U.S. patent application number 16/508706 was filed with the patent office on 2019-10-31 for synthesis of boronic ester and acid compounds.
The applicant listed for this patent is Millennium Pharmaceuticals, Inc.. Invention is credited to Vince Ammoscato, John E. Bishop, Fang-Ting Chiu, Achim Geiser, Jean-Marc Gomez, Robert Hett, Christoph Koellner, Vithalanand R. Kulkarni, Young Lo, Stephen Munk, I. Fraser Pickersgill.
Application Number | 20190330270 16/508706 |
Document ID | / |
Family ID | 34968044 |
Filed Date | 2019-10-31 |
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United States Patent
Application |
20190330270 |
Kind Code |
A1 |
Ammoscato; Vince ; et
al. |
October 31, 2019 |
SYNTHESIS OF BORONIC ESTER AND ACID COMPOUNDS
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.
Inventors: |
Ammoscato; Vince;
(Riverview, MI) ; Bishop; John E.; (Carlisle,
MA) ; Chiu; Fang-Ting; (Petersburg, VA) ;
Geiser; Achim; (Hunzenschwil, CH) ; Gomez;
Jean-Marc; (Bubendorf, CH) ; Hett; Robert;
(Unterageri, CH) ; Koellner; Christoph;
(Bubendorf, CH) ; Kulkarni; Vithalanand R.;
(Petersburg, VA) ; Lo; Young; (Petersburg, VA)
; Munk; Stephen; (Riverview, MI) ; Pickersgill; I.
Fraser; (Newton, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Millennium Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
34968044 |
Appl. No.: |
16/508706 |
Filed: |
July 11, 2019 |
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16508706 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y02P 20/55 20151101;
C07F 5/04 20130101; A61P 35/00 20180101; C07K 5/06191 20130101;
A61P 37/06 20180101; A61P 43/00 20180101; C07F 5/025 20130101; A61P
31/18 20180101 |
International
Class: |
C07K 5/06 20060101
C07K005/06; C07F 5/04 20060101 C07F005/04; C07F 5/02 20060101
C07F005/02 |
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): ##STR00051## wherein R.sup.1 is an
optionally substituted aliphatic or aromatic group; R.sup.2 is
hydrogen, a nucleofugic group, or an optionally substituted
aliphatic or aromatic group; R.sup.3 is a nucleofugic group or an
optionally substituted aliphatic or aromatic group; and R.sup.4 and
R.sup.5 are together an optionally substituted aliphatic group, and
R.sup.4 and R.sup.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.sup.1-R.sup.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): ##STR00052## wherein: R.sup.1 is an
optionally substituted aliphatic or aromatic group; R.sup.2 is
hydrogen, a nucleofugic group, or an optionally substituted
aliphatic or aromatic group; R.sup.3 is a nucleofugic group or an
optionally substituted aliphatic or aromatic group; and R.sup.4 and
R.sup.5 are together an optionally substituted aliphatic group, and
R.sup.4 and R.sup.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.sup.1-R.sup.5 is substituted with a heteroaromatic group; wherein
the carbon atom to which R.sup.1, R.sup.2, and R.sup.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.sup.4-R.sup.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): ##STR00053## wherein: R.sup.1 is an
optionally substituted aliphatic or aromatic group; R.sup.2 is
hydrogen, a nucleofugic group, or an optionally substituted
aliphatic or aromatic group; R.sup.3 is a nucleofugic group or an
optionally substituted aliphatic or aromatic group; and R.sup.4 and
R.sup.5 are together an optionally substituted aliphatic group, and
R.sup.4 and R.sup.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.sup.1-R.sup.5 is substituted with a heteroaromatic group; wherein
the carbon atom to which R.sup.1, R.sup.2, and R.sup.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.sup.1 is
C.sub.1-8 aliphatic, C.sub.6-10 aryl, or (C.sub.6-10
aryl)(C.sub.1-6 aliphatic).
7. The composition of any one of claims 1-3, characterized by at
least one of the following features: (a) R.sup.3 is chloro; (b)
R.sup.2 is hydrogen; and (c) R.sup.1 is C.sub.1-4 aliphatic
8. The composition of any one of claims 1-3, wherein the compound
of formula (I) is ##STR00054##
9. A composition comprising at least about ten moles of a boronic
ester compound of formula (I): ##STR00055## wherein: R.sup.1 is an
optionally substituted aliphatic or aromatic group; R.sup.2 is
hydrogen, a nucleofugic group, or an optionally substituted
aliphatic or aromatic group; R.sup.3 is a nucleofugic group or an
optionally substituted aliphatic or aromatic group; and R.sup.4 and
R.sup.5 are together an optionally substituted aliphatic group, and
R.sup.4 and R.sup.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.sup.1-R.sup.5 is substituted with a heteroaromatic group; wherein
the carbon atom to which R.sup.1, R.sup.2, and R.sup.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.sup.4-R.sup.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.sup.1, R.sup.2, and R.sup.3 are attached has a diastereomeric
ratio of at least about 97.3, relative to a chiral center in the
R.sup.4-R.sup.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.sup.3 is chloro; (b) the
boronic ester compound of formula (I) is: ##STR00056## (c) R.sup.2
is hydrogen; and (d) R.sup.1 is C.sub.1-4 aliphatic.
14. A large-scale process for preparing a boronic ester compound of
formula (I): ##STR00057## wherein: R.sup.1 is an optionally
substituted aliphatic or aromatic group; R.sup.2 is hydrogen, a
nucleofugic group, or an optionally substituted aliphatic or
aromatic group; R.sup.3 is a nucleofugic group or an optionally
substituted aliphatic or aromatic group; and R.sup.4 and R.sup.5
are together an optionally substituted aliphatic group, and R.sup.4
and R.sup.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.sup.1-R.sup.5 is substituted with a heteroaromatic group; said
process comprising: (a) providing a solution comprising: (i) a
boronic ester of formula (Q): ##STR00058## wherein R.sup.1,
R.sup.4, and R.sup.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): ##STR00059## to form a boron "ate" complex of formula
(II): ##STR00060## where Y is a nucleofugic group; M.sup.+ is a
cation; and each of R.sup.1 to R.sup.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): ##STR00061## wherein: R.sup.1 is an optionally
substituted aliphatic or aromatic group; R.sup.2 is hydrogen, a
nucleofugic group, or an optionally substituted aliphatic or
aromatic group; R.sup.3 is a nucleofugic group or an optionally
substituted aliphatic or aromatic group; and R.sup.4 and R.sup.5
are together an optionally substituted aliphatic group, and R.sup.4
and R.sup.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.sup.1-R.sup.5 is substituted with a heteroaromatic group; said
process comprising: (a) providing a solution comprising: (i) a
boronic ester of formula (III): ##STR00062## wherein R.sup.1,
R.sup.4, and R.sup.5 are as defined above; (ii) a compound of
formula (V): ##STR00063## where Y is a nucleofugic group, and
R.sup.2 and R.sup.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): ##STR00064## where M.sup.+ is a cation
derived from the base, and each of Y and R.sup.1 to R.sup.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): ##STR00065## wherein: R.sup.1 is an optionally
substituted aliphatic or aromatic group; R.sup.2 is hydrogen, a
nucleofugic group, or an optionally substituted aliphatic or
aromatic group; R.sup.3 is a nucleofugic group or an optionally
substituted aliphatic or aromatic group; and R.sup.4 and R.sup.5
are together an optionally substituted aliphatic group, and R.sup.4
and R.sup.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.sup.1-R.sup.5 is substituted with a heteroaromatic group; said
process comprising: (a) providing a solution comprising: (i) a
boronic acid compound of formula (VI): ##STR00066## wherein R.sup.1
is as defined above; (ii) a compound of formula
HO--R.sup.4-R.sup.5--OH, wherein R.sup.4 and R.sup.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): ##STR00067## wherein R.sup.1, R.sup.4, and R.sup.5 are as
defined above; (c) providing a solution comprising: (i) the boronic
ester of formula (III); (ii) a compound of formula (V):
##STR00068## wherein Y is a nucleofugic group, and R.sup.2 and
R.sup.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): ##STR00069## where M.sup.+ is a cation derived from
the base, and each of Y and R.sup.1 to R.sup.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.sup.2N(R).sub.2, wherein M.sup.2 is selected from the group
consisting of Li, Na, and K, and each Re, independently, is a
branched or cyclic C.sub.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): ##STR00070## or an acid addition salt
thereof, wherein R.sup.1 is an optionally substituted aliphatic or
aromatic group; and R.sup.4 and R.sup.5 are together an optionally
substituted aliphatic group, and R.sup.4 and R.sup.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.sup.1-R.sup.5 is
substituted with a heteroaromatic group; said process comprising:
(a) providing a boron "ate" complex of formula (II): ##STR00071##
where Y is a nucleofugic group; M.sup.+ is a cation; R.sup.2 is
hydrogen; R.sup.3 is a nucleofugic group; and each of R.sup.1,
R.sup.4, and R.sup.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): ##STR00072##
where each of R.sup.1 to R.sup.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.sup.1-N(Si(R.sup.6).sub.3).sub.2, where M.sup.1 is an alkali
metal and each R.sup.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.sup.1-R.sup.3 and a compound of formula
(VIII): ##STR00073## wherein each G is --Si(R.sup.6).sub.3 and
R.sup.1 to R.sup.5 are as defined above; and (d) removing the G
groups to form a compound of formula (VII): ##STR00074## 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-R.sup.3
has low solubility.
24. The process of claim 23, wherein M.sup.1 is Li and R.sup.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.degree. C. to about 50.degree. C.
27. The process of claim 26, wherein the reaction temperature is in
the range of about -50.degree. C. to about 25.degree. C.
28. The process of claim 26, wherein the reaction temperature is in
the range of about -30.degree. C. to about 0.degree. 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.sup.1-N(Si(R.sup.6).sub.3).sub.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): ##STR00075## wherein: P.sup.1 is an amino group blocking
moiety; R.sup.7 is selected from the group consisting of hydrogen,
C.sub.1-10aliphatic, optionally substituted C.sub.6-10aryl, or
C.sub.1-6aliphatic-R.sup.8; and R.sup.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): ##STR00076## wherein each
of P.sup.1, R.sup.1, R.sup.4, R.sup.5, and R.sup.7 is as defined
above.
35. The process of claim 34, wherein P.sup.1 is a cleavable
protecting group.
36. The process of claim 35, further comprising the steps: (f)
cleaving the protecting group P.sup.1 to form a compound of formula
(XI): ##STR00077## or an acid addition salt thereof, wherein each
of R.sup.1, R.sup.4, R.sup.5, and R.sup.7 is as defined above; (g)
coupling the compound of formula (XI) with a reagent of formula
P.sup.2--X, wherein P.sup.2 is an amino group blocking moiety and X
is a leaving group, to form a compound of formula (XII):
##STR00078## wherein each of P.sup.2, R.sup.1, R.sup.4, R.sup.5,
and R.sup.7 are as defined above; and (h) deprotecting the boronic
acid moiety to form a compound of formula (XIII): ##STR00079## or a
boronic acid anhydride thereof, wherein each of P.sup.1, R.sup.1,
and R.sup.7 are as defined above.
37. A large-scale process for preparing an aminoboronic ester
compound of formula (VIIa) or (VIIb): ##STR00080## or an acid
addition salt thereof, wherein: R.sup.1 is an optionally
substituted aliphatic, aromatic, or heteroaromatic group; and
R.sup.4 and R.sup.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): ##STR00081## where Y is a nucleofugic
group; M.sup.+ is a cation; R.sup.2 is hydrogen; R.sup.3 is a
nucleofugic group; and R.sup.4 and R.sup.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): ##STR00082## where each of
R.sup.1 to R.sup.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.sup.1-N(G).sub.2, where M.sup.1 is an
alkali metal and each G is an amino group protecting moiety, to
form a compound of formula (VIIIa) or (VIIIb): ##STR00083## wherein
each G and R.sup.1 to R.sup.5 are as defined above; and (d)
removing the G groups to form a compound of formula (VIIa) or
(VIIb): ##STR00084## or an acid addition salt thereof.
38. A large-scale process for forming a compound of formula (XIV):
##STR00085## or a boronic acid anhydride thereof, comprising the
steps: (aa) coupling a compound of formula (XVIII): ##STR00086## or
an acid addition salt thereof, with a compound of formula (XIX):
##STR00087## wherein: P.sup.1 is a cleavable amino group protecting
moiety; and X is OH or a leaving group; to form a compound of
formula (XX): ##STR00088## wherein P.sup.1 is as defined above,
said coupling step (aa) comprising the steps: (i) coupling the
compound of formula (XVII) 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.sup.1 to
form a compound of formula (XXI): ##STR00089## or an acid addition
salt thereof, said protecting group removing step (bb) comprising
the steps: (i) treating the compound of formula (XX) with HC in
ethyl acetate; (ii) adding heptane to the reaction mixture; and
(iii) isolating by crystallization the compound of formula (XXI) as
its HQ addition salt; (cc) coupling the compound of formula (XXI)
with a reagent of formula (XXI) ##STR00090## wherein X is a OH or a
leaving group, to form a compound of formula (XXIII): ##STR00091##
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 (XXII), an
organic boronic acid acceptor, a lower alkanol, a C.sub.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.
39. The process of claim 38, 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.
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): ##STR00092##
42. A large-scale process for forming a compound of formula (XIV):
##STR00093## or a boronic acid anhydride thereof. The process
comprises the steps: (a) providing a boron "ate" complex of formula
(XV): ##STR00094## wherein: R.sup.3 is a nucleofugic group; Y is a
nucleofugic group; and M.sup.+ 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):
##STR00095## 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.sup.1-N(Si(R.sup.6).sub.3).sub.2, where M.sup.1 is an alkali
metal and each R.sup.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): ##STR00096## wherein each G is
--Si(R.sup.6).sub.3; (d) removing the (R.sup.6).sub.3Si groups to
form a compound of formula (XVIII): ##STR00097## or an acid
addition salt thereof; (e') coupling the compound of formula (XVII)
with a compound of formula (XIXa): ##STR00098## wherein X is OH or
a leaving group, to form a compound of formula (XXIII):
##STR00099## 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.sup.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 (XIXa) wherein X is OH in the
presence of 2-(1H-benzotriazol-1-yl)-1,1,3-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.sub.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): ##STR00100##
48. A composition comprising at least one kilogram of a compound of
formula (XXIV): ##STR00101## 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): ##STR00102## wherein the compound of formula (XXIV)
constitutes at least 99% w/w of the composition.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 13/615,894, filed Sep. 14, 2012 (pending),
which is a divisional of U.S. patent application Ser. No.
12/706,063, filed Feb. 16, 2010, now U.S. Pat. No. 8,283,467, which
is a divisional of U.S. patent application Ser. No. 11/088,667,
filed Mar. 24, 2005, now U.S. Pat. No. 7,714,159, which claims the
benefit of U.S. Provisional Application Ser. No. 60/557,535, filed
Mar. 30, 2004 (expired). The entire contents of each of the
above-referenced patent applications are incorporated herein by
this reference.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention relates to the synthesis of boronic ester and
acid compounds. More particularly, the invention relates to
large-scale synthetic processes for the preparation of boronic
ester and acid compounds by Lewis acid promoted rearrangement of
boron "ate" complexes.
Background of the Invention
[0003] Boronic acid and ester compounds display a variety of
pharmaceutically useful biological activities. Shenvi et at, U.S.
Pat. No. 4,499,082 (1985), discloses that peptide boronic acids are
inhibitors of certain proteolytic enzymes. Kettner and Shenvi, U.S.
Pat. No. 5,187,157 (1993), U.S. Pat. No. 5,242,904 (1993), and U.S.
Pat. No. 5,250,720 (1993), describe a class of peptide boronic
acids that inhibit trypsin-like proteases. Kleeman et al., U.S.
Pat. No. 5,169,841 (1992), discloses N-terminally modified peptide
boronic acids that inhibit the action of renin. Kinder et al., U.S.
Pat. No. 5,106,948 (1992), discloses that certain tripeptide
boronic acid compounds inhibit the growth of cancer cells.
[0004] More recently, boronic acid and ester compounds have
displayed particular promise as inhibitors of the proteasome, a
multicatalytic protease responsible for the majority of
intracellular protein turnover. Ciechanover, Cell, 79: 13-21
(1994), discloses that the proteasome is the proteolytic component
of the ubiquitin-proteasome pathway, in which proteins are targeted
for degradation by conjugation to multiple molecules of ubiquitin.
Ciechanover also discloses that the ubiquitin-proteasome pathway
plays a key role in a variety of important physiological
processes.
[0005] Adams et al., U.S. Pat. No. 5,780,454 (1998), U.S. Pat. No.
6,066,730 (2000), U.S. Pat. No. 6,083,903 (2000), U.S. Pat. No.
6,297,217 (2001), U.S. Pat. Nos. 6,548,668, and 6,617,317 (2003),
hereby incorporated by reference in their entirety, describe
peptide boronic ester and acid compounds useful as proteasome
inhibitors. The references also describe the use of boronic ester
and acid compounds to reduce the rate of muscle protein
degradation, to reduce the activity of NF-.kappa.B in a cell, to
reduce the rate of degradation of p53 protein in a cell, to inhibit
cyclin degradation in a cell, to inhibit the growth of a cancer
cell, to inhibit antigen presentation in a cell, to inhibit
NF-.kappa.B dependent cell adhesion, and to inhibit HIV
replication.
[0006] Albanell and Adams, Drugs of the Future 27:1079-1092 (2002),
discloses that one such peptide boronic acid proteasome inhibitor,
bortezomib (N-2-pyrazinecarbonyl-L-phenylalanine-L-leucineboronic
acid), shows significant antitumor activity in human tumor
xenograft models and is undergoing clinical evaluation. Richardson
et al., New Engl. J. Med., 348.2609 (2003), reports the results of
a Phase 2 study of bortezomib, showing its effectiveness in
treating relapsed and refractory multiple myeloma.
[0007] Studies of boronic acid protease inhibitors have been
greatly advanced by the development of chemistry for the
preparation of functionalized boronic acid compounds, particularly
alpha-halo- and alpha-aminoboronic acids. Matteson and Majumdar, J.
Am. Chem. Soc., 1027590 (1980), discloses a method for preparing
alpha-chloroboronic esters by homologation of boronic esters, and
Matteson and Ray, J. Am. Chem. Soc., 1027591 (1980), reports that
chiral control of the homologation reaction can be achieved by the
use of pinanediol boronic esters. The preparation of
alpha-aminoboronic acid and ester compounds from the corresponding
alpha-chloroboronic esters has also been reported (Matteson et al.,
J. Am. Chem. Soc., 103:5241 (1981); Shenvi, U.S. Pat. No. 4,537,773
(1985)).
[0008] Matteson and Sadhu, U.S. Pat. No. 4,525,309 (1985),
describes an improved procedure for the homologation of boronic
esters by rearrangement of the intermediate boron "ate" complex in
the presence of a Lewis acid catalyst. The Lewis acid is reported
to promote the rearrangement reaction and to minimize epimerization
at the alpha-carbon atom. Rigorous exclusion of water and careful
control of Lewis acid stoichiometry are required for optimum
results, however. These features render the reaction difficult to
perform successfully on a production scale, and limit the
availability of pharmaceutically important boronic ester and acid
compounds, such as bortezomib. Thus, there remains a need in the
art for improved methods for the largescale production of boronic
ester and acid compounds.
DESCRIPTION OF THE INVENTION
[0009] The present invention provides improved synthetic processes
for the large-scale production of boronic ester and acid compounds.
These processes offer increased yield and purity, increased
throughput, and greater ease of handling as compared to prior art
methods. Notably, the processes described herein are suitable for
batch production on a large, multi-kilogram scale that is limited
only by the size of the available manufacturing capabilities. The
processes of the invention are particularly advantageous for the
synthesis of chiral boronic ester and acid compounds, including
alpha-aminoboronic ester and acid compounds. Regardless of scale,
the desired products are produced with very high chemical and
stereochemical purity.
[0010] The patent and scientific literature referred to herein
establishes knowledge that is available to those with skill in the
art. Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention relates. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods and materials are described
herein. The issued patents, applications, and references that are
cited herein are hereby incorporated by reference to the same
extent as if each was specifically and individually indicated to be
incorporated by reference. In the case of inconsistencies, the
present disclosure, including definitions, will control. In
addition, the materials, methods, and examples are illustrative
only and are not intended to be limiting.
[0011] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
10%.
[0012] The term "comprises" is used herein to mean "includes, but
is not limited to."
[0013] The term "aliphatic", as used herein, means a
straight-chain, branched or cyclic C.sub.1-12 hydrocarbon which is
completely saturated or which contains one or more units of
unsaturation, but which is not aromatic. For example, suitable
aliphatic groups include substituted or unsubstituted linear,
branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids
thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or
(cycloalkyl)alkenyl. In various embodiments, the aliphatic group
has 1-12, 1-8, 1-6, or 1-4 carbons.
[0014] The terms "alkyl", "alkenyl", and "alkynyl", used alone or
as part of a larger moiety, refer to a straight and branched chain
aliphatic group having from 1 to 12 carbon atoms, which is
optionally substituted with one, two or three substituents. For
purposes of the present invention, the term "alkyl" will be used
when the carbon atom attaching the aliphatic group to the rest of
the molecule is a saturated carbon atom. However, an alkyl group
may include unsaturation at other carbon atoms. Thus, alkyl groups
include, without limitation, methyl, ethyl, propyl, allyl,
propargyl, butyl, pentyl, and hexyl.
[0015] For purposes of the present invention, the term "alkenyl"
will be used when the carbon atom attaching the aliphatic group to
the rest of the molecule forms part of a carbon-carbon double bond.
Alkenyl groups include, without limitation, vinyl, 1-propenyl,
1-butenyl, 1-pentenyl, and 1-hexenyl. For purposes of the present
invention, the term "alkynyl" will be used when the carbon atom
attaching the aliphatic group to the rest of the molecule forms
part of a carbon-carbon triple bond. Alkynyl groups include,
without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, and
1-hexynyl.
[0016] The terms "cycloalkyl", "carbocycle", "carbocyclyl",
"carbocyclo", or "carbocyclic", used alone or as part of a larger
moiety, means a saturated or partially unsaturated cyclic aliphatic
ring system having from 3 to about 14 members, wherein the
aliphatic ring system is optionally substituted. Cycloalkyl groups
include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In
some embodiments, the cycloalkyl has 3-6 carbons. The terms
"cycloalkyl", "carbocycle", "carbocyclyl", "carbocyclo", or
"carbocyclic" also include aliphatic rings that are fused to one or
more aromatic or nonaromatic rings, such as decahydronaphthyl or
tetrahydronaphthyl, where the radical or point of attachment is on
the aliphatic ring.
[0017] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer
to an alkyl, alkenyl or alkoxy group, as the case may be,
substituted with one or more halogen atoms. As used herein, the
term "halogen" or "halo" means F, C, Br, or I. Unless otherwise
indicated, the terms "alkyl", "alkenyl", and "alkoxy" include
haloalkyl, haloalkenyl and haloalkoxy groups, including, in
particular, those with 1-5 fluorine atoms.
[0018] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to a C.sub.6-14 aromatic moiety comprising one to three
aromatic rings, which are optionally substituted. Preferably, the
aryl group is a C.sub.6-30 aryl group. Aryl groups include, without
limitation, phenyl, naphthyl, and anthracenyl. The term "aryl", as
used herein, also includes groups in which an aromatic ring is
fused to one or more non-aromatic rings, such as indanyl,
phenanthridinyl, or tetrahydronaphthyl, where the radical or point
of attachment is on the aromatic ring. The term "aryl" may be used
interchangeably with the term "aryl ring".
[0019] An "aralkyl" or "arylalkyl" group comprises an aryl group
covalently attached to an alkyl group, either of which
independently is optionally substituted. Preferably, the aralkyl
group is C.sub.6-10 aryl(C.sub.1-6)alkyl, including, without
limitation, benzyl, phenethyl, and naphthylmethyl.
[0020] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., heteroaralkyl, or "heteroaralkoxy",
refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or
10 ring atoms; having 6, 10, or 14 .pi. electrons shared in a
cyclic array; and having, in addition to carbon atoms, from one to
four heteroatoms selected from the group consisting of N, O, and S.
Heteroaryl groups include, without limitation, thienyl, furanyl,
pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,
isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,
benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl,
benzimidazolyl, benzthiazolyl, purinyl, quinolyl, isoquinolyl,
cinnolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pteridinyl,
carbazolyl, acridinyl, and phenazinyl. The terms "heteroaryl" and
"heteroar-", as used herein, also include groups in which a
heteroaromatic ring is fused to one or more nonaromatic rings,
where the radical or point of attachment is on the heteroaromatic
ring. Nonlimiting examples include tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and pyrido[3,4-d]pyrimidinyl. The term
"heteroaryl" may be used interchangeably with the term "heteroaryl
ring" or the term "heteroaromatic", any of which terms include
rings that are optionally substituted. The term "heteroaralkyl"
refers to an alkyl group substituted by a heteroaryl, wherein the
alkyl and heteroaryl portions independently are optionally
substituted.
[0021] As used herein, the terms "heterocycle", "heterocyclyl", or
"heterocyclic radical" refer to a stable 5- to 7-membered
monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that
is either saturated or partially unsaturated, and having, in
addition to carbon atoms, one or more, preferably one to four,
heteroatoms selected from the group consisting of N, O, and S,
wherein the nitrogen and sulfur heteroatoms are optionally oxidized
and the nitrogen atoms are optionally quaternized. The heterocyclic
ring can be attached to its pendant group at any heteroatom or
carbon atom that results in a stable structure, and any of the ring
atoms can be optionally substituted. Examples of such saturated or
partially unsaturated heterocyclic radicals include, without
limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,
pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl,
piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,
thiazepinyl, and morpholinyl. The terms "heterocycle",
"heterocycyl", and "heterocyclic radical", as used herein, also
include groups in which a non-aromatic heteroatom-containing ring
is fused to one or more aromatic or non-aromatic rings, such as
indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl,
where the radical or point of attachment is on the non-aromatic
heteroatom-containing ring. The term "heterocyclylalkyl" refers to
an alkyl group substituted by a heterocyclyl, wherein the alkyl and
heterocyclyl portions independently are optionally substituted.
[0022] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond
between ring atoms. The term "partially unsaturated" is intended to
encompass rings having one or multiple sites of unsaturation, but
is not intended to include aryl or heteroaryl moieties, as herein
defined.
[0023] The term "substituted", as used herein, means that one or
more hydrogen atoms of the designated moiety are replaced, provided
that the substitution results in a stable or chemically feasible
compound. A stable compound or chemically feasible compound is one
in which the chemical structure is not substantially altered when
kept at a temperature of 40.degree. C. or less, in the absence of
moisture or other chemically reactive conditions, for at least a
week, or a compound which maintains its integrity long enough to be
useful for the synthetic processes of the invention. The phrase
"one or more substituents", as used herein, refers to a number of
substituents that equals from one to the maximum number of
substituents possible based on the number of available bonding
sites, provided that the above conditions of stability and chemical
feasibility are met.
[0024] An aryl (including the aryl moiety in aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including the heteroaryl
moiety in heteroaralkyl and heteroarylalkoxy and the like) group
may contain one or more substituents. Examples of suitable
substituents on the unsaturated carbon atom of an aryl or
heteroaryl group include -halo, --NO.sub.2, --CN, --R*, --OR*,
SR.sup.o, --N(R.sup.+).sub.2, --NR.sup.+C(O)R*,
--NR.sup.+C(O)N(R.sup.+).sub.2, --NR.sup.+CO.sub.2R.sup.o,
--O--CO.sub.2R*, --O--C(O)R*, --CO.sub.2R*, --C(O)R*,
--C(O)N(R.sup.+).sub.2, --OC(O)N(R).sub.2, --S(O).sub.2R.sup.o,
--SO.sub.2N(R.sup.+).sub.2, --S(O)R.sup.o, and
--NR.sup.+SO.sub.2N(R.sup.+).sub.2. Each R.sup.+ independently is
selected from the group consisting of R*, --C(O)R*, --CO.sub.2R*,
and --SO.sub.2R*, or two R.sup.+ on the same nitrogen atom, taken
together with the nitrogen atom, form a 5-8 membered aromatic or
non-aromatic ring having, in addition to the nitrogen, 0-2 ring
heteroatoms selected from N, O, and S. Each R* independently is
hydrogen or an optionally substituted aliphatic, aryl, heteroaryl,
or heterocyclyl group. Each R.sup.o independently is an optionally
substituted aliphatic or aryl group.
[0025] An aliphatic group also may be substituted with one or more
substituents. Examples of suitable substituents on the saturated
carbon of an aliphatic group or of a non-aromatic heterocyclic ring
include, without limitation, those listed above for the unsaturated
carbon of an aryl or heteroaryl group.
[0026] The present inventors have discovered that the requirement
for scrupulously dry equipment, solvents, and reagents that
characterized previously described procedures for the Lewis acid
promoted rearrangement of boron "ate" complexes can be obviated by
use of an ether solvent that has low miscibility with water.
Remarkably, use of such a solvent permits the reaction to be run on
a multi-kilogram scale without deterioration in yield or purity. In
essence, the scale of the reaction is limited only by the size of
the available manufacturing capabilities.
[0027] In one aspect, therefore, the invention provides a
large-scale process for preparing a boronic ester compound of
formula (I):
##STR00001##
wherein: [0028] R.sup.1 is an optionally substituted aliphatic,
aromatic, or heteroaromatic group; [0029] R.sup.2 is hydrogen, a
nucleofugic group, or an optionally substituted aliphatic,
aromatic, or heteroaromatic group; [0030] R.sup.3 is a nucleofugic
group or an optionally substituted aliphatic, aromatic, or
heteroaromatic group; and [0031] each of R.sup.4 and R.sup.5,
independently, is an optionally substituted aliphatic, aromatic, or
heteroaromatic group, or R.sup.4 and R.sup.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.
[0032] The process comprises the steps:
[0033] (a) providing a boron "ate" complex of formula (II):
##STR00002##
where [0034] Y is a nucleofugic group; [0035] M.sup.+ is a cation;
and [0036] each of R.sup.1 to R.sup.5 is as defined above; and
[0037] (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: [0038] (i) a coordinating ether
solvent that has low miscibility with water; or [0039] (ii) an
ether solvent that has low miscibility with water and a
coordinating co-solvent.
[0040] The previously reported processes for Lewis acid promoted
rearrangement of boron "ate" complexes employ tetrahydrofuran, an
ether solvent that is fully miscible with water. Failure to employ
rigorously dried equipment, solvents, and reagents in these
processes results in a dramatic reduction in the diastereomeric
ratio. The hygroscopic Lewis acids, in particular, typically must
be flame-dried immediately prior to use in the reaction. Although
techniques for running moisture-sensitive reactions are familiar to
those of skill in the art and are routinely practiced on a
laboratory scale, such reactions are costly and difficult to scale
up.
[0041] Moreover, attempted scale-up of the prior art process
frequently results in a further deterioration in diastereameric
ratio during workup and isolation of the product boronic ester
compound. Matteson and Erdiik, Organometalics, 2:1083 (1983),
reports that exposure of alpha-haloboronic ester products to free
halide ion results in epimerization at the alpha-carbon center.
Without wishing to be bound by theory, the present inventors
believe that epimerization is particularly problematic during
reaction work-up and/or subsequent steps. For example,
epimerization is believed to occur during concentration of the
reaction mixture to remove the tetrahydrofuran solvent and exchange
it for a water-immiscible solvent. Failure to completely remove the
tetrahydrofuran also negatively impacts diastereomeric ratio during
the subsequent aqueous washes. Exposure of the product to halide
ion during these steps is difficult to avoid, particularly when the
reaction is performed on a large scale.
[0042] The present inventors have discovered that the rearrangement
of boron "ate" complexes is advantageously performed in an ether
solvent that has low miscibility with water. Use of such solvents
obviates the need for solvent exchange prior to the aqueous washes,
and the organic-soluble product is effectively shielded from
aqueous halide ion during the washes, even if performed on a large
scale. Preferably, the solubility of water in the ether solvent is
less than about 5% w/w, more preferably less than about 2% w/w. In
various embodiments, ether solvent that has low miscibility with
water constitutes at least about 70%, at least about 80%, at least
about 85%, at least about 90%, or at least about 95% v/v of the
reaction mixture.
[0043] The ether solvent preferably is one that is suitable for
routine use in large-scale production. As used herein, the term
"large-scale" refers to a reaction that utilizes at least about
five moles of at least one starting material. Preferably, a
large-scale process utilizes at least about 10, 20, 50, or 100
moles of at least one starting material.
[0044] For purposes of the invention, the term "ether" refers to
any of a class of chemical compounds characterized in having an
oxygen atom attached to two carbon atoms. An "ether solvent" is an
ether compound that exists in liquid form at the desired reaction
temperature and is capable of dissolving the starting material(s)
and/or product(s) of the reaction. Non-limiting examples of ether
solvents suitable for use in the process of the invention include
tert-butyl methyl ether, tert-butyl ethyl ether, tert-amyl methyl
ether, and isopropyl ether.
[0045] In one embodiment, the reaction mixture further comprises a
coordinating co-solvent. In another embodiment, the ether solvent
that has low miscibility with water is sufficiently coordinating
that a coordinating co-solvent is not necessary. For purposes of
the invention, the terms "coordinating co-solvent" and
"coordinating solvent" refer to a solvent that is capable of
coordinating the Lewis acid and solvating the ionic components of
the reaction. Hindered ether solvents, such as tert-butyl methyl
ether, are poorly coordinating and preferably are used with a
coordinating co-solvent. Nonlimiting examples of coordinating
co-solvents suitable for use in the practice of the invention
include tetrahydrofuran, dioxane, water, and mixtures thereof.
[0046] In some embodiments, the reaction mixture comprises at least
about 5% or at least about 10% v/v of a coordinating co-solvent.
Preferably, the amount of a water-miscible coordinating co-solvent
present in the reaction mixture is not so great as to interfere
with phase separation during the reaction or workup. In various
embodiments, the coordinating co-solvent constitutes no more than
about 20%, about 15%, or about 10% v/v of the reaction mixture.
[0047] As used herein, the term "nucleofugic" refers to any group
that is capable of undergoing nucleophilic displacement under the
rearrangement conditions of the present process. Such nucleofugic
groups are known in the art. Preferably, the nucleofugic group is a
halogen, more preferably chloro or bromo. In the course of the
rearrangement reaction converting the boron "ate" complex of
formula (II) into the boronic ester compound of formula (I), the
nucleofugic group Y is released as Y.sup.-. By way of example, when
Y is chloro, chloride ion is released in step (b).
[0048] The variable M.sup.+ is any cationic counterion for the
negatively charged tetravalent boron atom in the boron "ate"
complex of formula (II). In some preferred embodiments, M.sup.+ is
selected from the group consisting of Li.sup.+, Na.sup.+, and
K.sup.+. One of skill in the art will recognize that the salt
M.sup.+Y.sup.- is formed as a byproduct in the rearrangement
reaction of step (b).
[0049] The variable R.sup.1 preferably is a group with good
migratory aptitude. In some embodiments, R.sup.1 is C.sub.1-8
aliphatic, C.sub.6-10 aryl, or (C.sub.6-10 aryl)(C.sub.1-6
aliphatic), any of which groups is optionally substituted. In
certain embodiments, R.sup.1 is C.sub.1-4 aliphatic, particularly
isobutyl.
[0050] The variable R.sup.2 preferably is hydrogen, a nucleofugic
group, or an optionally substituted C.sub.1-8 aliphatic, C.sub.6-10
aryl, or (C.sub.6-10 aryl)(C.sub.1-6 aliphatic) group. The variable
R.sup.3 preferably is a nucleofugic group or an optionally
substituted C.sub.1-8 aliphatic, C.sub.6-10 aryl, or (C.sub.6-10
aryl)(C.sub.1-6 aliphatic) group. One of skill in the art will
recognize that functional substituents may be present on any of
R.sup.1, R.sup.2, or R.sup.3, provided that the functional
substituent does not interfere with the formation of the boron
"ate" complex of formula (II).
[0051] One embodiment of the invention relates to a process for
preparing a boronic ester compound of formula (I), wherein R.sup.3
is a nucleofugic group. Such compounds are useful as intermediates
for the synthesis of alpha-substituted boronic ester and acid
compounds, including alpha-aminoboronic ester and acid compounds,
as described below. In certain preferred embodiments, R.sup.5 is a
nucleofugic group and R.sup.2 is hydrogen.
[0052] The variables R.sup.4 and R.sup.5 can be the same or
different. In some embodiments, R.sup.4 and R.sup.5 are directly
linked, so that R.sup.4 and R.sup.5, taken together with the
intervening oxygen and boron atoms, form an optionally substituted
5- to 10-membered ring, which can have 0-2 additional ring
heteroatoms selected from N, O, or S. In some embodiments, the ring
is a 5- or 6-membered ring, preferably a 5-membered ring.
[0053] The present invention is particularly advantageous for the
Lewis acid promoted rearrangement of boron "ate" complexes of
formula (II), wherein R.sup.4 and R.sup.5 are directly linked and
together are a chiral moiety. One embodiment of the invention
relates to the rearrangement of such chiral boron "ate" complexes
to provide a boronic ester compound of formula (I) wherein the
carbon atom bearing R.sup.1, R.sup.2, and R.sup.3 is a chiral
center. The rearrangement reaction preferably proceeds with a high
degree of stereodirection by the R.sup.4-R.sup.5 chiral moiety to
provide the boronic ester compound of formula (I) having a
diastereomeric ratio at the carbon atom bearing R.sup.1, R.sup.2,
and R.sup.3 of at least about 96:4 relative to a chiral center in
the R.sup.4-R.sup.5 chiral moiety. Preferably, the diastereomeric
ratio is at least about 97:3.
[0054] The terms "stereoisomer", "enantiomer", "diastereomer",
"epimer", and "chiral center", are used herein in accordance with
the meaning each is given in ordinary usage by those of ordinary
skill in the art. Thus, stereoisomers are compounds that have the
same atomic connectivity, but differ in the spatial arrangement of
the atoms. Enantiomers are stereoisomers that have a mirror image
relationship, that is, the stereochemical configuration at all
corresponding chiral centers is opposite. Diastereomers are
stereoisomers having more than one chiral center, which differ from
one another in that the stereochemical configuration of at least
one, but not all, of the corresponding chiral centers is opposite.
Epimers are diastereomers that differ in stereochemical
configuration at only one chiral center.
[0055] As used herein, the term "diastereomeric ratio" refers to
the ratio between diastereomers which differ in the stereochemical
configuration at one chiral center, relative to a second chiral
center in the same molecule. By way of example, a chemical
structure with two chiral centers provides four possible
stereoisomers: R*R, R*S, S*R, and S*S, wherein the asterisk denotes
the corresponding chiral center in each stereoisomer. The
diastereomeric ratio for such a mixture of stereoisomers is the
ratio of one diastereomer and its enantiomer to the other
diastereomer and its enantiomer=(R*R+S*S):(R*S+S*R).
[0056] One of ordinary skill in the art will recognize that
additional stereoisomers are possible when the molecule has more
than two chiral centers. For purposes of the present invention, the
term "diastereomeric ratio" has identical meaning in reference to
compounds with multiple chiral centers as it does in reference to
compounds having two chiral centers. Thus, the term "diastereomeric
ratio" refers to the ratio of all compounds having R.sup.RR or S*S
configuration at the specified chiral centers to all compounds
having R*S or S*R configuration at the specified chiral centers.
For convenience, this ratio is referred to herein as the
diastereomeric ratio at the asterisked carbon, relative to the
second specified chiral center.
[0057] The diastereomeric ratio can be measured by any analytical
method suitable for distinguishing between diastereomeric compounds
having different relative stereochemical configurations at the
specified chiral centers. Such methods include, without limitation,
nuclear magnetic resonance (NMR), gas chromatography (GC), and high
performance liquid chromatography (HPLC) methods.
[0058] As discussed above, one embodiment of the invention is
directed to processes that provide a boronic ester compound of
formula (I) having a diastereomeric ratio at the carbon atom
bearing R.sup.1, R.sup.2, and R.sup.3 of at least about 96:4
relative to a chiral center in the R.sup.4-R.sup.5 chiral moiety.
One of skill in the art will recognize that the R.sup.4-R.sup.5
chiral moiety may itself contain more than one chiral center. When
R.sup.4-R.sup.5 does have more than one chiral center, it
preferably has high diastereomeric purity, and the diastereomeric
ratio at the carbon atom bearing R.sup.1, R.sup.2, and R.sup.3 can
be measured relative to any one of the chiral centers in
R.sup.4-R.sup.5.
[0059] In the processes of the invention, the R.sup.4-R.sup.5
chiral moiety preferably has a high level of enantiomeric purity.
For purposes of the invention, the term "enantiomeric purity" is
used to mean "enantiomeric excess", which is the amount by which
the major enantiomer is in excess of the minor enantiomer,
expressed as a percentage of the total. Preferably, the
R.sup.4-R.sup.5 chiral moiety has an enantiomeric purity of at
least about 98%, more preferably at least about 99%, still more
preferably at least about 99.5%, and most preferably at least about
99.9%.
[0060] When the R.sup.4-R.sup.5 chiral moiety has very high
enantiomeric purity, the diastereomeric ratio at the carbon atom
bearing R.sup.1, R.sup.2, R.sup.3 approximates the epimeric ratio
at that center, i.e., diastereomeric ratio.apprxeq.(R*R):(S*R) or
(R*S):(S*S).apprxeq.(R*):(S*). As used herein, the term "epimeric
ratio" refers to the ratio of product having one absolute
stereochemical configuration at a given chiral center to product
having the opposite absolute stereochemical configuration at the
corresponding chiral center. Preferably, the products have
identical stereochemical configuration at all other corresponding
chiral centers. In one embodiment, therefore, the invention relates
to the rearrangement of a chiral boron "ate" complex of formula
(II) to provide a boronic ester compound of formula (I) wherein the
epimeric ratio at the carbon atom bearing R.sup.1, R.sup.2, and
R.sup.3 is at least about 96:4, more preferably at least about
97:3.
[0061] Lewis acids suitable for use in the practice of the
invention are those capable of complexing with the nucleofugic
group to facilitate its displacement upon migration of R.sup.1.
Preferably, the Lewis acid is additionally capable of coordinating
with an oxygen atom attached to boron. Nonlimiting examples of
suitable Lewis acids include zinc bromide, zinc chloride, ferric
bromide, and ferric chloride. In certain preferred embodiments, the
Lewis acid is zinc chloride.
[0062] The contacting step preferably is performed at low
temperature, but may be performed at ambient or elevated
temperature. The selection of an appropriate reaction temperature
will depend largely on the Lewis acid employed, as well as the
migratory aptitude of the R.sup.1 moiety. One skilled in the art
will be able to select a suitable temperature in view of the
reaction conditions being used.
[0063] In some embodiments, the contacting step is performed at a
reaction temperature of at least about -100.degree. C., -78.degree.
C., or -60.degree. C. In some embodiments, the contacting step is
performed at a reaction temperature that is no greater than about
80.degree. C., 40.degree. C., or 30.degree. C. Any range
encompassing these high and low temperatures are included within
the scope of the invention. Preferably, the contacting step is
performed at a reaction temperature in the range of about
-100.degree. C. to about 80.degree. C., about -70.degree. C. to
about 40.degree. C., about -60.degree. C. to about 30.degree. C.,
or about -50.degree. C. to about 30.degree. C. In certain preferred
embodiments, the contacting step is begun at low temperature,
preferably in the range of about -70.degree. C. to about
-30.degree. C., and then the reaction mixture is allowed to warm,
preferably to ambient temperature.
[0064] Surprisingly, the process of the present invention requires
no special precautions to avoid the presence of water during the
rearrangement reaction itself. In some embodiments, moist Lewis
acid is employed, with minimal deterioration in diastereomeric
ratio. When used in reference to the Lewis acid, the term "moist"
means that the water content of the Lewis acid is greater than
about 100, 200, 500, or 1,000 ppm. Remarkably, the Lewis acid even
can be added to the reaction mixture in the form of an aqueous
solution without deleterious impact on diastereomeric ratio.
[0065] In some embodiments, therefore, the process of the invention
comprises the steps:
[0066] (a) providing a solution comprising a boron "ate" complex of
formula (II) and [0067] (i) a coordinating ether solvent that has
low miscibility with water; or [0068] (ii) an ether solvent that
has low miscibility with water and a coordinating co-solvent;
and
[0069] (b) adding to the solution of step (a) a Lewis acid solution
comprising water and a Lewis acid.
[0070] In some other embodiments, the Lewis acid solution comprises
tetrahydrofuran and a Lewis acid.
[0071] Thus, unlike the prior art process, the process of the
invention is readily amenable to large-scale production. In various
embodiments, at least about 5, 10, 20, 50, 100, 500, or 1000 moles
of boron "ate" complex of formula (II) is contacted with a Lewis
acid under conditions that afford the boroanic ester compound of
formula (I). The invention further provides a composition
comprising a boronic ester compound of formula (I), as described
herein, and an ether solvent that has low miscibility with water.
The composition preferably comprises at least about 5, 10, 20, 50,
100, 500, or 1000 moles of the boronic ester compound of formula
(I). In certain embodiments, R.sup.4 and R.sup.5 together are a
chiral moiety, and the compound of formula (I) present in the
composition has a diastereomeric ratio of at least about 96:4 at
the carbon atom bearing R.sup.1, R.sup.2, and R.sup.3, relative to
a chiral center in the R.sup.4-R.sup.5 chiral moiety.
[0072] Workup of the reaction preferably comprises washing the
reaction mixture with an aqueous solution and concentrating the
washed reaction mixture by removal of solvents to afford a residue
comprising the boronic ester compound of formula (I). Preferably,
the residue comprises at least about 5, 10, 20, 50, 100, 500, or
1000 moles of the boronic ester compound of formula (I). In those
embodiments wherein R.sup.4-R.sup.5 is a chiral moiety, the boronic
ester compound of formula (I) present in the residue preferably has
a diastereomeric ratio of at least about 96:4 at the carbon atom
bearing R.sup.1, R.sup.2, and R.sup.3, relative to a chiral center
in the R.sup.4-R.sup.5 chiral moiety. More preferably, the
diastereomeric ratio is at least about 97:3.
[0073] The boron "ate" complex of formula (II) can be prepared by
any known method, but preferably is prepared by reaction of a
boronic ester of formula (III):
##STR00003##
with a reagent of formula (IV):
##STR00004##
wherein each of M.sup.+, Y, and R.sup.1 to R.sup.5 are as defined
above for the boron "ate" complex of formula (II). In same
embodiments, the reaction is performed at a reaction temperature of
at least about -100.degree. C., -78.degree. C., or -60.degree. C.
In some embodiments, the reaction is performed at a reaction
temperature no greater than about 0.degree. C., -20.degree. C., or
-40.degree. C. Any range encompassing these high and low
temperatures are included within the scope of the invention. The
reaction preferably is performed at a reaction temperature in the
range of about -100.degree. C. to about 0.degree. C., about
-78.degree. C. to about -20.degree. C., or about -60.degree. C. to
about -40.degree. C. In some embodiments, the boron "ate" complex
of formula (II) is prepared in a solution comprising an ether
solvent having low miscibility with water, and the reaction mixture
is directly treated with a Lewis acid to effect rearrangement to
the boron ester compound of formula (I).
[0074] In some embodiments, the reagent of formula (IV) is formed
in situ. Such embodiments include the steps:
[0075] (i) providing a solution comprising a boronic ester of
formula (III), as defined above, and a compound of formula (V):
##STR00005##
wherein R.sup.2 and R.sup.3 are as defined above for the reagent of
formula (IV); and
[0076] (ii) treating the solution with a strong, sterically
hindered base to form the boron "ate" complex of formula (II).
[0077] In some embodiments, the sterically hindered base is an
alkali metal dialkylamide bases of formula M.sup.2N(R.sup.#).sub.2,
where M.sup.2 is Li, Na, or K, and each R.sup.#, independently is a
branched or cyclic C.sub.3-6 aliphatic. In situ formation of the
reagent of formula (IV) is especially advantageous in those
embodiments wherein Y is a nucleofugic group, due to the
instability of the reagent of formula (IV).
[0078] The boronic ester of formula (III) can be prepared by any
known method, but typically is prepared by esterification of the
corresponding boronic acid compound, e.g., by methods described in
Brown et al., Organometallics, 2: 1311-1316 (1983). Cyclic boronic
esters of formula (III) preferably are prepared by:
[0079] (a) providing a solution comprising: [0080] (i) a boronic
acid compound of formula R.sup.1--B(OH).sub.2; [0081] (ii) a
compound of formula HO--R.sup.4-R.sup.5--OH, wherein R.sup.4 and
R.sup.5, taken together, are an optionally substituted linking
chain comprising 2-5 carbon atoms and 0-2 heteroatoms selected from
the group consisting of O, N, and S; and [0082] (iii) an organic
solvent that forms an azeotrope with water; and
[0083] (b) heating the solution at reflux with azeotropic removal
of water.
[0084] As used in reference to R.sup.4 and R.sup.5, the term
"linking chain" refers to the shortest linear chain of atoms
connecting the oxygen atoms to which R.sup.4 and R.sup.5 are
attached. The linking chain optionally is substituted at any chain
atom, and one or more chain atoms also may form part of a ring
system that is spiro to, fused to, or bridging the linear linking
chain. By way of example, but not limitation, in some embodiments,
the compound of formula HO--R.sup.4-R.sup.5--OH is pinanediol,
having the structure:
##STR00006##
In such embodiments, the linking chain R.sup.4-R.sup.5 comprises
two carbon atoms, which together form one side of the
bicyclo[3.1.1]heptane ring system, and one of which additionally is
substituted with a methyl group.
[0085] In some embodiments, the compound of formula
HO--R.sup.4-R.sup.5--OH is a chiral diol, preferably one having
high diastereomeric and enantiomeric purity. One of skill in the
art will appreciate that in such embodiment, the compound of
formula HO--R.sup.4-R.sup.5--OH is employed as a chiral auxiliary
to direct the stereochemical configuration at the carbon bearing
R.sup.1, R.sup.2, and R.sup.3. Chiral diols useful as chiral
auxiliaries in organic synthesis are well-known in the art.
Nonlimiting examples include 2,3-butanediol, preferably
(2R,3R)-(-)-2,3-butanediol or (2S,3S)-(+)-2,3-butanediol;
pinanediol, preferably (1R,2R,3R,5S)-(-)-pinanediol or
(1S,2S,3S,5R)-(+)-pinanediol; 1,2-cyclopentanediol, preferably
(1S,2S)-(+)-trans-1,2-cyclopentanediol or
(1R,2R)-(-)-trans-1,2-cyclopentanediol; 2,5-hexanediol, preferably
(2S,5S)-2,5-hexanediol or (2R,5R)-2,5-hexanediol;
1,2-dicyclohexyl-1,2-ethanediol, preferably
(1R,2R)-1,2-dicyclohexyl-1,2-ethanediol or
(1S,2S)-1,2-dicyclohexyl-1,2-ethanediol; hydrobenzoin, preferably
(S,S)-(-)-hydrobenzoin or (R,R)-(+)-hydrobenzoin; 2,4-pentanediol,
preferably (R,R)-(-)-2A-pentanediol or (S,S,)-(+)-2,4-pentanediol;
erythronic .gamma.-lactone, preferably D-erythronic
.gamma.-lactone. Carbohydrates, e.g. a 1,2,5,6-symmetrically
protected mannitol, also may be used as chiral diols.
[0086] Nonlimiting examples of organic solvents suitable for use in
the esterification reaction include acetonitrile, toluene, hexane,
heptane, and mixtures thereof. In some embodiments, the organic
solvent is an ether solvent, preferably an ether solvent that has
low miscibility with water. In certain preferred embodiments, the
esterification reaction is performed in an ether solvent that has
low miscibility with water, and the product solution comprising the
boronic ester of formula (III) is used directly in the next step,
without isolation of the boronic ester.
[0087] As noted above, the process of the present invention for the
first time permits workup of large-scale reactions without
significant deterioration in diastereomeric ratio. In another
aspect, therefore, the invention provides a composition comprising
at least about 5, 10, 20, 50, 100, 500, or 1000 moles of a boronic
ester compound of formula (I):
##STR00007##
wherein [0088] R.sup.1 is an optionally substituted aliphatic,
aromatic, or heteroaromatic group; [0089] R.sup.2 is hydrogen, a
nucleofugic group, or an optionally substituted aliphatic,
aromatic, or heteroaromatic group; [0090] R.sup.3 is a nucleofugic
group or an optionally substituted aliphatic, aromatic, or
heteroaromatic group; and [0091] R.sup.4 and R.sup.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; [0092]
wherein the carbon atom to which R.sup.1, R.sup.2, and R.sup.3 are
attached is a chiral center, having a diastereomeric ratio of at
least about 96:4, preferably at least about 97:3, relative to a
chiral center in the R.sup.4-R.sup.5 chiral moiety.
[0093] Preferred values for R.sup.1 to R.sup.3 are as described
above. Preferably, solvents constitute less than about 30% w/w, 20%
w/w, 10% w/w, or 5% w/w of the composition according to this aspect
of the invention. In some embodiments, the boronic ester compound
of formula (I) constitutes at least about 70% w/w, 80% w/w, 90%
w/w, or 95% w/w of the composition.
[0094] One embodiment relates to the composition described above,
wherein at least one of the following features is present:
[0095] (a) R.sup.3 is chloro;
[0096] (b) the boronic ester compound (1) is
##STR00008##
[0097] (c) R.sup.2 is hydrogen; and
[0098] (d) R.sup.1 is C.sub.1-4 aliphatic.
[0099] All of the boronic ester compound of formula (I) present in
the composition may be produced in a single batch run. For purposes
of the invention, the term "batch run" refers to execution of a
synthetic process, wherein each step of the process is performed
only once. Preferably, the boronic ester compound of formula (I)
present in the composition is prepared in a single batch run of the
process according to the first aspect of the invention. One of
ordinary skill in the art will appreciate that preparation of a
given quantity of product by a single batch run of a large-scale
process is more efficient and provides a more homogeneous product
than preparation of the same quantity of product by repeated
execution of a small-scale process.
[0100] The boronic ester compounds of formula (I) wherein R.sup.3
is a nucleofugic group are useful as intermediates for the
synthesis of alpha-aminoboronic ester compounds. In another aspect,
therefore, the invention provides a large-scale process for
preparing an alpha-aminoboronic ester, preferably by a process
comprising the steps:
[0101] (a) providing a boron "ate" complex of formula (II):
##STR00009##
where [0102] Y is a nucleofugic group; [0103] M.sup.+ is a cation;
[0104] R.sup.1 is an optionally substituted aliphatic, aromatic, or
heteroaromatic group; [0105] R.sup.2 is hydrogen; [0106] R.sup.3 is
a nucleofugic group; and [0107] each of R.sup.4 and R.sup.5,
independently, is an optionally substituted aliphatic, aromatic, or
heteroaromatic group, or R.sup.4 and R.sup.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;
[0108] (b) contacting the boron "ate" complex of formula (II) with
a Lewis acid under conditions that afford the boronic ester
compound of formula (I):
##STR00010##
where each of R.sup.1 to R.sup.5 is as defined above, said
contacting step being conducted in a reaction mixture comprising.
[0109] (i) a coordinating ether solvent that has low miscibility
with water, or [0110] (ii) an ether solvent that has low
miscibility with water and a coordinating co-solvent; and
[0111] (c) treating the boronic ester compound of formula (I) with
a reagent of formula M.sup.1-N(G).sub.2, where M.sup.1 is an alkali
metal and each G individually or together is an amino group
protecting group to form a byproduct of formula ML-R and a compound
of formula (VIII):
##STR00011##
wherein each G and R.sup.1 to R.sup.5 are as defined above; and
[0112] (d) removing the G groups to form a compound of formula
(VII):
##STR00012##
or an acid addition salt thereof.
[0113] In some embodiments, in step (c), the boronic ester compound
of formula (I) is treated with a reagent of formula
M.sup.1-N(Si(R.sup.6).sub.3).sub.2 where M.sup.1 is an alkali metal
and each R.sup.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.
[0114] Reaction of the boronic ester compound of formula (I) with
the reagent of formula M.sup.1-N(G).sub.2 preferably is conducted
at a reaction temperature in the range of about -100.degree. C. to
about 50.degree. C., preferably about -50.degree. C. to about
25.degree. C., and more preferably about -30.degree. C. to about
0.degree. C. In some embodiments, R.sup.3 is halo, preferably
chloro, and M.sup.1 is Li. To facilitate isolation of the product
of formula (VIII), the reaction mixture preferably comprises an
organic solvent in which the byproduct M.sup.1-R.sup.3 has low
solubility. Nonlimiting examples of suitable organic solvents
include methylcyclohexane, cyclohexane, heptane, hexane, and
toluene. In some embodiments, step (c) further comprises filtering
the reaction mixture to remove M.sup.1-R.sup.3 and provide a
filtrate comprising the compound of formula (VIII). Preferably, the
filtrate is used directly in step (d).
[0115] In those embodiments wherein the reaction mixture comprises
an organic solvent in which the byproduct M.sup.1-R.sup.3 has low
solubility, the reaction mixture may additionally comprise a
solvent in which the byproduct M.sup.1-R.sup.3 has high solubility.
In such cases, the solvent in which the byproduct M.sup.1-R.sup.3
has high solubility preferably is removed prior to filtration of
the reaction mixture. By way of example, in some embodiments, a
reagent of formula M.sup.1-N(Si(R.sup.6).sub.3).sub.2 is added to
the reaction mixture as a solution comprising tetrahydrofuran. In
such embodiments, step (c) preferably further comprises removing
the tetrahydrofuran before filtering the reaction mixture.
[0116] Those of skill in the art are aware of various methods that
can be used to remove the protecting groups G in the compound of
formula (VIII), including, e.g., aqueous hydrolysis or treatment
with acid. The product alpha-aminoboronic ester of formula (VII)
has low stability and preferably is immediately derivatized
(Matteson et al., J. Am. Chem. Soc., 103:5241 (1981)) or is
isolated as an acid addition salt. In some embodiments, step (d)
comprises treating the compound of formula (VIII) with an acid and
isolating the compound of formula (VII) as the acid addition salt.
In certain preferred embodiments, the acid is trifluoroacetic acid,
and the compound of formula (VII) is isolated as the
trifluoroacetic acid addition salt.
[0117] As discussed above, the processes of the invention are
particularly well-suited for preparing alpha-aminoboronic ester
compounds of formula (VI), wherein the alpha carbon is a chiral
center. Thus, one embodiment of the invention relates to a
large-scale process for preparing an alpha-aminoboronic ester
compound of formula (VIIa) or (VIIb):
##STR00013##
or an acid addition salt thereof, wherein: [0118] R.sup.1 is an
optionally substituted aliphatic, aromatic, or heteroaromatic
group; and [0119] R.sup.4 and R.sup.5, taken together with the
intervening oxygen and boron atoms, farm an optionally substituted
chiral cyclic boronic ester; said process comprising.
[0120] (a) providing a boron "ate" complex of formula (IIa) or
(IIb):
##STR00014##
where
[0121] Y is a nucleofugic group;
[0122] M.sup.+ is a cation;
[0123] R.sup.2 is hydrogen;
[0124] R.sup.3 is a nucleofugic group; and
[0125] R.sup.4 and R.sup.5 are as defined above;
[0126] (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):
##STR00015##
where each of R.sup.1 to R.sup.5 is as defined above, said
contacting step being conducted in a reaction mixture comprising:
[0127] (i) a coordinating ether solvent that has low miscibility
with water; or [0128] (ii) an ether solvent that has low
miscibility with water and a coordinating co-solvent; and
[0129] (c) treating the boronic ester compound of formula (Ia) or
(Ib) with a reagent of formula M.sup.1-N(G).sub.2, where M.sup.1 is
an alkali metal and G is an amino group protecting moiety, to form
a compound of formula (VIIIa) or (VIIIb):
##STR00016##
wherein each G and R.sup.1 to R.sup.5 are as defined above; and
[0130] (d) removing the G groups to form a compound of formula
(VIIa) or (VIIb):
##STR00017##
or an acid addition salt thereof.
[0131] Preferred values for Y, M.sup.+, R.sup.1 to R.sup.5, and G
are as described above. The compound of formula (VIIa) or (VIIb)
preferably has a diastereomeric ratio at the alpha-carbon of at
least about 96:4, more preferably at least about 97:3, relative to
a chiral center in the R.sup.4-R.sup.5 chiral moiety.
[0132] The alpha-aminoboronic ester compounds of formula (VII) are
useful synthetic intermediates for the preparation of peptidyl
boronic ester compounds. In some embodiments, therefore, the
process according to this aspect of the invention further comprises
coupling the compound of formula (VII) with a compound of formula
(IX):
##STR00018##
wherein: [0133] P.sup.1 is an amino group blocking moiety; [0134]
R.sup.7 is selected from the group consisting of hydrogen,
C.sub.1-10aliphatic, optionally substituted C.sub.6-10aryl, or
C.sub.1-6aliphatic-R.sup.8; and [0135] R.sup.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 [0136] X is OH or a
leaving group; to form a compound of formula (X):
##STR00019##
[0136] wherein each of P.sup.1, R.sup.1, R.sup.4, R.sup.5, and
R.sup.7 is as defined above.
[0137] The leaving group X is any group capable of nucleophilic
displacement by the alpha-amino group of the compound of formula
(VII). In some embodiments, the moiety --C(O)--X is an activated
ester, such as an O--(N-hydroxysucccinimide) ester. In some
embodiments, an activated ester is generated in situ by contacting
a compound of formula (IX), wherein X is OH, with a peptide
coupling reagent. Examples of suitable peptide coupling reagents
include, without limitation, carbodiimide reagents, e.g.,
dicyclohexylcarbod imide (DCC) or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC); phosphonium
reagents, e.g., benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP reagent); and uronium reagents, e.g.,
O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU).
[0138] Those of skill in the art also are aware of procedures that
permit the direct coupling of silyl protected amines, without a
prior deprotection step. In such procedures, the silyl groups are
removed in situ under the coupling reaction conditions. In some
embodiments of the present invention, therefore, a compound of
formula (VII) is contacted with a compound of formula (IX) under
conditions that remove the (R.sup.6).sub.3Si groups in situ and
form a compound of formula (X).
[0139] For purposes of the invention, the term "amino-group
blocking moiety" refers to any group used to derivatize an amino
group, especially an N-terminal amino group of a peptide or amino
acid. The term "amino-group blocking moiety" includes, but is not
limited to, protecting groups that are commonly employed in organic
synthesis, especially peptide synthesis. See, for example, Gross
and Mienhoffer, eds., The Peptides, Vol. 3, Academic Press, New
York, 1981, pp. 3-88; Green and Wuts, Protective Groups in Organic
Synthesis, 3rd edition, John Wiley and Sons, Inc., New York, 1999.
Unless otherwise specified, however, it is not necessary for an
amino-group blocking moiety to be readily cleavable. Amino-group
blocking moieties include, e.g., alkyl, acyl, alkoxycarbonyl,
aminocarbonyl, and sulfonyl moieties. In some embodiments, the
amino-group blocking moiety is an acyl moiety derived from an amino
acid or peptide, or a derivative or analog thereof.
[0140] As used herein, the term "amino acid" includes both
naturally occurring and unnatural amino acids. For purposes of the
invention, a "derivative" of an amino acid or peptide is one in
which a functional group, e.g., a hydroxy, amino, carboxy, or
guanidino group at the N-terminus or on a side chain, is modified
with a blocking group. As used herein, an "analog" of an amino acid
or peptide is one which includes a modified backbone or side chain.
The term "peptide analog" is intended to include peptides wherein
one or more stereocenters are inverted and one or more peptide
bonds are replaced with a peptide isostere.
[0141] In some embodiments, P.sup.1 is a cleavable protecting
group. Examples of cleavable protecting groups include, without
limitation, acyl protecting groups, e.g., formyl, acetyl (Ac),
succinyl (Suc), or methoxysuccinyl (MeOSuc), and urethane
protecting groups, e.g., tert-butoxycarbonyl (Boc),
benzyloxycarbonyl (Cbz), or fluorenylmethoxycarbonyl (Fmoc).
[0142] In some such embodiments, the process according to this
aspect of the invention further comprises the steps:
[0143] (f) removing the protecting group P to form a compound of
formula (XI):
##STR00020##
or an acid addition salt thereof, wherein each of R.sup.1, R.sup.4,
R.sup.5, and R.sup.7 is as defined above; and
[0144] (g) coupling the compound of formula (XI) with a reagent of
formula P.sup.2--X, wherein P.sup.2 is any amino group blocking
moiety, as described above, and X is a leaving group, to form a
compound of formula (XII):
##STR00021##
wherein each of P.sup.2, R.sup.1, R.sup.4, R.sup.5, and R.sup.7 are
as defined above. One of skill in the art will recognize that in
those embodiments wherein P.sup.2 is an acyl group, including e.g.,
an acyl moiety derived from an amino acid or peptide, or an analog
or derivative thereof, the leaving group X may be generated in
situ, as discussed above for the compound of formula (IX).
[0145] In each of the compounds (X) and (XII), the boronic acid
moiety is protected as a boronic ester. If desired, the boronic
acid moiety can be deprotected by any method known in the art.
Preferably, the boronic acid moiety is deprotected by
transesterification in a biphasic mixture. More preferably, the
boronic acid deprotecting step comprises the steps:
[0146] (i) providing a biphasic mixture comprising the boronic
ester compound of formula (X) or (XII), an organic boronic acid
acceptor, a lower alkanol, a C.sub.5-8 hydrocarbon solvent, and
aqueous mineral acid;
[0147] (ii) stirring the biphasic mixture to afford the
corresponding deprotected boronic acid compound of formula (Xa) or
(XIII):
##STR00022##
[0148] (iii) separating the solvent layers; and
[0149] (iv) extracting the compound of formula (Xa), (XIII), or a
boronic acid anhydride thereof, into an organic solvent.
[0150] The organic boronic acid acceptor in step (i) preferably is
an aliphatic, aryl, or ar(aliphatic)boronic acid. In some
embodiments, the boronic acid acceptor is selected from the group
consisting of phenylboronic acid, benzylboronic acid, butylboronic
acid, pentylboronic acid, hexylboronic acid, and cyclohexylboronic
acid. In certain embodiments, the boronic acid acceptor is
isobutylboronic acid. In some embodiments, the boronic acid
acceptor is selected so that the boronic ester compound of formula
(III) is formed as a byproduct of the deprotection reaction. The
boroanic ester compound of formula (III) can then be used in
another batch run of the process described above. In such
embodiments, the moiety R.sup.4-R.sup.5 is effectively recycled,
which may be particularly advantageous if R.sup.4-R.sup.5 is an
expensive chiral moiety.
[0151] To enhance the purity of the product, the aqueous layer
containing the compound of formula (Xa) or (XIII) preferably is
washed to remove neutral organic impurities prior to the extracting
step (iv). In such embodiments, step (iii) preferably comprises the
steps:
[0152] (1) separating the solvent layers;
[0153] (2) adjusting the aqueous layer to basic pH;
[0154] (3) washing the aqueous layer with an organic solvent;
and
[0155] (4) adjusting the aqueous layer to a pH less than about
6.
[0156] In some embodiments, the invention relates to an improved
process for manufacturing the proteasame inhibitor bortezomib.
Thus, in one embodiment, the invention provides a large-scale
process for forming a compound of formula (XIV):
##STR00023##
or a boronic acid anhydride thereof. The process comprises the
steps:
[0157] (a) providing a boron "ate" complex of formula (XV):
##STR00024##
wherein
[0158] R.sup.3 is a nucleofugic group;
[0159] Y is a nucleofugic group; and
[0160] M.sup.+ is an alkali metal;
[0161] (b) contacting the boron "ate" complex of formula (XV) with
a Lewis acid under conditions that afford a boronic ester compound
of formula (XVI):
##STR00025##
said contacting step being conducted in a reaction mixture
comprising [0162] (i) a coordinating ether solvent that has low
miscibility with water; or [0163] (ii) an ether solvent that has
low miscibility with water and a coordinating co-solvent;
[0164] (c) treating the boronic ester compound of formula (XVI)
with a reagent of formula M.sup.1-N(G).sub.2, where M.sup.1 is an
alkali metal and each G individually or together is an amino group
protecting group, to form a compound of formula (XVII):
##STR00026##
[0165] (d) removing the G groups to form a compound of formula
(XVII):
##STR00027##
or an acid addition salt thereof;
[0166] (e) coupling the compound of formula (XVII) with a compound
of formula (XIX);
##STR00028##
wherein:
[0167] P.sup.1 is a cleavable amino group protecting moiety;
and
[0168] X is OH or a leaving group;
to form a compound of formula (XX):
##STR00029##
wherein P.sup.1 is as defined above;
[0169] (f) removing the protecting group Pt to form a compound of
formula (XXI):
##STR00030##
or an acid addition salt thereof;
[0170] (g) coupling the compound of formula (XXI) with a reagent of
formula (XXII)
##STR00031##
wherein X is a OH or a leaving group, to form a compound of formula
(XXII):
##STR00032##
[0171] (h) deprotecting the boronic acid moiety to form the
compound of formula (XIV) or a boronic acid anhydride thereof.
[0172] In some embodiments, the process is characterized by at
least one of the following features (1)-(5). In certain preferred
embodiments, the process is characterized by all five features
(1)-(5) below. [0173] (1) In the boron "ate" complex of formula
(XV), R.sup.3 and Y both are chloro. [0174] (2) The coupling step
(e) comprises the steps: [0175] (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-tetramethyluzonium
tetrafluoroborate (TBTU) and a tertiary amine in dichloromethane;
[0176] (ii) performing a solvent exchange to replace
dichloromethane with ethyl acetate; and [0177] (iii) performing an
aqueous wash of the ethyl acetate solution. [0178] (3) The
protecting group removing step (f) comprises the steps: [0179] (i)
treating the compound of formula (XX) with HCl in ethyl acetate;
[0180] (ii) adding heptane to the reaction mixture; and [0181]
(iii) isolating by crystallization the compound of formula (XXI) as
its HC addition salt. [0182] (4) The coupling step (g) comprises
the steps: [0183] (i) coupling the compound of formula (XX) with
2-pyrazinecarboxylic acid in the presence of TBTU and a tertiary
amine in dichloromethane; [0184] (ii) performing a solvent exchange
to replace dichloromethane with ethyl acetate; and [0185] (iii)
performing an aqueous wash of the ethyl acetate solution. [0186]
(5) The boronic acid deprotecting step (h) comprises the steps:
[0187] (i) providing a biphasic mixture comprising the compound of
formula (XXII), an organic boronic acid acceptor, a lower alkanol,
a C.sub.5-8 hydrocarbon solvent, and aqueous mineral acid; [0188]
(ii) stirring the biphasic mixture to afford the compound of
formula (XIV); [0189] (iii) separating the solvent layers; and
[0190] (iv) extracting the compound of formula (XIV), or a boronic
acid anhydride thereof, into an organic solvent.
[0191] Preferably, step (h)(iii) comprises the steps:
[0192] (1) separating the solvent layers;
[0193] (2) adjusting the aqueous layer to basic pH;
[0194] (3) washing the aqueous layer with an organic solvent;
and
[0195] (4) adjusting the aqueous layer to a pH less than about
6;
[0196] In another embodiment, the invention relates to a
large-scale process for forming a compound of formula (XIV)
##STR00033##
or a boronic acid anhydride thereof, comprising the steps:
[0197] (aa) coupling a compound of formula (XVIII):
##STR00034##
or an acid addition salt thereof, with a compound of formula
(XI):
##STR00035##
wherein
[0198] P.sup.1 is a cleavable amino group protecting moiety;
and
[0199] X is OH or a leaving group;
to form a compound of formula
##STR00036##
wherein P.sup.1 is as defined above, said coupling step (aa)
comprising the steps: [0200] (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;
[0201] (ii) performing a solvent exchange to replace
dichloromethane with ethyl acetate; and [0202] (iii) performing an
aqueous wash of the ethyl acetate solution;
[0203] (bb) removing the protecting group P.sup.1 to form a
compound of formula (XXI):
##STR00037##
or an acid addition salt thereof, said protecting group removing
step (bb) comprising the steps: [0204] (i) treating the compound of
formula (XX) with HC in ethyl acetate; [0205] (ii) adding heptane
to the reaction mixture; and [0206] (iii) isolating by
crystallization the compound of formula (XXI) as its HQ addition
salt;
[0207] (cc) coupling the compound of formula (XXI) with a reagent
of formula (XXI)
##STR00038##
wherein X is a OH or a leaving group, to form a compound of formula
(XXIII):
##STR00039##
said coupling step (cc) comprising the steps: [0208] (i) coupling
the compound of formula (XXI) with 2-pyrazinecarboxylic acid in the
presence of TBTU and a tertiary amine in dichloromethane; [0209]
(ii) performing a solvent exchange to replace dichloromethane with
ethyl acetate; and [0210] (iii) performing an aqueous wash of the
ethyl acetate solution; and
[0211] (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: [0212] (i) providing a
biphasic mixture comprising the compound of formula (XXII), an
organic boronic acid acceptor, a lower alkanol, a C.sub.5-8
hydrocarbon solvent, and aqueous mineral acid; [0213] (ii) stirring
the biphasic mixture to afford the compound of formula (XIV);
[0214] (iii) separating the solvent layers; and [0215] (iv)
extracting the compound of formula (XIV), or a boronic acid
anhydride thereof, into an organic solvent.
[0216] Preferably, step (dd)(iii) comprises the steps: [0217] (1)
separating the solvent layers; [0218] (2) adjusting the aqueous
layer to basic pH; [0219] (3) washing the aqueous layer with an
organic solvent; and [0220] (4) adjusting the aqueous layer to a pH
less than about 6;
[0221] The efficiency of the procesees described above is further
enhanced by telescoping steps, for example, by carrying a reaction
mixture or worked-up product solution from one reaction directly
into the following reaction, without isolation of the intermediate
product. For example, in some embodiments, step (e)(iii) or
(aa)(iii) affords an ethyl acetate solution comprising a compound
of formula (XX), and the ethyl acetate solution is directly
subjected in step (f) or (bb) to conditions effective to remove the
protecting group Pt. In some such embodiments, the protecting group
P.sup.1 is an acid-labile protecting group, for example,
tert-butoxycarbonyl (Boc), and the ethyl acetate solution from step
(e)(iii) or (aa)(iii) is treated with acid. In certain preferred
embodiments, the ethyl acetate solution from step (e)(iii) or
(aa)(iii) is dried azeotropically and then treated with gaseous
HCl.
[0222] When the deprotecting step (f) or (bb) is performed under
anhydrous conditions, as described above, the product of formula
(XXI) can be isolated by crystallization from the reaction mixture
as its HCl addition salt. Crystallization of the product salt is
promoted by addition of a hydrocarbon solvent such as n-heptane. In
some embodiments, the reaction mixture is partially concentrated
prior to addition of the hydrocarbon solvent. The present inventors
have discovered that crystallization of the compound of formula
(XXI) in this manner efficiently removes any tripeptide impurity
that may have formed during the coupling step (e) or (aa). Such
impurities are difficult to remove at later stages in the
synthesis.
[0223] Further telescoping of the process is possible by carrying
the product mixture from the coupling step (g) or (cc) directly
into the boronic acid moiety deprotecting step (h) or (dd).
Preferably, the organic solvent from the coupling reaction is first
replaced with ethyl acetate in order to facilitate aqueous washes.
A second solvent exchange into a hydrocarbon solvent then permits
the product solution from step (g) or (cc) to be used directly in
the biphasic boronic acid deprotecting step (h) or (dd), without
isolation of the compound of formula (XXIII).
[0224] Alternatively, a more convergent approach may be adopted for
the synthesis of the compound of formula (XIV). Thus, in yet
another embodiment, the invention provides a large-scale process
for forming a compound of formula (XIV)
##STR00040##
or a boronic acid anhydride thereof. The process comprises the
steps:
[0225] (a) providing a boron "ate" complex of formula (XV):
##STR00041##
wherein
[0226] R.sup.3 is a nucleofugic group;
[0227] Y is a nucleofugic group; and
[0228] M.sup.+ is an alkali metal;
[0229] (b) contacting the boron "ate" complex of formula (XV) with
a Lewis acid under conditions that afford a boronic ester compound
of formula (XVI):
##STR00042##
said contacting step being conducted in a reaction mixture
comprising: [0230] (i) a coordinating ether solvent that has low
miscibility with water; or [0231] (ii) an ether solvent that has
low miscibility with water and a coordinating co-solvent;
[0232] (c) treating the boronic ester compound of formula (XVI)
with a reagent of formula M.sup.1-N(Si(R.sup.6).sub.3).sub.2, where
M.sup.1 is an alkali metal and each R.sup.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):
##STR00043##
[0233] (d) removing the (R.sup.6)Si groups to form a compound of
formula (XVIII):
##STR00044##
or an acid addition salt thereof;
[0234] (e') coupling the compound of formula (XVIII) with a
compound of formula (XIXa):
##STR00045##
wherein X is OH or a leaving group, to form a compound of formula
(XXIII):
##STR00046##
and
[0235] (f') deprotecting the boronic acid moiety to form the
compound of formula (XIV) or a boronic acid anhydride thereof.
[0236] In some embodiments, the process is characterized by at
least one of the following features (1)-(3). In certain preferred
embodiments, the process is characterized by all three features
(1)-(3) below.
[0237] (1) In the boron "ate" complex of formula (XV), R.sup.3 and
Y both are chloro.
[0238] (2) The coupling step (e') comprises the steps: [0239] (i)
coupling the compound of formula (XVI) 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;
[0240] (ii) performing a solvent exchange to replace
dichloromethane with ethyl acetate; and [0241] (iii) performing an
aqueous wash of the ethyl acetate solution.
[0242] (3) The boronic acid deprotecting step (f) comprises the
steps: [0243] (i) providing a biphasic mixture comprising the
compound of formula (XXIII), an organic boronic acid acceptor, a
lower alkanol, a C.sub.5-8 hydrocarbon solvent, and aqueous mineral
acid; [0244] (ii) stirring the biphasic mixture to afford the
compound of formula (XIV); [0245] (iii) separating the solvent
layers; and [0246] (iv) extracting the compound of formula (XIV),
or a boronic acid anhydride thereof, into an organic solvent.
[0247] Preferably, step (f')(iii) comprises the steps:
[0248] (1) separating the solvent layers;
[0249] (2) adjusting the aqueous layer to basic pH;
[0250] (3) washing the aqueous layer with an organic solvent;
and
[0251] (4) adjusting the aqueous layer to a pH less than about
6;
[0252] In step (h)(iv), (dd)(iv), or (f')(iv) of the processes
described above, the compound of formula (XIV), or a boronic acid
anhydride thereof, preferably is extracted into ethyl acetate and
crystallized by addition of hexane or heptane. In some embodiments,
the process further comprises isolation of a boronic acid anhydride
of the compound of formula (XIV), preferably a trimeric boronic
acid anhydride of formula (XXIV):
##STR00047##
[0253] The processes of the invention permit the large-scale
manufacture of bortezomib of very high chemical and stereochemical
purity. Prior art processes were limited in scale and afforded
product of lower overall purity. In yet another aspect, therefore,
the invention provides a composition comprising at least one
kilogram of a compound of formula (XXIV):
##STR00048##
The compound of formula (XXIV) preferably is prepared according to
the process described above, and preferably constitutes at least
99% w/w of the composition according to this aspect of the
invention.
EXAMPLES
Abbreviations
[0254] BOC tert-butoxycarbonyl [0255] D.I. de-ionized [0256] DMF
N,N-dimethylformamide [0257] GC gas chromatography [0258] GC-MS gas
chromatography-mass spectrometry [0259] h hours [0260] HDPE high
density polyethylene [0261] HPLC high performance liquid
chromatography [0262] LDA lithium diisopropylamide [0263] LOD loss
on drying [0264] min minutes [0265] MTBE t-butyl methyl ether
[0266] RP-HPLC reverse phase high performance liquid chromatography
[0267] RPM revolutions per minute [0268] TBTU
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
[0269] THF tetrahydrofuran
Example 1: (R)--(S)-Pinanediol 1-ammonium
trifluoracetate-3-methylbutane-1-boronate Manufacturing Process
(1S)--(S)-Pinanediol-chloro-3-methylbutane-1-boronate
[0269] [0270] 1. (S)-Pinanediol-2-methylpropane-1-boronate (12.0
kg, 50.8 moles) was charged to a reaction vessel maintained under a
nitrogen atmosphere. [0271] 2. tert-Butyl methyl ether (53 kg) and
dichloromethane (225 kg) were charged and the resultant mixture was
cooled to -57.degree. C. with stirring. [0272] 3. Diisopropylamine,
(6.7 kg) was charged to another reaction vessel maintained under a
nitrogen atmosphere. [0273] 4. tert-Butyl methyl ether (27 kg) was
charged to the diisopropylamine and the resultant mixture was
cooled to -10.degree. C. with stirring. [0274] 5. n-Hexyllithium in
hexane (332 weight % solution) (17.6 kg) was added to the
diisopropylamine mixture over a period of 57 minutes, while the
reaction temperature was maintained at -10.degree. C. to -7.degree.
C. [0275] 6. This mixture (LDA-mixture) was stirred for 33 minutes
at -9.degree. C. to -7.degree. C. before it was used. [0276] 7.
Zinc chloride, (12.1 kg) was charged to a third reaction vessel
maintained under a nitrogen atmosphere. [0277] 8. tert-Butyl methyl
ether (16 kg) was charged to the zinc chloride and the resultant
mixture was warmed to 30.degree. C. with stirring. [0278] 9.
Tetrahydrofuran (53 kg) was added to the zinc chloride suspension
over a period of 18 minutes, while the reaction temperature was
maintained at 35.degree. C. to 40.degree. C. [0279] 10. This
mixture (ZnCl-mixture) was stirred for 4 hours and 28 minutes at
38.degree. C. to 39.degree. C. until it was used. [0280] 11. The
LDA-mixture (from #3-6) was added over a period of 60 minutes to
the reaction vessel containing
(S)-pinanediol-2-methylpropane-1-boronate, while the reaction
temperature was maintained at -60.degree. C. to -55.degree. C.
[0281] 12. A tert-butyl methyl ether rinse (10 kg) was used to
complete the addition. [0282] 13. The reaction mixture was stirred
for an additional 20 minutes at -59.degree. C. to -55.degree. C.
[0283] 14. The reaction mixture was warmed to -50.degree. C. over a
period of 11 minutes. [0284] 15. The ZnCl.sub.2-mixture (from
#7-10) was added over a period of 48 minutes to the reaction vessel
containing (S)-pinanediol-2-methylpropane-1-boronate and the
LDA-mixture, while the reaction temperature was maintained at
-50.degree. C. to -45.degree. C. [0285] 16. A tert-butyl methyl
ether rinse (10 kg) was used to complete the addition. [0286] 17.
The reaction mixture was stirred for an additional 30 minutes at
-45.degree. C. to -40.degree. C. and then warmed to 10.degree. C.
over a period of 81 minutes. [0287] 18. A 10% sulfuric acid
solution (72 kg) was added over a period of 40 minutes to the
reaction vessel, while the reaction temperature was maintained at
10.degree. C. to 21.degree. C. [0288] 19. The reaction mixture was
stirred for 16 minutes at ambient temperature, before the aqueous
phase was separated. [0289] 20. The organic phase was washed
successively with deionized (D.I.) water (32 kg), and 10% sodium
chloride solution (26.7 kg), each wash involved vigorous stirring
for 15 to 17 minutes at ambient temperature. [0290] 21. The
reaction mixture was concentrated under reduced pressure
(p.sub.min=81 mbar), maintaining an external (jacket/bath)
temperature of 50.degree. C. to 55.degree. C., providing a residue
which was dissolved in methylcyclohexane (56 kg). [0291] 22. The
reaction mixture was refluxed (in a Dean-Stark type condenser for
water separation) under reduced pressure (p.sub.min=67 mbar),
maintaining an external (jacket/bath) temperature of 50.degree. C.
to 55.degree. C. for 2 hours and 7 minutes, until no more water was
separated. [0292] 23. About 35 L of the solvents were distilled off
under reduced pressure (p.sub.min=81 mbar), maintaining an external
(jacket/bath) temperature of 50.degree. C. to 55.degree. C. [0293]
24. The resultant dry methylcyclohexane mixture containing
(1S)--(S)-pinanediol 1-chloro-3-methylbutane-1-boronate was cooled
to 14.degree. C.
(1R)--(S)-Pinanediol
1-bis(trimethylsilyl)amino-3-methylbutane-1-boronate
[0293] [0294] 1. Lithium bis(trimethylsilyl)amide in
tetrahydrofuran (19.4 weight % solution), (41.8 kg) was charged to
a reaction vessel maintained under a nitrogen atmosphere and cooled
to -19.degree. C. with stirring. [0295] 2. The methylcyclohexane
mixture containing (1S)--(S)-pinanediol
1-chloro-3-methylbutane-1-boronate was added over a period of 55
minutes, while the reaction temperature was maintained at
-19.degree. C. to -13.degree. C. [0296] 3. A methylcyclohexane
rinse (5 kg) was used to complete the addition. [0297] 4. The
reaction mixture was stirred for an additional 65 minutes at
-13.degree. C. to -12.degree. C. and then warmed to 25.degree. C.
over a period of 25 minutes. [0298] 5. A suspension of Celite (2.5
kg) in methylcyclohexane (22 kg) was added to the reaction mixture.
[0299] 6. The reaction mixture was concentrated under reduced
pressure (p.sub.min=25 mbar), maintaining an external (jacket/bath)
temperature of 45.degree. C. to 50.degree. C., providing a residue
which was dissolved in methylcyclohexane (36 kg). [0300] 7. A
sample was then removed for in-process testing for tetrahydrofuran
content by GC. [0301] 8. The tetrahydrofuran assay was 0.58%.
[0302] 9. The solids were removed by filtration, the filtrate was
filtered through a plug of Silica Gel (2.0 kg). [0303] 10. Both
filter units were washed with isopropyl ether (30 kg). [0304] 11.
The resultant methylcyclohexane/isopropyl ether mixture containing
(1R)--(S)-pinanediol
1-bis(trimethylsilyl)amino-3-methylbutane-1-boronate was stored in
a container at ambient temperature until it was used in the next
step.
(1R)--(S)-Pinanediol 1-ammonium
trifluroacetate-3-methylbutane-1-boronate
[0304] [0305] 1. Trifluoroacetic acid, (12 kg) was charged to
another reaction vessel maintained under a nitrogen atmosphere.
[0306] 2. Isopropyl ether (78 kg) was charged to the
trifluoroacetic acid and the resultant mixture was cooled to
-10.degree. C. with stirring. [0307] 3. The
methylcyclohexane/isopropyl ether mixture containing
(1R)--(S)-pinanediol
1-bis(trimethylsilyl)amino-3-methylbutane-1-boronate was added over
a period of 53 minutes causing product precipitation, while the
reaction temperature was maintained at -10.degree. C. to -5.degree.
C. [0308] 4. An isopropyl ether rinse (5 kg) was used to complete
the addition. [0309] 5. The reaction mixture was stirred for an
additional 8 hours and 20 minutes at -9.degree. C. to -7.degree. C.
[0310] 6. The solid was collected by filtration, washed with
isopropyl ether (70 kg) in two portions, and dried under reduced
pressure (pmin=56 mbar) at 41.degree. C. to 42.degree. C. for 2
hours and 15 minutes. [0311] 7. The solid was stirred with D.I.
water (60 kg) for 24 minutes at ambient temperature, before the
D.I. water was removed by filtration. [0312] 8. The solid was
washed with D.I. water (12 kg). [0313] 9. The solid was then dried
under vacuum (pmin=4 mbar) at 40.degree. C. to 44.degree. C. for 9
hours and 22 minutes, after that time the loss on drying was 0.51%,
which meets the .ltoreq.1% requirement. [0314] 10. The
intermediate, (1R)--(S)-pinanediol 1-ammonium
trifluoroacetate-3-methylbutane-1-boronate, crude, was then
packaged into single polyethylene bags in polypropylene drums and
labeled. The yield was 72%.
Recrystallization of (1R)--(S)-pinanediol 1-ammonium
trifluoroacetate-3-methylbutane-1-boronate, crude
[0314] [0315] 1. (1R)--(S)-Pinanediol 1-ammonium
trifluoroacetate-3-methylbutane-1-boronate, crude, (13 kg) was
charged to a reaction vessel maintained under a nitrogen
atmosphere. [0316] 2. Trifluoroacetic acid (31 kg) was charged to
the reaction vessel and the resultant mixture was cooled to
4.degree. C. with stirring. [0317] 3. Once all of the solid was
dissolved leaving a slightly turbid mixture, isopropyl ether (29
kg) was added over a period of 57 minutes, while the reaction
temperature was maintained at 2.degree. C. to 3.degree. C. [0318]
4. After complete addition the mixture was filtered through a
filter into a receiving vessel maintained under a nitrogen
atmosphere. [0319] 5. Reactor and filter were rinsed with a mixture
of trifluoroacetic acid (3.8 kg) and isopropyl ether (5 kg). The
rinse was added to the filtrate. [0320] 6. Isopropyl ether (126 kg)
was added over a period of 15 minutes causing product
precipitation, while the reaction temperature was maintained at
16.degree. C. to 18.degree. C. [0321] 7. The mixture was stirred at
16.degree. C. to 18.degree. C. for 15 min, then cooled to
-5.degree. C. over a period of 67 minutes, and stirred at
-3.degree. C. to -5.degree. C. under a nitrogen atmosphere for 89
minutes. [0322] 8. The solid was then isolated by filtration,
washed with isopropyl ether (48 kg) in two portions, and dried
under vacuum (pmin=2 mbar) at 34.degree. C. to 40.degree. C. for 2
hours and 55 minutes after that time the loss on drying was 032%,
which meets the .ltoreq.0.5% requirement. [0323] 9. The product,
(1R)--(S)-pinanediol1-ammonium
trifluoroacetate-3-methylbutane-1-boronate, was then packaged into
double polyethylene bags in fiber drums and labeled. The yield was
86%.
Example 2: N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic
anhydride Manufacturing Process
(1S,2S,3R,5S)-Pinanediol N-BOC-L-phenylalanine-L-leucine
boronate
[0323] [0324] 1. In a fume hood, a three-necked glass reaction
flask equipped with a Claisen head temperature recorder and a
mechanical stirrer was flushed with nitrogen. [0325] 2.
(1R)--(S)-Pinanediol 1-ammonium
trifluoroacetate-3-methylbutane-1-boronate (2.0 kg), was charged to
the flask. [0326] 3. BOC-L-phenylalanine (1.398 kg) was charged to
the flask. [0327] 4. 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyl
uronium tetrafluoroborate, TBTU (1.864 kg) was charged to the
flask. [0328] 5. Dichloromethane (15.8 L) was charged to the flask.
[0329] 6. The stirring motor was adjusted to provide stirring at
260 RPM. [0330] 7. Using an ice/water cooling bath, the reaction
mixture was cooled to 1.0.degree. C., maintaining a nitrogen
atmosphere. [0331] 8. N,N-Diisopropylethylamine (2.778 L) was
charged to a glass flask and transferred to the reaction mixture
over a period of 117 minutes using a peristaltic pump maintaining a
reaction temperature range of 0.7.degree. C.-2.1.degree. C. The
overall addition rate was 23.7 mL/min. [0332] 9. A dichloromethane
(0.2 L) rinse of the flask into the reaction mixture was used to
complete the addition. [0333] 10. The reaction mixture was stirred
for an additional 35 minutes. The temperature at the start of the
stir time was 1.8.degree. C., and 2.5.degree. C. at the end. [0334]
11. A sample was then removed for in-process testing by reverse
phase high performance liquid chromatography (RP-HPLC). The percent
conversion was determined to be 99.3%. [0335] 12. The reaction
mixture was transferred in approximately two equal halves to two
rotary evaporator flasks. The reaction mixture was concentrated
under reduced pressure using a rotary evaporator, maintaining an
external bath temperature of 29-30.degree. C. [0336] 13. Ethyl
acetate (4.0 L) was divided into two approximately equal portions
and charged to the two rotary evaporator flasks. [0337] 14. The
mixtures in each flask were again concentrated under reduced
pressure using a rotary evaporator, maintaining an external bath
temperature of 29-30.degree. C. [0338] 15. The residues in each
rotary evaporator flask were then transferred back to the reaction
flask using ethyl acetate (13.34 L). [0339] 16. In a glass flask
equipped with a stirrer, a 1% aqueous phosphoric acid solution was
prepared by mixing D.I. water (13.18 L) and phosphoric acid (0.160
kg). [0340] 17. In a glass flask equipped with a stirrer, a 2%
aqueous potassium carbonate solution (12.0 L) was prepared by
mixing DL water (11.76 L) and potassium carbonate (0.24 kg). [0341]
18. In a glass flask equipped with a stirrer, a 10% aqueous sodium
chloride solution (13.34 L) was prepared by mixing D.I. water (1334
L) and sodium chloride (1.334 kg). [0342] 19. D.I. water (1334 L)
was charged to the reaction flask containing the ethyl acetate
solution and the mixture stirred at 380 RPM for 7 minutes. The
layers were allowed to separate and the aqueous phase (bottom
layer) was transferred under vacuum to a suitable flask and
discarded. [0343] 20. Again, D.I. water (13.34 L) was charged to
the reaction flask containing the ethyl acetate solution and the
mixture stirred at 385 RPM for 7 minutes. The layers were allowed
to separate and the aqueous phase (bottom layer) was transferred
under vacuum to a suitable flask and discarded. [0344] 21. The 1%
phosphoric acid solution prepared in Step 16 was charged to the
reaction flask containing the ethyl acetate solution and the
mixture stirred at 365 RPM for 7 minutes. The layers were allowed
to separate and the acidic aqueous phase (bottom layer) was
transferred to a suitable flask and discarded. [0345] 22. The 2%
potassium carbonate solution prepared in Step 17 was charged to the
reaction flask containing the ethyl acetate solution and the
mixture stirred at 367 RPM for 7 minutes. The layers were allowed
to separate and the basic aqueous phase (bottom layer) was
transferred to a suitable flask and discarded. [0346] 23. The 10%
sodium chloride solution prepared in Step 18 was charged to the
reaction flask containing the ethyl acetate solution and the
mixture stirred at 373 RPM for 6 minutes. The layers were allowed
to separate and the aqueous phase (bottom layer) was transferred to
a suitable flask and discarded. [0347] 24. The ethyl acetate
solution was transferred to a rotary evaporator flask and
concentrated under reduced pressure using a rotary evaporator,
maintaining a bath temperature of 29-30.degree. C., to provide a
residue. [0348] 25. The residue was then redissolved in ethyl
acetate (4.68 L). [0349] 26. The solution was concentrated under
vacuum using a rotary evaporator, maintaining a bath temperature of
29-30.degree. C., to provide a residue once more. [0350] 27. Again,
the residue was then redissolved in ethyl acetate (4.68 L) and two
samples taken for determination of water content by Karl Fisher
titration. The water content of two samples was determined as
0.216% and 0.207%. [0351] 28. Using a further quantity of ethyl
acetate (12.66 L), the mixture was transferred from the rotary
evaporator flask to a dry reaction flask equipped with a
temperature recorder, a mechanical stirrer, and a fritted gas
dispersion tube, and purged with nitrogen.
(1S,2S,3R,5S)-Pinanediol L-phenylalanine-L-leucine boronate, HC
Salt
[0351] [0352] 1. The ethyl acetate solution containing
(1S,2S,3R,5S)-pinanediol N-BOC-L-phenylalanine-L-leucine boronate
was cooled using an ice/water cooling bath to -0.9.degree. C.
[0353] 2. Hydrogen chloride (1.115 kg) gas was bubbled into the
reaction mixture over a period of 1.48 hours. The temperature at
the start of the addition was -0.9.degree. C., and 6.8.degree. C.
at the end. [0354] 3. The reaction was then allowed to warm to
14.4.degree. C. over 50 minutes, while maintaining a nitrogen
atmosphere. [0355] 4. A sample was removed for in-process testing
by RP-HPLC. The percent conversion was 68.9% (area %). [0356] 5.
The reaction was stirred for 35 minutes. The temperature at the
start was 14.degree. C., and 14.8.degree. C. at the end. [0357] 6.
A sample was removed for in-process testing by RP-HPLC. The percent
conversion was 94.7% (area %). [0358] 7. The reaction was stirred
for approximately a further 50 minutes, maintaining a temperature
of 10.degree. C..+-.5.degree. C. [0359] 8. A sample was removed for
in-process testing by RP-HPLC. The percent conversion was 97.3%.
[0360] 9. The reaction was stirred for approximately a further 50
minutes, maintaining a temperature of 10.degree. C..+-.5.degree. C.
The final temperature was 14.6.degree. C. [0361] 10. A sample was
removed for in-process testing by RP-HPLC. The total reaction time
after addition of hydrogen chloride gas was four (4) hours. [0362]
11. The percent conversion was 99%. [0363] 12. A slurry was
observed. [0364] 13. n-Heptane (8.8 L) was charged to the reaction
mixture. [0365] 14. The slurry was stirred for 2 hours. The
temperature at the start of the stir time was 12.7.degree. C., and
15.3.degree. C. at the end. [0366] 15. The solid was isolated by
filtration on a Buchner funnel lined with a polypropylene felt
filter pad. [0367] 16. The solid was washed with n-heptane (4.68
L). [0368] 17. In a hood, the solid was transferred to three drying
trays at not more than 1'' deep and air-dried for 1 hour. [0369]
18. The solid was then dried at .ltoreq.35.degree. C. under a
vacuum of 27'' of Hg for 16 hours 28 minutes in a vacuum oven
equipped with a vacuum gauge and a temperature recorder. [0370] 19.
The solid was sampled from each drying tray to determine the % Loss
on Drying. The LOD was determined to be 0%, 0.02%, and 0.02% on the
three samples taken. [0371] 20. (1S,2S,3R,5S)-Pinanediol
L-phenylalanine-L-leucine boronate, HCl salt was then packaged into
double poly bags in fiber drums and labeled, and sampled. [0372]
21. The isolated yield was 1.87 k& 79.1%. The intermediate was
stored at 2-8.degree. C. until used in further manufacturing.
(1S,2S,3R,5S)-Pinanediol
N-(2-pyrazinecarbonyl-L-phenylalanine-L-leucine boronate
[0372] [0373] 1. In a fume hood a three-necked glass reaction flask
equipped with a Claisen head, temperature recorder and a mechanical
stirrer was flushed with nitrogen. [0374] 2.
(1S,2S,3R,5S)-Pinanediol L-phenylalanine-L-leucine boronate, HCl
salt (1.85 kg) was charged to the flask [0375] 3.
2-Pyrazinecarboxylic acid (0.564 kg) was charged to the flask.
[0376] 4. 2-(H-Benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
tetrafluoroborate, TBTU (1.460 kg) was charged to the flask [0377]
5. Dichloromethane (18.13 L) was charged to the flask. [0378] 6.
The stirring motor was adjusted to provide stirring at 272 RPM.
[0379] 7. Using a cooling bath, the reaction mixture was cooled to
-1.2.degree. C. [0380] 8. N,N-Diisopropylethylamine (1.865 kg) was
charged to a glass flask and transferred to the reaction over a
period of 50 minutes using a peristaltic pump maintaining a
reaction temperature range of -1.2.degree. C. to 2.8.degree. C.
[0381] 9. A dichloromethane rinse (0.37 L) of the flask into the
reaction mixture was used to complete the addition. [0382] 10. The
reaction mixture was allowed to warm and stirred for an additional
81 minutes. [0383] 11. The temperature at the start of the stir
time was 15.degree. C., and 24.9.degree. C. at the end. [0384] 12.
A sample was then removed for in-process testing by RP-HPLC. The
percent conversion was determined to be 99.9%. [0385] 13. The
reaction mixture was transferred in approximately two equal halves
to two rotary evaporator flasks. The reaction mixture was
concentrated under reduced pressure using two rotary evaporators,
maintaining an external bath temperature of 33-34.degree. C. [0386]
14. Ethyl acetate (12.95 L) was divided into two approximately
equal portions and charged to the two rotary evaporator flasks.
[0387] 15. The mixtures in each flask were then concentrated under
reduced pressure using a rotary evaporator, maintaining an external
bath temperature of 33-34.degree. C. [0388] 16. The residues in
each rotary evaporator flask were then transferred back to the
reaction flask using ethyl acetate (12.95 L). [0389] 17. In a glass
flask equipped with a stirrer, a 1% aqueous phosphoric acid
solution (12.34 L) was prepared by mixing D.I. water (12.19 L) and
phosphoric acid (0.148 kg). [0390] 18. In a glass flask equipped
with a stirrer, a 2% aqueous potassium carbonate solution (12.34 L)
was prepared by mixing D.I. water (12.09 L) and potassium carbonate
(0.247 kg). [0391] 19. In a glass flask equipped with a stirrer, a
10% aqueous sodium chloride solution (12.34 L) was prepared by
mixing D.I. water (12.34 L) and sodium chloride (1.234 kg). [0392]
20. D.I. water (1234 L) was charged to the reaction flask
containing the ethyl acetate solution and the mixture stirred at
382 RPM for 7 minutes. The layers were allowed to separate and the
aqueous phase (bottom layer) was transferred to a suitable flask
and discarded. [0393] 21. Again, D.I. water (12.34 L) was charged
to the reaction flask containing the ethyl acetate solution and the
mixture stirred at 398 RPM for 7 minutes. The layers were allowed
to separate and the aqueous phase (bottom layer) was transferred to
a suitable flask and discarded. [0394] 22. The 1% phosphoric acid
solution prepared in Step 17 was charged to the reaction flask
containing the ethyl acetate solution and the mixture stirred at
364 RPM for 8 minutes. The layers were allowed to separate and the
acidic aqueous phase (bottom layer) was transferred to a suitable
flask and discarded. [0395] 23. The 2% potassium carbonate solution
prepared in Step 18 was charged to the reaction flask containing
the ethyl acetate solution and the mixture stirred at 367 RPM for 8
minutes. The layers were allowed to separate and the basic aqueous
phase (bottom layer) was transferred to a suitable flask and
discarded. [0396] 24. The 10% sodium chloride solution prepared in
Step 19 was charged to the reaction flask containing the ethyl
acetate solution and the mixture stirred at 374 RPM for 8 minutes.
The layers were allowed to separate and the aqueous phase (bottom
layer) was transferred to a suitable flask and discarded. [0397]
25. The ethyl acetate solution was transferred under vacuum in
approximately two equal halves to two rotary evaporator flasks and
concentrated under reduced pressure using a rotary evaporator,
maintaining an external bath temperature of 34.degree. C. [0398]
26. n-Heptane (14.8 L) was divided into two approximately equal
portions and charged to the two rotary evaporator flasks. The
mixtures in each flask were then concentrated under reduced
pressure using a rotary evaporator, maintaining an external bath
temperature of 34.degree. C.
N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride,
Crude
[0398] [0399] 1. In a glass flask equipped with a stirrer, a 1N
solution of hydrochloric acid (22.2 L) was prepared by mixing D.I.
water (2036 L) and hydrochloric acid (1.84 kg). [0400] 2. In a
glass flask equipped with a stirrer, a 2N sodium hydroxide solution
(12.03 L) was prepared by mixing D.I. water (12.03 L) and sodium
hydroxide (0.962 kg). [0401] 3. The residues containing
(1S,2S,3R,5S)-pinanediol
N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronate in each
rotary evaporator flask were then transferred to a three-necked
glass reaction flask equipped with a temperature recorder and a
mechanical stirrer, using n-heptane (14.8 L) and methanol (14.8 L).
[0402] 4. The stirring motor was adjusted to provide stirring at
284 RPM. [0403] 5. 2-Methylpropaneboronic acid (0.672 kg) was
charged to the flask. [0404] 6. 1N hydrochloric acid prepared in
Step 1 (11.2 L) was charged to the flask. [0405] 7. The stirring
motor was adjusted to provide stirring at 326 RPM. [0406] 8. The
reaction mixture was stirred for 16.38 hours The start batch
temperature was 28.6.degree. C., and the end batch temperature was
21.6.degree. C. [0407] 9. A sample was then removed for in-process
testing by RP-HPLC. [0408] 10. The percent conversion was
determined to be 100%. [0409] 11. Stirring was stopped and the
biphasic mixture allowed to separate. [0410] 12. The n-heptane
layer (upper layer) was transferred to a suitable flask and
discarded. [0411] 13. n-Heptane (537 L) was charged to the reaction
flask and the mixture stirred at 381 RPM for 6 minutes. The layers
were allowed to separate and the n-heptane phase (upper layer) was
transferred to a suitable flask and discarded. [0412] 14. Again,
n-heptane (5.37 L) was charged to the reaction flask and the
mixture stirred at 340 RPM for 6 minutes. The layers were allowed
to separate and the n-heptane phase (upper layer) was transferred
to a suitable flask and discarded. [0413] 15. The aqueous methanol
solution was transferred in approximately two equal halves to two
rotary evaporator flasks and concentrated under reduced pressure
using a rotary evaporator, maintaining an external bath temperature
of 33-34.degree. C. 15 L of methanol were collected. [0414] 16.
Dichloromethane (5.37 L) was used to transfer the residue from the
rotary evaporator flasks back into the reaction flask. [0415] 17.
2N sodium hydroxide (11.2 L) prepared in Step 2 was charged to the
flask. [0416] 18. The dichloromethane layer (lower layer) was
transferred to a suitable flask and discarded. [0417] 19.
Dichloromethane (5.37 L) was charged to the flask and the mixture
stirred at 374 RPM for 6 minutes. The phases were allowed to
separate and the dichloromethane layer (lower layer) was
transferred to a suitable flask and discarded. [0418] 20. Again,
dichloromethane, (5.37 L) was charged to the flask and the mixture
stirred at 368 RPM for 8 minutes. The phases were allowed to
separate and the dichloromethane layer (lower layer) was
transferred to a suitable flask and discarded. [0419] 21.
Dichloromethane (5.37 L) was charged to the flask. [0420] 22. 1N
hydrochloric acid (10.7 L) was charged to the flask with stirring.
The pH of the aqueous phase was determined to be 6. [0421] 23.
Stirring was discontinued and the phases allowed to separate.
[0422] 24. The dichloromethane phase (lower layer) was transferred
under vacuum to a glass receiving flask. [0423] 25. Dichloromethane
(5.37 L) was charged to the flask and the mixture stirred at 330
RPM for 6 minutes. The phases were allowed to separate and the
dichloromethane layer (lower layer) was transferred to the glass
receiving flask. [0424] 26. Again, dichloromethane, (5.37 L) was
charged to the flask and the mixture stirred at 335 RPM for 6
minutes. The phases were allowed to separate and the
dichloromethane layer (lower layer) was transferred to the glass
receiving flask. [0425] 27. The dichloromethane extracts were
combined and transferred in approximately two equal halves to two
rotary evaporator flasks and concentrated under reduced pressure
using a rotary evaporator, maintaining an external bath temperature
of 33-34.degree. C. [0426] 28. Ethyl acetate (12.95 L) was divided
into two approximately equal portions and charged to the two rotary
evaporator flasks. The mixtures in each flask were then
concentrated under reduced pressure using a rotary evaporator,
maintaining an external bath temperature of 45-46.degree. C. [0427]
29. Again, ethyl acetate (12.95 L) was divided into two
approximately equal portions and charged to the two rotary
evaporator flasks. The mixtures in each flask were then
concentrated under reduced pressure using a rotary evaporator,
maintaining an external bath temperature of 45-46.degree. C., until
approximately 10% of the original volume remained. [0428] 30.
n-Heptane (10.2 L) was divided into two approximately equal
portions and charged to the two rotary evaporator flasks, and the
slurry stirred under a nitrogen atmosphere for 2.67 hours at
22-23.degree. C. [0429] 31. The solid was isolated by filtration on
a Buchner funnel, lined with a polypropylene felt filter pad.
[0430] 32. The solid was washed with n-heptane (2.96 L). [0431] 33.
In a hood, the solid was transferred to four drying trays and
air-dried for 1.25 hours. [0432] 34. The solid was then dried at
36-50.degree. C. under a vacuum of 27'' of Hg for 18 hours 27
minutes in a vacuum oven equipped with a vacuum gauge and a
temperature recorder. [0433] 35. The solid was sampled from each
tray to determine the % Loss on Drying (LOD). The LOD was
determined to be 0.38%, 0.62%, 0.71%, and 0.63% on the four samples
taken. [0434] 36. N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine
boronic anhydride, crude was packaged into two 5 L, HDPE,
tamper-proof wide-mouth bottles and labeled. [0435] 37. The
isolated yield was 1.314 kg, 83%.
Recrystallization of
N-(2-Pyrazinecarbonyl-L-phenylalanine-L-leucine boronic anhydride,
crude
[0435] [0436] 1. In a hood a glass reaction flask equipped with a
mechanical stirrer, a reflux condenser and a temperature recorder
was flushed with nitrogen. [0437] 2. Ethyl acetate (21 L) was
charged to the flask. [0438] 3. The ethyl acetate was heated to
66.8.degree. C. under a nitrogen atmosphere, using a hot
water/steam bath. [0439] 4.
N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride,
crude (1.311 kg) was slowly charged to the reaction flask. Charging
occurred over a period of 3 minutes. [0440] 5. The mixture was
stirred for 1 minute until all the solid had dissolved. The
temperature of the solution was 64.degree. C. [0441] 6. The heat
source was removed and the mixture was slowly cooled to 60.degree.
C. using a cold bath. [0442] 7. The hot ethyl acetate solution was
transferred into a receiving flask via poly tubing and a
polypropylene in-line filter capsule using a peristaltic pump.
[0443] 8. The mixture was allowed to cool to 272.degree. C., and
allowed to stand under a nitrogen atmosphere without stirring, for
17.75 hours. The final temperature was recorded as 20.5.degree. C.
[0444] 9. The mixture was cooled using an ice/water bath with
stirring for 2.33 hours. The temperature at the start of the stir
time was 3.8.degree. C., and -2.8.degree. C. at the end. [0445] 10.
The solid was isolated by filtration on a Buchner funnel lined with
a polypropylene felt filter pad. The filtrate was collected in a
collection flask. [0446] 11. The solid was washed with ethyl
acetate (2.62 L), cooled to 4.7.degree. C. [0447] 12. In a hood,
the solid was transferred to two drying trays. [0448] 13. The solid
was then dried at 51-65.degree. C. under a vacuum of 27'' of Hg for
19 hours 10 minutes in a vacuum oven equipped with a vacuum gauge
and a temperature recorder. [0449] 14. The solid was sampled to
determine the % Loss on Drying (LOD). The LOD was determined to be
0.65% and 0.62% on the two samples taken. [0450] 15.
N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride
was packaged into four 1 L, Type 3, Amber Wide-Mouth Bottles with
Teflon-Lined Caps and labeled. [0451] 16. The isolated yield was
1.132 kg, 863%. [0452] 17.
N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride
was stored at -25 to -15.degree. C.
Example 3: N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic
anhydride Convergent Synthesis
(1S,2S,3R,5S)-Pinanediol
N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronate
[0453] A solution of (1R)--(S)-Pinanediol 1-ammonium
trifluoroacetate-3-methylbutane-1-boronate (13.97 g) and
N-hydroxysuccinimide (6.23 g) of in 66 mL of DMF was cooled to
-5.degree. C., followed by the addition of dicyclohexylcarbodiimide
(10.83 g). The resulting suspension was stirred for one hour at a
temperature of -5 to 0.degree. C. To a solution of
N-(2-pyrazinecarbonyl)-L-phenylalanine (19.52 g; prepared by
coupling the preformed succinimide ester of pyrazinecarboxylic acid
with L-phenylalanine in dioxane-water) in 62 mL of DMF was added
N-methylmorpholine (5.7 mL) at a temperature of 0.degree. C., and
the resulting solution was added to the suspension. The suspension
was adjusted to pH 7 by the addition of another 5.7 mL of
N-methylmorpholine and stirred overnight, raising the temperature
slowly to 21.degree. C. After filtration, the filtercake was washed
twice with MTBE and the combined filtrates were diluted with 950 mL
of MTBE. The organic layer was washed with 20% aqueous citric acid
(3.times.150 mL), 20% aqueous NaHCO (3.times.150 mL), and brine
(2.times.). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated, yielding 255 g (95.5%) of the title
compound as a foam. As indicated by tlc this material contained
some minor impurities, including approximately 2% of cyclohexyl
urea.
N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic
anhydride
[0454] A solution of (1S,2S,3R,5S)-Pinanediol
N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronate (25.2 g)
in 207 mL of MeOH and 190 mL of hexane was cooled to 15.degree. C.,
and 109.4 mL of 1N HCl were added in portions, keeping the
temperature between 15 and 25.degree. C. 2-Methylpropaneboronic
acid (8.67 g) was then added under vigorous stirring, and the
stirring of the biphasic mixture was continued over night After
separation of the two phases, the lower layer was extracted once
with 75 mL of hexane. The lower layer was then concentrated in
vacuo until it became cloudy, followed by the addition of 109.4 mL
of 2N NaOH and 100 mL of Et.sub.2O. The two phases were separated
the lower layer was extracted with Et.sub.2O (4.times.100 mL each),
and then brought to pH 6.0 by the addition of 109 mL of 1N HCl.
After extraction with 100 mL of ethyl acetate, the lower layer was
adjusted to pH 6.0 with 1N HCl and extracted one more time with 75
mL of ethyl acetate. The combined ethyl acetate layers were washed
with semi-saturated brine (2.times.25 mL) and brine (2.times.25
mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to
afford 15.3 g (81.8%) of crude
N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride
as a foam. The crude material was dissolved in 150 mL of ethyl
acetate and concentrated in vacuo to a suspension, followed by the
addition of 150 mL of MTBE. The suspension was stored between 2 and
8.degree. C. over night, filtered, washed twice with MTBE, and
dried under high vacuum, yielding 10.69 g (572%) of
N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride
as a white solid.
Example 4: Measurement of Diastereomeric Ratio of
(1R)-(1S,2S,3R,5S)-Pinanediol-1-ammoniumtrifluoroacetate-3-methylbutane-1-
-boronate
[0455] The diastereomeric purity of
(1R)-(1S,2S,3R,5S)-pinanediol-1-ammoniumtrifluoroacetate-3-methylbutane-1-
-boronate (compound 1) was determined by non-chiral gas
chromatography (GC). [0456] Chemicals: Acetonitrile (pa. Bruker or
equivalent) [0457] Tetradecane (internal standard) (Fluka puriss.
or equivalent) [0458] Trifluoroacetic anhydride (TFAA) (p.a. Merck
or equivalent) [0459] Instrument: Trace-CC 2000 system or
equivalent [0460] Mobile phase: H.sub.2 [0461] Solvent A (with
internal standard) Approximately 300 mg of tetradecane were weighed
with an accuracy of 0.1 mg into a 100-mL volumetric flask. 1.5 mL
of TFAA were added and the flask was brought to volume with
acetonitrile. [0462] Sample Preparation: About 150 mg of the sample
were exactly weighed (within 0.1 mg) into a 10-mL volumetric flask.
The flask was brought to volume with Solvent A. The solution was
stored for 15 minutes before injection. [0463] GC Parameters:
[0464] Column: Rtx-200; 105 m.times.0.25 mm i.d..times.0.25 .mu.m
film [0465] Mobile phase: H.sub.2 [0466] Temp. program: 130.degree.
C. (0.5 min); 0.5.degree. C./min to 200.degree. C. (0 min);
30.degree. C./min to 300.degree. C. (2 min) [0467] Flow: 0.9 mL/min
(const. flow) [0468] Injector temperature: 250.degree. C. [0469]
Detector temperature: 250.degree. C. (FID) [0470] Split: 1:50
[0471] Injection volume: 1 .mu.L [0472] Substances
##STR00049##
[0472] Stability of the Solution
[0473] A stock solution of compound 1 was prepared by weighing
150.13 mg of compound 1 into a 10-mL volumetric flask and bringing
it to volume with Solvent A. Stability of this solution was tested
at ambient temperature over 48 hours. The stock solution was filled
in 6 separate GC vials. Injections onto the GC system were carried
out from these vials after 0, 12, 24, 48, and 72 hours (double
injection out of each vial. The area % of compound 1 and compound 2
were determined. No changes in area % were observed, indicating
that the solution is stable over 72 hours at ambient
temperature.
Specificity
[0474] Approximately 150 mg of a sample comprising compound 1 and
compound 2 were dissolved in Solvent A and injected to the GC
chromatographic system. The peak for compound 1 was well separated
from the peak for compound 2. Peak purity check by GC-MS showed no
other components co-eluting with compound 1 or compound 2.
Limit of Detection
[0475] The limit of detection (LOD) was defined to be that
concentration where the signal of compound 1 showed a signal to
noise ratio of at least 3:1. A previous blank measurement was
carried out to show that no other peaks interfered. The signal to
noise ratio was calculated by the equation:
S / N = H ( signal ) H ( baseline ) ##EQU00001## [0476] S/N=signal
to noise ratio [0477] H(signal)=height of signal for compound 1
[mm] [0478] H(baseline)=height of signal baseline [mm]
[0479] A sample concentration of 0.05% of the standard test sample
concentration was injected and showed a signal to noise ratio of
4.3. Therefore, the limit of detection is 0.0075 mg/mL
Limit of Quantitation
[0480] The limit of quantitation (LOQ) was defined to be that
concentration where the signal of compound 1 showed a signal to
noise ratio of at least 10.1. Signal to noise ratio was calculated
as described above. A sample concentration of 0.1% of the standard
sample concentration was injected and showed a signal to noise
ratio of 10.1. Therefore, the limit of quantitation is 0.015
mg/mL.
Example 5: Purity Assay for
N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic
anhydride
[0481] The purity of
N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride
(compound 3) was assayed by reverse phase HPLC. [0482] Reagents:
Water, HPLC grade [0483] Acetonitrile, HPLC grade [0484] Formic
acid, ACS grade, .gtoreq.98% pure [0485] 3% Hydrogen peroxide, ACS
grade or equivalent [0486] Instrument [0487] High performance
liquid chromatograph Autosampler capable of delivering
20-.upsilon.L injections and maintaining a temperature of 5.degree.
C. [0488] Pump capable of gradient delivery at 1.0 mL/min [0489] UV
detector capable of monitoring effluent at 270 nm [0490] Column
Symmetry C18 chromatographic column, 250 mm.times.4.6 mm ID,
5-.mu.m, Waters, cat# WAT054275. [0491] Sample Preparation:
Approximately 50 mg of compound 3 were accurately weighed into a
50-mL volumetric flask. Mobile Phase B (5 mL) was added and the
mixture was sonicated to dissolve compound 3 (approximately 30-60
seconds). The solution was allowed to reach room temperature,
diluted to volume with Mobile Phase A, and mixed well. Each sample
was prepared in duplicate and was stable for 7 days when stored at
2-8.degree. C. protected from light [0492] HPLC Parameters [0493]
Mobile phase A: acetonitrile/water/formic acid, 30:700.1 (v/v/v),
degassed [0494] Mobile phase B: acetonitrile/water/formic acid,
80:20:0.1 (v/v/v), degassed [0495] Flow rate: 1.0 mL/min [0496]
Detector: UV at 270 nm [0497] Injection Volume: 20 .mu.L [0498]
Column Temp: ambient [0499] Sample Tray Temp: 5.degree. C. [0500]
Gradient Program:
TABLE-US-00001 [0500] Time % A % B 0 100 0 15 100 0 30 0 100 45 0
100 47 100 0 55 100 0
Substances
##STR00050##
[0502] The retention time of compound 3 was typically between 10
and 14 minutes when using an HPLC system with a 1.3 minute dwell
volume. Compounds 4 and 5 co-eluted at longer retention time, with
a resolution of .gtoreq.2.0.
[0503] The relative retention of compound 3 in a sample
chromatogram to that in the standard chromatogram was calculated
according to the following equation
R r = t sam t std ##EQU00002##
[0504] Where: [0505] R.sub.r=relative retention [0506]
t.sub.sam=retention time of compound 3 peak in the sample
chromatogram, minutes [0507] t.sub.std=retention time of the drug
substance peak in the closest preceding standard chromatogram,
minutes
[0508] Assay results were calculated for each sample according to
the following equation:
% assay = A sam A std .times. W std .times. P W sam .times. 1 ( 100
- M 100 ) .times. 100 ##EQU00003##
[0509] Where: [0510] A.sub.sam=peak area response of compound 3 in
the sample preparation [0511] A.sub.std=mean peak area response of
compound 3 in the working standard preparation [0512]
W.sub.std=weight of the standard, mg [0513] P=assigned purity of
the standard (decimal format) [0514] W.sub.sam=weight of the
sample, mg [0515] M=moisture content of the sample, % [0516]
100=conversion to percent
[0517] Relative retention and impurity levels in each sample were
calculated according to the following equations:
R r = t i t ds ##EQU00004##
[0518] Where: [0519] R.sub.r=relative retention [0520]
t.sub.i=retention time of the individual impurity [0521]
t.sub.ds=retention time of the compound 3 peak
[0521] % I i = A i .times. W std .times. P .times. DF .times. RF i
A std , 1 % .times. W sam .times. 100 ##EQU00005##
[0522] Where: [0523] I.sub.i=individual impurity [0524]
A.sub.i=peak area response of individual impurity in the sample
preparation [0525] A.sub.std,1%=average peak area response of
compound 3 in the 1% standard preparation [0526] W.sub.std=weight
of the standard, mg [0527] W.sub.sam=weight of sample, mg [0528]
P=assigned purity of the standard (decimal format) [0529]
DF=dilution factor, 1/100 [0530] RF.sub.i=relative response factor
of individual impurity [0531] 100=conversion to percentage
factor
[0532] When assayed by this method,
N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucineboronic anhydride
from Example 2 showed total impurities of less than 1%.
[0533] While the foregoing invention has been described in some
detail for purposes of clarity and understanding, these particular
embodiments are to be considered as illustrative and not
restrictive. It will be appreciated by one skilled in the art from
a reading of this disclosure that various changes in form and
detail can be made without departing from the true scope of the
invention and appended claims.
* * * * *