. The method according to Claim 1, wherein P 1 is a benzyl group or a p-methoxybenzyl group.
  3. The method according to Claim 1 or 2, wherein P 3 is a benzyl group or a C 1-2 alkyl group.
  4. The method according to Claim 1, wherein P 1 and P 3 are both benzyl groups.
  5. The method according to any one of Claims 1 to 4, wherein the bonding position of the hydroxy group on the benzene ring in Formula (5) is the 4-position or 3-position, or wherein the bonding positions of the hydroxy group and the group -Y on the benzene ring in Formula (5) are preferably adjacent to each other.
  6. The method according to any one of Claims 1 to 4, wherein, in Formula (5), the bonding position of the hydroxy group on the benzene ring is the 4-position, and the bonding position of the group -Y on the benzene ring is the 3-position.
  7. The method according to any one of Claims 1 to 6, wherein the palladium catalyst to be used in Step 3 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl 2 (dppf)), wherein the reaction of Step 3 is preferably carried out in a sulfoxide solvent or an amide solvent, or wherein the base to be used in Step 3 is preferably an alkali metal acetate.
  8. The method according to any one of Claims 1 to 7, wherein Y is a boryl group (-B(OH) 2 ) or a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group.
  9. A compound represented by the following Formula (5a) or a salt thereof; wherein Y is a boryl group (-B(OH) 2 ) or its ester group.
  10. A compound represented by the following Formula (4a); wherein P 1a is a benzyl group or a p-methoxybenzyl group; P 2a is a tert-butoxycarbonyl group; P 32 is a benzyl group or a C 1-2 alkyl group; and Y is a boryl group (-B(OH) 2 ) or its ester group.
  11. A method for producing a radiolabeled compound represented by Formula (6) or a salt thereof, comprising the following Step 5; wherein R 1 is a hydrogen atom or a C 1-4 alkyl group; m is 0, 1 or 2; Y is a boryl group (-B(OH) 2 ) or its ester group; and Z is 211 At, 210 At, 123 I, 124 I, 125 I or 131 I, Step 5: a step of reacting a compound represented by Formula (5) or a salt thereof with a radionuclide selected from 211 At, 210 At, 123 I, 124 I, 125 I and 131 I, in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide, in water to obtain the radiolabeled compound represented by Formula (6) or a salt thereof.
  12. The method according to Claim 11, wherein the compound represented by Formula (5) or a salt thereof is produced by a method as defined in any one of Claims 1 to 12 and/or wherein the reaction is carried out in an organic solvent-free system, and/or wherein the reaction is carried out within the range of room temperature to 100°C, and/or wherein the radionuclide is 211 At or 131 I, and the reagent is selected from potassium iodide and N-bromosuccinimide, and/or further comprising a step of purifying the radiolabeled compound represented by Formula (6) or a salt thereof, and/or further comprising a step of stabilizing the radiolabeled compound represented by Formula (6) or a salt thereof by adding ascorbic acid.

Description

Technical Field The present invention relates to novel boronic acid compounds which are intermediates for producing radiolabeled tyrosine derivatives useful as anti-cancer drugs, and methods for producing the same, and methods for producing radiolabeled tyrosine derivatives using the same. Background Art Radiolabeled tyrosine derivatives such as astato(211At)-α-methyl-L-tyrosine (211At-AAMT) are drugs that are taken up into tumor cells via LAT1 amino acid transporter specifically expressed in tumors, and are expected to be useful as anti-cancer drugs (Patent Document 1). Patent Document 1 discloses that 211At-AAMT is conventionally produced by dissolving α-methyl-L-tyrosine (AMT) in sulfuric acid, adding mercury sulfate to the solution to introduce mercury on the benzene ring, and then subjecting the resulting compound to an astatine exchange reaction (hereinafter to be also referred to as the mercury method). Since this method requires use of mercury, which is a hazardous substance, it cannot be said to be a method suitable for the production of pharmaceuticals in terms of safety. In addition, the above method is not suitable for industrial production because the synthetic yield varies relatively greatly between production batches. Furthermore, iodine-substituted compounds and halogen-disubstituted compounds are produced as byproducts, which poses a problem in terms of purity. It has also been reported that the produced 211At-AAMT is unstable (Non-Patent Document 1). In addition, it is generally known that halogen is easily introduced into the 3-position of a tyrosine derivative by halogenation in the presence of an oxidant. However, this method is not effective only for astatine (Non-Patent Document 2). On the other hand, the present inventors have already reported that a boryl group (-B(OH)2) introduced into an aryl group has excellent astatine-substituting ability (Patent Document 2). Patent Document 3 discloses borylated amino acid compositions and a method of preparing the same. An examplary compound TLS00192 is based on tyrosine. Patent Document 4 discloses astato-labeled amino acid derivatives and methods for the preparation thereof. Non-Patent Document 3 describes the synthesis of piperazinomycin based on intramolecular O-arylation of arylboronic acid with phenol for formation of the macrocyclic biaryl ether. Non-Patent Document 4 discloses the preparation and stability of astatotyrosine. Document List Patent Document [Patent Document 1] WO 2019/176505[Patent Document 2] WO 2019/027059[Patent Document 3] WO 2020/180390[Patent Document 4] US 2021/000988 Non-Patent Document [Non-Patent Document 1] J Surg Oncol 1988; 37:192-7[Non-Patent Document 2] Int J Appl Radiat Isotop 1979; 30: 749-52[Non-Patent Document 3] Ghosh Samir et al., ARKIVOC 2009, no.7, pp. 72-78[Non-Patent Document 4] Visser et al., Int.J.Appl. Ratiation and Isotops, 1979, 99. 749-752 Summary of the Invention Problems to be Solved by the Invention The present invention aims to provide a method for producing radiolabeled tyrosine derivatives with good purity and stability, by a safe method suitable for industrial production of pharmaceuticals. Means of Solving the Problems The present inventors have focused on the production method described in Patent Document 2 as a production method that does not require use of hazardous substances such as mercury, and have conducted intensive studies in an attempt to produce tyrosine boronic acid derivatives or its esters as raw materials for the method, which resulted in the completion of the present invention. Accordingly, the present invention provides the following. [1] A method for producing a compound represented by Formula (5) or a salt thereof (hereinafter to be also referred to as Compound (5)), comprising the following Steps 1 to 4; wherein R1 is a methyl group;P1 is an ether-type hydroxy-protecting group;P2 is an amino-protecting group;P3 is a carboxy-protecting group;m is 0, 1 or 2;X is a halogen atom; andY is a boryl group (-B(OH)2) or its ester group,Step 1: a step of halogenating a compound represented by Formula (1) or a salt thereof (hereinafter to be also referred to as Compound (1)) to obtain a compound represented by Formula (2) or a salt thereof (hereinafter to be also referred to as Compound (2));Step 2: a step of protecting the amino group and carboxy group of the compound represented by Formula (2) or a salt thereof and protecting the hydroxy group of the compound or salt with an ether-type protecting group to obtain a compound represented by Formula (3) (hereinafter to be also referred to as Compound (3));Step 3: a step of reacting the compound represented by Formula (3) with a reagent for introducing boronic acid in the presence of a palladium catalyst and a base to obtain a compound represented by Formula (4) (hereinafter to be also referred to as Compound (4)); andStep 4: a step of removing the protecting groups for the carboxy group, amino group and hydroxy group of the