A method for debenzylating synthetic d-biotin

Abstract

The application discloses a method for synthesizing d-biotin by debenzylization. Bisdibenzyl biotin is subjected to debenzylization reaction with hydrogen bromide gas under the action of a nonpolar solvent and a free radical initiator to obtain d-biotin. The synthesis method disclosed by the application has mild reaction conditions, high product yield, high purity and less waste.

Description

Technical Field

[0001] This invention relates to the field of fine chemical technology, and in particular to a method for synthesizing d-biotin by debenzylation. Background Technology

[0002] d-Biotin (molecular formula C) 10 H 16 N2O3S, also known as vitamin H or coenzyme R, is an important water-soluble B vitamin. In current technologies, the final chemical step in the synthesis of d-biotin generally involves the removal of the protecting group (benzyl group) from dibenzylbiotin to obtain d-biotin. Commonly used debenzylating reagents include hydrobromic acid, concentrated sulfuric acid, and Lewis acids, with debenzylation temperatures typically above 100°C. Due to the demanding conditions of the debenzylation reaction, it suffers from low selectivity and low yield, making it the most critical chemical step in the synthesis of d-biotin.

[0003] Chinese patent document CN112390815A discloses a method for preparing d-biotin by de-benzylation of Lewis acid. Under an inert gas atmosphere, a debenzylating agent is mixed with an anhydrous organic solvent, and the mixture is heated to 50-100°C. At this temperature, dibenzylbiotin dissolved in the same anhydrous organic solvent is added dropwise to carry out the debenzylation reaction, yielding biotin. The debenzylating agent is selected from dried Lewis acid. Claim 3 specifies that the molar ratio of dibenzylbiotin to the debenzylating agent is 1:2-4. According to the embodiments described, the biotin yield of this preparation method is between 82.4% and 91.3%. This application has the following problems: 1. Judging from the structures of dibenzylbiotin and biotin, theoretically, the most reasonable debenzylating agent should be H2 or hydrogen halide, forming stable toluene and biotin or stable benzyl halide and biotin, respectively. However, there is no literature report on H2 debenzylation. The application uses Lewis acid as a debenzylidene reagent, and a reasonable reaction equation cannot be derived from elemental balance, indicating insufficient disclosure in the specification; 2. The yield of biotin preparation is between 82.4% and 91.3%, which is low; 3. The preparation method adds an excess of Lewis acid compared to the amount of dibenzylidene biotin, and the application does not disclose how this Lewis acid is recycled or how it is separated from biotin, which are quality and environmental issues that need to be addressed. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention discloses a method for synthesizing d-biotin via debenzylation, which features mild reaction conditions, high product yield, high purity, and minimal waste.

[0005] The specific technical solution is as follows:

[0006] A method for synthesizing d-biotin by debenzylation, wherein d-biotin is obtained by debenzylation of dibenzylbiotin with hydrogen bromide gas in a nonpolar solvent and under the action of a free radical initiator.

[0007] In existing technologies, whether the debenzylation reaction involves dibenzyl biotin with hydrohalic acid or concentrated sulfuric acid, the process involves first removing one benzyl group from dibenzyl biotin to form monobenzyl biotin; then, monobenzyl biotin removes a second benzyl group to form biotin (it's also possible that some dibenzyl biotin removes both benzyl groups simultaneously); finally, biotin undergoes ring-opening to remove a carbonyl group. To convert the carbonyl removal byproduct into biotin, some processes also include a ring-closing reaction between the ring-opening product and trichloromethyl carbonate (triphosgene). The optimal process is to stop the entire reaction at the biotin stage, controlling the monobenzyl biotin within a defined range while avoiding the biotin ring-opening reaction. The entire process described above falls under the category of ionic reactions. The debenzylation reaction rate decreases with decreasing feed concentration. If the reaction is incomplete, difficult-to-separate monobenzyl biotin may be carried into the final product, affecting product quality. When the concentration of hydrohalic acid or concentrated sulfuric acid is high, the reaction rate is fast, which easily leads to the ring-opening side reaction of biotin. This necessitates the ring-closure reaction via bis(trichloromethyl) carbonate (triphosgene), increasing the reaction process and resulting in low overall yield, significant safety risks, and excessive wastewater. The effect of reaction temperature on the reaction is similar to that of the concentration of hydrohalic acid or concentrated sulfuric acid; excessively high temperatures increase the proportion of biotin ring-opening products and decrease the overall yield. The synthetic process disclosed in this invention adds a nonpolar solvent and a free radical initiator to the reaction system of bisbenzylidene biotin and hydrohalic acid to appropriately modify the reaction pathway, reducing the adverse effects of raw material concentration on the reaction rate and lowering the reaction temperature, thus making the reaction conditions more moderate. Simultaneously, this synthetic process uses hydrogen bromide gas instead of the commonly used hydrohalic acid (hydrogen bromide aqueous solution) as the debenzylidene reagent. The overall result is that the debenzylidene reaction can be carried out under milder conditions, reducing the formation of by-products, increasing the reaction yield, and reducing the amount of waste.

[0008] In this invention, the structural formula of bisbenzylbiotin is as follows:

[0009] .

[0010] Preferably, the nonpolar solvent is selected from chlorobenzene and / or bromobenzene; hydrogen bromide and dibenzyl biotin both have relatively high solubility in chlorobenzene or bromobenzene, which can increase the rate of the debenzylation reaction. While maintaining a constant reaction rate, the reaction temperature can be lowered to improve reaction selectivity and increase the yield of d-biotin synthesis. Simultaneously, chlorobenzene and bromobenzene have the advantage of being less prone to ionic or radical substitution reactions with hydrogen bromide compared to other alkylbenzenes, reducing hydrogen bromide consumption.

[0011] Preferably, the mass ratio of the nonpolar solvent to dibenzylbiotin is (10~20):1.

[0012] The amount of nonpolar solvent added to the debenzylation reaction has a significant impact on the reaction yield. During debenzylation, benzyl carbocations or benzyl radicals are formed. These two intermediate states are highly unstable and easily undergo a series of side reactions with the feedstock dibenzylated biotin or the product d-biotin. Reducing the concentration of the feedstock and product can effectively reduce the number of side reactions, but it also slows down the reaction rate. The inventors analyzed samples taken during the debenzylation reaction and found that, under the technical solution of this application, the reaction was close to first-order in the early stages and close to zero-order in the later stages. That is, the reaction rate in the early stages is concentration-dependent, while the reaction rate in the later stages is independent of concentration. Increasing the solvent ratio can achieve higher selectivity for the debenzylation reaction, although the reaction rate decreases slightly. However, since the reaction mechanism is partially changed to a radical reaction, the decrease in reaction rate is not significant. The disadvantage is that it increases the load on the subsequent solvent recovery. To avoid this trade-off, a mass ratio of nonpolar solvent to the dibenzylated biotin of 10-20:1 is preferred.

[0013] This invention aims to transform the debenzylation reaction from an ionic reaction to a free radical reaction, thereby lowering the reaction temperature and improving the selectivity. Adding a free radical initiator can enhance the effectiveness of the free radical reaction and reduce its difficulty.

[0014] Preferably, the free radical initiator is selected from peroxide initiators and / or azo initiators.

[0015] The peroxide initiator is selected from common types in the art, such as benzoyl peroxide, methyl ethyl ketone peroxide, cyclohexanone peroxide, and diisopropyl percarbonate;

[0016] The azo initiator is selected from common types in the art, such as azobisisobutyronitrile and / or azobisisoheptanenitrile.

[0017] Further preferably, the free radical initiator is selected from benzoyl peroxide and / or azobisisobutyronitrile, both of which have the advantages of readily available raw materials and good performance.

[0018] Preferably, the mass ratio of the free radical initiator to bisbenzylbiotin is (0.001~0.01):1; more preferably, it is 0.0075:1.

[0019] The amount of free radical initiator added is closely related to process conditions such as reaction temperature and solvent dosage. While increasing the amount of free radical initiator can improve the free radical reaction effect after minimizing free radical quenching factors, it also presents risks such as excessively rapid reaction, reduced selectivity, and the risk of the free radical initiator or its derivatives being introduced into the product after the reaction. Using the free radical initiators mentioned above, controlling the amount of free radical initiator added to 0.1%~1% of the dibenzyl biomass yields the best results.

[0020] Preferably, the hydrogen bromide gas is obtained by dehydrating hydrobromic acid with a dehydrating agent;

[0021] Preferably, the hydrobromic acid content is 50-58 wt%; if the hydrobromic acid content is too low, a larger amount of dehydrating agent must be used to prepare gaseous hydrogen bromide with low water content. In this invention, a high concentration of hydrobromic acid with a mass content of 50-58% is preferably used, which can minimize the amount of dehydrating agent used and reduce the water content of gaseous hydrogen bromide.

[0022] Preferably, the average water content of the hydrogen bromide gas obtained after dehydration by the dehydrating agent is not higher than 10 wt%.

[0023] Compared to using hydrobromic acid directly as the debenzylidene reagent, the yield of d-biotin prepared was significantly lower. However, d-biotin prepared using hydrogen bromide gas with the aforementioned water content as a raw material exhibited higher yield and purity.

[0024] Preferably, the dehydrating agent is selected from salt-based dehydrating agents and / or molecular sieve-based dehydrating agents;

[0025] Specifically:

[0026] The salt dehydrating agent is selected from calcium bromide and / or zinc bromide;

[0027] The molecular sieve dehydrating agent is selected from one or more of 3Å molecular sieves, 4Å molecular sieves, and 5Å molecular sieves.

[0028] Further preferably, the dehydrating agent is selected from calcium bromide. The specific dehydration process includes:

[0029] First, anhydrous calcium bromide is added to a container, and hydrobromic acid is added to the container while heating. The hydrogen bromide gas generated after dehydration is introduced into the debenzylation reactor to carry out the debenzylation reaction. After the hydrobromic acid has been added, the container is heated and kept at a certain temperature for a period of time until the hydrogen bromide gas has completely escaped. Finally, the water-absorbing calcium bromide aqueous solution is distilled off by heating under negative pressure to form anhydrous calcium bromide and restore its water-absorbing activity.

[0030] Compared to molecular sieve desiccant, calcium bromide remains in a liquid state for part of the dehydration process after absorbing water, and has the characteristics of fast dehydration and high efficiency.

[0031] Preferably, the negative pressure heating dehydration is carried out at a temperature of 85~100℃ and a pressure of -0.085~-0.095MPa.

[0032] When calcium bromide is heated, its water absorption capacity decreases and the partial pressure of water vapor on its surface increases. Using a negative pressure of -0.085 to -0.095 MPa, the water bound to the calcium bromide can be easily removed to form anhydrous calcium bromide, thus restoring its water absorption capacity.

[0033] To reduce the waste of hydrobromic acid, when preparing hydrogen bromide gas, after the hydrobromic acid has been added, a small amount of nitrogen can be used to replace the hydrogen bromide gas in the gas phase space of the hydrogen bromide gas forming equipment with the benzyl bromide debromination equipment, thereby reducing the waste of this portion of hydrogen bromide gas.

[0034] Preferably, the mass ratio of hydrobromic acid to dehydrating agent is (0.1~0.5):1.

[0035] Experiments have shown that when the content of hydrobromic acid is 50-58 wt%, and the mass ratio of hydrobromic acid to dehydrating agent is controlled at (0.1-0.4):1, the average water content of hydrogen bromide gas can be guaranteed to be 5-10 wt%.

[0036] Further optimization is achieved by using a mass ratio of hydrobromic acid to dehydrating agent of (0.17~0.45):1.

[0037] Preferably, the molar ratio of hydrogen bromide gas to dibenzyl biotin is (8~20):1; more preferably (13~20):1.

[0038] Preferably, the debenzylation reaction is carried out at a temperature of 60-100°C. Lowering the debenzylation reaction temperature can reduce the occurrence of biotin ring-opening side reactions and reduce the trouble of subsequent cyclization reactions; more preferably, it is 60-80°C.

[0039] Preferably, the debenzylation reaction is carried out under visible light irradiation; more preferably, it is carried out under incandescent light irradiation.

[0040] Experiments have shown that the debenzylation reaction disclosed in this invention can be accelerated by visible light irradiation. Whether the reaction apparatus is shielded from light has a significant impact on the debenzylation reaction. Irradiation with visible light, especially incandescent light, can significantly accelerate the reaction rate and may also lower the reaction temperature while maintaining the same reaction rate, thereby improving the selectivity and yield of the debenzylation reaction.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] This invention discloses a method for synthesizing d-biotin through debenzylation, which features mild reaction conditions, minimal waste, and environmental friendliness.

[0043] The d-biotin synthesized by this method has high selectivity, high yield, and high purity. Detailed Implementation

[0044] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially. The features and performance of the present invention will be further described in detail below with reference to the embodiments.

[0045] The bisbenzylidene biotin used in the embodiments and comparative examples of this invention was prepared by the method in Chinese patent document CN 1616463 A, with a purity of 97.6 wt%.

[0046] Example 1

[0047] (1) Add 300g of anhydrous calcium bromide to a 500mL three-necked flask equipped with a thermometer and a reflux condenser. Weigh 90g of hydrobromic acid (HBr aqueous solution, HBr content: 56.5wt%) into a constant pressure dropping funnel. Insert the constant pressure dropping funnel into the feeding port of the three-necked flask for later use.

[0048] (2) Add 300g of chlorobenzene, 20.0g of dibenzylbiotin, and 0.15g of benzoyl peroxide to a 1000mL four-necked flask equipped with a thermometer, a stirrer, a reflux condenser, and a gas charging tube. Heat the outer wall of the four-necked flask with heat transfer oil to control the temperature of the materials in the four-necked flask at 80℃. Illuminate the top of the four-necked flask with a table lamp equipped with a 40W incandescent bulb.

[0049] (3) Connect the outlet of the reflux condenser on the three-necked flask to the gas filling tube of the four-necked flask through a fluororubber tube. Add hydrobromic acid from the constant pressure dropping funnel to the three-necked flask, controlling the dropping time to 6 hours. The hydrogen bromide gas generated in the three-necked flask is condensed by the condenser and enters the fluororubber tube, and finally enters the four-necked flask through the gas filling tube to undergo a debenzylation reaction with dibenzylbiotin. After the hydrobromic acid is added, continue to purge and maintain the temperature for 6 hours, for a total reaction time of 12 hours.

[0050] (4) After the hydrobromic acid is added, heat the outer wall of the three-necked flask with an electric heating mantle to control the temperature inside the flask to not exceed 85°C. When the temperature inside the three-necked flask reaches 85°C, stop the gas flow. The entire heating and gas flow time is about 2 hours. Adjust the condenser on the three-necked flask from reflux to recovery. Control the vacuum degree ≥ -0.085MPa and the temperature ≤ 100°C for dehydration under reduced pressure. The water content is 35.0g. The average water content of the hydrogen bromide gas is calculated to be 7.5wt%. After the dehydration under reduced pressure is completed, continue the next batch of dehydration reaction.

[0051] (5) After the reaction is complete, add 500g of boiling hot water to the four-necked flask and separate the organic layer while it is still hot. The organic layer is recycled to obtain chlorobenzene, and the byproduct benzyl bromide is utilized. After the aqueous layer is cooled, it is filtered. The filter cake is crude d-biotin, and the filtrate is dilute hydrobromic acid, which is concentrated and reused.

[0052] (6) Add all crude d-biotin, 500g deionized water, and 0.5g activated carbon to a clean 1000mL four-necked flask, and heat to reflux. After refluxing for 30 minutes, filter while hot. Allow the filtrate to cool naturally and crystallize. After crystallization, filter. Dry the filter cake in a vacuum oven to obtain 10.83g of d-biotin (purity: 99.5wt%), yield: 95.81%.

[0053] Example 2

[0054] The preparation process is basically the same as in Example 1, with the only difference being:

[0055] In step (2), the amount of chlorobenzene added as the reaction solvent is replaced with 200g.

[0056] The final yield of d-biotin in this embodiment was 10.67 g (purity: 99.6 wt%), with a yield of 94.49%.

[0057] Example 3

[0058] The preparation process is basically the same as in Example 1, with the only difference being:

[0059] In step (2), the amount of chlorobenzene added as the reaction solvent is replaced with 400g.

[0060] In this embodiment, 10.99 g of d-biotin (purity: 99.5 wt%) was finally obtained, with a yield of 97.22%.

[0061] Example 4

[0062] The preparation process is basically the same as in Example 1, with the only difference being:

[0063] In step (2), the debenzylation reaction temperature is increased to 100°C.

[0064] The final yield of d-biotin in this embodiment was 10.72 g (purity: 99.8 wt%), with a yield of 95.12%.

[0065] Example 5

[0066] The preparation process is basically the same as in Example 1, with the only difference being:

[0067] In step (2), the debenzylation reaction temperature is reduced to 60°C.

[0068] In this embodiment, 10.91 g of d-biotin (purity: 99.5%) was finally obtained, with a yield of 96.51%.

[0069] Example 6

[0070] The preparation process is basically the same as in Example 1, with the only difference being:

[0071] In step (1), the amount of hydrobromic acid used is increased to 135g.

[0072] The final yield of d-biotin in this embodiment was 10.87 g (purity: 99.7 wt%), with a yield of 96.35%.

[0073] Example 7

[0074] The preparation process is basically the same as in Example 1, with the only difference being:

[0075] In step (1), the amount of hydrobromic acid used is reduced to 53g.

[0076] In this embodiment, the final yield of d-biotin was 10.66 g (purity: 99.5 wt%), with a yield of 94.3%.

[0077] Example 8

[0078] The preparation process is basically the same as in Example 1, with the only difference being:

[0079] In step (2), the incandescent lamp above the four-necked flask is turned off.

[0080] The comparative example ultimately yielded 10.41 g of d-biotin (purity: 99.7 wt%), with a yield of 92.28%.

[0081] Comparative Example 1

[0082] The preparation process is basically the same as in Example 1, with the only difference being:

[0083] In step (2), no initiator was added.

[0084] The comparative example ultimately yielded 10.36 g of d-biotin (purity: 99.5 wt%), with a yield of 91.65%.

[0085] Comparative Example 2

[0086] (1) Add 300g of chlorobenzene, 90g of hydrobromic acid (content: 56.5wt%), 20.0g of dibenzylbiotin, and 0.15g of benzoyl peroxide to a 1000mL four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser. Heat the outer wall of the four-necked flask with heat transfer oil to control the temperature of the materials in the four-necked flask at 80℃. Irradiate the top of the four-necked flask with a 40W incandescent lamp to carry out the debenzylation reaction. The total reaction time is 12h.

[0087] (2) After the reaction is complete, add 500g of boiling hot water to the four-necked flask and separate the organic layer while it is still hot. The organic layer is recycled to obtain chlorobenzene, and the byproduct benzyl bromide is utilized. After the aqueous layer is cooled, it is filtered. The filter cake is crude d-biotin, and the filtrate is dilute hydrobromic acid, which is concentrated and reused.

[0088] (3) Add all crude d-biotin, 500g deionized water, and 0.5g activated carbon to a clean 1000mL four-necked flask, and heat to reflux. After refluxing for 30 minutes, filter while hot. Allow the filtrate to cool naturally and crystallize. After crystallization, filter again. Dry the filter cake in a vacuum oven. The final yield of this comparative example was 10.11g of d-biotin (purity: 99.5wt%), with a yield of 89.44%.

[0089] Comparative Example 3

[0090] (1) Add 135g of hydrobromic acid (content: 56.5wt%), 20.0g of dibenzylbiotin, and 0.15g of benzoyl peroxide to a 1000mL four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser. Heat the outer wall of the four-necked flask with heat transfer oil to control the temperature of the materials in the four-necked flask at 80℃. Irradiate the top of the four-necked flask with a 40W incandescent lamp to carry out the debenzylation reaction. The total reaction time is 12h.

[0091] (2) After the reaction is complete, add 300g of toluene to the four-necked flask and 500g of boiling hot water to the four-necked flask. Separate the organic layer while it is hot. The organic layer is recycled to obtain chlorobenzene, and the byproduct benzyl bromide is utilized. After the aqueous layer is cooled, it is filtered. The filter cake is crude d-biotin, and the filtrate is dilute hydrobromic acid, which is concentrated and reused.

[0092] (3) Add all of the crude d-biotin, 500g of deionized water, and 0.5g of activated carbon to a clean 1000mL four-necked flask, and heat to reflux. After refluxing for 30 minutes, filter while hot. Allow the filtrate to cool naturally and crystallize. After crystallization, filter. Dry the filter cake in a vacuum oven.

[0093] The comparative example ultimately yielded 10.02 g of d-biotin (purity: 99.6 wt%), with a yield of 88.73%.

[0094] Comparative Example 4

[0095] The preparation process is basically the same as in Example 1, except that:

[0096] In step (2), no initiator was added, and the incandescent lamp above the four-necked flask was turned off.

[0097] The comparative example ultimately yielded 10.03 g of d-biotin (purity: 99.6 wt%), with a yield of 88.82%.

[0098] Comparative Example 5

[0099] (1) Add 390g of hydrobromic acid (content: 56.5wt%) and 20.0g of dibenzyl biotin to a 1000mL four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser. Heat the outer wall of the four-necked flask with heat transfer oil and control the temperature of the materials in the four-necked flask to 80℃ to carry out the debenzylation reaction. The total reaction time is 12h.

[0100] (2) After the reaction is complete, add 300g of toluene to the four-necked flask and 500g of boiling hot water to the four-necked flask. Separate the organic layer while it is hot. The organic layer is recycled to obtain chlorobenzene, and the byproduct benzyl bromide is utilized. After the aqueous layer is cooled, it is filtered. The filter cake is crude d-biotin, and the filtrate is dilute hydrobromic acid, which is concentrated and reused.

[0101] (3) Add all of the crude d-biotin, 500g of deionized water, and 0.5g of activated carbon to a clean 1000mL four-necked flask, and heat to reflux. After refluxing for 30 minutes, filter while hot. Allow the filtrate to cool naturally and crystallize. After crystallization, filter. Dry the filter cake in a vacuum oven.

[0102] The comparative example ultimately yielded 9.23 g of d-biotin (purity: 99.5 wt%), with a yield of 81.65%.

[0103] Comparative Example 6

[0104] The preparation process is basically the same as that of Comparative Example 5, with the only difference being:

[0105] In step (1), the temperature of the material in the four-necked flask is controlled at 130°C.

[0106] The comparative example ultimately yielded 9.72 g of d-biotin (purity: 99.5 wt%), with a yield of 85.99%.

[0107] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. The specific examples used above to illustrate the present invention are only for the purpose of helping to understand the present invention and are not intended to limit the present invention. Those skilled in the art to which this invention pertains can make several simple deductions, modifications, substitutions, or combinations based on the concept of the present invention. These deductions, modifications, substitutions, or combinations also fall within the scope of the claims of the present invention.

Claims

1. A method for synthesizing d-biotin via debenzylation, characterized in that, Dibenzylbiotin undergoes a debenzylation reaction with hydrogen bromide gas in a nonpolar solvent and under the action of a free radical initiator to yield d-biotin.

2. The method for synthesizing d-biotin by debenzylation according to claim 1, characterized in that: The nonpolar solvent is selected from chlorobenzene and / or bromobenzene; The free radical initiator is selected from peroxide initiators and / or azo initiators.

3. The method for synthesizing d-biotin by debenzylation according to claim 2, characterized in that: The peroxide initiator is selected from one or more of benzoyl peroxide, methyl ethyl ketone peroxide, cyclohexanone peroxide, and diisopropyl percarbonate. The azo initiator is selected from azobisisobutyronitrile and / or azobisisoheptanenitrile.

4. The method for synthesizing d-biotin by debenzylation according to claim 1, characterized in that: The hydrogen bromide gas is obtained by dehydrating hydrobromic acid with a dehydrating agent; The average water content of the hydrogen bromide gas is not higher than 10 wt%.

5. The method for synthesizing d-biotin by debenzylation according to claim 4, characterized in that: The content of the hydrobromic acid is 50~58 wt%; The dehydrating agent is selected from salt-based dehydrating agents and / or molecular sieve-based dehydrating agents; The mass ratio of hydrobromic acid to dehydrating agent is (0.1~0.5):

1.

6. The method for synthesizing d-biotin by debenzylation according to claim 5, characterized in that: The salt dehydrating agent is selected from calcium bromide and / or zinc bromide; The molecular sieve dehydrating agent is selected from one or more of 3Å molecular sieves, 4Å molecular sieves, and 5Å molecular sieves.

7. The method for synthesizing d-biotin by debenzylation according to claim 6, characterized in that, The dehydrating agent is selected from calcium bromide.

8. The method for synthesizing d-biotin by debenzylation according to claim 4, characterized in that: The dehydrating agent, after absorbing water, regains its dehydrating ability by being heated under negative pressure. The negative pressure heating dehydration process involves a temperature of 85~100℃ and a pressure of -0.085~-0.095MPa.

9. The method for synthesizing d-biotin by debenzylation according to claim 1, characterized in that: The mass ratio of the nonpolar solvent to dibenzylbiotin is (10~20):1; The mass ratio of the free radical initiator to bisbenzylbiotin is (0.001~0.01):1; The molar ratio of hydrogen bromide gas to dibenzyl biotin is (8~20):

1.

10. The method for synthesizing d-biotin by debenzylation according to claim 1, characterized in that: The debenzylation reaction is carried out at a temperature of 60~100℃; The debenzylation reaction is carried out under visible light irradiation.