US2020369722A1PendingUtilityA1
Synthesis of boronic ester and acid compounds
Est. expiryMar 30, 2024(expired)· nominal 20-yr term from priority
Inventors:Vince AmmoscatoJohn E. BishopFang-Ting ChiuAchim GeiserJean-Marc GomezRobert HettChristoph KoellnerVithalanand R. KulkarniYoung S. LoStephen MunkI. Fraser Pickersgill
C07F 5/04C07F 5/02A61P 31/18C07F 5/025A61P 37/06A61P 35/00A61P 43/00C07K 5/06191Y02P20/55
74
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Claims
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
exact text as granted — not AI-modifiedWhat is claimed is:
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:
R 1 is an optionally substituted aliphatic or aromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 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.
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:
R 1 is an optionally substituted aliphatic or aromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 is substituted with a heteroaromatic group;
wherein the carbon atom to which R 1 , R 2 , and R 3 are attached is a chiral center, having a diastereomeric ratio of at least about 96:4, relative to a chiral center in the R 4 -R 5 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:
R 1 is an optionally substituted aliphatic or aromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 is substituted with a heteroaromatic group;
wherein the carbon atom to which R 1 , R 2 , and R 3 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.
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, tert-butyl ethyl ether, tert-amyl methyl ether, isopropyl ether, and mixtures thereof.
6 . The composition of any one of claims 1 - 3 , wherein R 1 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) R 3 is chloro; (b) R 2 is hydrogen; and (c) R 1 is C 1-4 aliphatic
8 . The composition of any one of claims 1 - 3 , wherein the compound of formula (I) is
9 . A composition comprising at least about ten moles of a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic or aromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 is substituted with a heteroaromatic group;
wherein the carbon atom to which R 1 , R 2 , and R 3 are attached is a chiral center, having a diastereomeric ratio of at least about 96:4, relative to a chiral center in the R 4 -R 5 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.
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 R 1 , R 2 , and R 3 are attached has a diastereomeric ratio of at least about 97:3, relative to a chiral center in the R 4 -R 5 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) R 3 is chloro; (b) the boronic ester compound of formula (I) is:
(c) R 2 is hydrogen; and
(d) R 1 is C 1-4 aliphatic.
14 . A large-scale process for preparing a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic or aromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 is substituted with a heteroaromatic group;
said process comprising:
(a) providing a solution comprising:
(i) a boronic ester of formula (III):
wherein R 1 , R 4 , and R 5 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 R 1 to R 5 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:
R 1 is an optionally substituted aliphatic or aromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 is substituted with a heteroaromatic group;
said process comprising:
(a) providing a solution comprising:
(i) a boronic ester of formula (III):
wherein R 1 , R 4 , and R 5 are as defined above;
(ii) a compound of formula (17):
where Y is a nucleofugic group, and R 2 and R 3 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 R 1 to R 5 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.
16 . A large-scale process for preparing a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic or aromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 is substituted with a heteroaromatic group;
said process comprising:
(a) providing a solution comprising:
(i) a boronic acid compound of formula (VI):
wherein R 1 is as defined above;
(ii) a compound of formula HO—R 4 —R 5 —OH, wherein R 4 and R 5 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 R 1 , R 4 , and R 5 are as defined above;
(c) providing a solution comprising:
(i) the boronic ester of formula (III);
(ii) a compound of formula (17):
wherein Y is a nucleofugic group, and R 2 and R 3 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 (II):
where M+is a cation derived from the base, and each of Y and R 1 to R 5 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.
17 . The process of claim 15 or 16 , wherein the sterically hindered base is an alkali metal dialkylamide base of formula M 2 N(R#)2, wherein M 2 is selected from the group consisting of Li, Na, and K, and each R#, independently, is a branched or cyclic C 3-6 aliphatic.
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:
R 1 is an optionally substituted aliphatic or aromatic group; and
R 4 and R 5 are together an optionally substituted aliphatic group, and R 4 and R 5 , 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 R 1 -R 5 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;
R 2 is hydrogen;
R 3 is a nucleofugic group; and
each of R 1 , R 4 , and R 5 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 R 1 to R 5 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 M 1 -N(Si(R 6 ) 3 ) 2 , where M 1 is an alkali metal and each R 6 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 M 1 -R 3 and a compound of formula (VIII):
wherein each G is —Si(R 6 ) 3 and R 1 to R 5 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 M 1 -R 3 has low solubility.
24 . The process of claim 23 , wherein M 1 is Li and R 3 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 M 1 -N(Si(R 6 ) 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:
P 1 is an amino group blocking moiety;
R 7 is selected from the group consisting of hydrogen, Cmoaliphatic, optionally substituted C 6-10 aryl, or C 1-6 aliphatic-R 8 ; and
R 8 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 P 1 , R 1 , R 4 , R 5 , and R 7 is as defined above.
35 . The process of claim 34 , wherein P 1 is a cleavable protecting group.
36 . The process of claim 35 , further comprising the steps:
(f) cleaving the protecting group P 1 to form a compound of formula (XI):
or an acid addition salt thereof, wherein each of R 1 , R 4 , R 5 , and R 7 is as defined above;
(g) coupling the compound of formula (XI) with a reagent of formula P 2 —X, wherein P 2 is an amino group blocking moiety and X is a leaving group, to form a compound of formula (XII):
wherein each of P 2 , R 1 , R 4 , R 5 , and R 7 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 P 1 , R 1 , and R 7 are as defined above.
37 . A large-scale process for preparing an aminoboronic ester compound of formula (VIM) or (VIIb):
or an acid addition salt thereof, wherein:
R 1 is an optionally substituted aliphatic, aromatic, or heteroaromatic group; and
R 4 and R 5 , 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 (IIb):
where
Y is a nucleofugic group;
M + is a cation;
R 2 is hydrogen;
R 3 is a nucleofugic group; and
R 4 and R 5 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 R 1 to R 5 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 M 1 -N(G)2, where M 1 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 R 1 to R 5 are as defined above; and
(d) removing the G groups to form a compound of formula (VIM) 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, comprising the steps:
(aa) coupling a compound of formula (XVIII):
or an acid addition salt thereof, with a compound of formula (XIX):
wherein:
P 1 is a cleavable amino group protecting moiety; and
X is OH or a leaving group;
to form a compound of formula (XX):
wherein P 1 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 P 1 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 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
(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.
39 . The process of claim 38 , wherein step (dd)(m) 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.
40 . The process of claim 39 , 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.
41 . The process of claim 40 , wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):
42 . 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:
R 3 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 (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 (XVI) with a reagent of formula M 1 -N(Si(R 6 )3) 2 , where M 1 is an alkali metal and each R 6 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(R 6 ) 3 ;
(d) removing the (R 6 ) 3 Si 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 (XIXa):
wherein X is OH or a leaving group, to form a compound of formula (XXIII):
and
(f′) deprotecting the boronic acid moiety to form the compound of formula (XIV) or a boronic acid anhydride thereof.
43 . The process of claim 42 , characterized by at least one of the following features (1)-(3):
(1) In the boron “ate” complex of formula (XV), R 3 and Y both are chloro. (2) The coupling step (e′) comprises the steps:
(i) coupling the compound of formula (XVIII) with a compound offormula (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.
44 . The process of claim 43 , 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.
45 . The process of claim 44 , wherein in step (f′)(iii)(3), the aqueous layer is washed with dichloromethane.
46 . The process of claim 44 , 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.
47 . The process of claim 46 , wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):
48 . 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 .
49 . 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.Cited by (0)
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