JPH0977726A - Production of tranexamic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To readily obtain clinically important high-purity tranexamic acid having strong antiplasmin activity and important without performing operations to separate the compound from isomers produced when carrying out the reaction. SOLUTION: Either of hydroxyl groups in trans-1,4-cyclohexanedimethanol (preferably having >=95% diastereomeric purity) is converted into an azide to introduce the azido group thereinto. The other hydroxymethyl group is then oxidized to introduce carboxyl group and the azido group is further reduced into amino group. Thereby, tranexamic acid which is the objective compound is obtained. The formation of the azido group is preferably carried out by reacting the trans-1,4-cyclohexanedimethanol with a sulfonyl chloride such as methanesulfonyl chloride in an amount of preferably 0.5-1.5 equiv. based on the objective compound in the presence of a base such as triethylamine in a solvent such as dichloromethane, providing a monosulfonic ester and then reacting the resultant monosulfonic ester with sodium azide, etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing tranexamic acid, which is characterized in that one hydroxyl group of trans-1,4-cyclohexanedimethanol is aminated and the other hydroxymethyl group is oxidized. The present invention relates to a method for producing tranexamic acid.

[0002]

BACKGROUND OF THE INVENTION Tranexamic acid [trans-4-aminomethylcyclohexanecarboxylic acid] is a clinically important compound having a strong antiplasmin activity. However, since its diastereomeric cis-4-aminomethylcyclohexanecarboxylic acid does not exhibit activity as an antiplasmin reagent, tranexamic acid free of this cis isomer is required.

Conventional tranexamic acid is, for example,
(1) p-Acetylaminomethylbenzoic acid was reduced under high pressure using Raney nickel to obtain a cyclohexane derivative, which was hydrolyzed to a deacetylated product, and the cis-trans mixture was used as a copper salt or a tosyl salt to obtain a difference in crystallinity. (2) p-trinitrile is oxidized with chromic acid to obtain p-cyanobenzoic acid, which is reduced under moderate pressure with Raney-cobalt to give p-tribenzoic acid. −
A method has been proposed in which aminomethylbenzoic acid is obtained, and further, reduction is carried out under atmospheric pressure using platinum oxide in glacial acetic acid and further cis-trans is separated in the same manner as described above. It is obtained as a trans-cis mixture because it is constructed by the reduction of redox.
It was difficult to reuse the cis isomer in addition to the separation operation required.

Therefore, an object of the present invention is to provide a method for producing tranexamic acid, which makes it possible to obtain tranexamic acid in a high yield and a high purity without requiring a separation operation of a cis form and a trans form. is there.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to find a method for producing diastereomerically pure tranexamic acid, and as a result, industrially high purity products can be easily obtained. Using trans-1,4-cyclohexanedimethanol as a starting material,
The inventors have found that the above object can be achieved by aminating one hydroxyl group of 4-cyclohexanedimethanol and oxidizing the other hydroxymethyl group to introduce a carboxyl group, and arrived at the present invention.

That is, according to the present invention, one hydroxyl group of trans-1,4-cyclohexanedimethanol is aminated,
The present invention provides a method for producing tranexamic acid, which comprises oxidizing a hydroxymethyl group on the other side to introduce a carboxyl group.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing tranexamic acid of the present invention will be described in detail below.

The trans-1,4-cyclohexanedimethanol used in the present invention has a diastereomer purity of preferably 90% or more, more preferably 95% or more. Here, the transformer-1,4-
The purity of cyclohexanedimethanol has a great influence on the purity of tranexamic acid in the final product, and therefore it is required that the purity is sufficiently high.

As an industrial method for producing 1,4-cyclohexanedimethanol, for example, there is a method in which 1,4-cyclohexanedicarboxylic acid dimethyl ester is hydrogenated in the presence of a copper chromium catalyst and then distilled. However, in this case, it is obtained as a mixture of about 70% trans form and about 30% cis form.

As a method for obtaining a pure trans form from this mixture, (1) a cis-trans mixture is subjected to trimethylsilylation and chromatographed on a diglycerol column, (2) the cis-trans mixture is subjected to a cyclodextrin-bonded silica gel column. , (3) a cis-trans mixture is converted to dibenzoate, selectively crystallized by utilizing the difference in crystallinity and then hydrolyzed again, (4) cis-trans There have been proposed methods such as a method of obtaining a mixture by distillation in the presence of an alkali, (5) a method of transesterification using lipase, and a method of separating and purifying the ester compound by conversely converting it to metallinosis. A highly pure trans form can be obtained by these methods. Further, the cis-isomer, cis-1,4-cyclohexanedimethanol separated here, can be isomerized and reused by heat treatment in the presence of an alkali.

The method for aminating the hydroxyl group of the above-mentioned trans 1,4-cyclohexanedimethanol is not particularly limited, but a method of azidation followed by reduction is preferable because the operation is simple.

As a method for azidating one hydroxyl group of the above trans-1,4-cyclohexanedimethanol, for example, methanesulfonic acid chloride, benzenesulfonic acid chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane. , P-toluenesulfonic acid chloride (tosyl chloride) or the like to give a monosulfonic acid ester, which is then reacted with sodium azide, lithium azide or the like.

As the solvent used in the azidation method, it is preferable to use a solvent having a relatively low polarity such as dichloromethane, chloroform and acetonitrile, and a solvent having a high polarity such as dimethylformamide and dimethylsulfoxide. When the above solvent is used, the dehydration reaction has priority and the reaction is difficult to proceed.

When the above sulfonic acid chloride is used in an excess equivalent amount with respect to the hydroxyl group to be reacted with trans-1,4-cyclohexanedimethanol, the monosulfonic acid ester of trans-1,4-cyclohexanedimethanol is used. Although the yield can be improved, a large amount of by-product trans-1,4-cyclohexanedimethanol diester is also generated, and the yield of trans-1,4-cyclohexanedimethanol monoester is low when an excessively small amount is used. However, the production of by-product trans-1,4-cyclohexanedimethanol diester is small. Here, unreacted trans-1,4-cyclohexanedimethanol can be reused. Therefore, for industrial application, the sulfonic acid chloride is preferably 0.3 to 1.7 equivalents, more preferably 0.5 equivalent to the trans-1,4-cyclohexanedimethanol. It is desirable to use it in an amount of up to 1.5 equivalents because it produces less by-products and a higher yield.

Unreacted trans-1,4-cyclohexanedimethanol, monotosyl-trans-1,4
The above monoester such as cyclohexanedimethanol and the above diester such as by-product ditosyl-trans-1,4-cyclohexanedimethanol can be easily separated by a column, but in some cases, the final product can be separated without separation in this state. It is also possible to separate at any stage.

Next, as a method for reducing the azido group to an amino group, any reducing method can be used.
A catalytic hydrogen reduction method using a reduction catalyst such as palladium carbon is preferable.

As a method of oxidizing the hydroxymethyl group of trans-1,4-cyclohexanedimethanol to introduce a carboxyl group, any oxidation method can be used, but chromium (IV) oxide, permanganate A method using an oxidizing agent such as potassium is preferable.

The step of reducing the azido group to an amino group may be carried out either before or after the formation of the carboxyl group, but is preferably carried out after the formation. That is, one hydroxyl group is azidated to produce a novel intermediate, trans-p-azidomethylcyclohexanemethanol, and then the other hydroxyl group is oxidized to introduce a carboxyl group, and then the azido group is reduced to give an amino group. It is preferable to carry out the reactions in the order of introducing.

[0019]

Next, the present invention will be described with reference to examples.
The invention is not limited by the examples below.

Example 1 Preparation of monotosyl-trans-1,4-cyclohexanedimethanol 216 mg of trans-1,4-cyclohexanedimethanol (purity 99% or more) was dissolved in 15 ml of methylene chloride, and 200 mg of p-toluenesulfonyl chloride, triethylamine. 0.29 ml and 4-dimethylaminopyridine 9 mg were added, the mixture was stirred at room temperature for 24 hours, saturated saline 10 ml was added, and the mixture was extracted 3 times with diethyl ether 30 ml. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to silica gel column chromatography 30 g, and from the fraction of ethyl acetate-hexane (volume ratio 1: 3), ditosyl-trans-1,4-cyclohexanedimethanol 64 mg (9%), ethyl acetate-hexane (volume ratio). 1: 1) stream monotosyl-
Trans-1,4-cyclohexanedimethanol 209
mg (47%), ethyl acetate-hexane (4: 1) stream-1,4-cyclohexanedimethanol 9
Obtained 4 mg (44%). Here, the unreacted trans-1,4-cyclohexanedimethanol was reused and the reaction was repeated. Therefore, the yield of the finally obtained monotosyl-trans-1,4-cyclohexanedimethanol (yield with respect to the raw material trans-1,4-cyclohexanedimethanol) was 84%.

Next, the obtained ditosyl-trans-1,
Infrared spectroscopic analysis (IR), ¹ H-NMR analysis, ¹³ C-NMR analysis of 4-cyclohexanedimethanol, monotosyl-trans-1,4-cyclohexanedimethanol and raw material trans-1,4-cyclohexanedimethanol, Measurements such as low resolution mass spectrum (MS) and high resolution mass spectrum (HRMS) are shown.

(Monotosyl-trans-1,4-cyclohexanedimethanol) IR (neat) ν: 3380, 1360, 1174c
^{m -1; 1 H-NMR (} 300MHz, CDC1 3) δ:
0.82-1.02 (m, 4H), 1.40 (br s, 1
H), 1.61 (br s, 1H), 1.67-1.88
(M, 4H), 2.00 (br s, 1H), 2.45
(S, 3H), 3.41 (d, 2H, J = 5.9H
z), 3.82 (d, 2H, J = 6.6 Hz), 7.3
5 (d, 2H, J = 8.8 Hz), 7.77 (d, 2
H, J = 8.1 Hz); ¹³ C-NMR (75 MHz, C
DC1 ₃ ) δ: 21.60 (q), 28.39 (t),
28.42 (t), 37.30 (d), 40.06
(D), 68.09 (t), 75.24 (t), 12
7.75 (d), 129.76 (d), 132.86
(S), 144.66 (s); MS m / z: 298.
(M ⁺ ), 95 (100%); HRMS Calcd
C ₁₅ H ₂₂ O ₄ S: 298.1239 (M ⁺ ), Foun
d: 298.1229; Anal. Calcd C ₁₅ H
₂₂ O ₄ S: C, 60.38; H, 7.43; S, 10.
74. Found: C, 60.23; H, 7, 36; S
10.80

(Ditosyl-trans-1,4-cyclohexyl
Xanthimethanol) mp 162-163 ° C; IR (Nujol) ν: 136
0.1163 cm^-1; ¹H-NMR (300 MHz, C
DCl_Three) Δ: 0.80-1.00 (m, 4H), 1.
45-1.80 (m, 6H), 2.45 (s, 6H),
3.79 (d, 4H, J = 6.6Hz), 7.34
(D, 4H, J = 8.1 Hz), 7.76 (d, 4H,
J = 8.4 Hz);¹³C-NMR (75 MHz, CDC
l_Three) Δ: 21.70, 28.09, 37.01, 7
4.86, 127.84, 129.84, 133.0
1, 144.72; MS m / z: 452 (M⁺), 1
09 (100%); HRMS Calcd C_{twenty two}H₂₈O
₆S₂: 452.1328 (M⁺), Found: 45
2.1324

(Trans-1,4-cyclohexanedimethanol) mp 62-64 ° C .; IR (Nujol) ν: 3388c
m ⁻¹ ; ¹ H-NMR (300 MHz, CDCl ₃ ) δ:
0.89-1.07 (m, 4H), 1.35-1.55
(M, 2H), 1.62 (br s, 2H), 1.74-
1.96 (m, 4H), 3.46 (d, 4H, J = 6.
2 Hz); ¹³ C-NMR (75 MHz, CDCl ₃ ).
δ: 28.96 (t), 40.66 (d), 68.62
(T); MS m / z: 126 (M ⁺ -18), 95 (1
_{00%); HRMS CalcdC 8 H} 14 O: 126.
1045 (M ⁺ -18), Found: 126.100.
7; Anal. _{Calcd C 8 H 16 O 2:} C, 66.
63; H, 11.18. Found: C, 66.46;
H, 11.13.

Preparation of trans-4-azidomethylcyclohexanemethanol 320 mg of monotosyl-trans-1,4-cyclohexanedimethanol was dissolved in 5 ml of N, N-dimethylformamide, and 140 mg of sodium azide was added to the mixture.
After stirring at C for 7 hours, 10 ml of water was added, and the mixture was extracted 3 times with 10 ml of diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was applied to 30 g of silica gel column chromatography, and 168 mg of the desired product was obtained from the fraction of ethyl acetate-hexane (volume ratio 1: 1).
(98%) was obtained.

Next, infrared spectroscopic analysis (IR) of the obtained trans-4-azidomethylcyclohexanemethanol,
¹ H-NMR analysis, ¹³ C-NMR analysis, low resolution mass spectrum (MS) and high resolution mass spectrum (HR
MS) etc. are shown.

(Trans-4-azidomethylcyclohexanemethanol) IR (neat) v: 3344,2092 cm ^-1 ; ¹ H
-NMR (300 MHz, CDC1 ₃ ) δ: 0.88-
1.10 (m, 4H), 1.36-1.65 (m, 3
H), 1.74-1.95 (m, 4H), 3.14.
(D, 2H, J = 7.0 Hz), 3.46 (d, 2H,
J = 6.2 Hz); ¹³ C-NMR (75 MHz, CDC
1 ₃ ) δ: 28.70 (t), 29.83 (t), 3
8.06 (d), 40.09 (d), 57.73
(T), 67.95 (t); MS m / z: 169 (M
⁺ ), 95 (100%); HRMS Calcd C ₈
H ₁₅ N ₃ O: 169.1215 (M ⁺ ), Found:
169.1192; Anal. CalcdC ₈ H ₁₅ N ₃
O: C, 56.78; H, 8.93; N, 24.83.
Found: C, 56.68; H, 9.04; N, 2
4.63.

Production of trans-4-azidomethylcyclohexanecarboxylic acid 2.75 g of chromium (VI) oxide was dissolved in 5 ml of water, and 7.0 ml of 50% sulfuric acid was added dropwise thereto under ice cooling. This was added dropwise under ice cooling to a solution of 1.16 g of trans-4-azidomethylcyclohexanemethanol dissolved in 10 ml of acetone, and the mixture was stirred at room temperature for 3 hours, and then isopropanol 1 was added.
0 ml was added. Then, the solvent was distilled off under reduced pressure, 10 ml of water was added to the residue, and the mixture was extracted 3 times with 30 ml of chloroform. Further, the solvent was distilled off under reduced pressure, 30 ml of diethyl ether was added to the residue, and a 10% aqueous sodium hydroxide solution 3
Extract 3 times with 0 ml. The aqueous layer was acidified with sulfuric acid and then extracted three times with 50 ml of chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 109 g (87%) of the target compound as a colorless solid. Recrystallization from hexane gave colorless scale crystals.

Next, the melting point and infrared spectroscopic analysis of the obtained trans-4-azidomethylcyclohexanecarboxylic acid (I
R), ¹ H-NMR analysis, ¹³ C-NMR analysis, low resolution mass spectrum (MS) and high resolution mass spectrum (HRMS) are shown.

(Trans-4-azidomethylcyclohexyl
Sancarboxylic acid) mp69-70 ° C; IR (Nujol) ν: 2096,
1690cm^-1;¹H-NMR (300 MHz, CDC
l_Three) Δ: 0.87-1.06 (m, 2H), 1.29
-1.62 (m, 3H), 1.74-1.88 (m, 2)
H), 1.94-2.07 (m, 2H), 2.21 (t
t, 1H, J = 3.5, 12.1Hz), 3.09
(D, 2H, J = 6.2 Hz), 11.37 (br s, 1
H);¹³C-NMR (75 MHz, CDCl_Three) Δ: 2
8.15 (t), 29.51 (t), 37.35
(D), 42.91 (d), 57.61 (t), 18
2.31 (s); MS m / z: 183 (M⁺), 81
(100%); HRMS Calcd C ₈H₁₃N_ThreeO
₂183.1008 (M⁺), Found: 183.
0986; Anal. Calcd C₈H₁₃N_ThreeO₂:
C, 52.45; H, 7.15; N, 22.94, Fo
und: C, 52.51; H, 7.10; N, 22.7.
3.

Preparation of tranexamic acid / hydrochloric acid Trans-4-azidomethylcyclohexanecarboxylic acid (190 mg) was dissolved in 1% hydrochloric acid (30 ml), 10% palladium carbon (10 mg) was added, and the mixture was stirred at room temperature for 10 hours under a hydrogen stream. The reaction mixture was filtered through Celite, and the solution was evaporated under reduced pressure to obtain 178 mg (89%) of hydrochloride of tranexamic acid as a colorless solid. This was recrystallized from a water-acetone system to obtain 141 mg (70%) of pure tranexamic acid hydrochloride as colorless needle crystals.

Next, infrared spectroscopic analysis (IR) of the obtained tranexamic acid / hydrochloride, melting point, ¹ H-NMR analysis, ¹³ C
-NMR measurements, low resolution mass spectra (MS) and high resolution mass spectra (HRMS) measurements are shown.
From the analytical values, it was possible to obtain extremely high-purity tranexamic acid (hydrochloride).

(Tranexamic acid / hydrochloride) mp 236-239 ° C .; IR (Nujol) ν: 292
6,1707 cm^-1; ¹H-NMR (300 MHz, D
₂O) δ: 0.99-1.19 (m, 2H), 1.31
-1.52 (m, 2H), 1.59-1.76 (m, 1
H), 1.79-1.94 (m, 2H), 1.95-
2.11 (m, 2H), 2.27-2.44 (m, 1
H), 2.88 (d, 2H, J = 7.3 Hz);¹³C-
NMR (75 MHz, D₂O) δ: 27.92, 28.
67, 34.88, 42.72, 45.02, 181.
03; MS m / z: 157 (M⁺-36), 36 (1
00%); HRMS Calcd C₈H_FifteenNO₂: 1
57.1103 (M⁺-36), Found: 157.
1131.

From the examples, extremely pure tranexamic acid (hydrochloride) was obtained by aminating one hydroxyl group of trans-1,4-cyclohexanedimethanol and oxidizing the other hydroxyl group to introduce a carboxylic acid group. It is clear that

[0035]

EFFECTS OF THE INVENTION According to the production method of the present invention, tranexamic acid can be obtained in a high yield and a high purity without the need to separate the cis form and the trans form.

Claims (3)

[Claims] 1. A method for producing tranexamic acid, which comprises aminating one hydroxyl group of trans-1,4-cyclohexanedimethanol and oxidizing the other hydroxymethyl group to introduce a carboxyl group. 2. The method for producing tranexamic acid according to claim 1, wherein the amination method comprises azidating and reducing the hydroxyl group. 3. The azido group is introduced by aziding one hydroxyl group of the trans-1,4-cyclohexanedimethanol, and then the other hydroxymethyl group is oxidized to introduce a carboxyl group. The method for producing tranexamic acid according to claim 1 or 2, wherein the amino group is reduced.