Apparatus and methods for the automated synthesis of small molecules

Patent metadata

Field	Value
Publication number	US-9862733-B2
Application number	US-201614996479-A
Country	US
Kind code	B2
Filing date	Jan 15, 2016
Priority date	Jul 23, 2010
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

Provided are methods for purifying N-methyliminodiacetic acid (MIDA) boronates from solution. Also provided are methods for deprotection of boronic acids from their MIDA ligands. The purification and deprotection methods can be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chemical compounds of interest. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated synthesis of small molecules using iterative cycles of deprotection, coupling, and purification in accordance with methods of the invention. Coupling and other reactions embraced by the invention include, without limitation, Suzuki-Miyaura coupling, oxidation, Swern oxidation, “Jones reagents” oxidation, reduction, Evans' aldol reaction, HWE olefination, Takai olefination, alcohol silylation, desilylation, p-methoxybenzylation, iodination, Negishi cross-coupling, Heck coupling, Miyaura borylation, Stille coupling, and Sonogashira coupling.

First claim

We claim:

1. A method of purifying an N-methyliminodiacetic acid (MIDA) boronate from a solution, comprising the steps of
diluting the solution with hexane, thereby selectively precipitating the MIDA boronate; and
isolating the precipitated MIDA boronate,

wherein the solution comprising the MIDA boronate is a THF solution.

2. The method of claim 1 , wherein the isolating comprises filtering the precipitated MIDA boronate.

3. The method of claim 1 , wherein the solution comprising the MIDA boronate is added dropwise to the hexane.

4. The method of claim 1 , wherein the volume of hexane is between about two times and about four times the volume of the solution.

5. The method of claim 1 , wherein the volume of hexane is about three times the volume of the solution.

6. The method of claim 1 , wherein the MIDA boronate is represented by

R 10 represents an organic group; B represents boron having sp 3 hybridization; R 20 is methyl; and R 21 , R 22 , R 23 and R 24 independently are selected from the group consisting of hydrogen and an organic group.

7. The method of claim 6 , wherein R 21 , R 22 , R 23 and R 24 are hydrogen.

8. The method of claim 1 , wherein the method is performed in the purification module of an automated small molecule synthesizer, said automated small molecule synthesizer comprising:
(a) a deprotection module, in fluid communication with
(b) a drying and degassing module, in fluid communication with
(c) a reaction module, in fluid communication with
(d) a purification module;
(e) at least one pump which can move liquid from one module to another; and
(f) a computer equipped with software;

wherein all of the modules are under control of the computer.

9. A method of purifying an N-methyliminodiacetic acid (MIDA) boronate from a solution, comprising the steps of
passing the solution through a silica plug;
passing a first liquid through the silica plug; and
passing a second liquid through the silica plug, thereby eluting the MIDA boronate in the second liquid,

wherein the first liquid comprises diethyl ether or the polarity of the first liquid is less than or equal to about the polarity of a mixture of 98.5:1.5 (v/v) Et 2 O:MeOH; the polarity of the second liquid is greater than or equal to about the polarity of tetrahydrofuran (THF); and the method is performed in the purification module of an automated small molecule synthesizer, said automated small molecule synthesizer comprising:
(a) a deprotection module, in fluid communication with
(b) a drying and degassing module, in fluid communication with
(c) a reaction module, in fluid communication with
(d) a purification module;
(e) at least one pump which can move liquid from one module to another; and
(f) a computer equipped with software,

wherein all of the modules are under control of the computer.

10. The method of claim 9 , wherein the first liquid comprises diethyl ether.

11. The method of claim 9 , wherein the first liquid is diethyl ether.

12. The method of claim 9 , wherein the first liquid is a mixture of diethyl ether and methanol.

13. The method of claim 9 , wherein first liquid is a mixture of diethyl ether and methanol; and the ratio of diethyl ether to methanol is 98.5:1.5 (v/v).

14. The method of claim 9 , wherein the second liquid is THF, MeCN, ethyl acetate or acetone.

15. The method of claim 9 , wherein the second liquid is THF.

16. The method of claim 9 , wherein the MIDA boronate is represented by

R 10 represents an organic group; B represents boron having sp 3 hybridization; R 20 is methyl; and R 21 , R 22 , R 23 and R 24 independently are selected from the group consisting of hydrogen and an organic group.

17. The method of claim 16 , wherein R 21 , R 22 , R 23 and R 24 are hydrogen.

18. A method of purifying an N-methyliminodiacetic acid (MIDA) boronate from a solution, comprising the steps of
diluting the solution with hexane, thereby selectively precipitating the MIDA boronate;
passing the diluted solution through a silica plug, thereby depositing the precipitated MIDA boronate on the silica plug;
passing a first liquid through the silica plug; and
passing a second liquid through the silica plug, thereby eluting the MIDA boronate in the second liquid,

wherein the first liquid comprises diethyl ether or the polarity of the first liquid is less than or equal to about the polarity of a mixture of 98.5:1.5 (v/v) Et 2 O:MeOH; the polarity of the second liquid is greater than or equal to about the polarity of tetrahydrofuran (THF); and the method is performed in the purification module of an automated small molecule synthesizer, said automated small molecule synthesizer comprising:
(a) a deprotection module, in fluid communication with
(b) a drying and degassing module, in fluid communication with
(c) a reaction module, in fluid communication with
(d) a purification module;
(e) at least one pump which can move liquid from one module to another; and
(f) a computer equipped with software,

wherein all of the modules are under control of the computer.

19. A method of deprotecting an N-methyliminodiacetic acid (MIDA) boronate, comprising the step of
contacting a solution comprising the MIDA boronate and a solvent with a solid-supported ammonium hydroxide reagent, thereby forming a boronic acid and a MIDA, wherein the method is performed in the deprotection module of an automated small molecule synthesizer, said automated small molecule synthesizer comprising:
(a) a deprotection module comprising the solid-supported ammonium hydroxide reagent, in fluid communication with
(b) a drying and degassing module, in fluid communication with
(c) a reaction module, in fluid communication with
(d) a purification module;
(e) at least one pump which can move liquid from one module to another; and
(f) a computer equipped with software,

wherein all of the modules are under control of the computer.

20. A method of deprotecting an N-methyliminodiacetic acid (MIDA) boronate, comprising the steps of
contacting a solution comprising the MIDA boronate and a solvent with an aqueous solution of NaOH, thereby forming a boronic acid and free MIDA ligand;
adding diethyl ether, thereby generating a biphasic mixture comprising an organic phase comprising the deprotected MIDA boronate and an aqueous phase; and isolating the organic phase comprising the boronic acid and free MIDA ligand; and
contacting the organic phase with one or more drying agents selected from the group consisting of magnesium sulfate, diatomaceous earth, and molecular sieves, thereby drying the organic phase comprising the boronic acid and free MIDA ligand,

wherein the method is performed in the deprotection module of an automated small molecule synthesizer, said automated small molecule synthesizer comprising:
(a) a deprotection module, in fluid communication with
(b) a drying and degassing module, in fluid communication with
(c) a reaction module, in fluid communication with
(d) a purification module;
(e) at least one pump which can move liquid from one module to another; and
(f) a computer equipped with software,

wherein all of the modules are under control of the computer.

Assignees

• Burke Martin D
• Gillis Eric P
• Ballmer Steven G
• Univ Illinois

Inventors

• Burke Martin D
• Gillis Eric P
• Ballmer Steven G

Classifications

• C07B61/00

  Other general methods · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• C07F5/04

  Esters of boric acids · CPC title

• C07C227/18

  by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters · CPC title

• Y02P20/55

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