An improved and practical synthesis of tranexamic acid

Article abstract of DOI:10.1021/op500395b

Tranexamic acid 1, a synthetic antifibrinolytic drug with the treatment being considered highly cost-effective in many countries, has been included in the WHO list of essential medicines. In this paper, we designed the synthesis of 1 via a novel seven-step route from the readily available starting material dimethyl terephthalate, performing with 99.6% purity in 59.2% overall yield. During the process, we successfully developed a direct and efficient method for the preparation of key intermediate methyl 4-(acetamidomethyl)benzoate by one-pot hydrogenation and acylation in acetic anhydride using Ni/Al₂O₃ as a catalyst. More importantly, it should be a straightforward and practical way to circumvent the usage of toxic reagents (CrO₃, Cl₂), solvent (CCl₄), and expensive catalyst (PtO₂), etc., that plagued the previous methodologies.

Full text of DOI:10.1021/op500395b

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Full Paper
An Improved and Practical Synthesis of Tranexamic Acid
Yuanyuan Xie, ZhenHua Li, Li Fang, Jian Wang, Liuhong Dong, and Yanna Guo
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500395b • Publication Date (Web): 05 Feb 2015
Downloaded from http://pubs.acs.org on February 9, 2015
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An Improved and Practical Synthesis of
Tranexamic Acid
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Zhenhua Li,1 Li Fang,1 Jian Wang,2 Liuhong Dong,2 Yanna Guo,2 and Yuanyuan Xie*,1
1
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals,
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.
R. China
2
Engineering Research Center of MiddleꢀHigh Pressure Catalytic Hydrogenation of Zhejiang
Province, Taizhou 317300, P. R. China
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For Table of Contents Use Only
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COOCH3
COOK
COCl
CONH2
Ac2O
BTC
NH3 H2O
KOH
MeOH/toluene
COOCH3
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DMF
toluene
COOCH3
COOCH3
COOCH3
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99.1%
93.0% (two steps)
91.9%
H
N
H
N
CN
CH2NH2
H2O
H2 (4.0 MPa)
Ba(OH)2
Ni-Al2O3
H2 (1.0 MPa)
Ru-Al2O3
H2 (7.0 MPa)
O
O
Ac2O
AcONa
EtOH/H2O
THF
MeONa
COOCH3
COOCH3
COOCH3
COOH
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82.1% (two steps)
85.2%
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Abstract
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Tranexamic acid 1, a synthetic antifibrinolytic drug with the treatment being considered highly
cost effective in many countries, has been included in the WHO list of essential medicines. In
this paper, we designed the synthesis of 1 via a novel sevenꢀstep route from the readily available
starting material dimethyl terephthalate, performing with 99.6% purity in 59.2% overall yield.
During the process, we successfully developed a direct and efficient method for the preparation
of key intermediate methyl 4ꢀ(acetamidomethyl)benzoate by oneꢀpot hydrogenation and
acylation in acetic anhydride using Ni/Al2O3 as catalyst. More importantly, it should be a
straightforward and practical way to circumvent the usage of toxic reagents (CrO3, Cl2), solvent
(CCl4) and expensive catalyst (PtO2), etc. that plagued the previous methodologies.
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Introduction
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Tranexamic acid, (transꢀ4ꢀaminomethylcyclohexane carboxylic acid) 1 (Figure 1), a synthetic
ωꢀamino acid with antifibrinolytic properties, was first approved by the FDA in 1986 as an
injection under the brand name of Cyklokapron.1 With the advantage of causing lesser side
effects compared to other antifibrinolytic drugs, 1 is usually used for the treatment of
dysfunctional uterine bleeding, and heavy bleeding associated with uterine fibroids.2 Moreover, 1
is also an important synthetic block for some compounds with potential biological activities.3
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Figure 1. Tranexamic Acid
During recent decades, numerous efforts have been made to find efficient methods to
synthesize 1. A common approach for kiloꢀscale synthesis involves catalytic hydrogenation of 4ꢀ
(aminomethyl)benzoic acid 4 over PtO2 to produce a mixture of cisꢀ and transꢀ4ꢀ
(aminomethyl)cyclohexaneꢀ1ꢀcarboxylic acid, then converted the resulting cisꢀ4ꢀ(aminoꢀ
methyl)cyclohexaneꢀ1ꢀcarboxylic acid into the desired trans isomer 1 by heating the mixture in
an aqueous solution of an acid or alkali (Scheme 1).4 There are two synthetic methods for the
preparation of the intermediate 4. In Method A, 4ꢀmethylbenzonitrile 2 was oxidated by CrO3
gave 4ꢀcyanobenzoic acid 3, followed by hydrogenation over Raney Cobalt to afford 4 with
45.0% yield.5 In Method B, 4ꢀmethylbenzoic acid 5 was chlorinated with Cl2 in the presence of
UV light or using azodiisobutyronitrile as catalyst. 4ꢀ(Chloromethyl)benzoic acid 6 was purified
by rectification and it was then ammonolyzed in the presence of urotropine to afford 4 with
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23.0% yield. It is worth mentioning that, during Method B, byꢀproducts 7 and 8 were formed and
they were quite difficult to separate.6 Additionally, containing both carboxyl and amino group,
the success of purification of 4 was highly dependent on the pH value, making the postꢀprocess
difficult to handle.
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Scheme 1. Original Methods for the Synthesis of Tranexamic Acid 1a
aReactions and conditions: (a) (1) AcOH, H2SO4, CrO3, 5ꢀ10 °C, 2 h, 25 °C, 1 h; (2) ice water,
NaHCO3; (3) HCl; (b) Raney Cobalt, 28.0% ammonia aqueous, H2O, H2 (0.3 MPa), 25 °C, 3 h;
(c) UV, Cl2, 100 °C, 3 h; (d) urotropine, H2O, NH3, 50 °C, 4 h; (e) (1) PtO2, H2SO4/H2O, H2
(0.15 MPa), 40 °C; (2) 90 °C, BaCO3, H2O; (3) Ba(OH)2, H2O/EtOH, H2 (2.0 MPa), 200 °C, 14 h;
(4) H2SO4/H2O.
Those methods mentioned above suffered from disadvantages such as: usage of expensive
metal catalysts renders the process economically nonviable and industrially unattractive.
Furthermore, some toxic reagents such as CrO3, Cl2 and poisonous solvents such as CCl4 have a
detrimental impact on the environment and human health. Although a few other existing
approaches have been documented in the literature, they were either cost ineffective or
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environment unfriendly, making those methods less easy to implement on a large scale.7 These
triggered our investigation of the process. Herein, we report an improved, sevenꢀstep synthesis of
1 from the readily available starting material dimethyl terephthalate (9, 1,4ꢀdimethyl benzeneꢀ
1,4ꢀdicarboxylate), which generates the title compound 1 with 99.6% purity in 59.2% overall
yield (Scheme 2).
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Scheme 2. Optimized Synthesis of Tranexamic Acid
Results and discussion
Preparation of potassium 4-(methoxycarbonyl)benzoate (10).
In the reported procedure for the conversion of 9 to 10, 1 equiv of potassium hydroxide was
added to methanol, the mixture was heated to reflux and gained 73.1ꢀ91.0% yield.8 Nevertheless,
we clearly observed a yield decrease of 10 when we increased the loading of 9 (Table 1, entries
1ꢀ2). The possible reason is that 10 precipitated from methanol as thick suspension which made
the stirring quite inefficient and resulted heat accumulation with increased formation of the byꢀ
product potassium terephthalate 16 (Scheme 3).
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Scheme 3. Selective Hydrolysis of 9 to Yield 10
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Surprisingly, increasing the volume of methanol had little effect on improving the selectivity.
A possible reason is that the excess of methanol dissolved 10 and made it easier to hydrolyse
further. Thus, we assumed that adding an antisolvent might work. On the basis of the aboveꢀ
mentioned observations, a trial run was performed on 100 gꢀscale: a mixture of 9 and 1 equiv of
potassium hydroxide in the presence of a mixed solvents of methanol and toluene with 1:1.1
volume ratio (Table 2, entry 3) afforded crude 10 with 97.8% purity in 99.1% yield (containing
2.1% of 16).
Table 1. Monohydrolysis of Dimethyl Terephthalate 9 in Methanola
Purity of crude 10c,d
Entry
Methanol/mL
Yield of crude 10b/%
10/%
96.6
86.3
87.8
89.4
16/%
2.8
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4
50e
98.8
98.9
92.5
86.8
1043f
1143g
2000h
13.6
12.0
10.6
aReaction conditions: 9 (0.52mol), 9: KOH = 1:1, 45ꢀ50 °C. bIsolated yield of crude 10.
cCrude 10 containing 10 and 16. dThe analysis of crude 10 based on HPLC. e9 (0.03mol), 9:
KOH:MeOH = 1:1:50, 45ꢀ50 °C. f9:MeOH = 1: 50. g9:MeOH = 1: 55. h9: MeOH = 1: 96.
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Table 2. Monohydrolysis of Dimethyl Terephthalate 9 in Methanol and Toluenea
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Purity of crude 10c,d
Volume ratio
Yield of
crude 10b/%
97.2
Entry
Methanol/mL
methanol:toluene
10/%
89.9
95.8
97.8
16/%
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4.0
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97.6
1:1.1
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b
aReaction conditions: 9 (0.52mol), 9: KOH:MeOH = 1:1:50, 45ꢀ50 °C. Isolated yield of crude
10. cCrude 10 containing 10 and 16. dThe analysis of crude 10 based on HPLC.
Conversion of the intermediate 10 to methyl 4-cyanobenzoate (13).
The subsequent transformation of intermediate 10 to methyl 4ꢀ(chlorocarbonyl)benzoate 11,
methyl 4ꢀcarbamoylbenzoate 12 and methyl 4ꢀcyanobenzoate 13 were carried out by
conventional chemistry without any difficulties (Scheme 4). The quantitative transformation of
10 to 11 was achieved by using bis(trichloromethyl)carbonate (BTC), which is more
environmental friendly than thionyl chloride.9 Then the resulting solid 11 reacted with aqueous
ammonia directly without other solvent to produce 12 in 93.0% yield. Crude 13 was obtained in
refluxing acetic anhydride serving both as dehydration agent and as solvent in 91.9% yield from
12, without using other complicated dehydrating agents.10 Then our focus shifted to the more
troublesome step, the formation of methyl 4ꢀ(acetamidomethyl)benzoate 14.
Scheme 4. Preparation of 13 from 10
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Preparation of methyl 4-(acetamidomethyl)benzoate (14).
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There have been numerous publications on the methods of hydrogenating nitrile compounds,
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from which it is known that hydrogenation of 13 to primary amine with good yields always
requires some complicated or expensive catalysts such as Pd/C, PtO2, Rh.11 The common
approach for hydrogenation of nitrile compound over Raney nickel in the presence of ammonia
did not work here. The reaction mixture contained 44.3% methyl 4ꢀ(aminomethyl)benzoate 18,
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21.9%
4ꢀ(aminomethyl)benzoic
acid
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methyl
4ꢀ((4ꢀ
(aminomethyl)benzamido)methyl)benzoate 20 and trace amounts of unidentified side products as
detected by LCꢀMS. We reckoned that under basic condition, the methyl ester group of 13 would
be hydrolyzed easily to generate 19, besides, 20 were formed by the dimerization of 18. But as
we knew that the basic condition was essential to prevent the formation of higher amines
(Scheme 5).12
Scheme 5. The Formation of Byꢀproducts
Facing such a predicament, we turned our attention to acidic condition.13 The reaction went
smoothly using catalyst NiꢀAl2O3 with anhydrous sodium acetate as cocatalyst and acetic
anhydride as solvent at 50 °C under hydrogen pressure of 1.0 MPa (Scheme 6). We attributed the
excellent result to the fact that the resulting primary amine was quickly acylated therefore
avoided the possible side reactions. Additionally, such an acidic condition also prevented the
methyl ester group from hydrolysis. The reaction mixture was distilled under reduced pressure to
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recover acetic acid and acetic anhydride, and the residue with a high degree of purity can be used
in the next reaction directly.
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Scheme 6. Hydrogenation and Acylation of 13 in One Step
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Preparation of trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (1).
Compound 14 with acetamide group was stable enough to be efficiently hydrogenated under
high pressure (7.0 MPa) with relatively economical catalyst RuꢀAl2O3 instead of expensive
catalysts such as RuꢀRhꢀPd/C, Ru/PDMF in 82.1% yield (calculated on 13) (Scheme 7).14
Scheme 7. Preparation of 1
Based on the reported method of isomerization of cis isomer into trans isomer,4b we attempted
to combine hydrolysis and isomeration of 15 in one step. The mixture of 15 and Ba(OH)2 with
ethanol and water as solvents was transformed smoothly to 1 at 250 °C and under hydrogen
pressure of 4.0 MPa. After adjusting the pH value and clarification, 1 was obtained with 99.6%
purity in 85.2% yield.
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Conclusions
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An improved and costꢀefficient synthetic method for practical synthesis of 1 was developed in
seven steps with overall yield of 59.2%. One of the key steps involved the transformation of 13
to the corresponding acylated primary amine 14 was accomplished by a process of oneꢀpot
hydrogenation and acylation. The resulting intermediate 14 was subsequently hydrogenated with
inexpensive catalyst RuꢀAl2O3 to generate 15 in excellent yield and purity. This novel synthetis
route has significant advantages, in terms of low cost, simple downstream processing and
environmental friendliness, which make it more attractive for pharmaceutical industry.
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Experimental section
General Methods. All solvents and reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The reactions were monitored by analytical thinꢀ
layer chromatography (TLC) on silica gel GF254 coated glass plates and visualized under UV
light (254 and 365 nm). Melting points (mp) were obtained on a digital melting point apparatus
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and uncorrected. H and 13C NMR were recorded at 400 and 100 MHz, respectively. The
chemical shifts are reported as δ ppm relative to tetramethylsilane (TMS). Mass spectra were
measured with a HRMSꢀAPCI instrument or a lowꢀresolution MS instrument using ESI
ionization. The HPLC analysis data is reported in area %, not adjusted to weight %.
Preparation of potassium 4-(methoxycarbonyl)benzoate 10. To a 2ꢀL roundꢀbottomed flask
was added potassium hydroxide (28.8 g, 0.52 mol), methanol (1043 mL, water content 0.27%)
and toluene (1147 mL). The mixture was stirred until dissolution, dimethyl terephthalate (9,
100.0 g, 0.52 mol) was added at 45 °C, and the mixture was stirred at 45 °C to 50 °C for 5.5 h.
Then the mixture was distilled under reduced pressure to cycled solvents, the residue was
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washed with dichloromethane (1000 mL) to remove the rest dimethyl terephthalate. The washed
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filter cake was dried at 50 °C to afford a white solid 10 (112.3 g, yield 99.1%, HPLC > 97.8%).
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Preparation of methyl 4-(chlorocarbonyl)benzoate 11. To a stirred mixture of potassium 4ꢀ
(methoxycarbonyl)benzoate (10, 106.8 g, 0.49 mol) and DMF (11.6 g, 0.16 mol) in toluene (750
mL) was added a solution of bis(trichloromethyl) carbonate (BTC, 59.3 g, 0.20 mol) in toluene
(150 mL) at 60 °C over a period of 40 min. The reaction mixture was heated to reflux. After the
completion of the reaction (monitored by TLC), the reaction mixture was cooled to room
temperature, and filtered to remove potassium chloride. The resulting solution was concentrated
to dryness under reduced pressure to give 11 as a light brown solid on cooling. This material was
used directly in the next step; mp = 53.3ꢀ54.1 °C (lit. mp 54ꢀ55 °C).15
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Preparation of methyl 4-carbamoylbenzoate 12. To a stirred solution of conc. aqueous
ammonia (453 mL, 6.00 mol) was added the crude methyl 4ꢀ(chlorocarbonyl)benzoate (11, 97.3
g, 0.49 mol) in portions at 0 °C over a period of 30 min. The mixture was stirred for 1 hour at
room temperature and then filtered, the filter cake was washed with brine and crystallized from
methanol, and dried at 50 °C to afford a white crystalline solid 12 (81.6 g, yield 93.0%,
calculated on 10, HPLC > 99.8%); mp = 204.6ꢀ206.0 °C (lit. mp 201ꢀ203 °C);16 1H NMR (400
MHz, DMSOꢀd6) δ 3.87 (s, 3H), 7.57 (br s, 1H), 7.96ꢀ8.02 (q, J = 8.4 Hz, 4H), 8.14 (br s, 1H);
13C NMR (100 MHz, DMSOꢀd6) δ 52.3, 127.6 (2C), 128.8 (2C), 131.5, 138.1, 165.4, 166.7;
Mass (ESI+) m/z 180.1 (M+H)+.
Preparation of methyl 4-cyanobenzoate 13. To a 500 mL roundꢀbottomed flask was added
methyl 4ꢀcarbamoylbenzoate (12, 86.0 g, 0.48 mol) and acetic anhydride (490.0 g, 4.80 mol).
The mixture was stirred at refluxing temperature. After the completion of the reaction (monitored
by TLC), the mixture was distilled to recycle acetic acid and the excess acetic anhydride,
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respectively. The residue was crystallized from petroleum to give a white crystalline solid 13
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(71.1 g, yield 91.9%, HPLC > 99.0%); mp = 62.4ꢀ63.1 °C (lit. mp 65ꢀ66 °C);17 1H NMR (400
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MHz, CDCl3) δ 3.95 (s, 3H), 7.73 (d, J = 8.4 Hz, 2H), 8.12 (d, J = 8.0 Hz, 2H); C NMR (100
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MHz, CDCl3) δ 52.7, 116.2, 117.8, 129.9 (2C), 132.0 (2C), 133.7, 165.1; Mass (ESI+) m/z 184.0
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(M+Na)+.
Preparation of methyl 4-(acetamidomethyl)benzoate 14. A mixture of methyl 4ꢀ
cyanobenzoate (13, 30.6 g, 0.19 mol), NiꢀAl2O3 (6.0 g, nickel content > 45%), anhydrous sodium
acetate (22.1 g, 0.27 mol) and acetic anhydride (220 mL) was stirred at 50 °C under hydrogen
pressure of 1.0 MPa for 2.5 hours. Then the mixture was filtered hot and the filtrate was distilled
to recycle acetic acid and the excess acetic anhydride, respectively. The residue formed a white
solid 14 and was used directly in the next step; mp = 112.5ꢀ113.6 °C (lit. mp 110ꢀ111 °C);18 1
H
NMR (400 MHz, CDCl3) δ 2.05 (s, 3H), 3.90 (s, 3H), 4.47 (d, J = 5.9Hz, 2H), 6.02 (s, 1H), 7.31
13
(d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H); C NMR (100 MHz, CDCl3) δ 23.2, 43.2, 52.1,
127.3 (2C), 129.0, 129.7 (2C), 143.4, 166.5, 169.9; Mass (ESI+) m/z 208.1 (M+Na)+.
Preparation of a mixture of cis- and trans-methyl 4-(acetamidomethyl)cyclohexane-1-
carboxylate 15. A mixture of methyl 4ꢀ(acetamidomethyl)benzoate (14, 33.2 g, 0.16 mol), Ruꢀ
Al2O3 (3.3 g), sodium methoxide (0.2 g, 0.004 mol) and THF (280 mL) was stirred at 130 °C
under hydrogen pressure of 7.0 MPa for 7 hours. Then the mixture was filtered hot and the
filtrate was distilled to recycle THF, the residue formed a light yellow oil 15 (33.3 g, yield 82.1%,
calculated on 13, HPLC: trans:cis = 1:3); Mass (ESI+) m/z 236.0 (M+Na)+.
Preparation of trans-4-(aminomethyl)cyclohexane-1-carboxylic acid 1. A mixture of cisꢀ and
transꢀmethyl 4ꢀ(acetamidomethyl)cyclohexaneꢀ1ꢀcarboxylate (15, 29.8 g, 0.14 mol, trans:cis =
1:3), ethanol (100 mL), water (200 mL) and Ba(OH)2 (97.8 g, 0.31 mol) was stirred at 250°C
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under hydrogen pressure of 4.0 MPa for 7.5 hours. Then the reaction mixture was put into a
roundꢀbottomed flask with water (200 mL) at 70 °C, the pH was adjusted to 6.3 using carbon
dioxide. Then the mixture was cooled to room temperature and filtered to remove barium
carbonate. The filtrate pH was adjusted to 5.3 using sulphuric acid, then filtered and washed with
water. The filtrate and water were combined and decolorized with activated charcoal (0.5 g) at
100 °C for 1 hour, then cooled to room temperature and filtered. The filtrate was distilled until
the liquid volume was concentrated to 50 mL, then ethanol (50 mL) was added to crystallize at
10 °C. The crystals were filtered and washed with ethanol and dried to obtain a white crystalline
solid 1 (18.7 g, yield 85.2%, HPLC > 99.6%); mp = 384.1ꢀ385.9 °C (decomp.) (lit. mp 384ꢀ
388 °C (decomp.));19 1H NMR (400 MHz, D2O + DMSOꢀd6) δ 0.73ꢀ1.35 (m, 4H), 1.41ꢀ1.58 (m,
1H), 1.59ꢀ1.86 (m, 4H), 1.87ꢀ2.01 (m, 1H), 2.69 (d, J = 7.0 Hz, 2H); 13C NMR (100 MHz, D2O +
DMSOꢀd6) δ 29.3 (2C), 29.4 (2C), 35.4, 45.2, 46.7, 185.4; Mass (ESI+) m/z 158.0 (M+H)+.
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Acknowledgment
We are grateful for the National Natural Science Foundation of China (No. 21376221 and
21276238) and Natural Science Foundation of Zhejiang province (No. LY13B020015) for
financial support. Cooperation from the colleagues analytical research and development is highly
appreciated.
Supporting Information Available
1
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Mass, H and C NMR spectra, HPLC and LCꢀMS chromatograms. This material is available
free of charge via the Internet at http://pubs.acs.org.
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