PROCESS FOR THE PREPARATION OF BORTEZOMIB
Field of the Invention
The present invention relates to a process for the preparation of bortezomib and its
intermediates.
Background of the Invention
Bortezomib, a monomeric boronic acid, is chemically [(lR)-3-methyl-l-[[(2S)-loxo-
3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid of Formula I .
FORMULA I
Bortezomib is useful for the treatment of patients with multiple myeloma and
patients with mantle cell lymphoma.
According to U.S. Publication 2005/240047, bortezomib can also exist in the form
of a boronic acid anhydride of Formula IA.
FORMULA IA
U.S. Publication 2005/240047 describes the following process for the preparation
of bortezomib or a boronic acid anhydride of Formula IA.
The above process involves the Lewis acid promoted rearrangement of the
compound of Formula II in tertiary-butyl methyl ether and dichloromethane to obtain the
compound of Formula III. U.S. Publication 2005/240047 says that the use of an ether
solvent that has low miscibility with water such as tertiary-butyl methyl ether in said step
obviates the requirement of rigorously dried equipments, solvents and reagents. U.S.
Publication 2005/240047 also mentions that failure to use rigorously dried equipments,
solvents and reagents result in a dramatic reduction in diastereomeric ratio.
Further process steps provided in U.S. Publication 2005/240047 for preparing
bortezomib or a boronic acid anhydride from the compound of Formula V invariably
involve the use of solvent exchange and tedious work-up procedure. For example, after
the preparation of compound of Formula VII in dichloromethane, the solvent system is
exchanged with ethyl acetate. The solvent exchange requires dividing the reaction mixture
into two portions in two rotary evaporator flasks. The deprotection of the compound of
Formula VII into the compound of Formula VIII is carried out by bubbling of hydrogen
chloride gas into the ethyl acetate solution containing a compound of Formula VII. The
above step requires slurry washing with heptane for 2 hours after the deprotection.
WO 2009/036281 describes a process for the preparation of compound of Formula
III by reacting the compound of Formula II with lithium diisopropylamide in the presence
of a Lewis acid, tetrahydrofuran and 4 to 8 moles of dichloromethane per mole of the
compound of Formula II. It further mentions that excess of dichloromethane is needed for
proper layer separation after quenching the reaction mixture with aqueous acid solution.
WO 2009/004350 describes a process for the preparation of bortezomib by
exposing the compound of Formula II to lithium amide base and a transition metal halide
in a solvent comprising at least 95% tetrahydrofuran by volume to provide the compound
of Formula III, which is further converted into bortezomib.
Summary of the Invention
The present inventors have developed industrially advantageous and efficient
processes for the preparation of bortezomib and its intermediates, which avoids the
drawbacks associated with reported processes. For example, the present processes do not
require excessive use of halogenated hydrocarbon solvent for preparing the compound of
Formula III; they avoid the use of water-immiscible ether solvents without impacting the
yield; they do not require additional slurry washing steps for purifying or isolating the
compound of Formula VIII; and they do not involve any solvent exchange and such
tedious work-up procedures. Thus, the present processes are economic and industrially
scalable for the preparation of bortezomib and its intermediates.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of
(3a5,,4 ,,6 ,,7aR)-2-(l-chloro-3-methylbutyl)-3a,5,5-trimethylhexahydro-4,6-methano-
1,3,2-benzodioxaborole of Formula III or its salts,
FORMULA III
wherein the process comprises reacting (3a ,4 ,6 ,7aR)-3a,5,5-trimethyl-2-(2-
methylpropyl)hexahydro-4,6-methano-l,3,2-benzodioxaborole of Formula II or its salts
FORMULA II
with lithium amide base and a Lewis acid in the presence of a water-miscible ether solvent
and a halogenated hydrocarbon solvent to obtain (3a5,,4 ,,6 ,,7aR)-2-(l-chloro-3-
methylbutyl)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborole of Formula
III or its salts, wherein the halogenated hydrocarbon solvent is less than about 3.8 molar
equivalents per mole of the compound of Formula II.
A second aspect of present invention provides a process for the preparation of N-
{(15,)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7a5,)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butyl}phenylalanine amide of Formula VIII or its salts,
FORMULA VIII
wherein the process comprises contacting tert-butyl [l-({(lS)-3-methyl-l-
[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-
yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate of Formula VII
FORMULA VII
with an acid in the presence of a hydrocarbon solvent to obtain the compound of Formula
VIII or its salts.
A third aspect of the present invention provides a process for the preparation of
bortezomib of Formula I or a boronic acid anh dride of Formula IA comprising
FORMULA I
FORMULA IA
reacting (3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethyl-2-(2-methylpropyl)hexahyd
methano-l,3,2-benzodioxaborole of Formula II or its salts
FORMULA II
with lithium amide base and Lewis acid in the presence of a water miscible
ether solvent and a halogenated hydrocarbon solvent to obtain
(3a5,,4 ,,6 ,,7aR)-2-(l-chloro-3-methylbutyl)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborole of Formula III or its salts,
FORMULA III
wherein the halogenated hydrocarbon solvent is less than about 3.8 molar
equivalents per mole of compound of Formula II,
reacting the compound of Formula III or its salts with M1-N(Si(CH3 )3)2,
where M1 is an alkali metal to obtain l,l,l-Trimethyl -N-{(l R)-3-methyl-l-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl }-N -(trimethylsilyl)silanamine of Formula IV or
its salts,
FORMULA IV
desilylating the compound of Formula IV or its salts to obtain (lR)-3-methyll-[(
3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butan-l -amine of Formula V or its salts,
FORMULA V
coupling the compound of Formula V or its salts with N-(tertbutoxycarbonyl)-
L-phenylalanine of Formula VI to obtain tert-butyl [1-
({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano- 1,3,2-benzodioxaborol-2-yl]butyl }amino)- 1-oxo-3-phenylpropan-2-
yl]carbamate of Formula VII,
FORMULA VI
FORMULA VII
deprotecting the compound of Formula VII in the presence of a hydrocarbon
solvent to obtain N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-
trimethylhexahydro-4,6-methano- 1,3,2-benzodioxaborol-2-
yl]butyl}phenylalanine amide of Formula VIII or its salts,
FORMULA VIII
coupling the compound of Formula VIII or its salts with pyrazine-2-
carboxylic acid of Formula IX to obtain N-{(l R)-3-methyl-l-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butyl }-N a-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
of Formula X, and
FORMULA IX
FORMULA X
g) deprotecting the compound of Formula X to obtain bortezomib or a boronic
acid anhydride of Formula IA.
(3a5,,4 ,,6 ,,7aR)-3a,5,5-Trimethyl-2-(2-methylpropyl)hexahydro-4,6-methano-
1,3,2-benzodioxaborole of Formula II or its salts may be prepared according to the method
provided in U.S. Publication 2005/240047 or PCT application WO 2009/004350.
(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethyl-2-(2-methylpropyl)hexahydro-4,6-methano- 1,3,2-
benzodioxaborole or its salts is reacted with lithium amide base and a Lewis acid in the
presence of a water-miscible ether solvent and a halogenated hydrocarbon solvent. The
water-miscible ether solvent may be, for example, tetrahydrofuran. The water-miscible
ether solvent comprises about 20% to about 93% by volume of the reaction mixture. The
halogenated hydrocarbon solvent may be selected from the group consisting of
dichloromethane, dichloroethane, chloroform and carbon tetrachloride. The halogenated
hydrocarbon solvent is less than about 3.8 molar equivalents per mole of compound of
Formula II. The Lithium amide base may be selected from the group consisting of lithium
diisopropylamide, lithium diethylamide and lithium dimethylamide. The Lewis acid used
could be any suitable Lewis acid generally known in organic chemistry. More
specifically, it may be selected from the group consisting of zinc chloride, zinc bromide,
boron trifluoride, boron trichloride, ferric chloride, ferric bromide and aluminum
trichloride. The reaction may be carried out at a temperature of about 20°C to about -80°C
for about 1 hour to about 100 hours. The reaction may be facilitated by stirring the
reaction mixture. (3a5,,4 ,,6 ,,7aR)-2-(l-chloro-3-methylbutyl)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborole of Formula III or its salts may be optionally isolated.
The isolation may be carried out by filtration, extraction, distillation, pH adjustment,
concentration, decantation, or a combination thereof.
(3a5,,4 ,,6 ,,7aR)-2-(l-chloro-3-methylbutyl)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborole of Formula III or its salts is reacted with M1-
N(Si(CH3)3)2, where M1 is an alkali metal, to obtain l,l,l-trimethyl -N-{(l R)-3-methyl-l-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-
yl]butyl}-iV-(trimethyl silyl)silanamine of Formula IV, or its salts. The alkali metal may
be, for example, lithium, sodium or potassium. The compound, M1-N(Si(CH3)3)2, maybe,
for example, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and
potassium bis(trimethylsilyl)amide. The reaction may be carried out at a temperature of
about 20°C to about -80°C for about 1 hour to about 100 hours. I,l,l-Trimethyl -N-{(1R)-
3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl }-N-(trimethylsilyl)silanamine of Formula IV or its salts may
be optionally isolated. The isolation may be carried out by filtration, extraction,
distillation, pH adjustment, concentration, decantation, or a combination thereof.
l,l,l-Trimethyl -N-{(l R)-3-methyl-l-[(3a5,45,65,7a R)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl }-N-(trimethylsilyl)silanamine of Formula
IV or its salts is desilylated in the presence of an organic solvent to obtain (lR)-3-methyll-[(
3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-
yl]butan-l -amine of Formula V, or its salts. The desilylation may be carried out using an
acid. The organic solvent may be an ether solvent or an ester solvent. The ether solvent
may be selected from the group consisting of dimethyl ether, diethyl ether, diisopropyl
ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, diglyme, 1,4-dioxane, ethyltert-
butyl ether, methyl-tert-butyl ether and methoxy ethane, or a mixture thereof. The
ester solvent may be selected from the group consisting of ethyl acetate, methyl acetate,
isopropyl acetate and butyl acetate, or a mixture thereof. The acid may be an organic acid,
for example, trifluoroacetic acid, or an inorganic acid. (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine of
Formula V or its salts may be optionally isolated. The isolation may be carried out by
filtration, extraction, distillation, pH adjustment, concentration, decantation, or a
combination thereof.
(lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butan-l -amine of Formula V or its salts is coupled with N-(tertbutoxycarbonyl)-
L-phenylalanine of Formula VI in the presence of a coupling agent, a
base and an organic solvent to obtain tert-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl} amino)- 1-oxo-
3-phenylpropan-2-yl]carbamate of Formula VII. The coupling agent may be selected from
the group consisting of 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), dicyclohexylcarbodiimide, 0-benzotriazole-N,N,N',N'-
tetramethyl-uronium-hexafluoro-phosphate, benzotriazol-l-yloxytripyrrolidinophosphonium
hexafluorophosphate and l-ethyl-3-(3-
dimethylaminopropyl)carbodiimide. The base may be selected from the group consisting
of metal alkoxides, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrides
and alkylamines. The base may be, for example, N ,N-diisopropylethylamine. The organic
solvent may be selected from the group consisting of dichloromethane, dichloroethane,
chloroform, dimethylformamide and 1,4-dioxane, or a mixture thereof. The tert-butyl [1-
({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butyl }amino)- 1-oxo-3-phenylpropan-2-yl]carbamate of Formula
VII may be optionally isolated. The isolation may be carried out by filtration, extraction,
distillation, pH adjustment, concentration, decantation, or a combination thereof.
Tert-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate
of Formula VII is deprotected in the presence of a hydrocarbon solvent to obtain N-{(1S)-
3-methyl-l-[(3a5 ,,4 ,,6 ,,7a5,)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl}phenylalanine amide of Formula VIII, or its salts. The
deprotection may be carried out in the presence of an acid. The acid may be an organic
acid or inorganic acid, for example, trifluoroacetic acid, hydrochloric acid, hydrobromic
acid or sulfuric acid. The hydrocarbon solvent may be an aromatic hydrocarbon solvent.
The aromatic hydrocarbon solvent may be, for example, toluene or xylene, or a mixture
thereof. N-{(15,)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7a5,)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide of Formula VIII or its salts may be
optionally isolated by filtration, concentration or decantation, or a combination thereof.
N-{(15)-3-Methyl-l-[(3a5,45,65,7a5)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide of Formula VIII or its salts is
coupled with pyrazine-2-carboxylic acid of Formula IX in the presence of a coupling
reagent, a base and an organic solvent to obtain N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-
2-ylcarbonyl)-L-phenylalaninamide of Formula X. The coupling agent may be selected
from the group consisting of 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), dicyclohexylcarbodiimide, 0-benzotriazole-N,N,N',N'-
tetramethyl-uronium-hexafluoro-phosphate, benzotriazol- 1-yloxytripyrrolidinophosphonium
hexafluorophosphate and l-ethyl-3-(3-
dimethylaminopropyl)carbodiimide. The base may be an organic base or an inorganic
base, for example, metal alkoxides, alkali metal hydroxides, alkali metal carbonates, alkali
metal hydrides or alkylamines. The base may be an alkylamine, for example, N,Ndiisopropylethylamine.
The organic solvent may be a polar solvent or a non polar solvent.
The organic solvent may be selected from the group consisting of dichloromethane,
dichloroethane, chloroform, dimethylformamide and 1,4-dioxane, or a mixture thereof. N-
{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butyl }-Na-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide of Formula
X may be optionally isolated. The isolation may be carried out by filtration, extraction,
distillation, pH adjustment, concentration, decantation, or a combination thereof.
N-{(l R)-3-Methyl-l-[(3a5,45,65,7a R)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl }-N a-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide of
Formula X is deprotected with an acid, an organic boronic acid acceptor and an alcoholic
solvent. The acid may be an organic acid or inorganic acid, for example trifluoroacetic
acid, hydrochloric acid or hydrobromic acid. The organic boronic acid acceptor may be,
for example, isobutyl boronic acid. The alcoholic solvent may be selected from the group
consisting of methanol, ethanol, n-propanol, propan-2-ol, butan-l-ol and butan-2-ol, or a
mixture thereof. Bortezomib or a boronic acid anhydride of Formula IA may be isolated
by filtration, extraction, distillation, pH adjustment, concentration, decantation, or a
combination thereof.
A fourth aspect of the present invention provides a process for the preparation of
bortezomib or a boronic acid anh dri de of Formula IA
FORMULA I
FORMULA IA
comprising:
a) coupling the (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine of Formula V or its
salts with N-(tert-butoxycarbonyl)-L-phenylalanine of Formula VI to obtain
tert-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-
phenylpropan-2-yl]carbamate of Formula VII,
FORMULA VII
deprotecting the compound of Formula VII to obtain ^-{(l^-S-methyl-l-
[(3a5,,4 ,,6 ,,7a5,)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl}phenylalanine amide of Formula VIII or its salts,
FORMULA VIII
coupling the compound of Formula VIII or its salts with pyrazine-2-
carboxylic acid of Formula IX to obtain N-{(l R)-3-methyl-l-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butyl }-N a-(pyrazin-2-ylcarbonyl)-Lphenyl
FORMULA X
deprotecting the compound of Formula X to obtain bortezomib or a boronic
acid anhydride of Formula IA,
wherein at least any two of the compound of Formula VII of step a),
compound of Formula VIII of step b) and compound of Formula X of step c)
are not isolated in any solid form.
The (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butan-l-amine of Formula V or its salts and N-(tertbutoxycarbonyl)-
L-phenylalanine of Formula VI may be prepared according to the method
provided in U.S. Publication 2005/240047 or PCT application WO 2009/004350. The
compound of Formula V or its salt is coupled with the compound of Formula VI to obtain
tert-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate of
Formula VII. The compound of Formula V may be dissolved in an organic solvent and
compound of Formula VI, a coupling agent and a base are added. The resultant reaction
mixture may be stirred and cooled to about -10° to about 15°C. The coupling agent may
be selected from the group consisting of 0-(benzotriazol-l-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (TBTU), dicyclohexylcarbodiimide, Obenzotriazole-
N ,N ,N ' ,N ' -tetramethyl-uronium-hexafluoro-phosphate, benzotriazol- 1-yloxytripyrrolidinophosphonium
hexafluorophosphate and l-ethyl-3-(3-
dimethylaminopropyl)carbodiimide. The base may be selected from the group consisting
of metal alkoxides, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrides
and alkylamines. The organic solvent may be a polar solvent or a non polar solvent. The
organic solvent may be selected from the group consisting of dichloromethane,
dichloroethane, chloroform, dimethylformamide and 1, 4-dioxane, or a mixture thereof.
The reaction mixture may be stirred for about 1 hour to about 100 hours. The reaction
mixture containing the compound of Formula VII may be subjected to layer separation
followed by deprotection, or the reaction mixture may be directly subjected to
deprotection to obtain the N-{(lS)-3-methy\-l-[(3aSAS,6S,TaS)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide
of Formula VIII, or salts thereof. The deprotection may be carried out with an acid. The
acid may be selected from a group consisting of trifluoroacetic acid, hydrochloric acid,
hydrobromic acid and sulfuric acid. The reaction mixture containing the compound
Formula VIII or salts thereof may be subjected to layer separation followed by coupling
with pyrazine-2-carboxylic acid of Formula IX, or the reaction mixture may be directly
subjected to coupling with the compound of Formula IX to obtain N-{(l R)-3-methyl-l-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-
yl]butyl }-Na-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide of Formula X. The coupling
reaction may involve the use of a coupling agent and a base. The coupling agent may be
selected from the group consisting of 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), dicyclohexylcarbodiimide, 0-benzotriazole-N,N,N',N'-
tetramethyl-uronium-hexafluoro-phosphate, benzotriazol- 1-yloxytripyrrolidinophosphonium
hexafluorophosphate and l-ethyl-3-(3-
dimethylaminopropyl)carbodiimide. The base may be selected from the group consisting
of metal alkoxides, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrides
and alkylamines. The temperature of the reaction mixture may be raised to about 20°C to
about 40°C. The reaction may be stirred for about 1 hour to about 24 hours. The reaction
mixture may be optionally washed subsequently with water, phosphoric acid solution and
potassium carbonate solution. The solvent from the reaction mixture containing the
compound of Formula X may be optionally recovered partially under vacuum.
The compound of Formula X is deprotected to obtain bortezomib or a boronic acid
anhydride of Formula IA. The deprotection may be carried out with an acid, an organic
boronic acid acceptor and an alcoholic solvent. The acid may be an organic acid or
inorganic acid, for example trifluoroacetic acid, hydrochloric acid or hydrobromic acid.
The organic boronic acid acceptor may be, for example, isobutyl boronic acid. The
alcoholic solvent may be selected from a group consisting of methanol, ethanol, npropanol,
propan-2-ol, butan-l-ol and butan-2-ol, or a mixture thereof. Bortezomib or a
boronic acid anhydride of Formula IA may be isolated by filtration, extraction, distillation,
pH adjustment, concentration, decantation, or a combination thereof. Bortezomib or a
boronic acid anhydride of Formula IA may be optionally recrystallized with a chlorinated
solvent, for example, dichloroethane, dichloromethane and chloroform or mixture thereof,
nitrile solvent, for example, acetonitrile, and ester solvent, for example, ethyl acetate,
methyl acetate and butyl acetate, or mixture thereof.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Preparation of (3a^4^6^7ar)-2-(l-Chloro-3-Methylbutyl)-3a,5,5-
Trimethylhexahydro-4,6-Methano-L3,2-Benzodioxaborole
Diisopropylamine (0.57 kg) and tetrahydrofuran (1.0 L) were added together and
the mixture was cooled to -30°C. 2.5 M solution of butyl lithium in hexane (2.2 L) was
added dropwise to the cooled mixture, and the temperature was maintained at -20°C to
-30°C. The mixture was stirred for 0.5 hours at -20°C to -30°C and a clear solution of
lithium diisopropyl amide was obtained.
In a separate round bottomed flask, zinc chloride (1.3 kg) and tetrahydrofuran (6 L)
were added together at 20°C. The mixture was stirred at 20°C for 0.5 hours and a clear
solution of zinc chloride was obtained.
In a separate round bottomed flask, (3a ,4 ,6 ,7aR)-3a,5,5-trimethyl-2-(2-
methylpropyl)hexahydro-4,6-methano-l,3,2-benzodioxaborole ( 1 kg) and tetrahydrofuran
(5 L) were added together at 20°C. Dichloromethane (1 L) was added to the mixture and
the mixture was cooled to -70°C. Lithium diisopropylamide solution was added slowly to
the mixture at -60°C to -70°C. The mixture was stirred for 0.5 hours at -65°C to -70°C.
Zinc chloride solution was added slowly to the mixture at -60°C to -70°C. The reaction
mixture was stirred for 1.5 hours at -60°C to -70°C. The temperature of mixture was
raised to 10°C in 2 hours to 3 hours and reaction progress was monitored by gas
chromatography. Sulfuric acid (0.6 L) was added to the mixture at 10°C to 15°C and
solvent was recovered under vacuum at 45°C. Hexanes (4 L) and water (4 L) were added
slowly at 20°C to the mixture and mixture was stirred for 0.5 hours at 20°C. Organic and
aqueous layers were separated and aqueous layer was washed with hexanes (2 L).
Combined organic layer was washed with water (3 x 3 L), concentrated under vacuum at
35°C to obtain the title compound.
Yield: 1.068 kg
Example 2 : Preparation of -Trimethyl-N-| (l r)-3-Meth l-l - (3as 4s 6s ar)-3a 5 5-
Trimethylhexahydro-4,6-Methano-L3,2-Benzodioxaborol-2-YllButyl|-N-
(Trimethylsilyl)Silanamine
In a round bottomed flask, 2.5 M butyl lithium (1.43 L) was added at 20°C. The
mixture was cooled to -5°C. Bis(trimethylsilyl)amine (0.57 kg) was added to the mixture
at temperature of -5°C to 0°C. After the addition of bis(trimethylsilyl)amine, temperature
of reaction mixture was raised to 20°C and mixture was stirred for 20 minutes at 20°C to
obtain lithium hexamethyldisilazide solution.
In a separate round bottomed flask, (3a ,4 ,6 ,7aR)-2-(l-chloro-3-methylbutyl)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborole (1 kg) and hexanes (8 L)
were added and temperature of reaction mixture was cooled to -70°C. Lithium
hexamethyldisilazide solution was added dropwise to the reaction mixture at -60°C to
-70°C. The mixture was stirred for 1 hour at -60°C to -70°C. The temperature of the
mixture was raised to 20°C in 2 hours to 3 hours and the mixture was stirred for 15 hours.
Reaction was monitored using gas chromatography. The mixture was filtered through a
Celite® bed (0.1 kg) bed and the Celite® bed was washed with hexanes (1 L). Hexanes
were recovered under vacuum at 35°C to 40°C to obtain the title compound.
Yield: 1.32 kg
Example 3: Preparation of r r)-3-Methyl-l-IT(2s)-l-C)xo-3-Phenyl-2-
lYPyrazinylcarbonyl) AminolPropyllAminol Butyl1Boronic Acid (Bortezomib)
Step A: Preparation of trifluoroacetic acid salt of (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine
l,l,l-Trimethyl -N-{(l R)-3-methyl-l-[(3a5,45,65,7a R)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl }-N -(trimethylsilyl)silanamine ( 1 kg) and
diisopropyl ether (6 L) were added together and the mixture was cooled to -10°C.
Trifluoroacetic acid (0.85 kg) was added dropwise to the mixture at -10°C to -5°C. The
reaction mixture was stirred at 0°C to -10°C for 2 hours. The mixture was filtered at 0°C
to -10°C, washed with diisopropyl ether ( 1 L) at 0°C and dried under vacuum at 40°C to
obtain the title compound.
Yield: 0.8 Kg
Step B : Preparation of -butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-
phenylpropan-2-yl]carbamate
(lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butan-l-aminium (1 kg), dichloromethane (8 L), 0-(benzotriazol-lyl)-
N,N,N',N'-tetramethyluronium tetrafluoroborate (0.93 kg) and N-(tertbutoxycarbonyl)-
L-phenylalanine (0.7 kg) were added together and mixture was cooled to
0°C. N,N-Diisopropylethylamine (1.4 L) was added to the mixture at 0°C to 5°C. The
mixture was stirred for 1 hour at 0°C. Temperature of the reaction mixture was raised to
20°C and the mixture was stirred for 1 hour. The mixture was washed subsequently with
water (2 X 5 L), 1% phosphoric acid solution (2 X 5 L), potassium carbonate solution (3
L) and sodium chloride solution (3 L). The organic solvent was recovered under vacuum
to obtain the title compound.
Yield: 1.35 kg
Step C: Preparation of N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide
r -B tyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate
(1 kg) and dichloromethane (6 L) were added together and the mixture was cooled to 0°C.
Hydrogen chloride gas was purged in to the reaction mixture and the reaction mixture was
stirred until completion of the reaction. Dichloromethane was recovered under vacuum to
obtain the title compound.
Yield: 0.83 kg
Step D: Preparation of N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide (1 kg), pyrazine-2-carboxylic acid
(0.305 kg), dichloromethane (10 L) and 0-(benzotriazol-l-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (0.79 kg) were added together and the temperature
of the mixture was maintained at 0°C. The N,N-diisopropylethylamine (1 L) was added to
the reaction mixture at 0°C to 5°C. The mixture was stirred for 1 hour at 0°C and the
temperature of the reaction mixture was raised to 20°C. The mixture was stirred for 1
hour at 20°C and solvent was recovered under vacuum partially to obtain a residue. Ethyl
acetate (12 L) was added to the residue and the mixture was subsequently washed with
water (2 X 5 L), 1% phosphoric acid solution (2 X 5 L), potassium carbonate solution (3
L) and sodium chloride solution (3 L). The organic solvent was recovered under vacuum
to obtain the title compound.
Yield: 1.3 kg
Step E : Preparation of [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)
amino]propyl]amino]butyl] boronic acid (Bortezomib)
N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide (1
kg), methanol (12 L) and hexanes (12 L) were added together at 20°C. The reaction
mixture was cooled to 0°C and IN hydrochloric acid (4.5 L) was added to the mixture at
0°C to 5°C. The isobutyl boronic acid (0.25 kg) was added to the reaction mixture and the
temperature was raised to 20°C. The reaction mixture was stirred until completion of the
reaction and two layers were separated. The methanol layer was washed with hexanes (8
L) and methanol was recovered under vacuum. The residue was basified with 8% sodium
hydroxide solution (8.2 L). The aqueous layer was washed with dichloromethane (6 L)
and IN hydrochloride acid solution (2 L) was added to the aqueous layer at 0°C to 5°C.
Mixture was extracted with dichloromethane (14 L), concentrated under vacuum at 20°C
to obtain the title compound.
Yield: 0.63 Kg
Example 4: Preparation of r(lr)-3-Methyl-l-IT(2s)-l-Oxo-3-Phenyl-2-
lYPyrazinylcarbonyl) AminolPropyllAminol Butyl1Boronic Acid (Bortezomib)
Step A: Preparation of trifluoroacetic acid salt of (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine
l,l,l-Trimethyl -N-{(l R)-3-methyl-l-[(3a5,45,65,7a R)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl }-N -(trimethylsilyl)silanamine (1 kg) and
diisopropyl ether (6 L) were added together and the mixture was cooled to -10°C.
Trifluoroacetic acid (0.85 kg) was added dropwise to the mixture at -10°C to -5°C. The
reaction mixture was stirred at 0°C to -10°C for 2 hours. The mixture was filtered at 0°C
to -10°C, washed with diisopropyl ether ( 1 L) at 0°C and dried under vacuum at 40°C to
obtain the title compound.
Yield: 0.73 kg
Step B : Preparation of -butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-
phenylpropan-2-yl] carbamate
(lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butan-l-aminium (1 kg), dichloromethane (8 L), 0-(benzotriazol-lyl)-
N,N,N',N'-tetramethyluronium tetrafluoroborate (0.93 kg) and N-(tertbutoxycarbonyl)-
L-phenylalanine (0.7 kg) were added together and the mixture was
cooled to 0°C. N,N-Diisopropylethylamine (1.4 L) was added to the mixture at 0°C to
5°C. The mixture was stirred for 1 hour at 0°C. Temperature of the reaction was raised to
20°C and the mixture was stirred for 1 hour. The mixture was washed subsequently with
water (2 X 5 L), 1% phosphoric acid solution (2 X 5 L), potassium carbonate solution (3
L) and sodium chloride solution (3 L). The organic solvent was recovered under vacuum
to obtain the title compound.
Yield: 1.38 kg
Step C: Preparation of N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide
-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate
(1 kg) and toluene (10 L) were added together and the mixture was cooled to 0°C.
Hydrogen chloride gas was purged in to the reaction mixture and reaction mixture was
stirred for 1 hour at 0°C. The mixture was filtered, washed with toluene (1 L) and dried
under vacuum at 40°C to obtain the title compound.
Yield: 0.52 kg
Step D: Preparation of N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide (1 kg), pyrazine-2-carboxylic acid
(0.305 kg), dichloromethane (10 L) and 0-(benzotriazol-l-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (0.79 kg) were added together and temperature of
the mixture was maintained at 0°C. The N,N-Diisopropylethylamine (1 L) was added to
the reaction mixture at 0°C to 5°C. The mixture was stirred for 1 hour at 0°C and
temperature of the reaction mixture was raised to 20°C. The mixture was stirred for 1
hour at 20°C and solvent was recovered under vacuum partially to obtain a residue. Ethyl
acetate (12 L) was added to the residue and the mixture was subsequently washed with (2
X 5 L), 1% phosphoric acid solution (2 X 5 L), potassium carbonate solution (3 L) and
sodium chloride (3 L) solution. The organic solvent was recovered under vacuum to
obtain the title compound.
Yield: 1.098 Kg
Step E : Preparation of [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)
amino]propyl]amino]butyl] boronic acid (Bortezomib)
The reaction was carried out similar to Step E of Example 3.
Yield: 0.56 kg
Example 5: Preparation of r(lr)-3-Methyl-l-IT(2s)-l-C)xo-3-Phenyl-2-
lYPyrazinylcarbonyl) AminolPropyllAminolButyll Boronic Acid (Bortezomib)
Step A: Preparation of trifluoroacetic acid salt of (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine
l,l,l-Trimethyl -N-{(l R)-3-methyl-l-[(3a5,45,65,7a R)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl }-N -(trimethylsilyl)silanamine ( 1 kg) and
diisopropyl ether (6 L) were added together and mixture was cooled to -10°C.
Trifluoroacetic acid (0.85 kg) was added dropwise to the reaction mixture at -10°C to
-5°C. The reaction mixture was stirred at 0°C to -10°C for 2 hours. The mixture was
filtered at 0°C to -10°C, washed with diisopropyl ether (1 L) at 0°C and dried under
vacuum at 40°C to obtain the title compound.
Yield: 0.8 Kg
Step B: Preparation of tert-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-
trimethylhexahydro-4,6-methano- 1,3,2-benzodioxaborol-2-yl]butyl }amino)- 1-oxo-3-
phenylpropan-2-yl]carbamate
(lR)-3-Methyl-l-[(3a5 ,,4 ',6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butan-l-aminium ( 1 kg), dimethylformamide (10 L), O-
(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.93 kg) and N-(tertbutoxycarbonyl)-
L-phenylalanine (0.7 kg) were added together and the mixture was
cooled to 0°C. N,N-diisopropylethylamine (1.26 L) was added to the reaction mixture at
0°C to 5°C. The mixture was stirred for 1 hour at 0°C. The temperature of the reaction
was raised to 20°C, water (150 L) was added to the mixture and the mixture was stirred for
2 hours. The mixture was filtered and dried under vacuum at 30°C to obtain the title
compound.
Yield: 1.25 kg
Step C: Preparation of N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide
tert-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate
(1 kg) and toluene (10 L) were added together and mixture was cooled to 0°C. Hydrogen
chloride gas was purged in to the reaction mixture and reaction mixture was stirred for 1
hour at 0°C. The mixture was filtered, washed with toluene (1 L) and dried under vacuum
at 40°C to obtain the title compound.
Yield: 0.89 kg
Step D: Preparation of N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide (1 kg), pyrazine-2-carboxylic acid
(0.305 kg), dichloromethane (10 L) and 0-(benzotriazol-l-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (0.79 kg) were added together and the temperature
of the mixture was maintained at 0°C. N,N-diisopropylethylamine ( 1 L) was added to the
reaction mixture at 0°C to 5°C. The mixture was stirred for 1 hour at 0°C and temperature
of reaction mixture was raised to 20°C. The mixture was stirred for 1 hour at 20°C and
solvent was recovered under vacuum. Ethyl acetate (12 L) was added to the residue and
mixture was subsequently washed with water (2 X 5 L), 1% phosphoric acid solution (2 X
5 L), potassium carbonate solution (3 L) and sodium chloride (3 L) solution. The organic
solvent was recovered under vacuum to obtain the title compound.
Yield: 1.05 Kg
Step E : Preparation of [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)
amino]propyl]amino]butyl] boronic acid (bortezomib)
The reaction was carried out similar to Step E of Example 3.
Yield: 0.438 Kg
Example 6: Preparation of (lr)-3-Methyl-l-IT(2s)-l-C)xo-3-Phenyl-2-
lYPyrazinylcarbonyl) AminolPropyllAminol Butyl1Boronic Acid (Bortezomib)
Step A: Preparation of trifluoroacetic acid salt of (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-
3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine
l,l,l-Trimethyl -N-{(l R)-3-methyl-l-[(3a5,45,65,7a R)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl }-N-(trimethylsilyl)silanamine ( 1 kg) and
diisopropyl ether (6 L) were added together and mixture was cooled to -10°C.
Trifluoroacetic acid (0.85 kg) was added dropwise at -10°C to -5°C. The reaction mixture
was stirred at 0°C to -10°C for 2 hours. The mixture was filtered at 0°C to -10°C, washed
with diisopropyl ether (1 L) at 0°C and dried under vacuum at 40°C to obtain the title
compound.
Yield: 0.73 kg
Step B : Preparation of -butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-
phenylpropan-2-yl]carbamate
(lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butan-l-aminium ( 1 kg), dimethylformamide (10 L), O-
(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.93 kg) and N-(tertbutoxycarbonyl)-
L-phenylalanine (0.7 kg) were added together and mixture was cooled to
0°C. N,N-diisopropylethylamine (1.26 L) was added at 0°C to 5°C. The mixture was
stirred for 1 hour at 0°C. The temperature of the reaction mixture was raised to 20°C and
water (150 L) was added to the mixture and stirred for 2 hours. The mixture was filtered
to obtain the title compound.
Yield: 1.22 kg
Step C: Preparation of N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide
r -b tyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate
(1 kg) and toluene (10 L) were added together and the mixture was cooled to 0°C.
Hydrogen chloride gas was purged in to the reaction mixture and the reaction mixture was
stirred for 1 hour at 0°C. The mixture was filtered, washed with toluene (1 L) and dried
under vacuum to obtain the title compound.
Yield: 0.879 kg
Step D: Preparation of N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide (1 kg), pyrazine-2-carboxylic acid
(0.275 kg), dimethylformamide (10 L) and 0-(benzotriazol-l-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (0.79 kg) were added together and the temperature
of the mixture was maintained at 0°C. The N,N-diisopropylethylamine (1.08 L) was
added to the reaction mixture at 0°C to 5°C. The mixture was stirred for 5 hours at 0°C.
Water (150 L) was added to the mixture and the mixture was stirred for 0.5 hours. The
solid obtained was filtered, washed with water (20 L x 2) and dried under vacuum at 30°C
to obtain the title compound.
Yield: 0.926 kg
Step E : Preparation of [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)
amino]propyl]amino]butyl] boronic acid (bortezomib)
The reaction was carried out similar to Step E of Example 3.
Yield: 0.448 Kg
Example 7: Preparation of (lr)-3-Methyl-l-IT(2s)-l-C)xo-3-Phenyl-2-
lYPyrazinylcarbonyl) AminolPropyllAminol Butyl1Boronic Acid (Bortezomib)
Bortezomib (1 g) and dichloromethane (5 mL) were added together and reaction
mixture was stirred for 2 hours. The mixture was filtered, washed with dichloromethane
(4 mL) and dried under vacuum at 40°C to obtain the title compound.
Yield: 0.7 g
Example 8: Preparation of r(lr)-3-Methyl-l-IT(2s)-l-C)xo-3-Phenyl-2-
(Pyrazinylcarbonyl) AminolPropyllAminolButyll Boronic Acid (Bortezomib):
Step A: Preparation of -butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-
phenylpropan-2-yl] carbamate
Trifluoroacetic acid salt of (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-
trimethylhexahydro-4,6-methano- 1,3,2-benzodioxaborol-2-yl]butan- 1-amine
( 1 kg), dichloromethane (8 L), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.915 kg) andiV-(te/t-butoxycarbonyl)-L-phenylalanine (0.69 kg) were
added together and mixture was cooled to 0°C. N,N-diisopropylethylamine (1.26 L) was
added to the reaction mixture at 0°C to 5°C. The mixture was stirred for 1 hour at 0°C.
The temperature of the reaction was raised to 20°C and mixture was stirred for 1 hour.
Mixture was washed subsequently with water (2 X 5 L), 1% phosphoric acid solution (5
L), 2.5% potassium carbonate solution (5 L) and water (2 X 5 L). The organic solvent was
recovered under vacuum to obtain the title compound.
Yield: 1.475 kg
Step B : Preparation of N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide
r -b t l [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate
(1 kg) and toluene (10 L) were added together and the mixture was cooled to 0°C.
Hydrogen chloride gas was purged in to the reaction mixture and the reaction mixture was
stirred for 1 hour at 0°C. The reaction mixture was concentrated to a volume of 3 L. The
mixture was filtered at 0°C, washed with toluene (0.5 L) and dried under vacuum at 40°C
to obtain the title compound.
Yield: 0.665 kg
Step C: Preparation of N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
N-{(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide (1 kg), pyrazine-2-carboxylic acid
(0.275 kg), dimethylformamide (10 L) and 0-(benzotriazol-l-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (0.79 kg) were added together and the temperature
of the mixture was maintained at 0°C. Diisopropylethyl amine (1.08 L) was added to the
reaction mixture at 0°C to 5°C. The mixture was stirred for 4.5 hours at 0°C. Water (150
L) was added to the mixture and the mixture was stirred for 0.5 hours. The solid was
filtered and washed with water (2 x 20 L) and dried under vacuum to obtain the title
compound.
Yield: 1.00 Kg
Step D: Preparation of [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)
amino]propyl]amino]butyl] boronic acid (bortezomib):
N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide (1
kg), methanol (12 L) and hexanes (12 L) were added together at 20°C. The reaction
mixture was cooled to 0°C and IN hydrochloric acid (4.36 L) was added to the mixture at
0°C to 5°C. Isobutyl boronic acid (0.24 kg) was added to the mixture and the temperature
was raised to 20°C. The reaction mixture was stirred till completion of the reaction and
two layers were separated. The methanol layer was washed with hexanes (5 L) and
methanol was recovered under vacuum to obtain a residue. The residue was basified with
25% w/v sodium hydroxide solution (1.4 L). The aqueous layer was washed with
dichloromethane (2 x 2 L) and IN hydrochloric acid solution (2 L) was added to the
aqueous layer at 20°C. The mixture was extracted with dichloromethane (4 L) and
concentrated under vacuum at 20°C to obtain the title compound.
Yield: 0.477 kg
Example 9: Preparation Of r(lr)-3-Methyl-l -rr(2s)-l-Oxo-3-Phenyl-2-
lYPyrazinylcarbonyl) AminolPropyllAminol Butyl1Boronic Acid (Bortezomib)
Step A: Preparation of N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
Trifluoroacetic acid salt of (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine ( 1 kg),
dichloromethane (8 L) were added together and the reaction mixture was cooled to 0°C.
N,N-diisopropylethylamine (1.84 L), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.745 kg) andiV-(te/t-butoxycarbonyl)-L-phenylalanine (0.56 kg) were
added to the mixture at 0°C to 5°C. The mixture was stirred until the completion of
reaction at 0°C. The mixture was washed subsequently with water (7 L), 1% phosphoric
acid solution (7 L), potassium carbonate solution (7 L) and water (7 L). The organic and
aqueous layers were separated. The organic layer was cooled to 0°C and sulfuric acid
(0.34 L) was added to the organic layer at 0°C. The mixture was stirred until completion
of the reaction. The reaction was quenched using 10% aqueous sodium bicarbonate
solution (10 L) and the organic layer was separated and washed with water (5 L). The
organic layer was separated and cooled to 0°C. N,N-diisopropylethylamine (0.56 kg),
pyrazine-2-carboxylic acid (0.203 kg) and 0-(benzotriazol-l-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (0.59 kg) were added to the organic layer at 0°C.
The temperature of the reaction mixture was raised to 20°C. The reaction mixture was
stirred for 12 hours at 20°C. The reaction mixture was subsequently washed with water (6
L), 1% phosphoric acid solution (6 L), 2.5% potassium carbonate solution (6 L) and water
(6 L). The organic solvent was recovered under vacuum to obtain the title compound.
Yield: 0.98 kg
Step B : Preparation of [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)
amino]propyl]amino]butyl] boronic acid (bortezomib)
N-{(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanol,
3,2-benzodioxaborol-2-yl]butyl}-Na-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide (1
kg), methanol (7 L), hexanes (7 L) and isobutyl boronic acid (0.197 kg) were added
together at 25°C. IN hydrochloride acid (7 L) was added to the reaction mixture at 20°C
to 30°C. The mixture was stirred until completion of reaction and two layers were
separated. The methanol layer was washed with hexanes (3 L) and methanol was
recovered under vacuum completely to obtain a residue. Dichloromethane (3 L) was
added to the residue and basified with 3.45% sodium hydroxide solution (2.25 L). The
aqueous layer was washed with dichloromethane (3 L) and IN hydrochloride acid solution
(2 L) was added to the aqueous layer at 0°C to 5°C. The mixture was extracted with
dichloromethane (5 L) and concentrated under vacuum at 20°C to obtain the title
compound.
Yield: 0.52 Kg
Example 10: Preparation of r(lr)-3-Methyl-l -riY2s)-l-Oxo-3-Phenyl-2-
lYPyrazinylcarbonyl) AminolPropyllAminolButyll Boronic Acid (Bortezomib)
(lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborol-2-yl]butan-l-aminium (1 kg), dichloromethane (8 L), 0-(benzotriazol-lyl)-
N,N,N',N'-tetramethyluronium tetrafluoroborate (0.93 kg) and N-(tertbutoxycarbonyl)-
L-phenylalanine (0.7 kg) were added together and the mixture was
cooled to 0°C. N,N-diisopropylethylamine (1.4 L) was added to the mixture at 0°C to 5°C
and the mixture was stirred for 1 hour at 0°C. Hydrochloride gas was purged in to the
reaction mixture and the mixture was stirred until the completion of reaction. Pyrazine-2-
carboxylic acid (0.327 kg) and 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.93 kg) were added to the mixture and temperature of the mixture was
maintained at 0°C. The N,N-diisopropylethylamine (3.67 L) was added to the reaction
mixture at 0°C to 5°C. The mixture was stirred for 1 hour at 0°C and the temperature of
the reaction mixture was raised to 20°C. The mixture was stirred for 1 hour at 20°C. The
reaction mixture was subsequently washed with water (2 x 3 L), 1% phosphoric acid
solution (2 x 7 L), 2.5% sodium bicarbonate solution (3 L) and water (3 L). The organic
solvent was recovered partially under vacuum to obtain an oil. Methanol (9.62 1), hexanes
(9.62 1) and isobutyl boronic acid (0.27 kg) were added to the oil at 20°C. IN
Hydrochloride acid (7.2 L) was added to the mixture at 25°C. The mixture was stirred
until completion of reaction and the layers were separated. The methanol layer was
washed with hexanes (3 L) and methanol was recovered under vacuum. The residue was
basified with 8% sodium hydroxide solution (7.2 L). The aqueous solution was washed
with dichloromethane (3 x 3 L) and IN hydrochloride acid solution (2 L) was added to the
aqueous layer at 20°C. The mixture was extracted with dichloromethane (3 L) and
concentrated under vacuum at 20°C to obtain the title compound.
Yield: 0.837 Kg

We claim:
1. A process for the preparation of (3a ,4 ,6 ,7aR)-2-(l-chloro-3-methylbutyl)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborole of Formula III or its salts,
FORMULA III
wherein the process comprises reacting (3a ,4 ,6 ,7aR)-3a,5,5-trimethyl-2-(2-
methylpropyl)hexahydro-4,6-methano-l,3,2-benzodioxaborole of Formula II or its
salts
Formula II
with lithium amide base and Lewis acid in the presence of a water-miscible ether
solvent and a halogenated hydrocarbon solvent to obtain (3aS,4S,6S,TaR)-2-(lchloro-
3-methylbutyl)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-
benzodioxaborole of Formula III or its salts, wherein the halogenated hydrocarbon
solvent is less than about 3.8 molar equivalents per mole of the compound of Formula
II.
2. A process for the preparation of bortezomib of Formula I or a boronic acid anhydride
of Formula IA com rising:
FORMULA I
FORMULA IA
a) reacting (3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethyl-2-(2-methylpropyl)hexahydro-
4,6-methano-l,3,2-benzodioxaborole of Formula II or its salts
FORMULA II
with lithium amide base and Lewis acid in the presence of a water-miscible
ether solvent and a halogenated hydrocarbon solvent to obtain
(3a5,,4 ,,6 ,,7aR)-2-(l-chloro-3-methylbutyl)-3a,5,5-trimethylhexahydro-
4,6-methano-l , -benzodioxaborole of Formula III or its salts,
FORMULA III
wherein the halogenated hydrocarbon solvent is less than about 3.8 molar
equivalents per mole of compound of Formula II;
b) reacting the compound of Formula III or its salts with M1-N(Si(CH3)3)2,
where M1 is an alkali metal to obtain l,l,l-trimethyl -N-{(l R)-3-methyl-l-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl }-N -(trimethylsilyl)silanamine of Formula IV or
its salts;
FORMULA IV
desilylating the compound of Formula IV or its salts to obtain (lR)-3-
methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butan-l -amine of Formula V or its salts;
FORMULA V
coupling the compound of Formula V or its salts with N-(tertbutoxycarbonyl)-
L-phenylalanine of Formula VI to obtain tert-butyl [1-
({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-
methano-l,3,2-benzodioxaborol-2-yl]butyl}amino)-l-oxo-3-phenylpropan-
2-yl]carbamate of Formula VII;
FORMULA VI
deprotecting the compound of Formula VII in the presence of a
hydrocarbon solvent to obtain N-{(15,)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7a5,)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-
yl]butyl}phen lalanine amide of Formula VIII or its salts;
coupling the compound of Formula VIII or its salts with pyrazine-2-
carboxylic acid of Formula IX to obtain N-{(l R)-3-methyl-l-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl }-N a-(pyrazin-2-ylcarbonyl)-Lphenylalaninamide
of
FORMULA IX
FORMULA X
g) deprotecting the compound of Formula X to obtain bortezomib or a boronic
acid anhydride of Formula IA.
3. A process according to claim 1 or 2, wherein the lithium amide base is lithium
diisopropylamide, lithium diethylamide or lithium dimethylamide.
4. A process according to claim 1 or 2, wherein the Lewis acid is zinc chloride, zinc
bromide, boron trifluoride, boron trichloride, ferric chloride, ferric bromide or
aluminum trichloride.
5. A process according to claim 1 or 2, wherein the halogenated hydrocarbon solvent is
dichloromethane.
6. A process according to claim 2, wherein M1-N(Si(CH3)3)2 is lithium
bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium
bis(trimethylsilyl)amide.
7. A process according to claim 2, wherein desilylation is carried out with the acid.
8. A process according to claim 7, wherein the acid is trifluoroacetic acid.
9. A process according to claim 2, wherein the coupling agent in step d) and step f ) is
0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU),
dicyclohexylcarbodiimide, 0-benzotriazole-N,N,N' ,N' -tetramethyl-uroniumhexafluoro-
phosphate, benzotriazol- 1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
10. A process for the preparation of N-{(15,)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7a5,)-3a,5,5-
trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl}phenylalanine
amide of Formula VIII or its salts,
FORMULA VIII
wherein the process comprises contacting tert-butyl [l-({(lS)-3-methyl-l-
[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-
yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate of Formula VII
FORMULA VII
with an acid in the presence of a hydrocarbon solvent to obtain the compound of
Formula VIII or its salts.
11. A process according to claim 2 or 10, wherein the hydrocarbon solvent is toluene or
xylene or mixture thereof.
12. A process for the preparation of bortezomib or a boronic acid anhydride of Formula
IA comprising:
FORMULA I
FORMULA IA
coupling the (lR)-3-methyl-l-[(3a5 ,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-
4,6-methano-l,3,2-benzodioxaborol-2-yl]butan-l-amine of Formula V or
its salts with N-(tert-butoxycarbonyl)-L-phenylalanine of Formula VI to
obtain tert-butyl [l-({(lS)-3-methyl-l-[(3aS,4S,6S,7aS)-3a,5,5-
trimethylhexahydro-4,6-methano- 1,3,2-benzodioxaborol-2-
yl]butyl}amino)-l-oxo-3-phenylpropan-2-yl]carbamate of Formula VII,
FORMULA VII
deprotecting the compound of Formula VII to obtain ^-{(l^-S-methyl-l-
[(3a5,,4 ,,6 ,,7a5,)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl}phenylalanine amide of Formula VIII or its
salts,
FORMULA VIII
c) coupling the compound of Formula VIII or its salts with pyrazine-2-
carboxylic acid of Formula IX to obtain N- {(lR)-3-Methyl- 1-
[(3a5,,4 ,,6 ,,7aR)-3a,5,5-trimethylhexahydro-4,6-methano- 1,3,2-
benzodioxaborol-2-yl]butyl }-N a-(pyrazin-2-ylcarbonyl)-Lphenylal
FORMULA X
) deprotecting the compound of Formula X to obtain bortezomib or a boronic
acid anhydride of Formula IA,
wherein at least any two of the compound of Formula VII of step a),
compound of Formula VIII of step b) and compound of Formula X of step
c) are not isolated in any solid form.
13. A process according to claim 12, wherein the coupling agent in step a) and step c) is
0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU),
dicyclohexylcarbodiimide, 0-benzotriazole-N,N,N' ,N'-tetramethyl-uroniumhexafluoro-
phosphate, benzotriazol- 1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
14. A process according to claim 12, wherein step b) is carried out with the acid.
15. A process according to claim 14, wherein the acid is trifluoroacetic acid, hydrochloric
acid, hydrobromic acid or sulfuric acid.
16. A process according to claim 15, wherein the step d) is carried out with the acid and
an organic boronic acid acceptor.
17. A process according to claim 16, wherein the acid is trifluoroacetic acid, hydrochloric
acid, hydrobromic acid or sulfuric acid.
18. A process according to claim 16, wherein the organic boronic acid acceptor is
isobutyl boronic acid.