Preparation method of tranexamic acid

Abstract

The invention relates to a preparation method of tranexamic acid, which comprises the following steps: by taking p-halobenzonitrile and nitromethane as raw materials, carrying out SNAr reaction in the presence of alkali to obtain p-nitromethylbenzonitrile, carrying out catalytic hydrolysis with sulfuric acid to obtain p-nitromethylbenzoic acid, and carrying out hydrogenation reaction on the p-nitromethylbenzoic acid and hydrogen under the catalysis of platinum black and sulfuric acid to generate 4-aminomethylcyclohexanoic acid. And carrying out conversion reaction under the catalysis of sulfuric acid to obtain a tranexamic acid crude product, and refining to obtain a tranexamic acid finished product. The process is easily available in raw materials, few in synthesis steps and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of tranexamic acid. Background Art

[0002] Tranexamic acid (the structural formula is shown as the following 1), chemically named trans-4-aminomethylcyclohexanecarboxylic acid, also known as tranexamic acid, is used as a hemostatic drug. Its pharmacological effects are as follows: 1) Antifibrinolytic effect: Tranexamic acid can strongly adsorb to the lysine binding site of the fibrin affinity site on plasmin and plasminogen, inhibiting the binding of plasmin and plasminogen to fibrin, thereby strongly inhibiting fibrinolysis caused by plasmin; 2) Hemostatic effect: Tranexamic acid can inhibit fibrinolysis to achieve hemostasis. Clinically, it can be used for: trauma or surgical bleeding in organs rich in plasminogen activators such as prostate, urethra, lung, brain, uterus, adrenal gland, thyroid gland, liver, etc.; used as an antagonist of thrombolytic drugs such as tissue-type plasminogen activator, streptokinase, and urokinase; fibrinolytic bleeding caused by induced abortion, placental abruption, stillbirth, and amniotic fluid embolism; used to prevent or reduce bleeding in hemophilia patients lacking factor VIII or factor IX after tooth extraction or oral surgery, etc.

[0003] In the existing literature, there are the following synthesis routes for tranexamic acid.

[0004] Route 1 (CN 111574388 A): p-Bromotoluene (2) reacts with carbon dioxide through a Grignard reaction to form p-methylbenzoic acid (3), 3 undergoes bromination hydrolysis to form p-hydroxymethylbenzoic acid (4), 4 is then ammonolyzed to p-aminomethylbenzoic acid (p-aminotoluic acid, 5), and finally 5 undergoes catalytic hydrogenation and transformation to form tranexamic acid (1). Currently, the mainstream preparation methods of tranexamic acid mainly use various derivatives of benzoic acid as starting materials (such as CN107954887A, CN108689870A, etc.), prepare p-aminomethylbenzoic acid through hydrogenation and transformation, and then reduce and transform it into tranexamic acid. Such methods have a long synthesis route, low yield, and high cost.

[0005] Route 2 (CN 113956173 A): 2-(Aminomethyl)-1,3-butadiene (6) reacts with acrylic acid through a (7) D-A reaction to form 4-(aminomethyl)-3-cyclohexene-1-carboxylic acid (8), and then undergoes catalytic hydrogenation with a highly stereoselective chiral catalyst to obtain tranexamic acid. The starting material 2-(aminomethyl)-1,3-butadiene (6) of this route is not easily available, and the chiral catalyst is expensive and not easily available, which affects its application in industrial production.

[0006] In view of the current deficiencies in the industrial production of tranexamic acid, the present invention proposes a new preparation process for tranexamic acid. The starting materials of this process are inexpensive and easily available, the steps are few, and the cost is relatively low, making it suitable for industrial production. Summary of the Invention

[0007] The object of the present invention is to overcome the defects of the prior art and provide a new method for preparing tranexamic acid. The method for synthesizing tranexamic acid has the advantages of inexpensive and easily available raw materials, short process route, low cost, and high product purity.

[0008] To achieve the above object, the present invention adopts the following technical solutions: A method for preparing tranexamic acid, which comprises the following steps: Step 1: S N SAr reaction: p-halobenzonitrile and nitromethane react in the presence of a base and a solvent through S N Ar reaction to form p-nitromethylbenzonitrile; Step 2: Hydrolysis reaction: p-nitromethylbenzonitrile is hydrolyzed in the presence of sulfuric acid catalyst to form p-nitromethylbenzoic acid; Step 3: Hydrogenation conversion reaction: p-nitromethylbenzoic acid undergoes a hydrogenation reduction reaction with hydrogen in the presence of platinum black and sulfuric acid catalyst to form 4-aminomethylcyclohexanoic acid, and then undergoes a high-temperature conversion reaction in the presence of sulfuric acid catalyst to obtain a crude product of tranexamic acid, which is refined to obtain a finished product of tranexamic acid.

[0009] Specifically, in step 1), the halogen in p-halobenzonitrile can be fluorine or chlorine, that is, the p-halobenzonitrile can be p-fluorobenzonitrile or p-chlorobenzonitrile, etc. Although the reaction of p-fluorobenzonitrile is milder and the yield is higher than that of p-chlorobenzonitrile, the price of p-fluorobenzonitrile is higher. Therefore, p-chlorobenzonitrile is preferably used. The molar ratio of p-halobenzonitrile to nitromethane can be 1:1.1 - 2.0, preferably 1:1.5.

[0010] Furthermore, in step 1), the base used can be one or more weak bases such as potassium carbonate, sodium carbonate, triethylamine, etc., preferably potassium carbonate. The molar ratio of p-halobenzonitrile to the base is 1:1.0 - 1.5, preferably 1:1.2; the solvent can be one or more of dimethyl sulfoxide, dimethylformamide, etc., preferably dimethyl sulfoxide. The dosage of the solvent is 2.5 - 5 times (V / W, ml / g) of p-halobenzonitrile, preferably 3 times.

[0011] Furthermore, in step 1), the reaction temperature is 70 - 110 °C (preferably 90 - 100 °C when using p-chlorobenzonitrile as the raw material), and the reaction time is 6 - 16 hours (preferably 8 hours when using p-chlorobenzonitrile as the raw material); after the reaction is completed, water is added, and the pH is adjusted to 3 - 4 with hydrochloric acid, a precipitate is formed, and solid-liquid separation is carried out to obtain p-nitromethylbenzonitrile.

[0012] Specifically, in step 2), the concentration of sulfuric acid used in the hydrolysis reaction is 30-70%, preferably 50%; the amount of sulfuric acid used is 1.3-1.7 times (W / W) the mass of p-nitrobenzonitrile, preferably 1.5 times. In step 2), the reaction temperature is 90-125 °C, preferably 105-115 °C; the reaction time is 2-3 hours.

[0013] Specifically, in step 3), the concentration of sulfuric acid used in the hydrogenation reaction is 5-15%, preferably 9%; the amount of sulfuric acid used is 9-13 times the mass of p-nitrobenzoic acid, preferably 11 times; the amount of platinum black catalyst used is 1-3% (W / W) the mass of p-nitrobenzoic acid, preferably 1.5%; the hydrogen pressure is 0.1-2 MPa, preferably 0.5-1.5 MPa; the reaction temperature is 30-60 °C, preferably 40-50 °C.

[0014] Further, in step 3), the concentration of sulfuric acid used in the conversion reaction is 10-16%, preferably 11-13%; the amount of sulfuric acid used is 5-10 times the mass of p-nitrobenzoic acid, preferably 7 times; the reaction temperature is 170-210 °C, preferably 190-200 °C, the reaction time is 5-8 hours, preferably 6 hours; after the reaction, the pH is adjusted to 5-6 with barium hydroxide, and then filtered to obtain the crude tranexamic acid.

[0015] Further, in step 3), the purification specifically includes: activated carbon adsorption, ethanol forced crystallization (the product has a large solubility in water, and the role of ethanol is to reduce the solubility so that more product can precipitate), and drying. During the purification process, the volume ratio of ethanol used to the mass of p-nitrobenzoic acid is 3-7 ml:1 g; the amount of activated carbon used is 1-3% (W / W) the mass of p-nitrobenzoic acid, preferably 2%.

[0016] The synthetic route of the method of the present invention is as follows. p-Halobenzonitrile (9) reacts with nitromethane in the presence of a base to obtain p-nitrobenzonitrile (10), which is hydrolyzed with sulfuric acid catalysis to obtain p-nitrobenzoic acid (11), and then tranexamic acid (1) is obtained through catalytic hydrogenation and conversion.

[0017] The raw materials of the present invention are easily available, the product quality is good, and it is suitable for industrial production. Compared with the existing methods, the preparation method of the present invention has the following advantages and beneficial effects: 1) The starting materials of the present invention are cheap and easily available. Most of the starting materials used in the existing synthetic routes are aminomethylbenzoic acid, and its synthetic process is relatively complex, with high costs and is not conducive to industrial production. The present invention uses p-chlorobenzonitrile and nitromethane as raw materials, which are of low price and sufficient market supply, and are conducive to industrial production; 2) In the method of the present invention, platinum black is added as a hydrogenation catalyst, and the expensive platinum black can be reused after the reaction is completed, thereby reducing the production cost; 3) In the transformation of the present invention, sulfuric acid is used as a catalyst instead of barium hydroxide, which reduces the consumption of sulfuric acid and barium hydroxide and lowers the production cost. Detailed implementation manners

[0018] The technical solutions of the present invention will be further introduced in detail below in combination with implementation examples, but the protection scope of the present invention is not limited thereto.

[0019] The synthesis route in the following implementation examples is as follows. p - Halobenzonitrile (9) and nitromethane undergo an SNAr reaction in the presence of a base to obtain p - nitromethylbenzonitrile (10), which is hydrolyzed with sulfuric acid catalysis to obtain p - nitromethylbenzoic acid (11), and then tranexamic acid (1) is obtained through catalytic hydrogenation and transformation.

[0020] In the examples, all raw materials used are ordinary commercially available products that can be directly purchased in the art or can be prepared by conventional methods in the art.

[0021] Room temperature refers to 25 ± 5 °C.

[0022] Example 1 Preparation of p - nitromethylbenzonitrile (10) 420 ml of dimethyl sulfoxide, 137.5 g (1.0 mol, 1.0 eq) of p - chlorobenzonitrile (9, X = Cl), 91.6 g (1.5 mol, 1.5 eq) of nitromethane, and 166 g (1.2 mol, 1.2 eq) of anhydrous potassium carbonate were added to a reaction flask, heated to 90 - 100 °C, stirred and reacted for 8 hours, cooled to room temperature, 1260 ml of water was added, the pH value was adjusted to 3 - 4 with hydrochloric acid (about 120 ml), a precipitate was formed, filtered, the filter cake was washed with water, and after drying, 131.8 g of p - nitromethylbenzonitrile was obtained, with a yield of 81%.

[0023] Example 2 Preparation of p - nitromethylbenzonitrile (10) 420 ml of dimethyl sulfoxide, 121.1 g (1.0 mol, 1.0 eq) of p - fluorobenzonitrile (9, X = F), 91.6 g (1.5 mol, 1.5 eq) of nitromethane, and 166 g (1.2 mol, 1.2 eq) of anhydrous potassium carbonate were added to a reaction flask, heated to 75 - 85 °C, stirred and reacted for 15 hours, cooled to room temperature, 1260 ml of water was added, the pH value was adjusted to 3 - 4 with hydrochloric acid (about 120 ml), a precipitate was formed, filtered, the filter cake was washed with water, and after drying, 139.8 g of p - nitromethylbenzonitrile was obtained, with a yield of 86%.

[0024] Example 3 Preparation of p - nitromethylbenzoic acid (11) In a reaction flask containing 130 g (0.80 mol) of p-nitrobenzyl cyanide (10), 200 g of a pre-prepared sulfuric acid solution (composed of 102 g of 98% concentrated sulfuric acid and 98 g of water, with a concentration of 50%) was added. The mixture was heated to 105 - 115 °C and stirred for 2.5 hours. After the reaction ended, the reaction solution was cooled to 80 °C, 130 g of water was added, and then it was cooled to 0 - 5 °C. After filtration and drying at 70 - 80 °C, 132.0 g of p-nitrobenzoic acid (11) was obtained, with a yield of 90%.

[0025] Example 4 Preparation of Tranexamic Acid (1) Into a hydrogenation autoclave, 100 g (0.55 mol) of p-nitrobenzoic acid (11), 1000 g of water, 100 g of 98% sulfuric acid, and 1.5 g of platinum black were added. The autoclave was sealed, stirring was started, and after nitrogen replacement, hydrogen was introduced. The reaction was carried out at a hydrogen pressure of 0.5 - 1.5 MPa and a temperature of 40 - 50 °C until the reaction solution no longer absorbed hydrogen (by closing all valves of the reaction autoclave and observing that the hydrogen pressure did not change significantly for 0.5 hours). After the reaction ended, nitrogen replacement was carried out, and filtration was performed. The obtained platinum black could be reused. The filtrate was concentrated to 800 ml (during this concentration process, sulfuric acid did not evaporate due to its high boiling point, so no additional new sulfuric acid was required for the subsequent conversion reaction), and a hydrogenation reaction solution was obtained.

[0026] The hydrogenation reaction solution was put into a high-pressure autoclave, the reaction autoclave was sealed, heated to 190 - 200 °C and stirred for 6 hours. After the reaction ended, it was cooled to room temperature, and barium hydroxide was slowly added to adjust the pH to 5.5 (about 170 g), and stirred for 2 hours. After filtration, the filter cake was washed with 200 ml of water. The filtrate and the washing liquid were combined, 2.0 g of activated carbon was added, boiled for 10 minutes, the activated carbon was filtered off, the filtrate was concentrated to 200 ml, cooled to room temperature, 500 ml of ethanol was added, filtered, and dried to obtain 70.2 g of tranexamic acid, with a yield of 81%. Content: 99.7% (Second Part of Chinese Pharmacopoeia 2020). The spectral data is as follows: 1 H NMR (400MHz, D2O, δ): 2.85~2.88 (2H, d),2.08~2.16(1H, tt), 1.91~1.98 (2H, m), 1.81~1.88 (2H, m), 1.64~1.67 (1H, m), 1.32~1.43(2H, qd), 1.00~1.11 (2H, qd); 13 C NMR (100MHz, D2O, δ): 188.9, 49.3, 47.8,37.9, 31.8, 31.7.

Claims

1. A method for preparing tranexamic acid, characterized in that, The steps include: Step 1: p-halobenzonitrile and nitromethane react in the presence of a base and a solvent to generate p-nitromethylbenzonitrile; Step 2: p-nitromethylbenzonitrile is hydrolyzed under the catalysis of sulfuric acid to generate p-nitromethylbenzoic acid; Step 3: p-Nitromethylbenzoic acid is hydrogenated with hydrogen in the presence of platinum black and sulfuric acid to generate 4-aminomethylcyclohexanoic acid, which is then converted into crude tranexamic acid in the presence of sulfuric acid, and refined to obtain finished tranexamic acid.

2. The method for preparing tranexamic acid as claimed in claim 1, wherein In step 1), the p-halobenzonitrile is p-fluorobenzonitrile or p-chlorobenzonitrile, and the molar ratio of p-halobenzonitrile to nitromethane is 1:1.1-2.

0.

3. The preparation method of tranexamic acid as claimed in claim 1, characterized in that, In step 1), the base used is one or more of potassium carbonate, sodium carbonate, and triethylamine, and the molar ratio of p-halobenzonitrile to the base is 1:1.0-1.5; the solvent is one or more of dimethyl sulfoxide and dimethylformamide.

4. The method for preparing tranexamic acid as claimed in claim 1, wherein In step 1), the reaction temperature is 70-110° C. and the reaction time is 6-16 hours. After the reaction is completed, water is added to adjust the pH to 3-4, precipitate, and separate the solid and liquid to obtain p-nitromethylbenzonitrile.

5. The method for preparing tranexamic acid as claimed in claim 1, wherein In step 2), the concentration of sulfuric acid used is 30-70%; the amount of sulfuric acid used is 1.3-1.7 times the mass of p-nitromethylbenzonitrile.

6. The method for preparing tranexamic acid according to claim 1, wherein In step 2), the reaction temperature is 90-125° C. and the reaction time is 2-3 hours.

7. The method for preparing tranexamic acid as claimed in claim 1, wherein In step 3), the concentration of sulfuric acid used in the hydrogenation reaction is 5-15%; the amount of sulfuric acid used is 9-13 times the mass of p-nitromethylbenzoic acid; the amount of platinum black used is 1-3% of the mass of p-nitromethylbenzoic acid; the hydrogen pressure is 0.1-2 MPa; and the reaction temperature is 30-60°C.

8. The method for preparing tranexamic acid as claimed in claim 1, wherein In step 3), the concentration of sulfuric acid used in the conversion reaction is 10-16%; the amount of sulfuric acid used is 5-10 times the mass of p-nitromethylbenzoic acid; the reaction temperature is 170-210° C., and the reaction time is 5-8 hours; after the reaction is completed, the pH is adjusted to 5-6, filtered, and a crude tranexamic acid product is obtained.

9. The method for preparing tranexamic acid as claimed in claim 1, wherein In step 3), the refining is specifically: activated carbon adsorption, ethanol crystallization and drying.

10. The method for preparing tranexamic acid according to claim 9, wherein During the refining process, the volume ratio of ethanol to the mass of p-nitromethylbenzoic acid is 3~7 ml:1g; the amount of activated carbon used is 1~3% of the mass of p-nitromethylbenzoic acid.

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