A method for synthesizing sodium taurocholate, a catalyst and a method for preparing the catalyst

Abstract

The application discloses a synthesis method of sodium taurocholate, a catalyst and a preparation method of the catalyst. The structural formula of the catalyst is shown as formula I. In the formula I, R is H, CO2Me or OMe, and R is n-C3H7 or n-C4H9. 1 2 The synthesis method of the sodium taurocholate comprises the following steps: reacting cholic acid and taurine in a solvent containing an organic base under the catalysis of the compound shown in the formula I, so as to obtain the sodium taurocholate. The synthesis method of the sodium taurocholate has the advantages of small toxicity of reagents, simple process, low production cost, high yield and convenient industrial production.​

Description

Technical Field

[0001] This invention relates to the preparation of sodium taurocholate, and more particularly to a method for synthesizing sodium taurocholate, a catalyst, and a method for preparing the catalyst, belonging to the field of organic synthesis technology. Background Technology

[0002] Sodium taurocholate is a conjugated sodium bile acid salt formed by the amidation of the amino group of taurine and the carboxyl group of cholic acid. It is widely found in the bile of animals such as cattle, sheep, and snakes, and is a major component utilized in bile-based drugs. In addition to its physiological functions as a bile acid, sodium taurocholate also stimulates hepatocytes to secrete bile, increases its solid content, promotes fat emulsification and absorption, and facilitates the absorption of fat-soluble vitamins. The pharmacological effects of sodium taurocholate are also extensive, including choleretic, antitussive, expectorant, antiasthmatic, antibacterial, anti-inflammatory, antihypertensive, and reduction of cardiac contraction amplitude and frequency. It can also relieve fever caused by various factors. However, because this substance is hydrophilic, it is difficult to separate and extract, and is mostly synthesized using chemical synthesis methods in production.

[0003] Currently, the commonly used synthesis methods for sodium taurocholate are the ethyl chloroformate method (CN 103755764 B) and the EEDQ method (CN113583079 B), both of which involve the use of ethyl chloroformate. Because ethyl chloroformate is a highly toxic substance and a hazardous chemical, it is subject to regulation by public security departments, thus imposing numerous restrictions on sodium taurocholate production enterprises. Furthermore, the use of highly toxic compounds causes significant environmental pollution, and residues in pharmaceuticals can endanger human health. Enterprises have invested heavily in eliminating the pollution and residues caused by ethyl chloroformate. However, sodium taurocholate has a wide range of applications and high demand; therefore, there is an urgent need to develop low-toxicity, unregulated catalysts to replace ethyl chloroformate in the synthesis of sodium taurocholate. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for synthesizing sodium taurocholate, a catalyst, and a method for preparing the catalyst. This method uses reagents with low toxicity, is not subject to public security regulations, has a simple process, low production cost, and high yield, making it suitable for industrial production.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] In a first aspect, the present invention provides a compound of formula I.

[0007]

[0008] In Equation I, R 1 For H, CO2Me or OMe, R 2 It is either n-C3H7 or n-C4H9.

[0009] Specifically, the compound represented by Formula I can be any one of Formulas I-1 to I-4:

[0010]

[0011] Secondly, the present invention provides a method for preparing the compound shown in Formula I above, comprising the following steps:

[0012] Under the action of a base, the compound shown in Formula II and the compound shown in Formula III react in a solvent to obtain the compound shown in Formula I.

[0013]

[0014] In Equation II, R 1 The definition is the same as that of Equation I;

[0015] In Formula III, R 2 The definition is the same as that of Equation I.

[0016] In the above preparation method, the molar ratio of the base, the compound shown in Formula II, and the compound shown in Formula III can be 1:(1-2):(1-1.5), specifically 1:1:1;

[0017] The alkali is any one of sodium bicarbonate, sodium carbonate, and sodium hydroxide.

[0018] In the above preparation method, the solvent is composed of a first solvent and a second solvent with a volume ratio of 1:(1-5), wherein the first solvent is methanol or ethanol, and the second solvent is dichloromethane or trichloromethane, such as a volume ratio of 1:1;

[0019] The reaction temperature is -10℃ to 20℃, and the time is 1 to 3 hours, such as 2 hours at 5℃.

[0020] As an example, in specific operation, the compound shown in Formula II is dissolved in the solvent, the base is added, the mixture is stirred at the specified temperature, and the compound shown in Formula III is added dropwise. After the addition is complete, the mixture is kept at the specified temperature to carry out the reaction.

[0021] In the above preparation method, the method further includes the following post-processing step after the reaction: adding water to the system after the reaction, extracting with an organic solvent and then evaporating to dryness; the organic solvent is any one of dichloromethane, chloroform, and diethyl ether.

[0022] Thirdly, the present invention provides a method for synthesizing sodium taurocholate, comprising the following steps:

[0023] In the presence of the compound shown in Formula I, cholic acid and taurine are reacted in a solvent containing an organic base to obtain sodium taurocholate.

[0024] In the above synthesis method, the molar ratio of cholic acid, taurine, organic base, compound of formula I, and solvent is 1:1:(1-4):(1-4):(10-20), specifically 1:1:1:1:10.1;

[0025] The solvent is any one of N,N-dimethylformamide, sulfoxide, and tetrahydrofuran;

[0026] The organic base is any one of triethylamine, pyridine, triethylenediamine (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0027] In the above synthesis method, the reaction temperature is 50-100℃ and the time is 1-4h, such as reacting at 80℃ for 3h.

[0028] In the above synthesis method, the method further includes the following post-processing step after the reaction is completed: adding alcohol and base to the system after the reaction, and collecting the precipitated solid;

[0029] The alcohol is methanol or ethanol;

[0030] The alkali is any one of sodium hydroxide, sodium carbonate, and sodium bicarbonate;

[0031] The molar ratio of the alkali to the alcohol is 1:(5-10), specifically 1:5.

[0032] Compared with the prior art, the present invention has the following characteristics:

[0033] 1) The method of the present invention is simple to operate, has a high yield, and produces products with high purity.

[0034] 2) The reagents used in the method of this invention have low toxicity, are inexpensive, are not subject to regulation, and are easy to scale up for industrial production.

[0035] 3) The reagents for the method of the present invention are widely available, the production cycle is short, and it can be mass-produced in a short time.

[0036] 4) The method of the present invention provides four alternative catalysts to EEDQ, making the production methods of sodium taurocholate more diversified. Attached Figure Description

[0037] Figure 1 The synthesis process route of catalyst (A) and sodium taurocholate (B) provided in the embodiments of the present invention.

[0038] Figure 2 The nuclear magnetic resonance hydrogen spectrum of catalyst I-1 prepared in Example 1 of this invention.

[0039] Figure 3The 1H NMR spectrum of catalyst I-2 prepared in Example 2 of this invention.

[0040] Figure 4 The nuclear magnetic resonance hydrogen spectrum of catalyst I-3 prepared in Example 3 of this invention.

[0041] Figure 5 The 1H NMR spectrum of catalyst I-4 prepared in Example 4 of this invention.

[0042] Figure 6 The 1H NMR spectra of sodium taurocholate prepared in Examples 1-5 of this invention are shown. Detailed Implementation

[0043] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0044] Unless otherwise specified, the methods used in the following embodiments are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0045] The specifications and sources of the reagents used in the following examples are as follows:

[0046] Quinoline, 6-methoxyquinoline, methyl 6-quinoline carboxylate, propyl chloroformate, butyl chloroformate, and benzyl chloroformate were all purchased from Bailingwei Technology Co., Ltd. Tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide, dichloromethane, chloroform, sodium hydroxide, sodium bicarbonate, and sodium carbonate were all purchased from Shanghai Guoyao Group Chemical Reagent Co., Ltd., and all were analytical grade reagents.

[0047] Example 1

[0048] according to Figure 1 The compound shown in Formula I-1 was prepared via the route illustrated, and sodium taurocholate was synthesized using this compound as a catalyst. The specific steps are as follows:

[0049] 12.9g of quinoline (i.e., the compound shown in formula II, R) was added. 1 =H)(0.1mol) was dissolved in a mixed solvent (ethanol:dichloromethane = 1:1, v / v), 8.4g of sodium bicarbonate (0.1mol) was added, and the mixture was stirred at 5°C while adding 12.2g of propyl chloroformate (i.e., the compound shown in formula III, R) dropwise. 2=n-C3H7)(0.1mol), after the addition was complete, the reaction was allowed to proceed for 2 hours, then a large amount of water was added, and the mixture was extracted with dichloromethane and evaporated to dryness to obtain the compound (R) shown in Formula I-1. 1 =H,R 2 =n-C3H7), yield 60%, purity 98%. The 1H NMR spectrum of the obtained product is shown below. Figure 2 The structure has been verified to be correct.

[0050] 40 g of cholic acid (0.1 mol), 12.5 g of taurine (0.1 mol), 10 g of triethylamine (0.1 mol), and 26 g of the compound shown in Formula I-1 (0.1 mol) were added to 500 mL of N,N-dimethylformamide. The mixture was reacted at 80 °C for 3 h. Then, 30 mL of ethanol and 4 g of sodium hydroxide were added, and the precipitated solid was sodium taurocholate, with a mass of 48.3 g, yield of 90%, and purity of 95%. The 1H NMR spectrum of the obtained product is shown below. Figure 6 The structure has been verified to be correct.

[0051] Example 2

[0052] according to Figure 1 The compound shown in Formula I-2 was prepared via the route illustrated, and sodium taurocholate was synthesized using this compound as a catalyst. The specific steps are as follows:

[0053] 12.9g of quinoline (i.e., the compound shown in formula II, R) was added. 1 =H, 0.1 mol) was dissolved in a mixed solvent (ethanol: dichloromethane = 1:1, v / v), 8.4 g of sodium bicarbonate (0.1 mol) was added, and the mixture was stirred at 5 °C while adding 13.6 g of butyl chloroformate (i.e., the compound shown in formula III, R) dropwise. 2 =n-C4H8)(0.1mol), after the addition was complete, the reaction was allowed to proceed for 2 hours, then a large amount of water was added, and the mixture was extracted with dichloromethane and evaporated to dryness to obtain the compound (R) shown in formula I-2. 1 =H,R 2 =n-C4H8), yield 61%, purity 97%. The 1H NMR spectrum of the obtained product is shown below. Figure 3 The structure has been verified to be correct.

[0054] 40 g of cholic acid (0.1 mol), 12.5 g of taurine (0.1 mol), 10 g of triethylamine (0.1 mol), and 27.5 g of the compound shown in Formula I-2 (0.1 mol) were added to 500 mL of N,N-dimethylformamide. The mixture was reacted at 80 °C for 3 h. Then, 30 mL of ethanol and 4 g of sodium hydroxide were added, and the precipitated solid was sodium taurocholate, with a mass of 49 g, yield of 92%, and purity of 95%. The 1H NMR spectrum of the obtained product is shown below. Figure 6 The structure has been verified to be correct.

[0055] Example 3

[0056] according to Figure 1 The compound shown in Formula I-3 was prepared via the route illustrated, and sodium taurocholate was synthesized using this compound as a catalyst. The specific steps are as follows:

[0057] 15.9g of 6-methoxyquinoline (i.e., the compound shown in Formula II, R) was added. 1 =OMe)(0.1mol) was dissolved in a mixed solvent (ethanol:dichloromethane = 1:1, v / v), 8.4g of sodium bicarbonate was added, and the mixture was stirred at 5°C while adding 12.2g of propyl chloroformate (i.e., the compound shown in formula III, R) dropwise. 2 =n-C3H7), after the addition was complete, and the reaction was allowed to proceed for 2 hours, a large amount of water was added, and the mixture was extracted with dichloromethane and evaporated to dryness to obtain the compound shown in formula I-3 (R). 1 =OMe,R 2 =n-C3H7), with a yield of 59% and a purity of 98%. The proton NMR spectrum of the obtained product is shown below. Figure 4 The structure has been verified to be correct.

[0058] 40 g of cholic acid (0.1 mol), 12.5 g of taurine (0.1 mol), 10 g of triethylamine (0.1 mol), and 26 g of the compound shown in formula I-3 (0.1 mol) were added to 500 mL of N,N-dimethylformamide. The mixture was reacted at 80 °C for 3 h. Then, 30 mL of ethanol and 4 g of sodium hydroxide were added, and the precipitated solid was sodium taurocholate, with a mass of 44 g, yield of 82%, and purity of 94%. The 1H NMR spectrum of the obtained product is shown below. Figure 6 The structure has been verified to be correct.

[0059] Example 4

[0060] according to Figure 1 The compound shown in Formula I-4 was prepared via the route illustrated, and sodium taurocholate was synthesized using this compound as a catalyst. The specific steps are as follows:

[0061] 18.7g of methyl 6-quinoline carboxylate (i.e., the compound shown in Formula II, R) was added. 1 =CO2Me)(0.1mol) was dissolved in a mixed solvent (ethanol:dichloromethane = 1:1, v / v), 8.4g of sodium bicarbonate (0.1mol) was added, and the mixture was stirred at 5°C while adding 12.2g of propyl chloroformate (i.e., the compound shown in formula III, R) dropwise. 2 =n-C3H7)(0.1mol), after the addition was complete, the reaction was allowed to proceed for 2 hours, then a large amount of water was added, and the mixture was extracted with dichloromethane and evaporated to dryness to obtain the compound (R) shown in formula I-4. 1 =CO2Me,R 2 =n-C3H7), with a yield of 60% and a purity of 97%. The proton NMR spectrum of the obtained product is shown below. Figure 5 The structure has been verified to be correct.

[0062] 40 g of cholic acid (0.1 mol), 12.5 g of taurine (0.1 mol), 10 g of triethylamine (0.1 mol), and 26 g of the compound shown in Formula I-4 (0.1 mol) were added to 500 mL of N,N-dimethylformamide. The mixture was reacted at 80 °C for 3 h. Then, 30 mL of ethanol and 4 g of sodium hydroxide were added, and the precipitated solid was sodium taurocholate, with a mass of 45 g, yield of 85%, and purity of 96%. The 1H NMR spectrum of the obtained product is shown below. Figure 6 The structure has been verified to be correct.

[0063] Comparative Example 1

[0064] Add 40g cholic acid (0.1mol), 12.5g taurine (0.1mol), 10g triethylamine (0.1mol), and 25g EEDQ (0.1mol) to 500mL of N,N-dimethylformamide. React at 80℃ for 3h. Then add 30mL ethanol and 4g sodium hydroxide. The precipitated solid is sodium taurocholate, with a mass of 43g, yield of 80%, and purity of 95%.

[0065] Comparative Example 2

[0066] 12.9g of quinoline (i.e., the compound shown in formula II, R) was added. 1 =H, 0.1 mol) was dissolved in a mixed solvent (ethanol: dichloromethane = 1:1), 8.4 g of sodium bicarbonate (0.1 mol) was added, and the mixture was stirred at 5 °C while adding 17 g of benzyl chloroformate (i.e., the compound shown in formula III, R) dropwise. 2 =Benzyl (0.1 mol), after the addition was complete, the reaction was allowed to proceed for 2 hours, followed by the addition of a large amount of water, extraction with dichloromethane, and drying to obtain the compound.

[0067] (2-ethoxy-1-benzyloxycarbonyl-1,2-dihydroquinoline).

[0068] 40 g of cholic acid (0.1 mol), 12.5 g of taurine (0.1 mol), 10 g of triethylamine (0.1 mol), and 31 g of 2-ethoxy-1-benzyloxycarbonyl-1,2-dihydroquinoline (0.1 mol) were added to 500 mL of N,N-dimethylformamide. The mixture was reacted at 80 °C for 3 h. Then, 30 mL of ethanol and 4 g of sodium hydroxide were added. The precipitated solid was sodium taurocholate, with a mass of 10.8 g, a yield of 20%, and a purity of 91%.

[0069] The comparison results of Examples 1-4 and Comparative Examples 1-2 show that catalysts I-1, I-2, I-3, and I-4 have higher catalytic efficiency in the synthesis of sodium taurocholate than EEDQ and can be used as alternatives to EEDQ. The introduction of benzyl groups on the quinoline group reduced the catalytic efficiency, indicating that substituents with excessive steric hindrance will reduce the catalytic efficiency.

[0070] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including modifications made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A method for synthesizing sodium taurocholate, comprising the following steps: Under the catalysis of the compound shown in Formula I, cholic acid and taurine are reacted in a solvent containing an organic base to obtain sodium taurocholate. The structural formula of the compound shown in Formula I is as follows: In Equation I, R 1 For H, R 2 It is n-C4H9.

2. The synthesis method according to claim 1, characterized in that: The molar ratio of cholic acid, taurine, organic base, and the compound shown in Formula I to the solvent is 1:1:(1~4):(1~4):(10~20). The solvent is any one of N,N-dimethylformamide, sulfoxide, and tetrahydrofuran; The organic base is any one of triethylamine, pyridine, triethylenediamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

3. The synthesis method according to claim 1 or 2, characterized in that: The reaction is carried out at a temperature of 50-100℃ for 1-4 hours.

4. The synthesis method according to claim 1 or 2, characterized in that: The method further includes the following post-processing steps after the reaction: adding alcohol and base to the system after the reaction, and collecting the precipitated solid; The alcohol is methanol or ethanol; The alkali is any one of sodium hydroxide, sodium carbonate, and sodium bicarbonate; The molar ratio of the base to the alcohol is 1:(5~10).

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