Improved oxazole Method for the Practical and Efficient Preparation of Pyridoxine Hydrochloride (Vitamin B6)

Article abstract of DOI:10.1021/op4001687

Vitamin B₆, a well-studied vitamin B, has been synthesized using an oxazole method for the past 20 years. The oxazole method provided 56.2% overall yield but also generated safety, environmental, and health problems, such as using toxic benzene as solvent and unstable, corrosive, and pollutive HCl and POCl₃ as reagents. To use the same equipment but the least amount of toxic agents, we developed new reaction conditions for the early steps. For example, we successfully replaced toxic HCl/benzene conditions with NaHSO₄/PhCH₃ conditions and also developed a novel and efficient dehydrating agent trichloroisocyanuric acid/Ph₃P/Et ₃N to synthesize the key intermediate 5-butoxy-4-methyl oxazole, instead of using phosphorus oxychloride. These improvements resolved safety, waste avoidance, and workup issues that plagued the previous methodologies. Our process comprised six easy synthetic steps and generated vitamin B₆ with 99.4% purity in 56.4% overall yield.

Full text of DOI:10.1021/op4001687

Article
pubs.acs.org/OPRD
Improved “Oxazole” Method for the Practical and Efficient
Preparation of Pyridoxine Hydrochloride (Vitamin B6)
Ye Zou,† Xiangjun Shi,† Genbao Zhang,‡ Zhenhua Li,† Can Jin,† and Weike Su*,†
†Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical
Sciences, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
‡Jiangxi Tianxin Pharmaceutical Company Ltd., Leping 333300, People’s Republic of China
ABSTRACT: Vitamin B6, a well-studied vitamin B, has been synthesized using an oxazole method for the past 20 years. The
oxazole method provided 56.2% overall yield but also generated safety, environmental, and health problems, such as using toxic
benzene as solvent and unstable, corrosive, and pollutive HCl and POCl3 as reagents. To use the same equipment but the least
amount of toxic agents, we developed new reaction conditions for the early steps. For example, we successfully replaced toxic
HCl/benzene conditions with NaHSO4/PhCH3 conditions and also developed a novel and efficient dehydrating agent
trichloroisocyanuric acid/Ph3P/Et3N to synthesize the key intermediate 5-butoxy-4-methyl oxazole, instead of using phosphorus
oxychloride. These improvements resolved safety, waste avoidance, and workup issues that plagued the previous methodologies.
Our process comprised six easy synthetic steps and generated vitamin B6 with 99.4% purity in 56.4% overall yield.
as the dehydrating agent5 in the synthesis of key intermediate
4-methyl-5-ethoxy oxazole (5) made this operation not very
INTRODUCTION
Vitamin B6 is a natural water-soluble vitamin, which has several
■
safe. Phosphoric anhydride is corrosive to equipment and is
isoforms include pyridoxine (PN), pyridoxal (PL), and
pyridoxamine (PM) (Figure 1).1 It plays an important role in
very irritating. It reacts vigorously with water and water-
containing substances and forms a hard or powderlike mass
which prevented the propeller from working and destroyed the
equipment. Considerable efforts were made by many research
teams to modify this method.6 Among which the way involved
in the cyclization with POCl3 in the presence of Et3N, as
reported by Zhou,7 appeared most attractive to people as it
drove the reaction to completion without byproduct and
Figure 1. Natural forms of vitamin B6.
avoided the defect which was mentioned above. Therefore, this
route was developed and streamlined, resulting in a six-step,
higher-yielding (56.2%) route (Scheme 1).
various cellular processes, such as metabolism of amino acids,
fatty acids, and carbohydrates, biosynthesis of heme, chlor-
ophyll, ethylene, and auxin, and transcriptional regulation.2 To
ensure the vital activity of most organisms, including the human
and plant organisms, all living organisms have to obtain vitamin
B6, either from biosynthesis or from foods and nutrients.
Vitamin B6 is widely distributed in foods; however, some
losses are experienced with prolonged exposure to heat, light,
or alkaline conditions during cooking, storage, and processing.
The development of convenient synthetic approaches to this
vitamin is therefore of great interest to the “nutritional
supplements” industry. The main commercial form of vitamin
B6 is pyridoxine hydrochloride.
Although many enterprises profitted from the finding of new
dehydrating agents, some drawbacks still existed in the process,
which would generate safety issues, environmental and health
problems, such as using toxic benzene as solvent and unstable,
corrosive, and pollutive hydrochloric acid and phosphorus
Scheme 1. “Oxazole” Method for the Synthesis of Pyridoxine
Hydrochloride
Harris and Folkers reported the first “pyridone” method3 for
the synthesis of pyridoxine hydrochloride in nine linear steps
(<1.3% overall yield) in 1939, which involved the condensation
of ethoxyacetylacetone and cyanoacetamide as the main stage.
Albeit a pioneering tour de force, the lengthy synthesis and low
overall yield of 1 could not stimulate a wave of exploration in
pyridoxine chemistry. In the early 1960s, Merck and Roche
reported a new “oxazole” method for the preparation of
pyridoxine,4 which led to an increase in the output of
pyridoxine and to a decrease in its cost on the world market
by a wide margin. However, the usage of phosphoric anhydride
Received: June 24, 2013
Published: November 13, 2013
© 2013 American Chemical Society
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oxychloride as reagents. Considering these disadvantages, we
have subjected this synthetic route to further studies and
intended to develop an efficient and commercially viable
process for vitamin B6. In this article, we describe an improved
process with an overall yield of 56.4% in six steps.
The experiments indicated that the Ph3P, solvent, and base
were to play a major role in the cyclization reaction.
As expected, the cyclization did not proceed when Ph3P was
absent. Experimental results showed that TCCA was prone to
react with Ph3P acutely to afford the key intermediate 11
(Scheme 4).10 Because the intermediate 11 was susceptible to
hydrolysis, it was not isolated and could be used in the
cyclization directly.
The activity of the dehydrating agents was proven to be
strongly solvent-dependent. Various solvents were examined for
the cyclization reaction, including dichloromethane, chloro-
benzene, toluene, ethyl acetate, acetonitrile, and acetone. As
shown in Figure 2, the best results were obtained in
dichloromethane and chlorobenzene with higher conversion.
Toluene and ethyl acetate furnished lower yields after the same
time span. These differences were most likely due to the poor
solubility of TCCA in toluene and ethyl acetate. Because
intermediate 11 was sensitive to water, this cyclization reaction
could not proceed well in undried acetonitrile or acetone, for
which absorbing water was easy in an ambient environment. In
addition, in order to complete the reaction, it needed a larger
amount of chlorobenzene than dichloromethane as a solvent.
So the use of dichloromethane would be appropriate for the
cyclization process.
RESULTS AND DISCUSSION
■
Preparation of Butyl 2-(2-Butoxy-2-oxoacetamido)-
propanoate (7). There have been numerous publications on
the synthesis of alkyl N-alkoxalyl alaninates.8 In the original
methods, the product 7 was acquired by azeotropic removal of
the formed water under the condition of using hydrochloric
acid as the catalyst, but hydrochloric acid was unstable to store
and transport due to its volatility, and it had a detrimental
impact on the environment after completion of the reaction. In
contrast with hydrochloric acid, sodium bisulfate was safe and
easy to handle, and it can reduce plant corrosion. So our
improved process used sodium bisulfate to replace hydrochloric
acid as the catalyst and reduced the amount of catalyst from 1
to 0.05 equiv.
The present work enables the manufacture of N-alkoxalyl
alaninates from L-alanine (2), which could be purchased
commercially. Compound 2 was reacted with oxalic acid in the
presence of sodium bisulfate as catalyst with azeotropic removal
of the formed water in butyl alcohol by toluene to afford 7
(Scheme 2). After simple washing and extraction removed the
After selecting the dichloromethane as a solvent for the
cyclization reaction, another key parameter was studied by
screening of bases. A series of bases such as Et3N, pyridine,
DBU, DABCO, N,N-dimethylaniline, N,N-diisopropyl-
ethylamine, and K2CO3 were screened in order to find a kind
of deacid reagent. The results showed that all of those bases did
not work well to afford the desired product except for Et3N.
Therefore, Et3N was found to be the suitable base for the
desired transformation.
Scheme 2. Simultaneous Esterification and Acylation of 2 To
Yield 7
After the reaction mixture was washed with water to remove
the triethylamine hydrochloride, the layers were separated in
order to acquire the product. In the original method for the
cyclization with POCl3/Et3N, it was hard to separate out the
water layer from the organic layer for the two layers almost
having the same color, which was caused by those black
phosphates (Figure 3A). In contrast, the layers were separated
easily in our new method (Figure 3B). Hence, these results
showed that the dehydrating agent of TCCA/Ph3P/Et3N was
more suitable in industrialization.
With 8 in hand, the remaining two-step saponification and
decarbonylation could be conducted according to the literature7
to complete the synthesis of 10 after a wet distillation process.
Then the distillation residue was cooled to room temperature
and filtered to recycle Ph3PO, which could also be further
transformed into Ph3P again according to the literature.11
Hence, Ph3P could be reused in our reaction, and the influence
on the environment by the phosphorus compounds had been
reduced.
catalyst and those unreacted materials, the resulting solution
was evaporated to remove the solvent and the dibutyl oxalate.
The crude 7 was finally obtained in 89.1% yield with 97.2%
purity. Crude 7 was used directly in the next step.
Conversion of 7 to 5-Butoxy-4-methyl Oxazole (10).
The key intermediates in the synthesis of 1 by the “oxazole”
method were 1,3-oxazoles, which were prepared with
dehydration agents such as POCl3.9 In our improved process,
10 was prepared from 7 with trichloroisocyanuric acid
(TCCA)/Ph3P/Et3N as dehydrating agents (Scheme 3).
POCl3 was a pungent liquid, and it also had the same questions
regarding storage and transport as hydrochloric acid. Besides,
the byproduct phosphates which formed by POCl3 were
difficult to recycle. In contrast with POCl3, TCCA and Ph3P
were inexpensive, stable, and safe. It is worth mentioning that
no method had yet been reported to synthesize oxazole
derivatives by using TCCA/Ph3P/Et3N as dehydrating agents.
Scheme 3. Improved Process for the Synthesis of 10
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Scheme 4. Formation of the Intermediate 11
Table 1. Synthesis of 1 by the Diels−Alder Reactions of 10
a
with 6 under Lewis Acid Catalyzed and Aromatization
b
entry
Lewis acid
yield (%)
1
2
3
4
5
AlCl3
FeCl3
ZnCl2
BF3
70
65
68
66
78
none
a
Standard reaction conditions: 1.0 equiv of 10, 13 equiv of 6, 0.05
b
equiv of Lewis acid, 150 °C, 15 h. The yield was calculated with 1.
Luckily, calcium oxide was found to increase the yield. When
0.05 equiv of calcium oxide was added, the yield of 1 increased
from 78 to 80%. After improving the Diels−Alder reaction, the
remaining aromatization could be conducted according to the
literature7 to complete the synthesis of pyridoxine hydro-
chloride (1) (Scheme 5).
Figure 2. Screening of solvents for the synthesis of 8. Standard
reaction conditions: 1 equiv of 7, 1.0 equiv of TCCA, 3.0 equiv of
Ph3P, 3.0 equiv of Et3N. Conversion to 8 determined by GLC
analyses.
Scheme 5. Preparation of 1 by the Diels−Alder Reaction and
Aromatization
CONCLUSION
Figure 3. Comparison of two kinds of dehydrating agents after the
cyclization reaction.
■
In conclusion, we have developed an efficient and commercially
viable process for the synthesis of pyridoxine hydrochloride (1).
L-Alanine (2) was used as the starting material, which was
transformed to 1 through six steps including esterification,
cyclization, decarbonylation, Diels−Alder reaction, hydrolysis,
and hydrochloride salt formation in 56.4% yield with 99.4%
purity (Scheme 6). Especially, a new, safe, and efficient
dehydrating agent TCCA/Ph3P/Et3N was developed for the
cyclization reaction to produce this key intermediate 8 with a
good yield. Notably, Ph3PO which formed in the cyclization
also could be recycled without complex purification. In the
other process of the route, some improvements were also
described.
Based on the above results, the successive cyclization of 7 to
oxazole derivative 8 followed by decarboxylation to oxazole 10
would be directly feasible without complex purifications in
79.2% yield. No byproduct appeared in this reaction.
Preparation of Vitamin B6 (1). Having achieved oxazole
10, our next task was to study the pyridoxine hydrochloride salt
formation. The dienophile 6 was less active and entered into
condensation with oxazole 10 at temperatures of 150 °C for 15
h. Using excess 6 to react with 10 was in practice a common
solution to promote the reaction. The Diels−Alder reaction
was examined under different conditions in order to optimize
the reaction conditions. It is well-known that Lewis acid can
ameliorate the conditions of the Diels−Alder reaction and
enhance its reactivity and selectivity.12 The Lewis acid mediated
Diels−Alder reactions were performed under solvent-free
conditions, which produced low yields (Table 1, entries 1−
4). These results were most likely due to the instability of 10
under acid environment. Hence, Lewis acid was not suitable for
this Diels−Alder reaction.
EXPERIMENTAL SECTION
■
All chemicals were purchased from commercial sources and
were used without further purification. All GC analysis was
conducted on an Agilent 7890A. GC conditions: SE-30 M
column, 30 m × 0.25 mm × 0.25 μm; carrier gas, nitrogen (1.2
mL/min); injection temp = 200 °C; detector temp = 260 °C;
oven temp = 190 °C. HPLC analysis for vitamin B6 was carried
out on an Agilent 1200 system equipped with a XDB-C18 250
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Scheme 6. Optimized Synthesis of Pyridoxine Hydrochloride
mm × 4.6 mm column and detected at 290 nm. Mobile phase:
A mixture of methanol, glacial acetic acid, and water (27:1:73)
containing 1.40 mg/mL of sodium 1-hexanesulfonate, flow rate
= 1 mL/min. 1H (400 MHz) NMR and 13C (101 MHz) NMR
spectra were recorded on a Varian spectrometer in CDCl3 or
D2O using tetramethylsilane (TMS) as internal standards.
Butyl 2-(2-Butoxy-2-oxoacetamido)propanoate (7). In
a reaction vessel equipped with thermometer, fractionating
column, water knockout trap, and reflux condenser, L-alanine 2
(44.5 g, 0.5 mol) and oxalic acid (90.0 g, 1.0 mol) were
dissolved in butyl alcohol (350 mL) at 70 °C. Sodium bisulfate
(3.0 g, 0.025 mol) and toluene (100 mL) were added into the
solution, and then the mixture was distilled off azeotropically to
remove the formed water until there no water appeared in the
water knockout trap. Toluene and butyl alcohol were recycled
from the reaction mixture at a reduced pressure. After being
cooled, toluene (100 mL) and water (75 mL) were added to
the residue and stirred at 50−55 °C for 5 min. The sodium
bisulfate, unreacted L-alanine, and oxalic acid were removed by
washing with water. Toluene was recycled by distillation at
room pressure followed by distillation to remove dibutyl oxalate
at 100 °C/1.4 kPa to afford the crude product 7 (125.2 g) as a
faint yellow oil. Yield: 89.1%. GC purity 97.2%. Mass: 274 (M +
H)+. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.0 Hz, 1H),
4.59 (p, J = 7.3 Hz, 1H), 4.29 (t, J = 6.7 Hz, 2H), 4.17 (t, J =
6.6 Hz, 2H), 1.79−1.69 (m, 2H), 1.69−1.59 (m, 2H), 1.52−
1.33 (m, 7H), 1.01−0.89 (m, 6H). 13C NMR (101 MHz,
CDCl3): δ 171.52, 159.85, 155.62, 66.95, 65.56, 48.54, 30.48,
30.29, 19.03, 18.99, 18.12, 13.65.
5-Butoxy-4-methyl Oxazole (10). Ph3P (345.8 g, 1.32
mol) and 7 (125.2 g, 0.44 mol) were dissolved in dichloro-
methane (1.4 L). Into the solution was added TCCA (102.1 g,
0.44 mol) gradually at 0 °C, and the mixture was heated to
reflux for 4 h. After being cooled to room temperature,
triethylamine (133.3 g, 1.32 mol) was added into the solution
drop by drop, and the reaction mixture was stirred until
completion of the reaction (followed by TLC, hexane/ethyl
acetate = 3:1). After the reaction mixture had been washed with
water to remove the triethylamine hydrochloride, the dichloro-
methane was distilled off to afford the crude product 8 as a
brown liquid. A 105 mL portion of aqueous sodium hydroxide
(21.2 g, 0.53 mol) solution was added into the aforementioned
crude product 8 and stirred for 30 min. Then the solvent was
removed under reduced pressure, and the reaction mixture was
cooled to 30 °C. After the pH of the residue was adjusted to 2−
2.5 by the addition of 3 mol/L hydrochloric acid, the mixture
was heated to 70 °C until no carbon dioxide was produced. The
resulting solution was adjusted to pH 8. The wet distillation
process was carried out to collect 0.9 L of distillate.
Dichloromethane (100 mL) was added to the distillate. The
layers were separated, and the organic phase was dried over
Na2SO4, filtered, and evaporated to give 10 (55.2 g, 79.2%)
with 99.2% purity. The distillation residue was cooled to room
temperature, and Ph3PO could precipitate from the water layer.
After the mixture had been filtered and distilled off azeotropi-
cally to remove water content, the Ph3PO (361.4 g, rate of
recovery = 98.5%) was obtained as a gray solid. Mass: 156 (M +
H)+. 1H NMR (400 MHz, CDCl3): δ 7.36 (s, 1H), 4.08 (t, J =
6.5 Hz, 2H), 2.04 (s, 3H), 1.70 (dt, J = 14.7, 6.6 Hz, 2H), 1.47
(dq, J = 14.7, 7.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 154.22, 141.83, 111.72, 74.10, 31.39,
18.88, 13.73, 10.04.
Pyridoxine Hydrochloride (1). A mixture of 10 (55.2 g,
0.35 mol), 6 (628.0 g, 4.42 mol), and calcium oxide (1 g, 17.8
mmol) was kept at 150 1 °C for 12 h. After the unreacted 6
was recycled by distillation under reduced pressure, 95%
ethanol (100 mL) and 0.1% HCl (300 mL) were added and the
mixture was stirred at room temperature for 10 h followed by
heating to 60 °C for 2 h. The ethanol and water were removed
from the reaction mixture at a reduced pressure. The residue
was adjusted to pH 8 by 3 mol/L HCl, and the mixture was
then heated under reflux for 1 h. After the solvent had been
distilled off, a 100 mL portion of 95% ethanol was added and
the mixture was stirred for 10 min. The solvent was then
distilled off, and brown yellow crystals of the crude product 1
(65.7 g) were obtained.
Purification. The crude product 1 (65.7 g) was dissolved in
water (60 mL). Activated carbon (8.0 g) was added, and the
resulting mixture was decolorized at 80 °C for 30 min. The
mixture was filtered, and activated carbon (8.0 g) was added
into the filter liquor. The resulting slurry was decolorized at 80
°C for 30 min once more. After the activated carbon was
removed by filtration, the filtrate was concentrated to give a
residue which was further crystallized using absolute alcohol
(100 mL) to obtain 1 (58.4 g, 80.0%) as white solid. HPLC
purity: 99.4%. Mp = 204.5−205.6 °C (lit. mp 204 °C).7 Mass:
170 (M + H)+. 1H NMR (400 MHz, D2O): δ 7.99 (s, 1H), 4.84
(s, 2H), 4.64 (s, 2H), 2.48 (s, 3H). 13C NMR (101 MHz,
D2O): δ 152.95, 143.12, 141.18, 137.16, 130.43, 58.70, 57.62,
15.00.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pharmlab@zjut.edu.cn. Telephone/fax: (+86)
57188320752.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the National Natural Science Foundation of
China (No. 21176222) and Natural Science Foundation of
Zhejiang province (No. ly2B02020) for financial support.
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