FORM 2
The Patent Act 1970
(39 of 1970)
&
The Patent Rules, 2005
COMPLETE SPECIFICATION
[See Section 10 and Rule 13]
IMPROVED PROCESS FOR PREPARATION OF
ARYLBORONIC ACID;
AARTI INDUSTRIES LIMITED, A COMPANY
INCORPORATED UNDER THE COMPANIES
ACT, 1956, HAVING ADDRESS, 71, UDYOG
KSHETRA, 2ND FLOOR, MULUND GOREGAON
LINK ROAD, MULUND (W) MUMBAI, 400080,
MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION
PARTICULARLY DESCRIBES THE INVENTION
AND THE MANNER IN WHICH IT IS TO BE
PERFORMED.
2
Field of the invention
The present invention relates generally to preparation of boronic acids and more
particularly, to an improved process for preparation of arylboronic acid.
Background 5 of the invention
The increasing importance of arylboronic acid as synthetic intermediates due to their
chemical and shelf stability for long periods has motivated the development of improved
and efficient methods to provide access to these important compounds.
10
Arylboronic acids, especially phenylbornic acids bearing electrophilic functional group for
e.g. carbonyl, alkoxycarbonyl, cyano and nitro are of importance in medicinal chemistry.
These are used as intermediates in the preparation of various drugs which are prescribed in
the treatment of diabetes, osteoporosis, hepatitis-C, convulsions and also in Cystic fibrosis.
15 Various methods are known in the prior art for the preparation of phenylboronic acids.
The most commonly utilized method to prepare these boron compounds is the reaction of
Grignard reagent with trialkyl borates. Literature references such as Journal of Organic
Chemistry, 70(22), 8948-8955; 2005 and Macromolecules, 36(4), 1009-1020; 2003
20 describe this method for preparation of arylboronic acid in detail. The method involves
treating aromatic halide with magnesium metal in tetrahydrofuran to yield aryl magnesium
halide at reflux temperature. Further, Grignard reagent is treated with trialkyl borate to
form phenylboronic acid. However, the method provides very low yield of about 50-60%.
Further, this approach cannot be applied to phenyl halide substrates bearing electrophilic
25 functional groups such as carbonyl, alkoxycarbonyl, cyano and nitro. In addition, Grignard
reagent formed at 60-65 °C is unstable in the presence of electrophillic functional group.
Reaction of organolithium compounds with trialkyl borates is another approach for
synthesis of boronic acids which is described in Inorganic Chemistry, 53(7), 3568-3578,
3
2014. However, preparation of organolithium compounds involves use of alkyl lithium
reagents like n-butyl lithium, t-butyl lithium and the like which are pyrophoric. In addition,
the reaction requires temperature of -60 to -70 °C which is tedious to maintain and results
in low yield of about 30-40%.
5
Another approach is disclosed in J. Org. Chem., 1995, 60, 7508, wherein arylboronic acids
are prepared using palladium catalyzed synthesis of pinacol-borane ester followed by
conversion to boronic acid. Such arylboronic esters can be prepared from aryl halides or
aryl triflates via palladium-catalyzed cross-coupling reactions with tetraalkoxydiboron or
10 dialkoxyhydroborane. However, these methods are not suitable for large-scale synthesis,
especially in industry, because borylating reagents such as tetraalkoxydiboron and
dialkoxyhydroborane are very expensive.
Although Grignard and organolithium reagents are easily synthesized from organohalides,
15 their high reactivity limits many applications in organic synthesis. They may act as bases
and undergo competing nucleophilic addition to other functional groups. These reactivity
and selectivity issues can be partially avoided by use of an iodine-magnesium exchange
protocol. Further, Grignard species obtained is reacted with trialkyl borate to form
corresponding phenylboronic acid.
20
Similar method is disclosed in PCT application WO2006/110173 wherein an aryl iodide
containing a functionality not normally compatible with formation of Grignard reagent
undergoes iodine-magnesium exchange with isopropyl magnesium chloride and then
undergoes reaction with trimethyl borate. The method provides around 60% yield.
25 However, this type of reaction is usually carried out in tetrahydrofuran which is difficult to
obtain in an anhydrous form. This leads to formation of impurities which are difficult to
remove from the desired product.
Accordingly, there is a need for an improved process for preparation of arylboronic acid
that overcomes the above mentioned drawbacks of the prior art.
4
Objects of the invention
An object of the present invention is to provide an improved process for preparation of
arylboronic acid bearing electrophilic functional group that gives higher 5 yield and better
purity.
Another object of the present invention is to provide the improved process for preparation
of arylboronic acid bearing electrophilic functional group which avoids use of costly and
10 hazardous reagents.
Yet another object of the present invention is to provide an improved process for
preparation of arylboronic acid bearing electrophilic functional group that is suitable for
industrial production.
15
Summary of the invention
Accordingly, the present invention teaches an improved process for preparation of
arylboronic acid of Formula 1. The process comprises reacting aryliodide substituted by an
20 electrophilic functional group of Formula 2 with alkyl magnesium halide in the presence of
a hydrocarbon solvent to form Grignard species of Formula 3. The temperature of the
reaction is maintained in a range of -40 to 0 °C. Further, Grignard species of Formula 3 is
treated with trialkyl borate to form compound of Formula 1. The temperature of the
reaction is maintained in a range of -30 to 10 °C.
25
5
wherein,
Group R is H or electrophillic functional group selected from carbonyl, 5 alkoxycarbonyl,
cyano and nitro,
X is selected from chloro and bromo
Group R is substituted at any one of ortho-, meta- and para- position with respect to iodo
10 group.
The present invention also relates to a process for preparation of phenylboronic acid of
Formula 4. The process comprises reacting phenyl iodide of Formula 5 with alkyl
magnesium halide in the presence of a hydrocarbon solvent to form Grignard species of
15 Formula 6. The temperature of the reaction is maintained in a range of -40 to 0 °C. Further,
Grignard species of Formula 6 is reacted in situ with trialkyl borate to form phenylboronic
acid of Formula 4. The temperature of the reaction is maintained in a range of -30 to 10 °C.
6
The present invention also relates to a process for preparation 5 of 3-(tert-
Butoxycarbonyl)phenylboronic acid of Formula 7. The process comprises reacting tertbutyl-
3-iodobenzoate of Formula 8 with alkyl magnesium halide in the presence of a
hydrocarbon solvent to form Grignard species of Formula 9. The temperature of the
reaction is maintained in a range of -40 to 0 °C. Preferably, the temperature is -25 to -30
10 °C. Further, Grignard species of Formula 9 is reacted in situ with trialkyl borate to form
compound of Formula 7. The temperature of the reaction is maintained in a range of -30 to
10 °C. Preferably, the temperature is -25 to 0 °C.
15
7
Detailed description of the invention
5 The foregoing objects of the present invention are accomplished and the problems and
shortcomings associated with the prior art, techniques and approaches are overcome by the
present invention as described below in the preferred embodiments.
An embodiment of the present invention teaches an improved process for preparation of
10 arylboronic acid of Formula 1. The process involves reacting aryliodide substituted by
electrophilic functional group of Formula 2 with alkyl magnesium halide in the presence of
a hydrocarbon solvent to form Grignard species of Formula 3. The temperature of the
reaction is maintained in a range of -40 to 0 °C. The alkyl magnesium halide is selected
from isopropyl magnesium chloride and isopropyl magnesium bromide. The hydrocarbon
15 solvent is selected from aliphatic hydrocarbon solvent such as heptane, cyclohexane,
octane, iso-octane and aromatic hydrocarbon solvent such as benzene, xylene and toluene.
Further, Grignard species of Formula 3 is treated with trialkyl borate to form arylboronic
acid of Formula 1. The temperature of the reaction is maintained in a range of -30 to 10 °C.
20 The trialkyl borate is selected from trimethyl borate, triethyl borate and tri-isopropyl
borate.
The reaction scheme of preparing compound of Formula 1 is represented below:
8
Group R is H or an electrophillic functional group selected from carbonyl, alkoxycarbonyl,
cyano and nitro. Group R is substituted at any one of ortho-, meta- and para- position with
respect 5 to iodo group.
X in compound of Formula 3 is selected from chloro and bromo.
In another embodiment, the present invention provides an improved process for
10 preparation of phenylboronic acid of Formula 4. The process comprises reacting phenyl
iodide of Formula 5 with alkyl magnesium halide in the presence of a hydrocarbon solvent
to form Grignard species of Formula 6. The temperature of the reaction is maintained in a
range of -40 to 0 °C. The alkyl magnesium halide is selected from isopropyl magnesium
chloride and isopropyl magnesium bromide.
15
Specifically, prior to addition of alkyl magnesium halide, 1-4 volume of the hydrocarbon
solvent is distilled out from a reaction mixture of phenyl iodide of Formula 5 and the
hydrocarbon solvent. The hydrocarbon solvent is selected from aliphatic hydrocarbon
solvent such as heptane, cyclohexane, octane, iso-octane and aromatic hydrocarbon solvent
20 is selected from benzene, xylene and toluene.
Further, Grignard species of Formula 6 is reacted in situ with trialkyl borate to form
phenylboronic acid of Formula 4. The temperature of the reaction is maintained in a range
9
of -30 to 10 °C. The trialkyl borate is selected from trimethyl borate, triethyl borate and triisopropyl
borate.
The reaction scheme of preparing compound of Formula 4 is represented below:
5
X in compound of Formula 6 is selected from chloro and bromo.
In yet another embodiment, the present invention teaches an improved process for
10 preparation of 3-(tert-Butoxycarbonyl)phenylboronic acid of Formula 7. The process
comprises reacting tert-butyl-3-iodobenzoate of Formula 8 with alkyl magnesium halide in
the presence of a hydrocarbon solvent to form Grignard species of Formula 9. The
temperature of the reaction is maintained in a range of -40 to 0 °C. Preferably, the
temperature is -25 to -30 °C. The alkyl magnesium halide is selected from isopropyl
15 magnesium chloride and isopropyl magnesium bromide, preferably isopropyl magnesium
chloride.
Specifically, prior to addition of alkyl magnesium halide, 1-4 volume of the hydrocarbon
solvent is distilled out from a reaction mixture of tert-butyl-3-iodobenzoate and the
20 hydrocarbon solvent. This results in effective removal of moisture from the reaction
mixture which avoids formation of impurity tert-butyl benzoate due to moisture.
10
The hydrocarbon solvent is selected from aliphatic hydrocarbon solvent such as heptane,
cyclohexane, octane, iso-octane and aromatic hydrocarbon solvent such as benzene, xylene
and toluene. Preferably, the reaction is carried out in toluene.
Further, Grignard species of Formula 9 is reacted in situ with trialkyl 5 borate to form
compound of Formula 7. The temperature of the reaction is maintained in a range of -30 to
10 °C. Preferably, the temperature is -25 to 0 °C. The trialkyl borate is selected from
trimethyl borate, triethyl borate and tri-isopropyl borate, preferably trimethyl borate.
10 The reaction scheme of preparing compound of Formula 7 is represented below:
X in compound of Formula 9 is selected from chloro and bromo.
15
In this one embodiment tert-butyl-3-iodobenzoate is prepared by esterification of 3-
iodobenzoic acid with tert-butanol in presence of pyridine and p-toluenesulfonyl chloride.
In the reaction, pyridine acts as a base as well as solvent. The reaction is carried out at 10-
30°C, preferably at 25-30 °C.
20
11
EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and
enhancements to the described examples and implementations and other implementations
can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts 5 and types of
reactants and reaction conditions that can be utilized in practicing the disclosure. It will be
apparent, however, that the disclosure can be practiced with other amounts and types of
reactants and reaction conditions than those used in the examples, and the resulting devices
various different properties and uses in accordance with the disclosure above and as
10 pointed out hereinafter.
Example 1
Preparation of phenylboronic acid
Toluene (500 ml) was charged to iodobenzene (50 g) under inert atmosphere. The reaction
15 mixture was heated to 70-80 °C and toluene (150 ml) was distilled out from the reaction
mass at very low vacuum pressure. The reaction mass was cooled to -25 to -30 °C.
Isopropyl magnesium chloride (187 ml) was added to the reaction mass drop wise. After
completion of Grignard reaction, the reaction mass was cooled to -20 to -25 °C and
trimethyl borate (75.7 g) was charged. The mass was maintained at 0-10 °C till completion
20 of the reaction. Water (250 ml) was added to the reaction mixture and stirred for half an
hour. Toluene (150) was added to the mass and stirred for half an hour at room
temperature. pH of the reaction mass was adjusted to 6.5 by concentrated hydrochloric
acid. The reaction mass was stirred for half an hour at room temperature. The aqueous and
organic layers were separated and organic layer was distilled under reduced pressure to
25 yield phenylboronic acid as pale yellow solid (28 g). Melting Point = 217 °C.
12
Example 2
Preparation of tert-butyl-3-iodobenzoate
Pyridine (2.5 L) was cooled to 20-25 °C and charged to 3-iodobenzoic acid (500 g). The
reaction mixture was stirred for 10-15 minutes at 20-25 °C. p-Toluenesulfonyl chloride
(768 g) was added and the reaction mass was stirred at 20-25 °C for 30-5 45 minutes. Tertbutanol
(298 g) was charged at 20-25 °C and the reaction mass was gradually brought to
room temperature and maintained for 6 hours. The reaction mass was quenched after
completion of the reaction in ice-cold water (12.5 L) and stirred for 30 minutes. Toluene
(2.5 L) was added to the reaction mass and stirred for 15-20 minutes at 25-30 °C. The
10 organic and aqueous layers were separated and toluene layer was washed with water (1500
ml). The organic layer was dried over sodium sulfate, distilled under vacuum at 55-60 °C
and degassed. The oily residue was stripped off using toluene (200 ml) and degassed to
yield tert-butyl-3-iodobenzoate (565 g) as brown oil.
Yield = 92.1%
15 HPLC Purity = 99.5%
LCMS: M+1 = 305
Example 3
Preparation of tert-butyl-3-iodobenzoate
20
Pyridine (5 L) was cooled to 20-25 °C and charged to 3-iodobenzoic acid (1 kg). The
reaction mixture was stirred for 10-15 minutes at 20-25 °C. To the reaction mass, p-
Toluenesulfonyl chloride (1.536 kg) was charged and the reaction mass was stirred at 20-
25 °C for 30-45 minutes. Tert-butanol (0.596 kg) was added to the reaction mass at 20-25
25 °C and maintained for 6 hours at room temperature. The reaction mass was quenched in
ice-cold water (25 L) and stirred for 30 minutes. To the reaction mass, Toluene (5 L) was
added and stirred for 15-20 minutes at 25-30 °C. The toluene and water layers were
separated and toluene layer was washed with water (3 L). The toluene layer was dried over
sodium sulfate, distilled under vacuum at 55-60 °C and degassed. The oily residue was
13
stripped off using toluene (400 ml) and degassed to yield tert-butyl-3-iodobenzoate (600 g)
as brown oil.
Yield = 93%
HPLC Purity = 99.6%
5 LCMS: M+1 = 305
Example 4
Preparation of 3-(tert-Butoxycarbonyl)phenylboronic acid
10 Toluene (500 ml) was charged to tert-butyl-3-iodobenzoate (50 g) under inert atmosphere.
The reaction mixture was heated to 100-110 °C and toluene (150 ml) was distilled out from
reaction mass. The reaction mass was cooled to -25 to -30 °C. Isopropyl magnesium
chloride (125 ml) was added to the reaction mass dropwise. After completion of Grignard
reaction, reaction mass was cooled to -20 to -25 °C and trimethyl borate (50.80 g) was
15 charged. The mass was maintained at 0-10 °C till completion of the reaction. Water (250
ml) was added to the reaction mixture and stirred for half an hour. Toluene (150) was
added to the reaction mass and stirred for half an hour at room temperature. pH of the
reaction mass was adjusted to 6.5 by concentrated hydrochloric acid. The reaction mass
was stirred for half an hour at room temperature. The aqueous and organic layers were
20 separated and organic layer was distilled under reduced pressure to yield crude 3-(tert-
Butoxycarbonyl)phenylboronic acid as yellowish solid (36 g). The crude 3-(tert-
Butoxycarbonyl)phenylboronic acid was purified as follows:
Toluene (36 ml) and cyclohexane (36 ml) was added to the crude solid obtained
and heated to 70-75 °C for 2 hours. Water (36 ml) was added to the reaction mass at 70-75
25 °C and heating was continued with constant stirring for 3 hours. The mass was cooled to
25-30 °C and cyclohexane (72 ml) was charged. The reaction mass was cooled to 5-15 °C
and stirred for 3 hours. The suspension obtained was filtered and cake was washed with
cyclohexane (36 ml) and suck dried. The cake was dried under vacuum at room
temperature to yield 3-(tert-Butoxycarbonyl)phenylboronic acid (34 g) as off-white solid.
14
Yield = 94%
HPLC Purity = 99.5%
LCMS: M+1 = 223
Example 5
Preparation of 3-(tert-Butoxycarbonyl)5 phenylboronic acid
Under inert atmosphere, toluene (10 L) was added to tert-butyl-3-iodobenzoate (1 kg). The
reaction mixture was heated to 100-110 °C. Toluene (3 L) was distilled out from reaction
mass. The reaction mass was cooled to -25 to -30 °C. To the reaction mass, isopropyl
10 magnesium chloride (2.5 L) was added dropwise. The reaction mass was cooled to -20 to -
25 °C. Trimethyl borate (1.016 Kg) was charged to Grignard species formed. The mass
was maintained at 0-10 °C and water (5 L) was added to the reaction mixture and stirred
for half an hour. Toluene (3 L) was added to the mixture and stirred for half an hour at
room temperature. pH of the reaction mass was adjusted to 6.5 using concentrated
15 hydrochloric acid. The reaction mass was stirred for half an hour at room temperature. The
aqueous and organic layers were separated and organic layer was distilled under reduced
pressure to yield crude 3-(tert-Butoxycarbonyl)phenylboronic acid as pale solid (723.6 g).
The crude 3-(tert-Butoxycarbonyl)phenylboronic acid was purified as follows:
To the crude solid obtained, toluene (724 ml) and cyclohexane (724 ml) was added
20 and the mixture was heated to 70-75 °C for 2 hours. Water (724 ml) was added at 70-75 °C
and heating was continued with constant stirring for 3 hours. The mass was cooled to 25-
30 °C and cyclohexane (1.448 L) was charged. The reaction mass was cooled to 5-15 °C
and stirred for 3 hours. The suspension obtained was filtered and cake was washed with
cyclohexane (724 ml) and suck dried. The cake was dried under vacuum at room
25 temperature to yield 3-(tert-Butoxycarbonyl)phenylboronic acid (683.6 g) as off-white
solid.
Yield = 94.5%
HPLC Purity = 99.5%
LCMS: M+1 = 223
15
We claim:
1. An improved process for preparation of arylboronic acid of Formula 1
wherein, R is H or an electrophilic functional group selected 5 from carbonyl,
alkoxycarbonyl, cyano and nitro
comprising the steps of:
a) reacting aryliodide substituted by an electrophilic functional group of Formula 2 with
10 alkyl magnesium halide in the presence of a hydrocarbon solvent to form Grignard species
of Formula 3; and
wherein,
15 R is H or an electrophillic functional group selected from carbonyl, alkoxycarbonyl,
cyano and nitro,
X is chloro or bromo
b) treating Grignard species of Formula 3 with trialkyl borate.
16
2. The process as claimed in claim 1, wherein R is substituted at any one of ortho-, metaand
para- position with respect to iodo.
3. The process as claimed in claim 1, wherein the temperature in step a) is maintained in a
range 5 of -40 to 0 °C.
4. The process as claimed in claim 1, wherein the temperature in step b) is maintained in a
range of -30 to 10 °C.
10 5. The process as claimed in claim 1, wherein the alkyl magnesium halide used in step a)
is selected from isopropyl magnesium chloride and isopropyl magnesium bromide.
6. The process as claimed in claim 1, wherein the hydrocarbon solvent used in step a) is
selected from aliphatic hydrocarbon solvent such as heptane, cyclohexane, octane, iso15
octane and aromatic hydrocarbon solvent such as benzene, xylene, toluene.
7. The process as claimed in claim 1, wherein the trialkyl borate used in step b) is selected
from trimethyl borate, triethyl borate and tri-isopropyl borate.
20 8. An improved process for preparation of phenylboronic acid of Formula 4
comprising the steps of:
a) reacting phenyl iodide of Formula 5 with alkyl magnesium halide in the presence of a
hydrocarbon solvent to form Grignard species of Formula 6; and
17
wherein, X is chloro or bromo
b) reacting Grignard species of Formula 6 in situ with 5 trialkyl borate.
9. The process as claimed in claim 8, wherein 1-4 volume of the hydrocarbon solvent is
distilled out prior to addition of alkyl magnesium halide from a reaction mixture of
phenyliodide of Formula 5 and the hydrocarbon solvent.
10
10. The process as claimed in claim 8, wherein the temperature in step a) is maintained in
a range of -40 to 0 °C.
11. The process as claimed in claim 8, wherein the temperature in step b) is maintained in
15 a range of -30 to 10 °C.
12. The process as claimed in claim 8, wherein the alkyl magnesium halide used in step a)
is selected from isopropyl magnesium chloride and isopropyl magnesium bromide.
20 13. The process as claimed in claim 8, wherein the hydrocarbon solvent used in step a) is
selected from aliphatic hydrocarbon solvent such as heptane, cyclohexane, octane, isooctane
and aromatic hydrocarbon solvent such as benzene, xylene, toluene.
18
14. The process as claimed in claim 8, wherein the trialkyl borate used in step b) is
selected from trimethyl borate, triethyl borate and tri-isopropyl borate.
15. An improved process for preparation of 3-(tert-Butoxycarbonyl)phenylboronic acid of
5 Formula 7
comprising the steps of:
a) reacting tert-butyl-3-iodobenzoate of Formula 8 with alkyl magnesium halide in the
10 presence of a hydrocarbon solvent to form Grignard species of Formula 9; and
wherein, X is chloride or bromide
15 b) reacting Grignard species of Formula 9 with trialkyl borate
16. The process as claimed in claim 15, wherein 1-4 volume of the hydrocarbon solvent is
distilled out prior to addition of alkyl magnesium halide from a reaction mixture of tertbutyl-
3-iodobenzoate of Formula 8 and hydrocarbon solvent.
20
19
17. The process as claimed in claim 15, wherein the temperature in step a) is maintained in
a range of -40 to 0 °C.
18. The process as claimed in claim 15, wherein the temperature in step a) is maintained in
a range of 5 -25 to -30 °C.
19. The process as claimed in claim 15, wherein the temperature in step b) is maintained
in a range of -30 to 10 °C.
10 20. The process as claimed in claim 15, wherein the temperature in step b) is maintained
in a range of -25 to 0 °C.
21. The process as claimed in claim 15, wherein the alkyl magnesium halide used in step
a) is selected from isopropyl magnesium chloride and isopropyl magnesium bromide.
15
22. The process as claimed in claim 15, wherein the hydrocarbon solvent used in step a) is
selected from aliphatic hydrocarbon solvent such as heptane, cyclohexane, octane, isooctane
and aromatic hydrocarbon solvent such as benzene, xylene, toluene.
20 23. The process as claimed in claim 15, wherein the trialkyl borate in stage b) is selected
from trimethyl borate, triethyl borate and tri-isopropyl borate.
25
20
24. The process as claimed in claim 15, wherein tert-butyl-3-iodobenzoate of Formula 8 is
prepared by esterification of 3-iodobenzoic acid with tert-butanol in the presence of ptoluenesulfonyl
chloride and pyridine.