Preparation method of tinine acid

Abstract

The invention discloses a preparation method of tininic acid, and belongs to the field of organic synthesis. According to the method disclosed by the invention, 2-thiophenecarbonyl chloride is taken as an initial raw material, the tinine acid is efficiently prepared through three steps of reaction, and the specific steps are as follows: S1, 2-thiophenecarbonyl chloride is subjected to esterification reaction under the condition of alcohol to generate an intermediate I (2-thiophenecarboxylic acid ester compound); s2, carrying out Fries rearrangement on the intermediate I under the action of aluminum chloride to generate an intermediate II (a hydroxyl aryl thiophene ketone compound); and S3, carrying out nucleophilic substitution on the intermediate II and sodium chloroacetate to generate the final product tinine acid. The synthetic route is simple, the raw materials are cheap and easy to obtain, the reaction condition is mild, the operation is simple and convenient, the product yield is high, the purity is excellent, the problems of complex flow, relatively high cost, poor environmental friendliness and the like in the existing synthetic process of the tinine acid are effectively solved, and the synthetic method is suitable for industrial large-scale production and has remarkable economic value and application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis of chemical drugs, and more particularly to a method for preparing tenic acid. Background Technology

[0002] Tenic acid is a nonsteroidal anti-inflammatory drug (NSAID) with good anti-inflammatory and analgesic activities. Its chemical structure contains a thiophene ring and a carboxyl functional group. It exerts its pharmacological effects by inhibiting prostaglandin synthesis and is clinically used to relieve pain and swelling caused by inflammation such as rheumatoid arthritis and osteoarthritis. Furthermore, tenic acid has the characteristics of low gastrointestinal irritation and high bioavailability, making it a promising drug for market applications.

[0003] Existing technologies for the synthesis of tinic acid have many shortcomings: some synthetic routes use expensive thiophene derivatives as starting materials, resulting in high production costs; some methods involve complicated reaction steps (more than three steps), making it difficult to separate and purify intermediate products, and the overall yield is low (usually below 60%); and some processes use toxic and harmful catalysts or solvents, posing environmental pollution risks and not in line with the trend of green chemical development.

[0004] Therefore, developing a method for synthesizing tinic acid that uses inexpensive and readily available raw materials, has a simple synthetic route, mild reaction conditions, is environmentally friendly, and yields a high amount is of great significance for industrial production. Summary of the Invention

[0005] This invention addresses the shortcomings of existing tinic acid synthesis processes by providing a method for preparing tinic acid. Using 2-thiopheneformyl chloride as the starting material, tinic acid is efficiently prepared through a three-step reaction involving esterification, Fries rearrangement, and nucleophilic substitution. This method has advantages such as low raw material cost, simple steps, convenient operation, and excellent yield and purity, making it suitable for large-scale industrial production.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] A method for preparing tinic acid, using 2-thiophenecarboxyl chloride as a starting material, includes the following steps:

[0008] S1, 2,3-dichlorophenol and 2-thiophene carboxyl chloride undergo esterification under alcoholic conditions to generate intermediate I, which is a 2-thiophene carboxyl ester compound.

[0009] S2. Intermediate I undergoes the Fries rearrangement reaction under the action of aluminum chloride to generate intermediate II, which is a hydroxyarylthiophene ketone compound.

[0010] S3 and intermediate II undergo a nucleophilic substitution reaction with sodium chloroacetate to produce the final product, tinidic acid.

[0011] Further, in step S1, the esterification reaction specifically includes:

[0012] 2,3-Dichlorophenol and 2-thiophenecarboxyl chloride were esterified in a reaction solvent at a molar ratio of 1:1 to 1:3. One of pyridine or diisopropylethylamine was added to the system in a molar ratio of 1.0 to 1.2:1 to 2-thiophenecarboxyl chloride. The reaction occurred under alcoholic conditions, with the amount of alcohol being 1.0 to 1.5 times that of 2-thiophenecarboxyl chloride. After the reaction was complete, intermediate I was obtained. The reaction formula is as follows:

[0013] .

[0014] Further, in step S1, the alcohol is one of methanol, ethanol, propanol, isopropanol, and n-butanol.

[0015] Further, in step S1, the solvent for the esterification reaction is a solvent-free system or an inert organic solvent, and the inert organic solvent is one of dichloromethane, chloroform, diethyl ether, and petroleum ether, and the molar ratio of the solvent to 2-thiopheneformyl chloride is 10~50:1.

[0016] Furthermore, in step S1, the esterification reaction is carried out at a temperature of 20~60℃ for 2~6h.

[0017] Furthermore, in step S1, the esterification reaction also includes the addition of an organic base as an acid-binding agent, the organic base being one of triethylamine, pyridine, or diisopropylethylamine; the molar ratio of the organic base to 2-thiophenecarboxyl chloride is 1.0~1.2:1.

[0018] Further, in step S2, the Fries rearrangement reaction specifically involves: intermediate I reacting with anhydrous aluminum chloride in a molar ratio of 1:1.5~3.0 to undergo a Fries rearrangement, yielding intermediate II; the solvent for the rearrangement reaction is one of nitrobenzene, dichloroethane, or tetrachloroethane, and the molar ratio of the solvent to intermediate I is 20~40:1; the reaction formula is as follows:

[0019] .

[0020] Furthermore, in step S2, the temperature of the Fries rearrangement reaction is 80~120℃, and the reaction time is 4~8h.

[0021] Further, in step S3, the nucleophilic substitution reaction specifically involves:

[0022] Intermediate II reacts with sodium chloroacetate at a molar ratio of 1:1.5-1:4 under nucleophilic substitution conditions to produce the final product, tinic acid, chemically known as 2-(4-hydroxy-2-thiophenecarboxy)acetic acid. The solvent for the nucleophilic substitution reaction is one or more of water, ethanol, acetone, and N,N-dimethylformamide, with a solvent-to-intermediate II molar ratio of 10-40. The reaction equation is as follows:

[0023] .

[0024] Furthermore, in step S3, the nucleophilic substitution reaction is carried out at a temperature of 50-80°C for 3-7 hours.

[0025] Compared with the prior art, the present invention has the following significant advantages:

[0026] (1) Starting materials are cheap and readily available: 2-thiophene carboxyl chloride is a commonly used intermediate in the chemical industry. It is inexpensive and has a stable supply, which greatly reduces the synthesis cost;

[0027] (2) The synthetic route is simple and efficient: the target product can be obtained in only three steps. The steps are few and the process is short. The intermediate products are easy to separate and purify, which reduces the complexity of the process.

[0028] (3) Mild reaction conditions: The reaction temperature of each step is within the range of 20~120℃, no high temperature and high pressure equipment is required, the operation is safe and the energy consumption is low;

[0029] (4) Good environmental friendliness: The catalyst aluminum chloride used can be recycled and reused, and the solvents are mostly common inert solvents or water-ethanol mixtures, which are low in toxicity, easy to handle, and meet the requirements of green chemical industry.

[0030] (5) High product yield and purity: The total yield can reach 75%~80%, which is much higher than the existing technology, and the purity of the final product is ≥97.5%, which meets the pharmaceutical grade standard;

[0031] (6) Strong industrial applicability: The reaction process is stable and easy to operate. No special equipment is required. It is easy to scale up production and has significant economic value and application prospects.

[0032] In summary, the method for preparing tenic acid provided by this invention efficiently prepares tenic acid through a three-step reaction involving esterification, Fries rearrangement, and nucleophilic substitution, using 2-thiopheneformyl chloride as the starting material. The structure of the compound was characterized and confirmed by 1H NMR, 13C NMR, HRMS, and single-crystal X-ray diffraction. This method features a simple synthetic route, readily available and inexpensive raw materials, mild reaction conditions, easy operation, high product yield, and excellent purity. It effectively solves the problems of complex processes, high costs, and poor environmental friendliness in existing tenic acid synthesis processes, making it suitable for large-scale industrial production and possessing significant economic value and application prospects. Attached Figure Description

[0033] Figure 1 The NMR spectrum of intermediate I (methyl 2-thiophenecarboxylate) provided in Example 1 of the present invention.

[0034] Figure 2 The NMR spectrum of intermediate II (2-acetyl-4-hydroxythiophene) provided in Example 1 of the present invention.

[0035] Figure 3 The NMR spectrum of tenic acid provided in Example 1 of this invention. Detailed Implementation

[0036] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] The purpose of this invention is to provide a method for preparing tinic acid, the specific steps of which are as follows:

[0038] (1) Esterification reaction: 2,3-Dichlorophenol and 2-thiophenecarboxyl chloride undergo esterification reaction in a reaction solvent at a molar ratio of 1:1 to 1:3 under C1-C4 alcohol conditions to generate intermediate I (2-thiophenecarboxylate). The C1-C4 alcohol is one of methanol, ethanol, propanol, isopropanol, and n-butanol, preferably methanol or ethanol, and its amount is 1.0-1.5 times that of 2-thiophenecarboxyl chloride; one of pyridine and diisopropylethylamine is added to the system, and its molar ratio with 2-thiophenecarboxyl chloride is 1.0-1.2:1. The reaction solvent is a solvent-free system or an inert organic solvent, wherein the inert organic solvent is one of dichloromethane, chloroform, diethyl ether, and petroleum ether; the esterification reaction temperature is 20~60℃, and the reaction time is 2~6h; preferably the reaction temperature is 30~40℃, the reaction time is 3~4h, and the amount of solvent used is 10~50 times (molar ratio) of the amount of 2-thiophenecarboxyl chloride used.

[0039] Its reaction formula is:

[0040]

[0041] The esterification reaction can also be carried out by adding an organic base as an acid-binding agent, wherein the organic base is one of triethylamine, pyridine, or diisopropylethylamine; the molar ratio of the acid-binding agent to 2-thiophenecarboxyl chloride is 1.0 to 1.2:1.

[0042] (2) Fries rearrangement reaction: Intermediate I undergoes a Fries rearrangement reaction in anhydrous aluminum chloride at a molar ratio of 1:1.5~3.0, whereby the alkoxy group of the ester group migrates to the ortho position of the thiophene ring, generating intermediate II (hydroxyarylthiophenone) with hydroxyl and carbonyl structures. The solvent for the rearrangement reaction is one of nitrobenzene, dichloroethane, and tetrachloroethane, preferably nitrobenzene; the rearrangement reaction temperature is 80~120℃, and the reaction time is 4~8h; preferably, the reaction temperature is 90~100℃, the reaction time is 5~6h, and the amount of solvent used is 20~40 times (molar ratio) of the amount of intermediate I.

[0043] Its reaction formula is:

[0044]

[0045] (3) Nucleophilic substitution reaction: The hydroxyl group of intermediate II has strong nucleophilic activity and undergoes a nucleophilic substitution reaction with sodium chloroacetate at a molar ratio of 1:1.5~4. The hydroxyl group replaces the chlorine atom in sodium chloroacetate to generate sodium tinnitrate, which, after acidification, yields free tinnitrile. The solvent for the nucleophilic substitution reaction is one or more of water, ethanol, acetone, and N,N-dimethylformamide, preferably a mixed solvent of water and ethanol (volume ratio 1:1~3:1). The amount of solvent used is 10-40 times (molar ratio) of the amount of intermediate II. The reaction temperature is 50~80℃, and the reaction time is 3~7h; preferably, the reaction temperature is 60~70℃, and the reaction time is 4~5h.

[0046] Its reaction formula is:

[0047]

[0048] After the reaction in step (3) is completed, the purification steps of acidification, filtration and recrystallization are also included: add hydrochloric acid to the reaction solution to adjust the pH to 2~3, precipitate solid, filter and collect the precipitate, and recrystallize with ethanol-water (volume ratio of 1:1~3:1) mixed solvent to obtain high-purity tinidic acid.

[0049] The products from each step are washed, dried or purified by distillation before proceeding to the next reaction step. The final product, tenic acid, has a yield of 80-88% and a purity of ≥98.5% (HPLC detection).

[0050] The structures of these compounds were characterized and confirmed by 1H NMR, 13C NMR, HRMS, and single-crystal X-ray diffraction.

[0051] Example 1

[0052] 1. Preparation of intermediate I (methyl 2-thiophenecarboxylate):

[0053] In a dry 250 mL three-necked flask, 2-thiophenecarboxyl chloride (20.0 g, 0.128 mol) and anhydrous methanol (30 mL, 0.743 mol) were added. Triethylamine (13.0 g, 0.128 mol) was slowly added dropwise with stirring, and the addition temperature was controlled at 20–30 °C. After the addition was complete, the temperature was raised to 35 °C and the reaction was maintained at this temperature for 3 h. After the reaction was completed, excess methanol and triethylamine hydrochloride were removed by vacuum distillation. The residue was dissolved in dichloromethane (50 mL) and washed successively with saturated sodium bicarbonate solution (30 mL × 2) and saturated brine (30 mL). The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized to obtain intermediate I (18.2 g, yield 92.3%).

[0054] The NMR spectrum of intermediate I (methyl 2-thiophenecarboxylate) is as follows: Figure 1 As shown, the 1H NMR (400 MHz, Chloroform-d) values ​​are δ 8.03 (d, J = 3.8, 1.3 Hz, 1H), 7.71 (d, J = 5.0, 1.3 Hz, 1H), 7.40 (dd, J = 7.9, 1.8 Hz, 1H), and 7.30–7.17 (m, 3H).

[0055] 2. Preparation of intermediate II (2-acetyl-4-hydroxythiophene):

[0056] In a dry 250 mL three-necked flask, nitrobenzene (80 mL) and anhydrous aluminum chloride (34.1 g, 0.256 mol) were added. The mixture was heated to 80 °C with stirring, and intermediate I (18.2 g, 0.118 mol) was slowly added. The temperature was raised to 95 °C and the reaction was maintained for 5 h. After the reaction was completed, the reaction solution was slowly poured into ice water (200 mL), stirred for 30 min, and the pH was adjusted to 2-3 with hydrochloric acid. A solid precipitated, and the precipitate was collected by filtration. The precipitate was washed with petroleum ether (30 mL × 2) and dried to obtain intermediate II (15.6 g, yield 85.7%).

[0057] The NMR spectrum of intermediate II (2-acetyl-4-hydroxythiophene) is shown below. Figure 2Shown, 1H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 5.0, 1.2 Hz, 1H), 7.44 (d, 1H), 7.34 (d, J = 8.4Hz, 1H), 7.14 (t, J = 4.9, 3.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.03 (s, 1H).

[0058] 3. Preparation of tinic acid:

[0059] In a 250 mL round-bottom flask, intermediate II (15.6 g, 0.101 mol), sodium chloroacetate (12.3 g, 0.106 mol), and a water-ethanol mixture (2:1, 90 mL, v / v) were added. The mixture was heated to 65 °C with stirring and maintained at this temperature for 4 h. After the reaction was complete, the mixture was cooled to room temperature, and hydrochloric acid was added to adjust the pH to 2-3. A large amount of white solid precipitated. The precipitate was collected by filtration and recrystallized from the ethanol-water mixture (1:1, 50 mL, v / v). After drying, tinic acid (16.8 g, yield 78.5%) was obtained, with a purity of 98.3% as determined by HPLC.

[0060] Tinidolate NMR image as follows Figure 3 Shown, 1H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J =4.9, 1.2 Hz, 1H), 7.43 (d, J = 3.8, 1.2 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.14 (t, J = 4.9, 3.8 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 4.84 (s, 2H).

[0061] Example 2

[0062] 1. Preparation of intermediate I (ethyl 2-thiophenecarboxylate):

[0063] In a dry 250 mL three-necked flask, 2-thiophenecarboxyl chloride (20.0 g, 0.128 mol) and anhydrous ethanol (40 mL, 0.688 mol) were added. The mixture was heated to 40 °C with stirring and maintained at this temperature for 4 h (no acid-binding agent was required). After the reaction was complete, excess ethanol was removed by vacuum distillation. The residue was dissolved in dichloromethane (50 mL) and washed successively with saturated sodium bicarbonate solution (30 mL × 2) and saturated brine (30 mL). The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized to obtain intermediate I (19.5 g, yield 91.1%).

[0064] 2. Preparation of Intermediate II:

[0065] Referring to step 2 of Example 1, intermediate I (19.5 g, 0.117 mol) and anhydrous aluminum chloride (31.2 g, 0.234 mol) were reacted in nitrobenzene (80 mL) at 100 °C for 6 h to obtain intermediate II (16.2 g, yield 84.3%).

[0066] 3. Preparation of tinic acid:

[0067] Referring to step 3 of Example 1, intermediate II (16.2 g, 0.104 mol) and sodium chloroacetate (12.9 g, 0.110 mol) were reacted in a water-ethanol mixed solvent (volume ratio 3:1, 100 mL) at 70 °C for 5 h. After acidification and recrystallization, tinic acid (17.5 g, yield 77.2%) was obtained, with a purity of 98.8% as determined by HPLC.

[0068] Example 3

[0069] 1. Preparation of intermediate I (ethyl 2-thiophenecarboxylate):

[0070] In a dry 250 mL three-necked flask, 2-thiophenecarboxyl chloride (20.0 g, 0.128 mol) and isopropanol (30 mL, 0.743 mol) were added. Pyridine (15.1 g, 0.128 mol) was slowly added with stirring. The mixture was heated to 30 °C with stirring and kept at this temperature for 4 h. After the reaction was completed, excess isopropanol was removed by vacuum distillation. The residue was dissolved in dichloromethane (50 mL) and washed successively with saturated sodium bicarbonate solution (30 mL × 2) and saturated brine (30 mL). The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized to obtain intermediate I (19.9 g, yield 92.8%).

[0071] 2. Preparation of Intermediate II:

[0072] Referring to step 2 of Example 1, intermediate I (19.9 g, 0.117 mol) and anhydrous aluminum chloride (31.2 g, 0.234 mol) were reacted in tetrachloroethane (80 mL) at 90 °C for 6 h to obtain intermediate II (16.3 g, yield 85.0%).

[0073] 3. Preparation of tinic acid:

[0074] Referring to step 3 of Example 1, intermediate II (16.3 g, 0.104 mol) and sodium chloroacetate (12.9 g, 0.110 mol) were reacted in a water-ethanol mixed solvent (volume ratio 2:1, 100 mL) at 70 °C for 5 h. After acidification and recrystallization, tinic acid (17.9 g, yield 79.0%) was obtained, with a purity of 97.9% as determined by HPLC.

[0075] Example 4

[0076] 1. Preparation of intermediate I (ethyl 2-thiophenecarboxylate):

[0077] In a dry 250 mL three-necked flask, 2-thiophenecarboxyl chloride (20.0 g, 0.128 mol) and n-butanol (30 mL, 0.743 mol) were added. Diisopropylethylamine (15.1 g, 0.128 mol) was slowly added with stirring. The mixture was heated to 35 °C with stirring and kept at this temperature for 4 h. After the reaction was completed, excess isopropanol was removed by vacuum distillation. The residue was dissolved in dichloromethane (40 mL) and washed successively with saturated sodium bicarbonate solution (30 mL × 3) and saturated brine (30 mL). The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized to obtain intermediate I (20.0 g, yield 93.1%).

[0078] 2. Preparation of Intermediate II:

[0079] Referring to step 2 of Example 1, intermediate I (20.0 g, 0.117 mol) and anhydrous aluminum chloride (31.2 g, 0.234 mol) were reacted in dichloroethane (80 mL) at 110 °C for 7 h to obtain intermediate II (16.2 g, yield 84.5%).

[0080] 3. Preparation of tinic acid:

[0081] Referring to step 3 of Example 1, intermediate II (16.2 g, 0.104 mol) and sodium chloroacetate (12.9 g, 0.110 mol) were reacted in a water-ethanol mixed solvent (volume ratio 2:1, 150 mL) at 75 °C for 5 h. After acidification and recrystallization, tinic acid (17.7 g, yield 78.3%) was obtained, with a purity of 98.3% as determined by HPLC.

Claims

1. A method for preparing tinic acid, characterized in that, Using 2-thiophenecarboxyl chloride as the starting material, the process includes the following steps: S1, 2,3-dichlorophenol and 2-thiophene carboxyl chloride undergo esterification under alcoholic conditions to generate intermediate I, which is a 2-thiophene carboxyl ester compound. S2. Intermediate I undergoes the Fries rearrangement reaction under the action of aluminum chloride to generate intermediate II, which is a hydroxyarylthiophene ketone compound. S3 and intermediate II undergo a nucleophilic substitution reaction with sodium chloroacetate to produce the final product, tinidic acid.

2. The method for preparing tenic acid according to claim 1, characterized in that, In step S1, the esterification reaction specifically includes: 2,3-Dichlorophenol and 2-thiophenecarboxyl chloride were esterified in a reaction solvent at a molar ratio of 1:1 to 1:

3. One of pyridine or diisopropylethylamine was added to the system in a molar ratio of 1.0 to 1.2:1 to 2-thiophenecarboxyl chloride. The reaction occurred under alcoholic conditions, with the amount of alcohol being 1.0 to 1.5 times that of 2-thiophenecarboxyl chloride. After the reaction was complete, intermediate I was obtained. The reaction formula is as follows: 。 3. The method for preparing tinic acid according to claim 2, characterized in that, In step S1, the alcohol is one of methanol, ethanol, propanol, isopropanol, and n-butanol.

4. The method for preparing tenic acid according to claim 2, characterized in that, In step S1, the solvent for the esterification reaction is a solvent-free system or an inert organic solvent. The inert organic solvent is one of dichloromethane, chloroform, diethyl ether, and petroleum ether, and the molar ratio of the solvent to 2-thiophenecarboxyl chloride is 10~50:

1.

5. The method for preparing tinic acid according to claim 1, characterized in that, In step S1, the esterification reaction is carried out at a temperature of 20-60°C for 2-6 hours.

6. The method for preparing tinic acid according to claim 1, characterized in that, In step S1, the esterification reaction further includes the addition of an organic base as an acid-binding agent. The organic base is one of triethylamine, pyridine, or diisopropylethylamine. The molar ratio of the organic base to 2-thiophenecarboxyl chloride is 1.0 to 1.2:

1.

7. The method for preparing tinic acid according to claim 1, characterized in that, In step S2, the Fries rearrangement reaction specifically involves: intermediate I reacting with anhydrous aluminum chloride in a molar ratio of 1:1.5~3.0 to undergo a Fries rearrangement, yielding intermediate II; the solvent for the rearrangement reaction is one of nitrobenzene, dichloroethane, or tetrachloroethane, and the molar ratio of the solvent to intermediate I is 20~40:1; the reaction formula is as follows: 。 8. The method for preparing tinic acid according to claim 1, characterized in that, In step S2, the temperature of the Fries rearrangement reaction is 80~120℃, and the reaction time is 4~8h.

9. The method for preparing tinic acid according to claim 1, characterized in that, In step S3, the nucleophilic substitution reaction specifically involves: Intermediate II reacts with sodium chloroacetate at a molar ratio of 1:1.5-1:4 under nucleophilic substitution conditions to produce the final product, tinic acid, chemically known as 2-(4-hydroxy-2-thiophenecarboxy)acetic acid. The solvent for the nucleophilic substitution reaction is one or more of water, ethanol, acetone, and N,N-dimethylformamide, with a solvent-to-intermediate II molar ratio of 10-40. The reaction equation is as follows: 。 10. The method for preparing tinic acid according to claim 1, characterized in that, In step S3, the nucleophilic substitution reaction is carried out at a temperature of 50-80°C for 3-7 hours.

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