Process for the preparation of a biotin intermediate, cyclic anhydride

Abstract

The application relates to a preparation method of a biotin intermediate cyclic anhydride, which comprises the following steps: under the condition of a catalyst, carrying out a dehydration reaction on a cyclic acid metal salt (II) and acetic anhydride in an aromatic hydrocarbon solvent to generate the cyclic anhydride (I). The method replaces the cyclic acid in the current process with the cyclic acid metal salt with better stability, omits the use of hydrochloric acid in the production of the cyclic acid, reduces the side reaction in the cyclic anhydride synthesis reaction process, effectively improves the purity and yield of the cyclic anhydride, and has a wide industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing a biotin intermediate, cyclic anhydride. Background Technology

[0002] Biotin, also known as vitamin H or coenzyme R, is a water-soluble vitamin belonging to the B vitamin group, specifically vitamin B7. It is essential for the synthesis of vitamin C, indispensable for the normal metabolism of fats and proteins, and a necessary nutrient for maintaining natural growth, development, and normal bodily functions. Biotin is a coenzyme for many carboxylases, acting as a CO2 carrier in carboxylase reactions and playing a crucial role in carbon dioxide fixation in organisms.

[0003] Biotin readily binds to a protein in egg whites. Consuming large amounts of raw egg whites can hinder biotin absorption, leading to biotin deficiency, which can cause symptoms such as hair loss, weight loss, and dermatitis. Biotin plays a crucial role in biochemical pathways such as fat synthesis and glycemia. Biotin is a lifesaver for those suffering from baldness, not only effectively preventing hair loss and scalp exposure, but also preventing premature graying of hair, a common problem in modern society. It also plays an important role in maintaining healthy skin.

[0004] Currently, the mainstream process route in the market is the total synthesis method using fumaric acid as the starting material. This method uses readily available raw materials, and after years of process optimization, the overall yield has been significantly improved, the cost has been significantly reduced, and the product quality is stable. However, this method also has obvious disadvantages: the process route is long, there are many by-products, a relatively large amount of waste, and the process control conditions are relatively high.

[0005] The intermediate for synthesizing biotin, cyclic anhydride, full name: 1,3-dibenzylimidazoline-2H-furano[3,4]imidazoline-2,4,6-trione, has the following chemical structure:

[0006]

[0007] Cyclic anhydrides are key intermediates in biotin synthesis. For example, patents such as "A Stereoselective Synthesis Method of Lactones," "A Method for Manufacturing (+)-Biotin," and "A Method for Preparing (4S,5R)-Half-Esters," as well as the doctoral dissertation "Asymmetric Total Synthesis of (+)-Biotin and Research on Related Reactions," all mention the use of cyclic anhydrides as raw materials to synthesize chiral lactones, intermediates for biotin. The synthesis of cyclic anhydrides presents significant waste problems, including high COD in wastewater and a large amount of hazardous waste such as tar.

[0008] Cyclic anhydrides are synthesized from the intermediate 1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid, as shown in the following chemical reaction formula:

[0009]

[0010] This reaction mainly involves intramolecular dehydration of the two carboxyl groups, and there are several methods. The patent "Method for Manufacturing (+)-Biotin" uses acetyl chloride as a dehydrating agent; however, acyl chlorides are highly irritating and produce hydrochloric acid and acetic acid as byproducts. The literature "Study on the Asymmetric Total Synthesis of d-Biotin (II)" uses acetic anhydride as a dehydrating agent, producing acetic acid as a byproduct. Separation of cyclic anhydride, hydrochloric acid, and acetic acid can be achieved through centrifugation, but the acidic conditions require sophisticated equipment, and even small leaks can create a poor working environment. Alternatively, byproduct acetic acid can be separated by toluene-entrained distillation, but this extends the operation cycle, increases energy consumption, and the distilled toluene containing acetic acid needs to be treated before use.

[0011] The paper "Asymmetric Total Synthesis of (+)-Biotin and Related Reactions" describes a toluene reflux dehydration method, stating that the dehydration reaction can be quantitatively completed in 10 hours without any dehydration reagents, producing no byproducts such as acetic acid or hydrochloric acid, and that the toluene can be recycled. However, research has revealed that this method requires high temperatures and long reaction times. Furthermore, the intermediate 1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid is unstable at high temperatures and inevitably decomposes; the decomposition rate increases rapidly with increasing temperature and time.

[0012] Using a dehydrating agent can shorten the reaction time to as little as 2 hours, but it is easy to produce byproducts such as acetic acid. Without a dehydrating agent, the reaction time can be as long as 10 hours, and more raw materials decompose.

[0013] Therefore, there is an urgent need to improve the preparation method of cyclic anhydride, a key intermediate in biotin synthesis, in order to overcome the many problems mentioned above in the industrial production of cyclic anhydride. Summary of the Invention

[0014] In view of the above-mentioned shortcomings of the current technology, the purpose of this invention is to provide a method for preparing biotin intermediate cyclic anhydride. This method replaces the raw material cyclic acid with a cyclic acid metal salt, which not only effectively avoids the decomposition side reaction of cyclic acid at high temperature, but also omits the acid precipitation operation in the synthesis of cyclic acid, thus effectively improving the purity and yield of cyclic anhydride.

[0015] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0016] A method for preparing a biotin intermediate cyclic anhydride (I) includes the following steps: under acidic conditions as a catalyst, a cyclic metal salt (II) and acetic anhydride undergo a dehydration reaction in an aromatic hydrocarbon solvent to generate cyclic anhydride (I).

[0017]

[0018] Where R represents an alkali metal.

[0019] The acidic substance is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, or acetic acid, preferably acetic acid.

[0020] The aromatic hydrocarbon solvent is benzene, xylene, or trimethylbenzene, preferably toluene.

[0021] The cyclic acid metal salt (II) is a sodium cyclic acid salt, a potassium cyclic acid salt, or a lithium cyclic acid salt.

[0022] The molar ratio of the cyclic metal salt (II) to acetic anhydride is 1:1.0-1.5, preferably 1:1.0.

[0023] The dehydration reaction temperature is 90–110°C, preferably 90°C.

[0024] The dehydration reaction time is 2-4 hours, preferably 2 hours.

[0025] The starting material for synthesizing cyclic anhydrides, 1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid (hereinafter referred to as cyclic acid), is unstable at high temperatures. Cyclic acids are obtained by bromination of fumaric acid via bromination, benzylamine substitution, and triphosgene cyclization to yield the sodium or potassium salts of the cyclic acid, followed by acid precipitation with hydrochloric acid. The sodium or potassium salts of cyclic acids are relatively stable and do not easily decompose at high temperatures. Their molecular structures are as follows:

[0026]

[0027] Research has shown that, under the catalysis of acetic acid and using acetic anhydride as a dehydrating agent, the metal salts of cyclic acids can also be converted into cyclic anhydrides in a reaction time as short as 2 hours. The by-product acetate can be separated by appropriate methods.

[0028] The process route has been changed as follows:

[0029]

[0030] The specific method is as follows: the precursor cyclic acid metal salt is not separated and dried by hydrochloric acid precipitation, but is directly crystallized and dried in the form of cyclic acid metal salt, thus eliminating the need for hydrochloric acid. The dried cyclic acid metal salt and acetic anhydride are thoroughly mixed in toluene, catalyzed with a small amount of acetic acid, and the mixture is heated to 90°C for 2 hours. The reaction system is then cooled to obtain a mixture of cyclic anhydride, acetate, and toluene. Since both cyclic anhydride and acetate are insoluble in toluene, they cannot be separated by centrifugation or other means. In fact, they can be directly applied to the next esterification reaction without separation, because the subsequent reaction still uses toluene as a solvent. After the reaction is completed, the product will dissolve in toluene, while the acetate will remain insoluble. At this point, the by-product acetate can be separated by centrifugation and filtration. After purification by adjusting the pH appropriately, the by-product acetate can be recovered.

[0031] In this invention, unless otherwise specified:

[0032] The term "cyclic anhydride" refers to the chemical name: 1,3-dibenzylimidazoline-2H-furano[3,4]imidazoline-2,4,6-trione, whose chemical structure is as follows:

[0033]

[0034] The term "cyclic acid" refers to the chemical name 1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid, whose chemical structure is as follows:

[0035]

[0036] The technical solution of the present invention has at least the following beneficial technical effects:

[0037] 1) Existing processes require the use of hydrochloric acid to separate potassium or sodium cyclic esters through acid precipitation. This invention eliminates the need for hydrochloric acid precipitation and instead uses concentration, cooling and crystallization to crystallize out sodium or potassium cyclic esters, thus saving the use of hydrochloric acid, reducing raw material consumption, and also reducing wastewater volume and salt content in the wastewater.

[0038] 2) In this invention, cyclic salts are used to replace cyclic acids in the synthesis of cyclic anhydrides. Since the sodium and potassium salts of cyclic acids are more stable than cyclic acids, fewer side reactions such as decomposition occur during the reaction process. The yield is 2 percentage points higher than that of the existing process and 10 percentage points higher than that of the process of dehydrating by reflux of toluene.

[0039] 3) In this invention, the reaction does not require distillation of toluene carrying acetic acid, which reduces distillation operations, lowers energy consumption, and shortens the process cycle by omitting distillation operations.

[0040] 4) Due to the reduction of side reactions and distillation operations, the quality of subsequent intermediates was improved, with the purity of subsequent intermediates increasing by 9 percentage points, according to tests.

[0041] 5) In existing processes, the byproducts of acetic acid and solvent toluene are mixed together, requiring the addition of large amounts of potassium hydroxide or sodium hydroxide to recover potassium acetate and toluene separately, generating a large amount of saline wastewater. In this invention, the byproducts of potassium acetate or sodium acetate can be recovered as industrial-grade potassium acetate or sodium acetate through centrifugal separation, without generating saline wastewater. Detailed Implementation

[0042] The embodiments of the present invention will now be clearly and completely described in conjunction with examples. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0043] The cyclic acid metal salts in the following examples are obtained from the intermediate cyclic acid synthesis process. In the conventional process, the aqueous solution of the cyclic acid metal salt is evaporated, cooled, crystallized, and then dried to obtain the cyclic acid metal salt.

[0044] Example 1

[0045] 1) Weigh 43.92g of potassium cyclic ester (water content <0.05%) (containing 0.1mol of potassium cyclic ester), add 300mL of toluene, 10.21g of acetic anhydride (0.1mol) and 0.3g of acetic acid (0.005mol), stir and heat to 90℃ and keep warm for 2 hours.

[0046] 2) After the reaction is complete, continue heating to reflux and distill acetic acid and toluene azeotropically through a distillation column. Stop distillation once the distilled toluene is neutral. The toluene and acetic acid mixture can be reused in the next batch; subsequent batches do not require the addition of acetic acid. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride, potassium acetate, and toluene, which can be used directly in the next step without separation. Analysis showed that the system contained 33.35 g (0.09916 mol) of cyclic anhydride, with a molar yield of 99.16%.

[0047] 3) Regardless of the process used in the next esterification reaction, the potassium acetate byproduct can be recovered by filtration after the reaction is completed.

[0048] Example 2

[0049] 1) Weigh 40.65g (0.1mol) of sodium cyclic ester salt (moisture <0.05%), add 300mL of toluene, 10.2g of acetic anhydride (0.1mol) and 0.3g of acetic acid (0.005mol), stir and heat to 90℃ and keep warm for 2 hours.

[0050] 2) After the reaction is complete, continue heating to reflux. Pass the solution through a distillation column; acetic acid and toluene will azeotropically distill off. Stop distillation once the distilled toluene is neutral. The toluene and acetic acid mixture can be reused in the next batch; subsequent batches do not require the addition of acetic acid. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride, sodium acetate, and toluene. Do not separate the mixture and use it directly in the next step. The system contained 33.21 g (0.09874 mol) of cyclic anhydride, with a molar yield of 98.74%.

[0051] 3) Regardless of the process used in the next esterification reaction, once the reaction is complete, the potassium sodium acetate byproduct can be filtered and recovered.

[0052] Both potassium cyclic acid salts and sodium cyclic acid salts can be used as starting materials, with little difference in yield. The choice can be based on the specific raw materials used in the current process.

[0053] Example 3

[0054] 1) Weigh 43.92g of potassium cyclic ester (water content <0.05%) (containing 0.1mol of potassium cyclic ester), add 300mL of toluene, 15.32g of acetic anhydride (0.15mol) and 0.3g of acetic acid (0.005mol), stir and heat to 90℃ and keep warm for 2 hours.

[0055] 2) After the reaction is complete, continue heating to reflux and pass the mixture through a distillation column. Acetic acid and toluene are azeotropically distilled off. Distillation is stopped once the distilled toluene is neutral. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride, sodium acetate, and toluene. This mixture is used directly in the next step without separation. The system contained 33.36 g (0.09918 mol) of cyclic anhydride, with a molar yield of 99.18%. 5.0 g (0.04898 mol) of residual acetic anhydride remained in the system.

[0056] Increasing the amount of acetic anhydride did not significantly improve the molar yield, but left a considerable amount of acetic anhydride residue in the system. No acetic anhydride residue was found in Examples 1 and 2.

[0057] Example 4

[0058] 1) Weigh 43.92g of potassium cyclic ester (water content <0.05%) (containing 0.1mol of potassium cyclic ester), add 300mL of toluene, 10.21g of acetic anhydride (0.1mol) and 0.3g of acetic acid (0.005mol), stir and heat to 110℃ and keep warm for 2 hours.

[0059] 2) After the reaction is complete, continue heating to reflux and distill acetic acid and toluene azeotropically through a distillation column. Stop distillation once the distilled toluene is neutral. The toluene and acetic acid mixture can be reused in the next batch; subsequent batches do not require the addition of acetic acid. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride, potassium acetate, and toluene. This mixture is used directly in the next step without separation. Analysis showed that the system contained 33.14 g (0.09853 mol) of cyclic anhydride, with a molar yield of 95.53%.

[0060] 3) Regardless of the process used in the next esterification reaction, the potassium acetate byproduct can be recovered by filtration after the reaction is completed.

[0061] Example 5

[0062] 1) Weigh 43.92g of potassium cyclic ester (water content <0.05%) (containing 0.1mol of potassium cyclic ester), add 300mL of toluene, 10.21g of acetic anhydride (0.1mol) and 0.3g of acetic acid (0.005mol), stir and heat to 90℃ and keep warm for 4 hours.

[0063] 2) After the reaction is complete, continue heating to reflux and distill acetic acid and toluene azeotropically through a distillation column. Stop distillation once the distilled toluene is neutral. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride, potassium acetate, and toluene. Do not separate the mixture and proceed directly to the next step. Analysis showed that the system contained 33.05 g (0.09826 mol) of cyclic anhydride, with a molar yield of 98.26%.

[0064] Example 6

[0065] 1) Weigh 43.92g of potassium cyclic ester (water content <0.05%) (containing 0.1mol of potassium cyclic ester), add 300mL of toluene, 10.21g of acetic anhydride (0.1mol) and 0.49g of sulfuric acid (0.005mol), stir and heat to 90℃ and keep warm for 1 hour.

[0066] 2) After the reaction is complete, continue heating to reflux and pass the mixture through a distillation column to azeotropically distill off the acetic acid and toluene. Stop distillation once the distilled toluene is neutral. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride, potassium acetate, potassium sulfate, and toluene. This mixture is used directly in the next step without separation. Analysis showed that the system contained 33.28 g (0.09895 mol) of cyclic anhydride, with a molar yield of 98.95%.

[0067] Using sulfuric acid instead of acetic acid as a catalyst, the initial system contained potassium sulfate. However, since subsequent batches used recycled acetic acid toluene, no potassium sulfate residue remained. In practical applications, using acetic acid for the first time is more reasonable. This example demonstrates that other acids can also catalyze the reaction.

[0068] Comparative Example 1

[0069] 1) Weigh 37.31g of cyclic acid (water content <0.05%) (containing 0.1mol of cyclic acid), add 300mL of toluene and 10.21g of acetic anhydride (0.1mol), stir and heat to 90℃ and keep warm for 2 hours.

[0070] 2) After the reaction is complete, continue heating to reflux and pass the distillation column to azeotropically distill off acetic acid and toluene. Stop distillation once the distilled toluene is neutral. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride and toluene, which is used directly in the next step without separation. Analysis showed that the system contained 29.85 g (0.08875 mol) of cyclic anhydride, with a molar yield of 88.75%. The system contained an unknown impurity with a purity of approximately 9%. This is 10.41 percentage points lower in molar yield and 9 percentage points lower in intermediate purity than in Example 1.

[0071] Comparative Example 2

[0072] 1) Weigh 37.31g of cyclic acid (water content <0.05%) (containing 0.1mol of cyclic acid), add 300mL of toluene and 11.23g of acetic anhydride (0.11mol), stir and heat to 90℃ and keep warm for 2 hours.

[0073] 2) After the reaction is complete, continue heating to reflux and distill acetic acid and toluene azeotropically through a distillation column. Stop distillation once the distilled toluene is neutral. After distillation, cool to 0°C to obtain a mixture of cyclic anhydride and toluene, which is used directly in the next step without separation. Analysis showed that the system contained 30.17 g (0.08875 mol) of cyclic anhydride, with a molar yield of 89.70%. The system contained an unknown impurity with a purity of approximately 8.6%. This represents a 9.46 percentage point decrease in molar yield and an 8.6 percentage point decrease in intermediate purity compared to Example 1.

[0074] Although increasing the amount of acetic anhydride can reduce impurities and increase the molar yield to some extent, it is still far lower than the molar yield in Example 1. Excess acetic anhydride remains in the system.

[0075] Comparative Example 3

[0076] 1) Weigh 37.31g of cyclic acid (water content <0.05%) (containing 0.1mol of cyclic acid), add 300mL of toluene and 10.21g of acetic anhydride (0.1mol), stir and heat to 90℃ and keep warm for 1.5 hours.

[0077] 2) After the reaction is complete, the temperature is further increased to reflux, and the acetic acid and toluene are azeotropically distilled through a distillation column. Distillation is stopped once the distilled toluene is neutral. After distillation, the temperature is lowered to 0°C to obtain a mixture of cyclic anhydride and toluene, which is used directly in the next step without separation. Analysis showed that the system contained 27.05 g (0.08042 mol) of cyclic anhydride, with a molar yield of 80.42%. The system contained approximately 6% of unknown impurities and 8% of unreacted cyclic acid. The molar yield is 18.74 percentage points lower than that in Example 1, and the intermediate purity is 14 percentage points lower.

[0078] The original process, by shortening the reaction time, could not ensure complete reaction. Although it reduced the amount of impurities, it also increased the amount of residual raw materials. Acetic anhydride in the system also did not react completely, leaving a significant amount of residue.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit the technical solutions. Those skilled in the art should understand that any modifications or equivalent substitutions to the technical solutions of the present invention without departing from the spirit and scope of the present invention should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing a biotin intermediate cyclic anhydride (I), comprising the following steps: Under acidic catalytic conditions, cyclic metal salt (II) and acetic anhydride undergo a dehydration reaction in an aromatic hydrocarbon solvent to produce cyclic anhydride (I). The molar ratio of cyclic metal salt (II) to acetic anhydride is 1:1.0-1.

5. The dehydration reaction temperature is 90-110℃, and the dehydration reaction time is 2-4 hours. Wherein, the cyclic acid metal salt (II) is a sodium cyclic acid salt, a potassium cyclic acid salt, or a lithium cyclic acid salt; The acidic substance is acetic acid; The aromatic hydrocarbon solvent is toluene.

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