Method of 4-boronophenylalanine production

Patent metadata

Field	Value
Publication number	US-11098067-B2
Application number	US-201916971275-A
Country	US
Kind code	B2
Filing date	Feb 19, 2019
Priority date	Feb 20, 2018
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention relates to a method of production of 4-boronophenylalanine (BPA) from 4-iodophenylalanine, in which all the functional groups of the amino acid are protected by benzyl protection method, and which uses isopropyl magnesium halogenide stabilized by a complexation base, and subsequent condensation of the resulting Grignard reagent with a boric acid ester. The final reaction step, catalytic hydrogenolysis or transfer hydrogenolysis of protecting groups on the amino acid, occurs after hydrolysis of the boronate ester groups.

First claim

The invention claimed is:

1. A method for production of 4-boronophenylalanine from 4-iodophenylalanine, comprising
a first reaction step comprising substeps of protecting the carboxy functional group of 4-iodophenylalanine as a benzyl ester and protecting the amino group of 4-iodophenylalanine as a dibenzyl or benzyloxycarbonyl derivative, and then substituting the iodine in the resulting protected 4-iodophenylalanine with magnesium halogenide by reaction with isopropyl magnesium halogenide stabilized with a complexation base to obtain 4-magnesium halogenide of the protected phenylalanine,
a second reaction step comprising substeps of substituting 4-magnesium halogenide of the protected phenylalanine obtained in the first reaction step with boric acid ester of the general formula B(OR) 3 , where R is aliphatic alkyl with a number of carbon atoms from 1 to 10, phenyl, or benzyl, and hydrolyzing the resulting boronic ester group to obtain protected 4-boronophenylalanine, and
a third reaction step comprising substeps of deprotecting the protected 4-boronophenylalanine obtained in the second reaction step by catalytic hydrogenolysis or transfer hydrogenolysis with Pd catalyst, and then precipitating the reaction mixture with one or more bases to obtain 4-boronophenylalanine.

2. The method according to claim 1 , wherein
in the first reaction step, the protected 4-iodophenylalanine reacts with isopropyl magnesium halogenide stabilized with a complexation base, where the halogenide is chloride or bromide, and the complexation base is selected from the group consisting of bis[2-(N,N-dimethylamino)ethyl] ether, N,N,N′,N′-tetramethylenediamine, 1,4-diazabicyclo[2,2,2]octane, N-methylmorpholine and N,N,N′,N′,N′-pentamethyldiethylenetriamine, at a temperature in a range of −20 to 20° C. in ethereal medium, at a molar ratio of isopropyl magnesium halogenide to the protected 4-iodophenylalanine in a range of 1 to 1.5, to obtain the 4-magnesium halogenide of the protected phenylalanine,
in the second reaction step, the 4-magnesium halogenide is substituted with boric acid ester at a temperature in a range of −70 to 0° C. and at a molar ratio of the boric acid ester to the 4-magnesium halogenide of the protected phenylalanine in a range of 1 to 2, and the resulting boronic ester group is subsequently hydrolyzed in an aqueous acid medium at a temperature in a range of 0 to 50° C. to obtain the protected 4-boronophenylalanine, and in the third reaction step, the catalytic hydrogenolysis cleavage of the protecting groups is performed at a hydrogen pressure in a range of 0.1 to 10 MPa and at a temperature in a range of 15 to 120° C., in the aqueous alcohol medium, in the presence of an organic or inorganic acid, with Pd catalyst in an amount in a range of 1 to 150 wt. %, based on the protected 4-boronophenylalanine, and the reaction mixture is precipitated by one or more bases to a pH in a range of 5 to 8 at a temperature in a range of 0 to 50° C. to obtain 4-boronophenylalanine.

3. The method according to claim 1 , wherein the complexation base in the first reaction step is bis[2-(N,N-dimethylamino)ethyl] ether.

4. The method according to claim 1 , wherein the substitution reaction in the first reaction step is performed at a temperature in a range of −5 to 5° C. in tetrahydrofuran medium, at a molar ratio of isopropyl magnesium halogenide to protected 4-iodophenylalanine of 1.2.

5. The method according to claim 1 , wherein the boric acid ester used in the second reaction step is methyl or ethyl ester and the reaction is performed at a temperature in a range of −25 to −15° C.

6. The method according to claim 1 , wherein the ratio of the boric acid ester to 4-magnesium halogenide of the protected phenylalanine in the second reaction step is 1.5.

7. The method according to claim 2 , wherein the aqueous acid medium in the second reaction step is 3 to 5 M hydrochloric acid at the temperature in a range of 5 to 25° C.

8. The method according to claim 1 , wherein the catalytic hydrogenolysis cleavage is performed, wherein the Pd catalyst is Pd on carbon in a quantity in a range of 1 to 10 wt. %, based on the protected 4-boronophenylalanine, at a temperature in a range of 30 to 70° C. and at hydrogen pressure in a range of 0.5 to 2 MPa.

9. The method according to claim 1 , wherein the transfer hydrogenolysis in the third reaction step is performed using Pd on silica (Pd content 20%) in a quantity in a range of 20 to 50 wt. %, based on the protected 4-boronophenylalanine, with addition of formic acid at a temperature in a range of 50 to 70° C.

10. The method according to claim 1 , wherein the deprotection in the third reaction step is performed in reaction medium of aqueous ethanol with water content in a range of 20 to 50 vol. %, in the presence of hydrochloric acid in a quantity in a range of 0.5 to 3 molar equivalents HCl, based on the protected 4-boronophenylalanine.

11. The method according to claim 1 , wherein the precipitation in the third reaction step is performed at pH in a range of 6 to 7 at a temperature in a range of 5 to 15° C. with NaOH or KOH.

12. The method according to claim 1 , wherein the second reaction step is followed by an additional purification of the produced protected 4-boronophenylalanine by extraction with one or more ester solvents, and washing with sodium hydrogencarbonate solution and water to obtain purified protected 4-boronophenylalanine.

13. The method according to claim 1 , wherein said method is carried out with an L-configuration of phenylalanine and/or with boron compounds enriched with the 10 B isotope.

14. A 4-magnesiumhalogenide of the protected phenylalanine of formula 2:

where R 1 and R 2 are benzyl, or R 1 is benzyloxycarbonyl, R 2 is H; Bn is benzyl; X is Cl or Br as an intermediate product in the production of 4-boronophenylalanine.

15. A protected 4-boronophenylalanine of formula 3:

where R 1 and R 2 are benzyl, or R 1 is benzyloxycarbonyl, R 2 is H; Bn is benzyl; R 3 is Cl to C10 alkyl, phenyl, or benzyl
as an intermediate product in the production of 4 boronophenylalanine.

16. The method according to claim 9 , wherein the formic acid is used in an amount in a range of 7 to 15% of molar excess.

17. The method according to claim 10 , wherein the amount of HCl is in a range of 1 to 2 molar equivalents.

18. The method of claim 12 , wherein the one or more ester solvents comprise ethyl acetate.

19. The method of claim 12 , wherein the additional purification of the protected 4-boronophenylalanine further comprises purification with active carbon.

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Zahradnik Petr
• Sturc Antonin
• Malinak Jiri
• Koci Jan

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07B49/00

  Grignard reactions · CPC title

• C07F3/02

  Magnesium compounds · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• C07B63/02

  by treatment giving rise to a chemical modification · CPC title