US2018265546A1PendingUtilityA1
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
A61P 43/00A61P 35/00A61P 31/18A61P 37/06C07F 5/025C07K 5/06191C07F 5/02Y02P20/55C07F 5/04
67
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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-modified1 .- 49 . (canceled)
50 . A large-scale process for preparing a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic, aromatic, or heteroaromatic group; and
each of R 4 and R 5 , independently, is an optionally substituted aliphatic, aromatic, or heteroaromatic group, or R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0-2 additional ring heteroatoms selected from N, O, or S;
said process comprising:
(a) providing a boron “ate” complex of formula (I):
where
Y is a nucleofugic group;
M + is a cation; and
each of R 1 to R 5 is as defined above; and
(b) 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.
51 . The process of claim 50 , wherein the reaction mixture comprises a coordinating co-solvent.
52 . The process of claim 51 , wherein the coordinating co-solvent is selected from the group consisting of tetrahydrofuran, dioxane, water, and mixtures thereof.
53 . The process of claim 52 , wherein the coordinating co-solvent constitutes no more than about 20% v/v of the reaction mixture.
54 . The process of claim 52 , wherein the coordinating co-solvent constitutes no more than about 15% v/v of the reaction mixture.
55 . The process of claim 50 , wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 2% w/w.
56 . The process of claim 55 , wherein the ether solvent that has low miscibility with water is selected from the group consisting of tert-butyl methyl ether, tert-butyl ethyl ether, tert-amyl methyl ether, isopropyl ether, and mixtures thereof.
57 . The process of claim 56 , wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.
58 . The process of claim 50 , wherein at least about 5 moles of the boron “ate” complex of formula (II) are provided in step (a).
59 . The process of claim 50 , wherein at least about 20 moles of the boron “ate” complex of formula (II) are provided in step (a).
60 . The process of claim 50 , wherein at least about 50 moles of the boron “ate” complex of formula (II) are provided in step (a).
61 . The process of claim 50 , wherein at least about 100 moles of the boron “ate” complex of formula (II) are provided in step (a).
62 . The process of claim 50 , wherein the Lewis acid is selected from the group consisting of zinc chloride, zinc bromide, ferric chloride, and ferric bromide.
63 . The process of claim 62 , wherein the Lewis acid is moist.
64 . The process of claim 62 , wherein in step (a) the boron “ate” complex of formula (fi) is provided in a solution comprising an ether solvent that has low miscibility with water, and the contacting step (b) comprises the steps:
(i) providing a solution comprising a Lewis acid and tetrahydrofuran; and
(ii) adding the Lewis acid solution to the solution of the boron “ate” complex of formula (II) from step (a).
65 . The process of claim 62 , wherein in step (a) the boron “ate” complex of formula (I) is provided in a solution comprising an ether solvent that has low miscibility with water, and the contacting step (b) comprises the steps:
(i) providing a solution comprising a Lewis acid and water; and
(ii) adding the Lewis acid solution to the solution of the boron “ate” complex of formula (II) from step (a).
66 . The process of claim 50 , wherein Y is a halogen.
67 . The process of claim 50 , wherein Y is chloro.
68 . The process of claim 50 , wherein R 1 is C 1-8 aliphatic, C 6-10 aryl, or (C 6-10 aryl)(C 1-6 aliphatic).
69 . The process of claim 50 , wherein M + is selected from the group consisting of Li + , Na + , and K + .
70 . The process of claim 50 , wherein R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5-membered ring.
71 . The process of claim 70 , wherein R 4 and R 5 together are a chiral moiety.
72 . The process of claim 71 , wherein the boron “ate” complex of formula (II) is:
73 . The process of claim 71 , wherein step (b) provides the boronic ester compound of formula (I) wherein the carbon atom bearing R 1 , R 2 , and R 3 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.
74 . The process of claim 71 , wherein step (b) provides the boronic ester compound of formula (I) wherein the carbon atom bearing R 1 , R 2 , and R 3 is a chiral center having a diastereomeric ratio of at least about 97:3 relative to a chiral center in the R 4 -R 5 chiral moiety
75 . The process of claim 71 , characterized by at least one of the following features:
(a) the contacting step (b) is conducted in a reaction mixture comprising tert-butyl methyl ether, (b) the Lewis acid is zinc chloride; (c) at least about 5 moles of the boronic ester of formula (II) are provided in step (a); (d) the contacting step (b) is performed at a reaction temperature in the range of about −60° C. to about −30° C.; (e) the Lewis acid is moist; (f) Y is chloro; (g) R 3 is chloro; (h) R 2 is hydrogen; and (i) R 1 is C 1-4 aliphatic.
76 . The process of claim 75 , characterized by at least two of the features (a)-(h).
77 . The process of claim 75 , characterized by at least three of the features (a)-(h).
78 . The process of claim 75 , characterized by all eight of the features (a)-(h).
79 . The process of claim 71 , further comprising:
(c) washing the reaction mixture with an aqueous solution; and (d) concentrating the washed reaction mixture by removal of solvents to afford a residue comprising the boronic ester compound of formula (I).
80 . The process of claim 75 , wherein the residue comprises at least about five moles of the boronic ester compound of formula (I).
81 . The process of claim 80 , wherein the boronic ester compound of formula (I) present in the residue has a diastereomeric ratio of at least about 96:4 at the carbon atom bearing R 1 , R 2 , and R 3 , relative to a chiral center in the R 4 -R 5 chiral moiety.
82 . The process of claim 80 , wherein the boronic ester compound of formula (I) present in the residue has a diastereomeric ratio of at least about 97:3 at the carbon atom bearing R 1 , R 2 , and R 3 , relative to a chiral center in the R 4 -R 5 chiral moiety.
83 . 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, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic, aromatic, or heteroaromatic group; and
each of R 4 and R 5 , independently, is an optionally substituted aliphatic or aromatic group, or R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0-2 additional ring heteroatoms selected from N, O, or S.
84 . 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, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic, aromatic, or heteroaromatic group; and
each of R 4 and R 5 , independently, is an optionally substituted aliphatic or aromatic group, or R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0-2 additional ring heteroatoms selected from N, O, or S;
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.
85 . 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, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic, aromatic, or heteroaromatic group; and
each of R 4 and R 5 , independently, is an optionally substituted aliphatic or aromatic group, or R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0-2 additional ring heteroatoms selected from N, O, or S;
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.
86 . The composition of any one of claims 83 - 85 , wherein the solubility of water in the ether solvent is less than about 2% w/w.
87 . The composition of any one of claims 83 - 85 , 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.
88 . The composition of any one of claims 83 - 85 , wherein R 1 is C 1-8 aliphatic, C 6-10 to aryl, or (C 6-10 aryl)(C 1-6 aliphatic).
89 . The composition of any one of claims 83 - 85 , 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
90 . The composition of any one of claims 83 - 85 , wherein R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5-membered ring.
91 . The composition of any one of claims 83 - 85 , wherein the compound of formula (I) is
92 . A composition comprising at least about ten moles of a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or 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 5- to 10-membered chiral ring having 0-2 additional ring heteroatoms selected from N, O, or S;
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; and
wherein the boronic ester compound of formula (I) constitutes at least about 70% w/w of the composition.
93 . The composition of claim 85 comprising at least about 20 moles of the boronic ester compound of formula (I).
94 . The composition of claim 85 , 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.
95 . The composition of claim 85 , wherein all of the boronic ester compound of formula (I) present in the composition is produced in a single batch run.
96 . The composition of claim 85 , wherein all of the boronic ester compound of formula (I) present in the composition is produced in a single batch run of the process according to claim 50 .
97 . The composition of claim 85 , 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.
98 . A large-scale process for preparing a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic, aromatic, or heteroaromatic group; and
each of R 4 and R 5 , independently, is an optionally substituted aliphatic, aromatic, or heteroaromatic group, or R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0-2 additional ring heteroatoms selected from N, O, or S;
said process comprising:
(a) providing a solution comprising:
(i) a boronic ester of formula (II):
wherein R 1 , R 4 , and R 5 are as defined above; and
(ii) an ether solvent that has low miscibility with water,
(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 (I) 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.
99 . A large-scale process for preparing a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic, aromatic, or heteroaromatic group; and
each of R 4 and R 5 , independently, is an optionally substituted aliphatic, aromatic, or heteroaromatic group, or R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0-2 additional ring heteroatoms selected from N, O, or S;
said process comprising:
(a) providing a solution comprising:
(i) a boronic ester of formula (II):
wherein R 1 , R 4 , and R 5 are as defined above;
(ii) a compound of formula (V):
where Y is a nucleofugic group, and R 2 and R 3 are as defined above; and
(iii) a solvent comprising:
(1) a coordinating ether solvent that has low miscibility with water, or
(2) an ether solvent that has low miscibility with water and a coordinating co-solvent;
(b) treating the solution of step (a) with a strong, sterically hindered base to form a boron “ate” complex of formula (i):
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).
100 . A large-scale process for preparing a boronic ester compound of formula (I):
wherein:
R 1 is an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic, aromatic, or heteroaromatic group;
R 3 is a nucleofugic group or an optionally substituted aliphatic, aromatic, or hetoaromatic group; and
R 4 and R 5 , taken together, form an optionally substituted linking chain comprising 2-5 carbon atoms and 0-2 heteroatoms selected from the group consisting of O, N, and S;
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 (V):
wherein Y is a nucleofugic group, and R 2 and R 3 are as defined above; and
(iii) a solvent comprising:
(1) a coordinating ether solvent that has low miscibility with water, or
(2) an ether solvent that has low miscibility with water and a coordinating co-solvent;
(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).
101 . The process of claim 99 or 100 , 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.
102 . The process of claim 100 , wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, hexane, heptane, and mixtures thereof.
103 . The process of claim 100 , wherein the organic solvent in step (a) is an ether solvent that has low miscibility with water.
104 . The process of claim 103 , wherein the solutions in steps (a) and (c) each comprise the same ether solvent.
105 . The process of claim 104 , 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).
106 . 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, aromatic, or heteroaromatic group; and
each of R 4 and R 5 , independently, is an optionally substituted aliphatic, aromatic, or heteroaromatic group, or R 4 and R 5 , taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0-2 additional ring heteroatoms selected from N, O, or S;
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;
(c) treating the boronic ester compound of formula (I) with a reagent of formula M 1 -N(Si(R 6 )) 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 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.
107 . The process of claim 106 , wherein the reaction mixture in step (c) comprises an organic solvent in which the byproduct M 1 -R 3 has low solubility.
108 . The process of claim 107 , wherein M 1 is Li and R 3 is Cl.
109 . The process of claim 108 , 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.
110 . The process of claim 106 , wherein the reaction in step (c) is conducted at a reaction temperature in the range of about −100° C. to about 50° C.
111 . The process of claim 110 , wherein the reaction temperature is in the range of about −50° C. to about 25° C.
112 . The process of claim 110 , wherein the reaction temperature is in the range of about −30° C. to about 0° C.
113 . The process of claim 106 , 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.
114 . The process of claim 113 , wherein the acid is trifluoroacetic acid.
115 . The process of claim 106 , wherein step (c) further comprises filtering the reaction mixture to provide a filtrate comprising the compound of formula (Viii).
116 . The process of claim 115 , 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.
117 . The process of claim 115 , wherein the filtrate is used directly in step (d).
118 . The process of claim 106 , further comprising the step:
(e) coupling the compound of formula (Vii) with a compound of formula (X):
wherein:
P 1 is an amino group blocking moiety;
R 7 is selected from the group consisting of hydrogen, C 1-10 aliphatic, 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.
119 . The process of claim 118 , wherein P 1 is a cleavable protecting group.
120 . The process of claim 119 , 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.
121 . A large-scale process for preparing an aminoboronic ester compound of formula (VIIa) 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;
(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 (VIIa) or (VIIb):
or an acid addition salt thereof.
122 . 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:
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,
(c) treating the boronic ester compound of formula (XVI) with a reagent of formula M 1 -N(G) 2 , where M 1 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
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;
(f) removing the protecting group P 1 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):
and
(h) deprotecting the boronic acid moiety to form the compound of formula (XIV) or a boronic acid anhydride thereof.
123 . The process of claim 122 , characterized by at least one of the following features (1)-(5):
(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 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 (XX)) as its HCl addition salt;
(4) the coupling step (g) comprises 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
(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 5-8 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.
124 . The process of claim 123 , characterized by all five features (1)-(5).
125 . The process of claim 123 , 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.
126 . The process of claim 125 , wherein in step (h)(iii)(3), the aqueous layer is washed with dichloromethane.
127 . The process of claim 125 , 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.
128 . The process of claim 127 , wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):
129 . 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 (XV), or a boronic acid anhydride thereof, into an organic solvent.
130 . The process of claim 129 , 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.
131 . The process of claim 130 , 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.
132 . The process of claim 131 , wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):
133 . 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;
(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):
(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 (XVII) with a compound of formula (XIXa):
wherein X is OH or a leaving group, to form a compound of formula (XXII):
and
(f′) deprotecting the boronic acid moiety to form the compound of formula (XIV) or a boronic acid anhydride thereof.
134 . The process of claim 133 , characterized by at least one of the following features (1)-(3):
(1) In the boron “ate” complex of formula (XP), R 3 and Y both are chloro. (2) The coupling step (e) comprises the steps:
(i) coupling the compound of formula (XVII) 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.
135 . The process of claim 134 , 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.
136 . The process of claim 135 , wherein in step (f)(iii)(3), the aqueous layer is washed with dichloromethane.
137 . The process of claim 135 , 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.
138 . The process of claim 137 , wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):
139 . 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 122 or 129 .
140 . 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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