SYNTHESIS OF BORONIC ESTER AND ACID COMPOUNDS

• US 20100174072A1
• Filed: 02/16/2010
• Published: 07/08/2010
• Est. Priority Date: 03/30/2004
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Pickersgill, I. Fraser, Chiu, Fang-Ting, Ammoscato, Vince, Lo, Young, Kulkarni, Vithalanand R., Munk, Stephen, Koellner, Christoph, Geiser, Achim, Hett, Robert, Bishop, John E., Gomez, Jean-Marc
• Granted Patent: US 8,283,467 B2
• Time in Patent Office: Days
• US Class Current: 544/229
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the synthesis of boronic ester and acid compounds. More particularly, the invention provides improved synthetic processes for the large-scale production of boronic ester and acid compounds, including the peptide boronic acid proteasome inhibitor bortezomib.

Claims

1. A composition comprising an ether solvent that has low miscibility with water and at least about ten moles of a boronic ester compound of formula (I):

wherein;

R¹ is an optionally substituted aliphatic or aromatic group;

R² is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;

R³ is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

4. The composition of any one of claims 1-3, wherein the solubility of water in the ether solvent is less than about 2% w/w.

5. The composition of any one of claims 1-3, wherein the ether solvent is selected from the group consisting of tert-butyl methyl ether, text-butyl ethyl ether, text-amyl methyl ether, isopropyl ether, and mixtures thereof.

6. The composition of any one of claims 1-3, wherein R¹ is C_1-8 aliphatic, C_6-10 aryl, or (C_6-10 aryl)(C_1-6 aliphatic).

7. The composition of any one of claims 1-3, characterized by at least one of the following features:

(a) R³ is chloro;

(b) R² is hydrogen; and

(c) R¹ is C_1-4 aliphatic

8. The composition of any one of claims 1-3, wherein the compound of formula (I) is

2. A composition comprising an ether solvent that has low miscibility with water and at least about ten moles of a boronic ester compound of formula (I):

wherein;

R¹ is an optionally substituted aliphatic or aromatic group;

R² is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;

R³ is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

wherein the carbon atom to which R¹, R², and R³ are attached is a chiral center, having a diastereomeric ratio of at least about 96;

4, relative to a chiral center in the R⁴-R⁵ chiral moiety;

wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

3. A composition comprising an ether solvent that has low miscibility with water and at least about ten moles of a boronic ester compound of formula (I):

wherein;

R¹ is an optionally substituted aliphatic or aromatic group;

R² is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;

R³ is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

wherein the carbon atom to which R¹, R², and R³ are attached is a chiral center, having an epimeric ratio of at least about 96;

4;

wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

10. The composition of claim 3 comprising at least about 20 moles of the boronic ester compound of formula (I).

11. The composition of claim 3, wherein the carbon atom to which R¹, R², and R³ are attached has a diastereomeric ratio of at least about 97:

3, relative to a chiral center in the R⁴-R⁵ chiral moiety.

12. The composition of claim 3, wherein all of the boronic ester compound of formula (I) present in the composition is produced in a single batch run.

13. The composition of claim 3, wherein at least one of the following features is present:

(a) R³ is chloro;

(b) the boronic ester compound of formula (I) is;

(c) R² is hydrogen; and

(d) R¹ is C_1-4 aliphatic.

9. A composition comprising at least about ten moles of a boronic ester compound of formula (I):

wherein;

R¹ is an optionally substituted aliphatic or aromatic group;

R² is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;

R³ is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

wherein the carbon atom to which R¹, R², and R³ are attached is a chiral center, having a diastereomeric ratio of at least about 96;

4, relative to a chiral center in the R⁴-R⁵ chiral moiety;

wherein the boronic ester compound of formula (I) constitutes at least about 70% w/w of the composition;

wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

14. A large-scale process for preparing a boronic ester compound of formula (I):

wherein;

R¹ is an optionally substituted aliphatic or aromatic group;

R² is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;

R³ is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

said process comprising;

(a) providing a solution comprising;

(i) a boronic ester of formula (III);

wherein R¹, R⁴, and R⁵ are as defined above; and

(ii) an ether solvent that has low miscibility with water, wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture;

(b) treating the solution with a reagent of formula (IV);

to form a boron “

ate”

complex of formula (II);

where

Y is a nucleofugic group;

M⁺ is a cation; and

each of R¹ to R⁵ are as defined above; and

(c) contacting the boron “

ate”

complex of formula (II) with a Lewis acid under conditions that afford the boronic ester compound of formula (I), said contacting step being conducted in a reaction mixture comprising;

(i) a coordinating ether solvent that has low miscibility with water;

or

(ii) an ether solvent that has low miscibility with water and a coordinating co-solvent, provided that the coordinating co-solvent constitutes no more than about 20% v/v of the reaction mixture;

wherein the solubility of water in the ether solvent in (i) or (ii) that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent in (i) or (ii) that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

15. A large-scale process for preparing a boronic ester compound of formula (I):

wherein;

R¹ is an optionally substituted aliphatic or aromatic group;

R² is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;

R³ is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

said process comprising;

(a) providing a solution comprising;

(i) a boronic ester of formula (III);

wherein R¹, R⁴, and R⁵ are as defined above;

(ii) a compound of formula (V);

where Y is a nucleofugic group, and R² and R³ are as defined above; and

(iii) a solvent comprising;

(aa) a coordinating ether solvent that has low miscibility with water;

or

(bb) an ether solvent that has low miscibility with water and a coordinating co-solvent, provided that the coordinating co-solvent constitutes no more than about 20% v/v of the reaction mixture;

wherein the solubility of water in the ether solvent in (aa) or (bb) that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent in (aa) or (bb) that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture;

(b) treating the solution of step (a) with a strong, sterically hindered base to form a boron “

ate”

complex of formula (II);

where M⁺ is a cation derived from the base, and each of Y and R¹ to R⁵ are as defined above; and

(c) contacting the boron “

ate”

complex of formula (II) with a Lewis acid in a solution comprising an ether solvent that has low miscibility with water to form the boronic ester compound of formula (I), wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

17. The process of claim 15 or 16, wherein the sterically hindered base is an alkali metal dialkylamide base of formula M²N(R^#)₂, wherein M² is selected from the group consisting of Li, Na, and K, and each R^#, independently, is a branched or cyclic C_3-6 aliphatic,

16. A large-scale process for preparing a boronic ester compound of formula (I):

wherein;

R¹ is an optionally substituted aliphatic or aromatic group;

R² is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;

R³ is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

said process comprising;

(a) providing a solution comprising;

(i) a boronic acid compound of formula (VI);

wherein R¹ is as defined above;

(ii) a compound of formula HO—

R⁴-R⁵—

OH, wherein R⁴ and R⁵ are as defined above; and

(iii) an organic solvent that forms an azeotrope with water;

(b) heating the solution of step (a) at reflux, with azeotropic removal of water, to form a boronic ester of formula (III);

wherein R¹, R⁴, and R⁵ are as defined above;

(c) providing a solution comprising;

(i) the boronic ester of formula (III);

(ii) a compound of formula (V);

wherein Y is a nucleofugic group, and R² and R³ are as defined above; and

(iii) a solvent comprising;

(aa) a coordinating ether solvent that has low miscibility with water;

or

(bb) an ether solvent that has low miscibility with water and a coordinating co-solvent, provided that the coordinating co-solvent constitutes no more than about 20% v/v of the reaction mixture;

wherein the solubility of water in the ether solvent in (aa) or (bb) that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent in (aa) or (bb) that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture;

(d) treating the solution from step (c) with a strong, sterically hindered base to form a boron “

ate”

complex of formula (If);

where M⁺ is a cation derived from the base, and each of Y and R¹ to R⁵ are as defined above; and

(e) contacting the boron “

ate”

complex of formula (II) with a Lewis acid in a solution comprising an ether solvent that has low miscibility with water to form the boronic ester compound of formula (I), wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

18. The process of claim 16, wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, hexane, heptane, and mixtures thereof.

19. The process of claim 16, wherein the organic solvent in step (a) is an ether solvent that has low miscibility with water, wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w.

20. The process of claim 19, wherein the solutions in steps (a) and (c) each comprise the same ether solvent.

21. The process of claim 20, wherein step (b) provides a product solution comprising the boronic ester of formula (III), and the product solution from step (b) is used in step (c) without isolation of the boronic ester of formula (III).

22. A large-scale process for preparing an aminoboronic ester compound of formula (VII):

or an acid addition salt thereof, wherein;

R¹ is an optionally substituted aliphatic or aromatic group; and

R⁴ and R⁵ are together an optionally substituted aliphatic group, and R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and

none of the variables R¹-R⁵ is substituted with a heteroaromatic group;

said process comprising;

(a) providing a boron “

ate”

complex of formula (II);

where

Y is a nucleofugic group;

M⁺ is a cation;

R² is hydrogen;

R³ is a nucleofugic group; and

each of R¹, R⁴, and R⁵ are as defined above;

(b) contacting the boron “

ate”

complex of formula (II) with a Lewis acid under conditions that afford the boronic ester compound of formula (I);

where each of R¹ to R⁵ is as defined above, said contacting step being conducted in a reaction mixture comprising;

(i) a coordinating ether solvent that has low miscibility with water;

or

(ii) an ether solvent that has low miscibility with water and a coordinating co-solvent, provided that the coordinating co-solvent constitutes no more than about 20% v/v of the reaction mixture;

wherein the solubility of water in the ether solvent in (i) or (ii) that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent in (i) or (ii) that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture;

(c) treating the boronic ester compound of formula (I) with a reagent of formula M¹-N(Si(R⁶)₃)₂, where M¹ is an alkali metal and each R⁶ independently is selected from the group consisting of alkyl, aralkyl, and aryl, where the aryl or aryl portion of the aralkyl is optionally substituted, to form a byproduct of formula M¹-R³ and a compound of formula (VIII);

wherein each G is —

Si(R⁶)₃ and R¹ to R⁵ are as defined above; and

(d) removing the G groups to form a compound of formula (VII);

or an acid addition salt thereof.

23. The process of claim 22, wherein the reaction mixture in step (c) comprises an organic solvent in which the byproduct M¹-R³ has low solubility.

24. The process of claim 23, wherein M¹ is L¹ and R³ is Cl.

25. The process of claim 24, wherein the reaction mixture in step (c) comprises an organic solvent selected from the group consisting of methylcyclohexane, cyclohexane, heptane, hexane, toluene, and mixtures thereof.

26. The process of claim 22, wherein the reaction in step (c) is conducted at a reaction temperature in the range of about −

100°

C. to about 50°

C.

27. The process of claim 26, wherein the reaction temperature is in the range of about −

50°

C. to about 25°

C.

28. The process of claim 26, wherein the reaction temperature is in the range of about −

30°

C. to about 0°

C.

29. The process of claim 22, wherein step (d) comprises treating the compound of formula (VIII) with an acid and isolating the compound of formula (VII) as the acid addition salt.

30. The process of claim 29, wherein the acid is trifluoroacetic acid.

31. The process of claim 22, wherein step (c) further comprises filtering the reaction mixture to provide a filtrate comprising the compound of formula (VIII).

32. The process of claim 31, wherein in step (c), the reagent of formula M¹-N(Si(R⁶)₃)₂ is added to the reaction mixture as a solution comprising tetrahydrofuran, and step (c) further comprises removing the tetrahydrofuran before filtering the reaction mixture.

33. The process of claim 31, wherein the filtrate is used directly in step (d).

34. The process of claim 22, further comprising the step:

(e) coupling the compound of formula (VII) with a compound of formula (IX);

wherein;

P¹ is an amino group blocking moiety;

R⁷ is selected from the group consisting of hydrogen, C_1-10aliphatic, optionally substituted C_6-10aryl, or C_1-6aliphatic-R⁸; and

R⁸ is selected from the group consisting of alkoxy, alkylthio, optionally substituted aryl, heteroaryl, and heterocyclyl groups, and optionally protected amino, hydroxy, and guanidino groups; and

X is OH or a leaving group;

to form a compound of formula (X);

wherein each of P¹, R¹, R⁴, R⁵, and R⁷ is as defined above.

35. The process of claim 34, wherein P¹ is a cleavable protecting group.

36. The process of claim 35, further comprising the steps:

(f) cleaving the protecting group P¹ to form a compound of formula (XI);

or an acid addition salt thereof, wherein each of R¹, R⁴, R⁵, and R⁷ is as defined above;

(g) coupling the compound of formula (XI) with a reagent of formula P²—

X, wherein P² is an amino group blocking moiety and X is a leaving group, to form a compound of formula (XII);

wherein each of P², R¹, R⁴, R⁵, and R⁷ are as defined above; and

(h) deprotecting the boronic acid moiety to form a compound of formula (XIII);

or a boronic acid anhydride thereof, wherein each of P¹, R¹, and R⁷ are as defined above.

37. A large-scale process for preparing an aminoboronic ester compound of formula (VIIa) or (VIIb):

or an acid addition salt thereof, wherein;

R¹ is an optionally substituted aliphatic, aromatic, or heteroaromatic group; and

R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted chiral cyclic boronic ester;

said process comprising;

(a) providing a boron “

ate”

complex of formula (IIa) or (ITh);

where

Y is a nucleofugic group;

M⁺ is a cation;

R² is hydrogen;

R³ is a nucleofugic group; and

R⁴ and R⁵ are as defined above;

(b) contacting the boron “

ate”

complex of formula (IIa) or (IIb) with a Lewis acid under conditions that afford a boronic ester compound of formula (Ia) or (Ib);

where each of R¹ to R⁵ is as defined above, said contacting step being conducted in a reaction mixture comprising;

(i) a coordinating ether solvent that has low miscibility with water;

or

(ii) an ether solvent that has low miscibility with water and a coordinating co-solvent, provided that the coordinating co-solvent constitutes no more than about 20% v/v of the reaction mixture;

wherein the solubility of water in the ether solvent in (i) or (ii) that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent in (i) or (ii) that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture;

(c) treating the boronic ester compound of formula (Ia) or (Ib) with a reagent of formula M¹-N(G)₂, where M¹ is an alkali metal and each G is an amino group protecting moiety, to form a compound of formula (VIIIa) or (VIIIb);

wherein each G and R¹ to R⁵ are as defined above; and

(d) removing the G groups to form a compound of formula (VIIa) or (VIIb);

or an acid addition salt thereof.

38. A large-scale process for forming a compound of formula (XIV):

or a boronic acid anhydride thereof, said process comprising;

(a) providing a boron “

ate”

complex of formula (XV);

wherein;

R³ is a nucleofugic group;

Y is a nucleofugic group; and

M⁺ is an alkali metal;

(b) contacting the boron “

ate”

complex of formula (XV) with a Lewis acid under conditions that afford a boronic ester compound of formula (XVI);

said contacting step being conducted in a reaction mixture comprising an ether solvent that has low miscibility with water, wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w, and wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture;

(c) treating the boronic ester compound of formula (XVI) with a reagent of formula M¹-N(G)_z, where M¹ is an alkali metal and each G individually or together is an amino group protecting group, to form a compound of formula (XVII);

(d) removing the G groups to form a compound of formula (XVIII);

or an acid addition salt thereof;

(e) coupling the compound of formula (XVIII) with a compound of formula (XIX);

wherein;

P¹ is a cleavable amino group protecting moiety; and

X is OH or a leaving group;

to form a compound of formula (XX);

wherein P¹ is as defined above;

(f) removing the protecting group P¹ to form a compound of formula (XXI);

or an acid addition salt thereof;

(g) coupling the compound of formula (XXI) with a reagent of formula (XXII)

wherein X is a OH or a leaving group, to form a compound of formula (XXIII);

(h) deprotecting the boronic acid moiety to form the compound of formula (XIV) or a boronic acid anhydride thereof.

39. The process of claim 38, characterized by at least one of the following features (1)-(5):

(1) in the boron “

ate”

complex of formula (XV), R³ and Y both are chloro;

(2) the coupling step (e) comprises the steps;

(i) coupling the compound of formula (XVIII) with a compound of formula (XIX) wherein X is OH in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution.

(3) the protecting group removing step (f) comprises the steps;

(i) treating the compound of formula (XX) with HCl in ethyl acetate;

(ii) adding heptane to the reaction mixture; and

(iii) isolating by crystallization the compound of formula (XXI) as its HCl addition salt;

(4) the coupling step (g) comprises the steps;

(i) coupling the compound of formula (XXI) with 2-pyrazine-carboxylic acid in the presence of TBTU and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution; and

(5) the boronic acid deprotecting step (h) comprises the steps;

(i) providing a biphasic mixture comprising the compound of formula (XXIII), an organic boronic acid acceptor, a lower alkanol, a C_5-8hydrocarbon solvent, and aqueous mineral acid;

(ii) stirring the biphasic mixture to afford the compound of formula (XIV);

(iii) separating the solvent layers; and

(iv) extracting the compound of formula (XIV), or a boronic acid anhydride thereof, into an organic solvent.

40. The process of claim 39, characterized by all five features (1)-(5).

41. The process of claim 39, wherein step (h)(iii) comprises the steps:

(1) separating the solvent layers;

(2) adjusting the aqueous layer to basic pH;

(3) washing the aqueous layer with an organic solvent; and

(4) adjusting the aqueous layer to a pH less than about 8.

42. The process of claim 41, wherein in step (h)(iii)(3), the aqueous layer is washed with dichloromethane.

43. The process of claim 41, wherein in step (h)(iv), the compound of formula (XIV), or a boronic acid anhydride thereof, is extracted into dichloromethane, the solvent is exchanged to ethyl acetate, an the compound of formula (XIV), or a boronic acid anhydride thereof, is crystallized by addition of hexane or heptane.

44. The process of claim 43, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

55. A composition comprising at least one kilogram of a compound of formula (XXIV):

wherein the compound of formula (XXIV) is prepared according to the process of claim 38 or 45.

45. A large-scale process for forming a compound of formula (XIV):

or a boronic acid anhydride thereof, comprising the steps;

(aa) coupling a compound of formula (XVIII);

or an acid addition salt thereof, with a compound of formula (XIX);

wherein;

P¹ is a cleavable amino group protecting moiety; and

X is OH or a leaving group;

to form a compound of formula (XX);

wherein P′

is as defined above, said coupling step (aa) comprising the steps;

(i) coupling the compound of formula (XVIII) with a compound of formula (XIX) wherein X is OH in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution;

(bb) removing the protecting group P¹ to form a compound of formula (XXI);

or an acid addition salt thereof, said protecting group removing step (bb) comprising the steps;

(i) treating the compound of formula (XX) with HCl in ethyl acetate;

(ii) adding heptane to the reaction mixture; and

(iii) isolating by crystallization the compound of formula (XXI) as its HCl addition salt;

(cc) coupling the compound of formula (XXI) with a reagent of formula (XXII)

wherein X is a OH or a leaving group, to form a compound of formula (XXIII);

said coupling step (cc) comprising the steps;

(i) coupling the compound of formula (XXI) with 2-pyrazinecarboxylic acid in the presence of TIBTU and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution; and

(dd) deprotecting the boronic acid moiety to form the compound of formula (XIV) or a boronic acid anhydride thereof, said deprotecting step (dd) comprising the steps;

(i) providing a biphasic mixture comprising the compound of formula (XXIII), an organic boronic acid acceptor, a lower alkanol, a C_5-8 hydrocarbon solvent, and aqueous mineral acid;

(ii) stirring the biphasic mixture to afford the compound of formula (XIV);

(iii) separating the solvent layers; and

(iv) extracting the compound of formula (XIV), or a boronic acid anhydride thereof, into an organic solvent.

46. The process of claim 45, wherein step (dd)(iii) comprises the steps:

(1) separating the solvent layers;

(2) adjusting the aqueous layer to basic pH;

(3) washing the aqueous layer with an organic solvent; and

(4) adjusting the aqueous layer to a pH less than about 8.

47. The process of claim 46, wherein in step (dd)(iv), the compound of formula (XIV), or a boronic acid anhydride thereof, is extracted into dichloromethane, the solvent is exchanged to ethyl acetate, an the compound of formula (XIV), or a boronic acid anhydride thereof, is crystallized by addition of hexane or heptane.

48. The process of claim 47, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

49. A large-scale process for forming a compound of formula (XIV):

or a boronic acid anhydride thereof. The process comprises the steps;

(a) providing a boron “

ate”

complex of formula (XV);

wherein;

R³ is a nucleofugic group;

Y is a nucleofugic group; and

M⁺ is an alkali metal;

(b) contacting the boron “

ate”

complex of formula (XV) with a Lewis acid under conditions that afford a boronic ester compound of formula (XVI);

said contacting step being conducted in a reaction mixture comprising;

(i) a coordinating ether solvent that has low miscibility with water;

or

(ii) an ether solvent that has low miscibility with water and a coordinating co-solvent, provided that the coordinating co-solvent constitutes no more than about 20% v/v of the reaction mixture;

wherein the solubility of water in the ether solvent in (i) or (ii) that has low miscibility with water is less than about 5% w/w; and

wherein the ether solvent in (1) or (ii) that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture;

(c) treating the boronic ester compound of formula (XVI) with a reagent of formula M¹-N(Si(R⁶)₃)₂, where M¹ is an alkali metal and each R⁶ independently is selected from the group consisting of alkyl, aralkyl, and aryl, where the aryl or aryl portion of the aralkyl is optionally substituted, to form a compound of formula (XVII);

wherein each G is —

Si(R⁶)₃;

(d) removing the (R⁶)₃Si groups to form a compound of formula (XVIII);

or an acid addition salt thereof;

(e′

) coupling the compound of formula (MR) with a compound of formula (XIXa);

wherein X is OH or a leaving group, to form a compound of formula (XXIII);

(f′

) deprotecting the boronic acid moiety to form the compound of formula (XIV) or a boronic acid anhydride thereof.

50. The process of claim 49, characterized by at least one of the following features (1)-(3):

(1) In the boron “

ate”

complex of formula (XV), R³ and Y both are chloro.

(2) The coupling step (e′

) comprises the steps;

(i) coupling the compound of formula (XVIII) with a compound of formula (XIXa) wherein X is OH in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution.

(3) The boronic acid deprotecting step (f′

) comprises the steps;

(i) providing a biphasic mixture comprising the compound of formula (XXIII), an organic boronic acid acceptor, a lower alkanol, a C_5-8 hydrocarbon solvent, and aqueous mineral acid;

(ii) stirring the biphasic mixture to afford the compound of formula (XIV);

(iii) separating the solvent layers; and

(iv) extracting the compound of formula (XIV), or a boronic acid anhydride thereof, into an organic solvent.

51. The process of claim 50, wherein step (f′

)(iii) comprises the steps;

(1) separating the solvent layers;

(2) adjusting the aqueous layer to basic pH;

(3) washing the aqueous layer with an organic solvent; and

(4) adjusting the aqueous layer to a pH less than about 8.

52. The process of claim 51, wherein in step (f)(iii)(3), the aqueous layer is washed with dichloromethane.

53. The process of claim 51, wherein in step (f′

)(iv), the compound of formula (XIV), or a boronic acid anhydride thereof, is extracted into dichloromethane, the solvent is exchanged to ethyl acetate, an the compound of formula (XIV), or a boronic acid anhydride thereof, is crystallized by addition of hexane or heptane,

54. The process of claim 53, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

56. A composition comprising at least one kilogram of a compound of formula (XXIV):

wherein the compound of formula (XXIV) constitutes at least 99% w/w of the composition.