Yield-efficient process for the production of highly pure 2-methyl-1,4-
naphthoquinone and its derivatives
The present invention discloses a method for the preparation of high purity 2-methyl-
1,4-naphthoquinone (Menadione, 2 isomer) and its derivatives, in which the 6-methyl-
,4-naphthoquinone isomer (6 isomer) formed as a byproduct during the 2-methylnaphthalene
oxidation is extracted selectively as a bisulfite adduct. The bisulfite
solution is then treated in a recovery step (involving a -cleavage reaction to form pure
Menadione) which allows minimizing the Menadione losses due to the bisulfite solution
treatment.
Background of the invention
Several processes for producing Menadione are known in the art.
One common technique is the oxidation of 2-methyl-naphthalene by using sodium
dichromate in aqueous sulfuric acid solution. In this case, despite the low selectivity
for, the 2-isomer, the high degree of destruction of the 6-isomer due to the added
excess hexavalent chromium results in a final product containing a high content of
Menadione. For example, the US 3,751 ,437 discloses that although the reaction
selectivity for the 2-methyl-1 ,4-naphthoquinone is not very high (50-53%), the final
product is mainly composed of Menadione (94-97%), some unreacted 2-methylnaphthalene
(2-MNA) and small amounts of undefined impurities. The main drawbacks
of this process are the very low selectivity of the reaction for the formation of the 2-
methyl-1 ,4-naphthoquinone isomer, the need for excessive amounts of highly toxic
hexavalent chromium as oxidizing agent and the creation of significant amounts of
basic chromium sulfate as the reaction byproduct.
In order to resolve these problems related to the process described above, the use of
other oxidizing agents has been proposed in the state of the art. However, in all the
proposed alternatives using other oxidizing agents, the 6 isomer is present in the final
product mixture at much higher ratios. For example, when hydrogen peroxide (in the
presence of a methyltrioxorhenium catalyst) is used to oxidize 2-MNA, the final methylquinones
are composed of 86% of 2 isomer and 14% of 6 isomer i.e. a ratio of 2 to 6
isomer of 7:1 (W. Adam, W. A. HerrmannJ. Lin, C. R. Saha-Moeller, R. W. Fischer and
J.D. G. Correia, «Homogeneous catalytic oxidation of arenes and a new synthetis of
vitamin K3, Angew. Chem. Int. Ed. Engl., 33, p.2475-2477 (1994)). In another
example, when 2-MNA is oxidized using ammonium persulfate (in the presence of
catalytic amounts of cerium ammonium sulfate and silver nitrate), the ratio of the 2 to 6
isomer was around 3:1 (J. Skarzewski, «Cerium catalyzed persulfate oxidation of
polycyclic aromatic hydrocarbons to quinones, Tetrahedron, 40, p4997-5000 (1984)).
The use of eerie sulfate as oxidant in an acetonitrile-sulfuric acid mixture also resulted
in relatively high amounts of 6 isomer in the final product, i.e. 2 to 6 isomer ratio of
6.5:1 (IN 157224 A).
While the use of highly toxic hexavalent chromium as well as the creation of a
considerable amount of the basic chromium sulfate is avoided in the methods of the
state of the art cited above, the final reaction mixture contains significant amounts of
the 6 isomer which is quite difficult to separate from the desired 2 isomer due to the
similar properties of the two isomers. There are different proposals in the art to
separate the two isomers. The most relevant strategies are:
• Avoiding the creation of the 6 isomer by using a different raw material and a
Diels-Alder reaction
• Separating the undesired 6 isomer by its selective transformation in methylanthraquinone
• Treating the final product mixture with an aqueous bisulfite solution to separate
the 6 isomer
However, all of these strategies suffer from major disadvantages:
The US 5,770,774 proposes to avoid making the 6-isomer by using 2-methyl-1 ,4-
benzoquinone as raw material. This product is reacted with 1,3-butadiene in a Diels-
Alder reaction to make 2-methyl-4a,5,8,8a-tetrahydro-1 ,4-naphthoquinone, which is
then oxidized to 2-methyl-1 ,4-naphthoquinone.
There are several problems associated with this procedure. For one, the raw material
2-methyl-1 ,4-benzoquinone is expensive and not readily available in large amounts.
Furthermore, 1,3-butadiene is a highly toxic agent. Finally, the reaction presupposes
the presence of a Lewis acid catalyst in order to proceed.
The US 5,329,026 discloses the reaction of 6-methyl-1 ,4-naphthoquinone with 1,3-
butadiene to make 1,4,4a, 9a-tetrahydro-6-methylanthraquinone. The latter molecule
can then be oxidized to the methyl-anthraquinone by adding sodium hydroxide and
bubbling air as oxidation agent. The 2-methyl-1 ,4-naphthoquinone isomer hardly
undergoes the same Diels-Alder reaction with the 1,3-butadiene due to the steric
hindrance and difference in electron density.
In addition to the problems of the previous process (use of highly toxic 1,3-butadiene),
there are further disadvantages associated with this process: it has to be conducted at
high temperatures (ca. 120°C) and high reaction pressure, thus necessitating the use
of expensive apparatuses like autoclaves with a high energy consumption.
Furthermore, the reaction time is very long (up to 4 hours).
The Japanese Application 60252445 A discloses the treatment of the final product
mixture with an aqueous bisulfite solution to separate the 6-isomer. The organic
solvent containing the starting and the final products of the 2-MNA oxidation reaction is
first cooled down to precipitate part of the 2-MNQ formed during the oxidation. The
remaining solvent phase is then treated with a bisulfite solution to extract most of the 6
isomer as well as part of the 2-isomer as bisulfite adduct that is soluble in the aqueous
phase. Due to the fact that the 6-isomer reacts much faster than the 2-isomer, the
remaining solvent phase presents a much higher ratio of 2- to 6-isomer. The organic
phase is cooled down to obtain 2-MNQ crystals (94% purity). The solvent filtrate is
treated in a selective bisulfitation step in which typically 25-30% of 2-MNQ is extracted
in order to reach around 90% 6-MNQ extraction rates (this represents around 8 to 10%
of the total 2-MNQ produced during the oxidation step). The aqueous solution
containing bisulfite adducts of 2-MNQ and 6-MNQ becomes a waste.
The 2-MNQ crystals from the first crystallization are dissolved in the organic phase
and recrystallized (around 65% precipitation yield). The 2-MNQ produced contains still
on average 2% of the 6-MNQ isomer. The aqueous phase of the oxidation step is
extracted in an extraction step using extra solvent that is then combined with the
solvent from the second crystallization step. The obtained mixture needs to go
through an additional step of solvent evaporation in order to concentrate the organic
phase before its use in the next oxidation cycle. The overall process is presented in
Figure 1.
There are various drawbacks associated with the process as described above.
Firstly, significant amounts of 2-MNQ (around 8% in first cycle of example 3 and
around 10% overall assuming a yield of 2-MNQ crystals of 55% and the assumed 65%
overall yield for a cerium sulfate process) are lost in the bisulfitation step and not
recovered.
Second, the produced 2-MNQ is not of a very high purity after the first crystallization
due to the fact that the selective bisulfitation is not carried out before this
crystallization. The purity of 2-MNQ even after the second (final) crystallization is less
than 98% due to the fact that 10% of the original 6-MNQ is still left in the solvent after
the selective bisulfitation (a higher extraction rate results in excessively high 2-MNQ
extraction and loss rates).
Third, an important part of the produced 2-MNQ is recycled back to the oxidation
reactor (around 35% in the example 3) which may result in overoxidation and further
losses of 2-MNQ.
Fourth, the organic phase of the extraction of the aqueous phase from the oxidation
step is mixed with the filtrate from step 4 (after the second crystallization) and before it
gets recycled it needs to be concentrated by evaporation. This adds additional steps
and costs to the process.
Chengying et al later proposed an approach similar to the Japanese patent based on
using 2-MNQ precipitation, followed by bisulfitation reaction and finally the redissolution
of the precipitated 2-MNQ in the initial solvent phase to separate the 6
isomer from the 2 isomer (eProcess improvement on synthesis of 2-methyl-1 ,4-
naphthoquinone», Song Chengying, Wang Liucheng, Zhao Jianhong and Xu
Haisheng, Chemical Reaction Engineering and Technology, vol. 23, No.4, August
2007). Contrary to the Japanese patent approach, the ratio of 2-MNQ to solvent
proposed by these authors seems very low (a weight ratio of solvent to 2-MNQ of 4
compared to between 12 and 120 in the case of the Japanese patent). At this ratio,
around 95% of the 2-MNQ formed will precipitate at the first crystallization step.
However, this will be accompanied also by a high rate of 6-MNQ precipitation resulting
in a low purity of the first 2-MNQ crystals. Therefore, despite high extraction rates of
dissolved 6-MNQ at the bisulfitaion step, once the first 2-MNQ crystals are redissolved
in the solvent phase after the selective bisulfiation step, the residual 6-MNQ
in the final 2-MNQ obtained in the second crystallization step should be significantly
higher than the 0,5% claimed by the authors resulting in a relatively low purity of final
2-MNQ product.
Problem underlying the invention
The technical problem to be solved is to devise a method for producing Menadione
and Menadione derivatives which overcomes the disadvantages of the processes
disclosed in the state of the art.
Specifically, the process to produce Menadione and Menadione derivatives shall avoid
the use of aggressive oxidizing agents like hexavalent chromium, without
compromising the purity of the Menadione or its derivatives.
Furthermore, the envisaged process shall avoid the application of high temperatures
and pressures as well as toxic reagents.
Finally, the envisaged process shall achieve a selectivity, yield and purity that is at
least comparable, if not better than what is currently known in the art.
Description of the invention:
The technical problem outlined above is surprisingly solved by a process to produce
Menadione and its derivatives as disclosed in the claims.
Specifically, the method according to the invention is based on treating the organic
phase from the oxidation step of 2-MNA with an aqueous solution of a bisulfite salt in
such a manner that the 6-MNQ isomer is reacted with a higher selectivity than that of
2-MNQ. The organic phase after the selective bisulfitation step (SB), is then sent to
another bisulfitation step in which most of the remaining 2-MNQ and 6-MNQ are
extracted as bisulfite adducts in the aqueous bisulfite solution. The final organic phase
containing very small residual amounts of 2-MNQ is enriched in 2-MNA and recycled
back to the oxidation step. The aqueous phase from the SB step is then sent to a
recovery step in which (if necessary) the interfering bisulfite ions are removed from the
solution and the pH is increased to more than 8,5, more preferably to between 10 and
12 and most preferably between 11 and 12 in the presence of the organic phase
(preferably from the non selective bisulfitation step). In an alternative embodiment, the
increase in pH is carried out in the absence of a solvent and the precipitated 2-MNQ
may then be recovered as a solid by a liquid-solid separation method such as filtration.
The organic phase from the recovery step may be cooled down to precipitate very
pure 2-MNQ solid that may be separated by any solid-liquid separation method. The
obtained 2-MNQ presents a very high purity in terms of absence of the 6-MNQ isomer
due to the fact that the bisulfite adduct of the 6-MNQ isomer hardly undergoes the -
cleavage reaction during the recovery step. The remaining organic phase may be sent
to the non selective bisulfitation step to convert most of the residual 2-MNQ into 2-
MNQ bisulfite adduct along with the solvent phase from the SB step and be recycled to
the oxidation step as mentioned before. The bisulfite adduct of 2-MNQ contained in
the aqueous phase from the non selective bisulfitation step may be precipitated by
known methods (e.g. cooling, salt addition, solvent addition, etc) and dried to obtain
the solid form of the bisulfite adduct of Menadione. Alternatively, it may be used to
form other derivatives of vitamin K3 such as MNB, MPB, etc, at a high yield and high
purity.
The residual amount of 2-MNQ contained in the spent oxidant solution after the 2-MNA
oxidation step may be extracted using the solvent from the non selective bisulfitation
step before its recycling to the oxidation step.
Figure 2 shows the different steps involved in the method according to the invention.
The solid Menadione obtained from the recovery step preferably contains less than
0.5% w/w% of the 6-MNQ isomer, more preferably 0,2% and most preferably less than
0,1%, which is considerably less than the typical 2% content reported in the state of
the art, e.g. the Japanese patent 60-252445. The preferred 2-MNQ recovery yields
according to the invention are around 90%, more preferably 92% and most preferably
95%. Furthermore, with an extraction rate during SB step of preferably 30%, more
preferably 28% and most preferably 25% of the 2-MNQ produced during the oxidation
step, the total loss of 2-MNQ due to SB and recovery step combined would be around
1,5% to 3% which is again considerably lower than the 8% to 10% losses observed
when selective bisulfitation is used without combination with the recovery step (e.g.
Japanese patent 60-252445) .
The 2-MNA oxidation step preferably takes place at a temperature in the range of 0 to
100 °C, more preferably 25-60 °C and most preferably 25-40 °C.
The 2-MNA oxidation step according to the invention can be executed using any
suitable oxidizing agent known in the art. However, it may be preferred that said
oxidizing agent is selected from the group consisting of a Ce(lll)/Ce(IV) salt redox
couple.
The selective bisulfitation step according to the invention may be carried out at a
temperature in the range of 0-70 °C, more preferably 10-50 °C and most preferably 25-
40 °C. Any bisulfite salt capable of dissolving in water may be used as a bisulfitation
agent. However, it may be preferred that the bisulfite salt is selected from the group
consisting of sodium or potassium bisulfite. Preferably, the bisulfite solution according
to the invention has a concentration of 0,1 to 4 M, more preferably 0,5 to 2 M and most
preferably 0,5 M.
The non-selective bisulfitation step according to the invention may be carried out at a
temperature in the range of 0-70 °C, more preferably 10-50 °C and most preferably 25-
40 °C. Any bisulfite salt may be used as a bisulfitation agent. However, it may be
preferred that the bisulfite salt is selected from the group consisting of sodium or
potassium bisulfite.
It has also been observed that the selectivity of the selective bisulfitation varies
according to the agitation conditions. As the agitation is increased, a higher extraction
yield of 6-MNQ may be obtained at a lower 2-MNQ extraction rate, which also
minimizes the losses of 2-MNQ as it may be seen from examples 1 to 3. Thus, it may
be preferred that the selective bisulfitation takes place under agitation. However, the
agitation should not be too vigorous as to result in the formation of a stable emulsion
between the organic phase and the aqueous bisulfite solution. The determination of
the precise agitation conditions is within the routine capability of the skilled person.
Also the other derivatives of vitamin K3 produced from the current proposed method
show an important improvement in the quality of the final product. For example, MNB
produced using the proposed process contains no detectable amounts of the 6 isomer
derivative, whereas without the SB step, the final MNB contains typically between
0.1% and 1% of the 6 isomer derivative. Also, the application of this approach allows
maximizing the precipitation yield of the vitamin K3 derivatives, as the very low
concentration of the 6 isomer bisulfite adduct allows maximizing the precipitation rate
of the 2 isomer adduct or its derivatives without provoking the precipitation of the 6
isomer adduct derivatives which would result in a less pure vitamin K3 derivative.
The present invention contemplates the production of Menadione and its derivatives. It
may be especially preferred that said derivatives are selected from the group
consisting of Menadione bisulfite adducts that may be isolated as organic salts
containing an inorganic cation such as sodium (MSB) or potassium or an organic
cation as protonated forms of compounds such as Nicotinamide (MNB),
dimethylPyrimidinol (MPB), p-Amino-Benzoic acid, etc.
In summary, the present invention has several advantages compared to the prior art:
In comparison to the methods according to the state of the art, the use of
oxidizing agents other than hexavalent chromium or an excess amount of it
becomes possible without compromising the purity of the vitamin K3 or its
derivatives produced.
In comparison to the methods in the art which propose the use of Diels-Alder
reactions, the application of high temperatures, high pressures and highly toxic
reagents is avoided.
Specifically in comparison with the approach according to the Japanese patent
60-252445, the following improvements have been achieved:
o The total loss of 2-MNQ due to the combined SB-Recovery steps is
between 1,5% and 3%, compared to 8% to 10% for the Japanese patent
o The residual concentration of the 6-MNQ isomer in the isolated 2-MNQ
solid is less than 0,2% compared to the typical average of 2% reported in
the Japanese patent
o The use of higher agitation conditions also results in improved
selectivities.
o The need for the evaporation step of the combined organic phases of the
extraction of the aqueous phase (from the oxidation step) and the filtrate
from crystallization step is avoided by doing a second bisulfitation and by
using the final organic phase for the extraction of the aqueous phase of
the oxidation step.
o A very small fraction of the formed 2-MNQ is recycled back to the
oxidation step which minimizes additional losses due to overoxidation of
already formed 2-MNQ (less than 2% of 2-MNQ is sent back to oxidation
step compared to up to 30% in the Japanese patent).
The process according to the invention will be further explained in the following, nonlimiting
examples.
Example 1
380 ml of a sodium bisulfite solution having a bisulfite concentration of 0,5 M were
transferred to a 2 liter reactor containing 1580 ml of a water immiscible aliphatic
solvent containing 0,0214 M of 2-MNQ and 0,0042 M of 6-MNQ. The reactor was
equipped with a conventional 4 blade propeller and the agitation speed was set to 400
rpm. Samples of the organic phase were taken and analyzed by GC to determine the
residual concentration of the 2 and 6 MNQ isomers. The results are presented in table
1 below:
Table 1
As it may be seen, after 30 minutes of reaction, the 2 to 6 isomer ratio in the organic
phase has increased from the original value of 5,1 to more than 29 (around 97% of the
,4-methyl-naphthoquinone in the solvent is the 2 isomer).
Example 2
400 ml of a sodium bisulfite solution having a bisulfite concentration of 0,5 M were
transferred to a 2 liter reactor containing 1600 ml of a water immiscible aliphatic
solvent containing 0,0247 M of 2-MNQ and 0,0052 M of 6-MNQ. The reactor was
equipped with a conventional 4 blade propeller. In order to improve the agitation
conditions compared to those used in the prior example, two baffles were installed in
the reactor and the agitation speed was set to 500 rpm. Samples of the organic phase
were taken and analyzed by GC to determine the residual concentration of the 2 and 6
MNQ isomers. The results are presented in table 2 below:
Table 2
It may be seen that the more vigorous agitation results in a better selectivity for 6
isomer extraction. In fact compared to example 1, to reach an organic phase
containing 97% of the 2 isomer, only 26% of the 2-MNQ contained in the original
solvent was extracted (compared to around 45% for the agitation conditions of
example 1). Also the higher agitation allows to reach the 97% content in the solvent in
a much shorter time (13 minutes compared to 30 minutes in example 1).
It is also important to see that the residence time has also an effect on the selectivity
since after certain period, the purity does not improve but the fraction of extracted 2-
MNQ increases.
Example 3
750 ml of a sodium bisulfite solution having a bisulfite concentration of 0,5 M were
transferred to a 4 liter reactor containing 3000 ml of a water immiscible aliphatic
solvent containing 0,0229 M of 2-MNQ and 0,0042 M of 6-MNQ. The reactor was
equipped with a Silverstone propeller instead of the conventional agitation propellers
used in examples 1 and 2. The agitation speed was 3400 rpm. Samples of the
organic phase were taken and analyzed by GC to determine the residual concentration
of the 2 and 6 MNQ isomers. The results are presented in table 3 below:
2-MNQ % of 2 isomer in
2-MNQ Extracte 6-MNQ Extract to 6- the total methyl-
Bisulfitati in d in ed MNQ 1,4-
on Time solvent 2-MNQ solvent 6-MNQ ratio in naphthoquinone
(sec) (M) fraction (M) fraction solvent in solvent
0 0.0229 0% 0.0042 0% 5.5 85%
60 0.0220 4% 0.0030 28% 7.3 88%
180 0.021 1 8% 0.0024 43% 8.9 90%
300 0.0205 10% 0.0016 62% 12.9 93%
420 0.0191 16% 0.0010 77% 19.9 95%
540 0.0184 19% 0.0007 82% 25.1 96%
600 0.0182 20% 0.0006 84% 28.2 97%
720 0.0177 23% 0.0005 88% 34.3 97%
Table3
It may be seen that the more vigorous agitation results in even higher selectivity for 6
isomer extraction. In fact compared to example 1, to reach an organic phase
containing 97% of the 2 isomer, only 20% of the 2-MNQ contained in the original
solvent was extracted (compared to around 45% for the agitation conditions of
example 1 and 26% for example 2). Also the higher agitation again allows to reach
the 97% content in the solvent in a much shorter time (10 minutes compared to 30
minutes in example 1 and 13 minutes for example 2).
Example 4
An organic phase containing 430 parts of 2-MNA, 65 parts of 2-MNQ and 14 parts of
6-MNQ was oxidized in a continuous mode by a eerie and cerous methanesulfonate
aqueous mixture. The organic phase at the oxidation step outlet contained 17 parts of
2-MNA, 275 parts of 2-MNQ and 56 parts of 6-MNQ. The organic phase was then put
in contact with a sodium bisulfite solution to form the bisulfite adduct of both isomers.
The organic phase at the bisulfitation reactor outlet contained 28 parts of 2-MNQ and 4
parts of 6-MNQ representing 90% and 94% of extraction during bisulfitation for the 2
and 6 isomers, respectively. The analysis of the final aqueous phase showed a
concentration of 0,92 M for the 2-MSB and 0,19 M for the 6-MSB adducts. The
aqueous phase was then mixed in equimolar ratio with a solution of nicotinamide in
water and then concentrated sulfuric acid was added gradually over a period of 150
minutes. Starting from the end of the sulfuric acid addition, samples of the solid MNB
were taken from the suspension and washed with water and analyzed for the presence
of the 6 isomer of the Methyl-naphthoquinone Nicotinamide Bisulfite (6-MNB). As it
may be seen from table 4 below, the concentration of the 6-MNB starts to increase
after 4 hours of elapsed time between the end of acid addition and the solid filtration to
reach up to 0,72% and even 2,74% after 5 hours.
Waiting time before 6-MNB in final
filtration (min.) MNB solid (%)
5 0.1 3%
65 0.20%
125 0.16%
185 0.18%
245 1.15%
305 2.74%
Table 4
Example 5
2-MNA was oxidized in the same manner as described in example 4. However, in this
case the organic phase was reacted continuously with an aqueous solution of sodium
bisulfite in a selective bisulfitation reactor in which the residence time and agitation
conditions were set so that 78-79% of the 6-MNQ and only 25- 28% of the 2-MNQ
were extracted from the organic phase as their bisulfite adduct. Once the
concentration of residual sodium bisulfite reached 0,5 M, fresh concentrated sodium
bisulfite solution was added to the selective bisulfitation and equivalent volumes of the
aqueous phase were removed from the reactor so that the concentration of all species
in the aqueous phase remained practically constant. Table 5 below shows the
concentration of adducts of the 2 and 6 isomers in the removed aqueous phase.
Table 5
During the continuous operation of the selective bisulfitation reactor, 4 samples of the
organic phase were taken and reacted with the same sodium bisulfite solution in a
consecutive way in order to increase the concentration of the residual 2-MSB and
therefore mimic a continuous bisulfitation reaction. The results in terms of 2-MNQ and
6-MNQ concentrations in the initial and final solvent phase as well as the
concentration of the 2-MSB and 6-MSB in the aqueous bisulfite solution are presented
in table 6 below.
Table 6
100 parts of the final aqueous bisulfite solution containing 0,499 M of 2-MSB and
0,0024 M of 6-MSB were then used to prepare MNB by addition of an aqueous
solution containing 15 parts of water and 6 parts of nicotinamide. 4,1 3 parts of sulfuric
acid 93% were added gradually to the mixture over a period of 30 minutes. After a
waiting period of 60 minutes, the precipitated MNB was filtered and washed with water
and the solid MNB was then dried and analyzed for the presence of 6-MNB impurity.
The concentration of the residual 2-MSB reached 0,07 M corresponding to 83% of
precipitation efficiency. In another experiment, the MNB precipitation was performed
with the same amounts of the same products, but the solid precipitated MNB was
filtered after 5 hours of waiting and then washed, dried and analyzed for the presence
of 6-MNB. The residual concentration of 2-MSB after 5 hours was at 0,06 M
corresponding to more than 85% of MNB precipitation. The composition of the solid
MNB samples obtained after 1 and 5 hours are presented in table 7 below.
Table 7
Compared to the results presented in example 4, it may be seen that even after 5
hours of waiting period before filtration, the amount of 6-MNB is more than 140 times
less (0,012% compared to 2,74% in example 4).
The aqueous phase from the selective bisulfitation step was treated in a recovery step
in which the aqueous phase is treated with an alkali reagent (in this case NaOH 10%)
to increase the solution pH (in this case 11) in the presence of an organic solvent in
order to recover the 2-MSB adduct as 2-MNQ and minimize the losses of vitamin K3
due to the selective bisulfitation step. The experiment was carried out four times to
mimic a continuous recovery step and to produce enough organic phase volume for
the next step in which the obtained 2-MNQ was transformed in its bisulfite adduct. As
it may be seen in table 8 below, in all the recovery experiments, the amount of 6-MNQ
in the solvent was very small representing in average around 6% of the total methylnaphthoquinones
in the final organic phase.
*based on converted MSB
Table 8
The organic phase from the 2-MNQ recovery experiments were then made to react
with a sodium bisulfite solution to transform the 2-MNQ into its water soluble bisulfite
adduct (2-MSB). The same bisulfite solution was used repeatedly to mimic a
5 continuous bisulfitation reaction and in order to reach a high 2-MSB concentration.
The amount of the bisulfite adduct of the 6 isomer (6-MSB) was at a non detectable
limit (see table 9 below).
Table 9
10
The obtained aqueous solution of 2-MSB was then used to produce MNB. 75 parts of
the final aqueous bisulfite solution containing 0,749 M of 2-MSB and <0,0001 M of 6-
MSB was then used to prepare MNB by addition of an aqueous solution containing 17
15 parts of water and 6,8 parts of nicotinamide. 4,64 parts of sulfuric acid 93% was
added gradually to the mixture over a period of 30 minutes. After a waiting period of
300 minutes, the precipitated MNB was filtered and washed with water and the solid
MNB was then dried and analyzed for the presence of 6-MNB impurity. No detectable
amount of 6-MNB was found in the precipitated MNB. The concentration of the
20 residual 2-MSB reached 0,055 M corresponding to around 92% of precipitation
efficiency.
Example 6
25
An aqueous 0,08 M sodium bisulfite solution containing 0,1524 M of 2-MSB and
0,0284 M of 6-MSB was treated with 10% NaOH solution in the presence of an
organic solvent. The final organic phase was then separated, cooled to -15 °C during
12 hours and filtered to separate the precipitated 2-MNQ solid. The experiment was
30 repeated 4 times and the results are presented in table 10 below:
*After cooling a -15 C during 12 hours
Table 10
The average precipitation yield was around 58%. The solids obtained were combined
and dried under vacuum at around 34 kPa (-20inch Hg) in the presence of P20 5 during
72 hours. The final dry solid sowed a 2-MNQ content of more than 98,5% and less
than 0,1 3% of 6-MNQ.
Claims
A process for the production of 2-methyl-1 ,4-naphthoquinone and its bisulfite
adducts, comprising the following steps:
a) oxidizing 2-methyl-naphthalene (2-MNA) to achieve an organic phase
containing 2-methyl-naphthoquinone (2-MNQ) and 6-methylnaphthoquinone
(6-MNQ);
b) subjecting said organic phase to treatment with an aqueous solution
of a bisulfite salt to extract preferentially the 6-MNQ isomer from the
organic phase;
c) separating said organic phase from the aqueous phase;
d) subjecting the organic phase of process step c) to a second
bisulfitation step with an aqueous solution of a bisulfite salt, resulting
in an organic phase containing 2-MNA and trace amounts of 2-MNQ
and an aqueous phase containing 2-MSB and trace amounts of 6-
MSB;
e) optionally removing interfering bisulfite ions from the aqueous phase
of process step c);
f) raising the pH of the aqueous phase from step c) or e) to higher than
8,5 in the presence of a solvent resulting in an organic phase
containing 2-MNQ;
g) combining the organic phase from step f) with the organic phase
being treated in the process step d);
h) recycling the organic phase from step d) back to step a) to be used as
solvent for the oxidation reaction of 2-MNA.
The process according to claim 1, whereby the organic phase from step c) is
used to produce pure solid 2-MNQ by cooling and by separating the
precipitated 2-MNQ by any known solid-liquid separation method before
being subjected to the second bisulfitation in step d).
The process according to claim 1, whereby said aqueous phase from
process step d) is isolated and the bisulfite adduct of the 2 isomer is
precipitated and isolated or used as a reactant to prepare other Vitamin K3
derivatives.
Process according to claim 1, whereby the step e) for the removal of
interfering bisulfite ions is effected by a method selected from the group
consisting of selective precipitation, ion exchange treatment, membrane
treatment or conversion into inert ions.
The process according to claim 1, whereby process step f) is performed in
the absence of an organic solvent and the 2-MNQ is isolated as a
precipitated solid by any solid-liquid separation method.
The process according to any of claims 1-2, whereby process step a)
preferably takes place at a temperature in the range of 0-100 °C more
preferably 25-60 °C and most preferably 25-40 °C.
7 .) The process according to any of claims 1-2, whereby process step a)
employs an oxidizing agent selected from the group consisting of a
Ce(lll)/Ce(IV) salt redox couple.
8.) The process according to claim 7 , whereby the spent cerium salt is reoxidized
by using an electrochemical cell.
9.) The process according to any of claims 1-2, whereby process step b) as well
as process step d) are carried out at a temperature in the range of 0-70 °C,
more preferably 10-50 °C and most preferably 25-40 °C.
10.) The process according to any of claims 1-2, whereby process step b) as well
as process step d) use a solution containing a bisulfite salt, preferably
selected from the group consisting of sodium or potassium bisulfite.
11.) The process according to any of claims 1-2, whereby said bisulfite solution
in process step b) preferably has a concentration of 0,1-4 M, more
preferably 0,5-2 M and most preferably 0,5 M.