Biotin intermediate substances, methods for their preparation, standards containing them and uses thereof
Patent Information
- Application Number
- CN202611021229.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-07-09
- Publication Date
- 2026-10-13
AI Technical Summary
[0003](3aR，6aS)-1,3-二苄基-4,5-双(羟甲基)咪唑烷-2-酮是在制备D生物素以及生物素中间体手性内酯过程中的一个重要中间体，但现有技术中暂未公开能够直接制备高纯度的上述中间体的方法
[0066]本发明提供的生物素中间体物质的制备方法可以直接获得高纯度的生物素中间体物质。该纯度可直接作为标准品应用在生物素制备中的转化率的测试以及生物素手性内酯的制备过程中的产物纯度的测试。本发明提供的生物素中间体物质的制备方法简单，原料易得，安全环保。
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Abstract
Description
Technical Field
[0001] This invention relates to a biotin intermediate substance and its preparation method, a standard containing the same substance and its applications. Background Technology
[0002] Biotin, also known as vitamin B7, vitamin H, or coenzyme R, is a water-soluble B vitamin. It plays an important role in human metabolism and in maintaining hair and skin. Currently, the most common process involves using fumaric acid as a starting material to chemically synthesize biotin D.
[0003] (3aR, 6aS)-1,3-dibenzyl-4,5-bis(hydroxymethyl)imidazolidine-2-one is an important intermediate in the preparation of biotin and biotin intermediate chiral lactone, but there is currently no disclosed method for directly preparing the above intermediate in high purity. Summary of the Invention
[0004] To address the aforementioned deficiencies in the existing technology, this invention provides a biotin intermediate substance, its preparation method, a standard containing the intermediate substance, and its applications. The preparation method of this biotin intermediate substance can directly obtain a high-purity biotin intermediate substance, which can be directly used as a standard in biotin preparation.
[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.
[0006] This invention provides a method for preparing a biotin intermediate, comprising the following steps:
[0007] S1. After reducing the first and second solutions, the solvent is removed to obtain the reactants.
[0008] The first solution comprises (3aS,6aR)-biotin chiral lactone and a first solvent, and the second solution comprises a reducing agent and a second solvent.
[0009] S2. The reactants are extracted with an extractant and then allowed to stand to obtain an aqueous phase and an oil phase; the standing temperature is 20-75℃.
[0010] S3. The oil phase is subjected to solvent removal treatment to obtain the biotin intermediate substance.
[0011] In this invention, the chemical name of the (3aS,6aR)-biotin chiral lactone is (3aS,6aR)-1,3-dibenzyltetrahydrofuranimidazole-2,4-dione, and its structural formula is shown in Formula I below.
[0012]
[0013] I.
[0014] In this invention, the chemical name of the biotin intermediate is (3aR, 6aS)-1,3-dibenzyl-4,5-bis(hydroxymethyl)imidazolidine-2-one, and its structural formula is shown in Formula II below.
[0015]
[0016] II.
[0017] In this invention, preferably, the mass ratio of (3aS,6aR)-biotin chiral lactone to the first solvent is 1:(1-5), for example, 1:1, 1:2, 1:3, 1:3.1, 1:4, 1:4.6, 1:5 or 1:6.2.
[0018] In this invention, preferably, the mass ratio of the reducing agent to the second solvent is 1:(4-20), for example, 1:5, 1:9, 1:10, 1:15 or 1:20.
[0019] In this invention, preferably, the mass ratio of the (3aS,6aR)-biotin chiral lactone to the reducing agent is 1:(0.2-1), for example, 1:0.2, 1:0.3, 1:0.4, 1:0.6, 1:0.8 or 1:1.
[0020] In this invention, preferably, the first solvent and the second solvent are of the same type.
[0021] In this invention, preferably, the first solvent includes one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
[0022] In this invention, preferably, the second solvent comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
[0023] In this invention, preferably, the reducing agent includes one or more of LiBH4, NaBH4, KBH4, Zn(BH4)2, Ca(BH4)2, NaBH(OAc)3 and NaBH3CN.
[0024] In this invention, preferably, the temperature of the reduction reaction is 10-100℃, for example, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃ or 100℃.
[0025] In this invention, preferably, the reduction reaction time is 0.5-4 hours, for example, 0.5 hours, 1 hour, 2 hours, 3 hours or 4 hours.
[0026] In some specific implementations, stirring is performed during the reduction reaction.
[0027] In this invention, in step S1, the solvent removal process is, for example, vacuum evaporation.
[0028] The absolute pressure of the vacuum evaporation is 100-5000 Pa, for example, 100 Pa, 500 Pa, 1000 Pa, 2000 Pa, 2500 Pa, 3000 Pa, 4000 Pa or 5000 Pa.
[0029] The temperature for vacuum evaporation is 20-50℃, for example, 20℃, 30℃, 35℃, 40℃ or 50℃.
[0030] The time for vacuum evaporation is 0.5-2 hours, for example, 0.5 hours, 1 hour, 1.5 hours or 2 hours.
[0031] In this invention, the oil phase includes a biotin intermediate.
[0032] In this invention, preferably, the extractant includes a first extractant and a second extractant, wherein the first extractant and the second extractant are immiscible.
[0033] Preferably, the first extractant is water and the second extractant is an organic solvent.
[0034] Preferably, the organic solvent includes one or more of toluene, ethyl acetate, benzene, n-hexane, and n-butane.
[0035] Preferably, the mass ratio of the second extractant to the (3aS,6aR)-biotin chiral lactone is 1:(0.1-1), for example, 0.2:1.
[0036] Preferably, the mass ratio of the first extractant to the (3aS,6aR)-biotin chiral lactone is (1-10):1, for example, 5:1 or 8:1.
[0037] In this invention, preferably, the extraction temperature is 20-60°C, for example, 20°C, 30°C, 40°C, 50°C or 60°C.
[0038] In this invention, preferably, the extraction time is 0.1-4h, for example 0.1h, 0.5h, 1h, 2h, 3h or 4h.
[0039] In this invention, preferably, the settling temperature is 20-60°C, for example, 20°C, 30°C, 40°C, 50°C or 60°C.
[0040] In this invention, preferably, the settling time is 0.1-4h, for example 0.1h, 0.5h, 1h, 2h, 3h or 4h.
[0041] In this invention, in step S3, preferably, the solvent removal process is rotary evaporation.
[0042] Preferably, the temperature of the rotary evaporation is 30-60°C, for example, 30°C, 40°C, 45°C, 50°C or 60°C.
[0043] Preferably, the rotary evaporation time is 0.5-4 hours, for example, 0.1 hours, 1 hour, 2 hours, 3 hours or 4 hours.
[0044] Preferably, the absolute pressure of the rotary evaporation is 100-5000 Pa, for example, 100 Pa, 500 Pa, 1000 Pa, 2000 Pa, 3000 Pa, 4000 Pa or 5000 Pa.
[0045] In this invention, preferably, after the solvent removal process in step S3, the process further includes washing and drying steps.
[0046] Preferably, the detergent used in the washing process includes one or more of toluene, ethyl acetate, benzene, n-hexane, and n-butane.
[0047] Preferably, the mass ratio of the detergent used in the washing process to the (3aS,6aR)-biotin chiral lactone is (0.1-1):1, for example, 0.2:1 or 0.3:1.
[0048] Preferably, the washing is performed 1-5 times, for example 3 times.
[0049] In some specific implementations, the detergent is removed by suction filtration after washing.
[0050] In this invention, there are no particular limitations on the drying method, as long as it can remove the detergent.
[0051] Preferably, the drying is oven drying.
[0052] The drying process, for example, is carried out using an oven.
[0053] Preferably, the drying temperature is 50-80°C, for example, 60°C or 70°C.
[0054] Preferably, the drying time is 1-12 hours, for example, 4 hours, 5 hours or 6 hours.
[0055] The present invention also provides a biotin intermediate substance prepared by the above-mentioned method for preparing biotin intermediate substances.
[0056] The present invention also provides a standard comprising the biotin intermediate as described above.
[0057] In this invention, preferably, the standard is composed of the biotin intermediate.
[0058] Preferably, the purity of the biotin intermediate is 95.9% or higher, for example, 96.1%, 96.8%, 97.8%, 98.0%, 98.5%, 99.0% or 99.3%.
[0059] The present invention also provides an application of the above-mentioned standard in the preparation of biotin.
[0060] In this invention, the standard can be used to test the conversion rate in biotin preparation.
[0061] In this invention, the standard can be used to test the purity of the product during the preparation process of biotin chiral lactone.
[0062] The tests may employ chromatography and / or mass spectrometry.
[0063] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.
[0064] The reagents and raw materials used in this invention are all commercially available.
[0065] The positive and progressive effects of this invention are as follows:
[0066] The method for preparing biotin intermediates provided by this invention can directly obtain high-purity biotin intermediates. This purity can be directly used as a standard for testing the conversion rate in biotin preparation and for testing the product purity in the preparation of biotin chiral lactones. The method for preparing biotin intermediates provided by this invention is simple, uses readily available raw materials, and is safe and environmentally friendly. Attached Figure Description
[0067] Figure 1 The mass spectrometry (ESI-MS) spectrum of Example 1 is shown.
[0068] Figure 2 This is the hydrogen spectrum of Example 1.
[0069] Figure 3 This is the carbon spectrum of Example 1. Detailed Implementation
[0070] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.
[0071] Example 1
[0072] First solution: Weigh 3.22g of (3aS,6aR)-biotin chiral lactone and dissolve it in 10g of tetrahydrofuran to form the first solution (the mass ratio of (3aS,6aR)-biotin chiral lactone to the first solvent is 1:3.1).
[0073] Second solution: LiBH4 is dissolved in tetrahydrofuran to form a second solution with a mass concentration of 10% (the mass ratio of reducing agent to second solvent is 1:9).
[0074] The preparation method of biotin intermediates includes the following steps:
[0075] S1. Mix the first solution and the second solution (controlling the mass ratio of (3aS,6aR)-biotin chiral lactone and reducing agent to 1:0.2) to carry out the reduction reaction (stirring during the reduction reaction, temperature 50℃, time 1h) and then desolventize to obtain the reactants.
[0076] The solvent removal process involves vacuum evaporation at an absolute pressure of 2500 Pa, a temperature of 35 °C, and a time of 1 hour.
[0077] S2. The reactants were extracted with water as the first extractant and toluene as the second extractant (at 50°C for 0.5 h), and then allowed to stand (at 50°C for 15 min) to obtain an aqueous phase and an oil phase.
[0078] The mass ratio of the second extractant to (3aS,6aR)-biotin chiral lactone is 5:1, and the mass ratio of the first extractant to (3aS,6aR)-biotin chiral lactone is 5:1.
[0079] S3. After solvent removal from the oil phase, the oil phase is washed and dried to obtain the biotin intermediate.
[0080] The solvent removal process involves rotary evaporation at a temperature of 40°C for 1 hour and an absolute pressure of 1000 Pa. After rotary evaporation, the dry solvent (toluene) is recovered to obtain a solid product.
[0081] In the washing process, toluene was used as the detergent, and the mass ratio of detergent to (3aS,6aR)-biotin chiral lactone was 0.2:1. The detergent was removed by filtration, and 0.2 times the amount of (3aS,6aR)-biotin chiral lactone was added as detergent. The washing was repeated 3 times, and the solid product turned white.
[0082] The solid product was placed in an oven and dried at 80°C for 6 hours to obtain 2.5g of biotin intermediate.
[0083] Example 2
[0084] First solution: Weigh 3.22g of (3aS,6aR)-biotin chiral lactone and dissolve it in 15g of tetrahydrofuran to form the first solution (the mass ratio of (3aS,6aR)-biotin chiral lactone to the first solvent is 1:4.6).
[0085] Second solution: LiBH4 is dissolved in tetrahydrofuran to form a second solution with a mass concentration of 20% (the mass ratio of reducing agent to second solvent is 1:4).
[0086] The preparation method of biotin intermediates includes the following steps:
[0087] S1. Mix the first solution and the second solution (controlling the mass ratio of (3aS,6aR)-biotin chiral lactone and reducing agent to 1:0.4) to carry out the reduction reaction (stirring during the reduction reaction, temperature 50℃, time 1h) and then desolventize to obtain the reactants.
[0088] The solvent removal process involves vacuum evaporation at an absolute pressure of 500 Pa, a temperature of 40 °C, and a time of 0.5 h.
[0089] S2. The reactants were extracted with water as the first extractant and n-hexane as the second extractant (at 50°C for 0.5 h), and then allowed to stand (at 50°C for 15 min) to obtain an aqueous phase and an oil phase.
[0090] The mass ratio of the second extractant to (3aS,6aR)-biotin chiral lactone is 5:1, and the mass ratio of the first extractant to (3aS,6aR)-biotin chiral lactone is 5:1.
[0091] S3. After solvent removal from the oil phase, the oil phase is washed and dried to obtain the biotin intermediate.
[0092] The solvent removal process involves rotary evaporation at 45°C for 2 hours under an absolute pressure of 1000 Pa. After rotary evaporation, the dry solvent (n-hexane) is recovered to obtain a solid product.
[0093] In the washing process, hexane was used as the detergent, and the mass ratio of detergent to (3aS,6aR)-biotin chiral lactone was 0.3:1. The detergent was removed by filtration, and 0.3 times the amount of (3aS,6aR)-biotin chiral lactone was added as detergent. The washing was repeated 3 times, and the solid product turned white.
[0094] The solid product was placed in an oven and dried at 70°C for 5 hours to obtain 2.3g of biotin intermediate.
[0095] Example 3
[0096] First solution: Weigh 3.22g of (3aS,6aR)-biotin chiral lactone and dissolve it in 10g of tetrahydrofuran to form the first solution (the mass ratio of (3aS,6aR)-biotin chiral lactone to the first solvent is 1:3.1).
[0097] Second solution: NaBH4 is dissolved in tetrahydrofuran to form a second solution with a mass concentration of 20% (the mass ratio of reducing agent to second solvent is 1:4).
[0098] The preparation method of biotin intermediates includes the following steps:
[0099] S1. Mix the first solution and the second solution (controlling the mass ratio of (3aS,6aR)-biotin chiral lactone and reducing agent to 1:0.3) to carry out the reduction reaction (stirring during the reduction reaction, temperature 40℃, time 2h) and then desolventize to obtain the reactants.
[0100] The solvent removal process involves vacuum evaporation at an absolute pressure of 2500 Pa, a temperature of 35 °C, and a time of 1 hour.
[0101] S2. The reactants were extracted with water as the first extractant and ethyl acetate as the second extractant (at 50°C for 1 hour), and then allowed to stand (at 50°C for 30 minutes) to obtain an aqueous phase and an oil phase.
[0102] The mass ratio of the second extractant to (3aS,6aR)-biotin chiral lactone is 5:1, and the mass ratio of the first extractant to (3aS,6aR)-biotin chiral lactone is 5:1.
[0103] S3. After solvent removal from the oil phase, the oil phase is washed and dried to obtain the biotin intermediate.
[0104] The solvent removal process involved rotary evaporation at 40°C for 1 hour under an absolute pressure of 1000 Pa. After rotary evaporation, the dry solvent (ethyl acetate) was recovered to obtain a solid product.
[0105] In the washing process, ethyl acetate was used as the detergent, and the mass ratio of detergent to (3aS,6aR)-biotin chiral lactone was 0.3:1. The detergent was removed by filtration, and 0.3 times the amount of (3aS,6aR)-biotin chiral lactone was added as detergent. The washing was repeated 3 times, and the solid product turned white.
[0106] The solid product was placed in an oven and dried at 60°C for 4 hours to obtain 2.0 g of biotin intermediate.
[0107] Example 4
[0108] The first and second solutions are the same as in Example 1.
[0109] In the preparation method of biotin intermediate, the second extractant and detergent in steps S2 and S3 are replaced with n-butane, and the other conditions are the same as in Example 1.
[0110] 1.8g of biotin intermediate was obtained.
[0111] Example 5
[0112] The first and second solutions are the same as in Example 1.
[0113] In the preparation method of biotin intermediate, the standing temperature in step S2 is replaced with 60°C and the time is replaced with 4 hours, while the other conditions are the same as in Example 1.
[0114] 1.7g of biotin intermediate was obtained.
[0115] Example 6
[0116] First solution: Weigh 3.22g of (3aS,6aR)-biotin chiral lactone and dissolve it in 20g of tetrahydrofuran to form the first solution (the mass ratio of (3aS,6aR)-biotin chiral lactone to the first solvent is 1:6.2).
[0117] The second solution and the biotin intermediate were prepared using the same method as in Example 1, yielding 2.2 g of biotin intermediate.
[0118] Example 7
[0119] The first solution is the same as in Example 1.
[0120] Second solution: LiBH4 is dissolved in tetrahydrofuran to form a second solution with a mass concentration of 20% (the mass ratio of reducing agent to second solvent is 1:4).
[0121] In the preparation method of biotin intermediate, the mass ratio of (3aS,6aR)-biotin chiral lactone to reducing agent was controlled at 1:0.4, and the other conditions were the same as in Example 1, yielding 2.0g of biotin intermediate.
[0122] Example 8
[0123] The first and second solutions are the same as in Example 1.
[0124] In the preparation method of biotin intermediate, in step S2, the mass ratio of the second extractant to (3aS,6aR)-biotin chiral lactone is 8:1, the mass ratio of the first extractant to (3aS,6aR)-biotin chiral lactone is 8:1, and the other conditions are the same as in Example 1.
[0125] 2.1g of biotin intermediate was obtained.
[0126] Example 9
[0127] In the first solution, tetrahydrofuran was replaced with 2-methyltetrahydrofuran, and the other conditions were the same as in Example 1.
[0128] In the second solution, LiBH4 was replaced with Ca(BH4)2, and the other conditions were the same as in Example 1.
[0129] The preparation method of the biotin intermediate is the same as in Example 1.
[0130] 1.6g of biotin intermediate was obtained.
[0131] Example 10
[0132] In the first solution, tetrahydrofuran was replaced with 1,4-dioxane, and the other conditions were the same as in Example 1.
[0133] In the second solution, LiBH4 was replaced with Ca(BH4)2, and the other conditions were the same as in Example 1.
[0134] The preparation method of the biotin intermediate is the same as in Example 1.
[0135] 1.6g of biotin intermediate was obtained.
[0136] Comparative Example 1
[0137] In the preparation method of biotin intermediate, the reducing agent LiBH4 is not added, and the other conditions are the same as in Example 1.
[0138] Comparative Example 1 could not obtain biotin intermediates.
[0139] Comparative Example 2
[0140] The first and second solutions are the same as in Example 1.
[0141] In the preparation method of biotin intermediate, the standing temperature in step S2 is replaced with 80°C and the time is replaced with 6 hours, while the other conditions are the same as in Example 1.
[0142] 1.3g of biotin intermediate was obtained.
[0143] Comparative Example 3
[0144] The first and second solutions are the same as in Example 1.
[0145] In the preparation method of biotin intermediate, step S2 is omitted, that is, the reactants obtained in S1 are directly subjected to rotary evaporation, washing and drying to remove tetrahydrofuran, and the remaining conditions are the same as in Example 1.
[0146] 4.2g of biotin intermediate was obtained.
[0147] Example 1
[0148] The biotin intermediates obtained in the examples and comparative examples were subjected to the following tests:
[0149] 1. Mass spectrometry (ESI-MS) test: The test instrument is a QDa mass spectrometer detector manufactured by Waters Corporation. The test method and data processing method are as follows: In positive ion mode, a full scan of ions in the m / z range of 50-1250 is performed. The data is processed in a centered manner and the average mass spectrum of the chromatographic peak is displayed. The cone voltage is 25V.
[0150] 2. Nuclear Magnetic Resonance (NMR) Test: The testing instrument was a nuclear magnetic resonance spectrometer manufactured by Bruker AG, Switzerland, with proton (H) spectrum. 1 The H NMR test conditions were as follows: deuterated dimethyl sulfoxide (DMSO-d6) was used as the solvent, tetramethylsilane (TMS) was used as the internal standard, and the measurement frequency was 400.2 MHz. Figure 3 For carbon spectrum ( 13 The C NMR test conditions were as follows: DMSO-d6 was used as the solvent, and the measurement frequency was 100.6 MHz. All tests were performed at 25°C.
[0151] The mass spectrometry (ESI-MS) spectrum of Example 1 is as follows: Figure 1 As shown, the proton spectrum of Example 1 is as follows: Figure 2 As shown, the carbon spectrum of Example 1 is as follows: Figure 3 As shown.
[0152] According to Figure 1-3 As can be seen, the structural formula of the biotin intermediate in Example 1 is shown in Formula II below.
[0153]
[0154] II.
[0155] Example 2
[0156] The purity of the biotin intermediates obtained in the examples and comparative examples was tested under the following conditions:
[0157] High-performance liquid chromatography (HPLC) was used for testing. The chromatographic column was a C18 packing material with an average particle diameter of 5 μm, a column diameter of 4.6 mm, and a length of 250 mm.
[0158] Detection wavelength: 210 nm; flow rate: 1.0 mL / min; column temperature: 30 ℃; injection volume: 10 μL; run time: 35 min.
[0159] The gradient elution procedure is listed in Table 1:
[0160] Table 1
[0161]
[0162] The mobile phase A was acetonitrile:buffer salt = 20:80 (v / v); the mobile phase B was acetonitrile:buffer salt = 80:20 (v / v); and the diluent was acetonitrile:water = 50:50 (v / v). Buffer salt preparation: 1.35 g of potassium dihydrogen phosphate was dissolved in 0.45 mL of phosphoric acid in 500 mL of purified water, filtered, and degassed.
[0163] The test results are listed in Table 2.
[0164] Table 2
[0165]
[0166] As can be seen from the above, the method for preparing biotin intermediates provided by this invention can directly obtain biotin intermediates with a purity of over 95.9%. This purity of biotin intermediate can be directly used as a standard for testing the conversion rate in biotin preparation and for testing the purity of products in the preparation of biotin chiral lactones. The method for preparing biotin intermediates provided by this invention is simple, uses readily available raw materials, and is safe and environmentally friendly.
[0167] Compared with Comparative Example 1 and the Example, without the addition of a reducing agent, the biotin intermediate could not be obtained.
[0168] Compared with Comparative Example 2 and the Example, the temperature of the static setting was too high, which caused the purity of the biotin intermediate to decrease significantly to 41.5%.
[0169] In Comparative Example 3, step S2 was omitted, resulting in a significant decrease in the purity of the biotin intermediate to 53.3%.
[0170] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.
Claims
1. A method for preparing a biotin intermediate, characterized in that, It includes the following steps: S1. After reducing the first and second solutions, the solvent is removed to obtain the reactants. The first solution comprises (3aS,6aR)-biotin chiral lactone and a first solvent, and the second solution comprises a reducing agent and a second solvent. S2. The reactants are extracted with an extractant and then allowed to stand to obtain an aqueous phase and an oil phase; the standing temperature is 20-75℃. S3. The oil phase is subjected to solvent removal treatment to obtain the biotin intermediate substance.
2. The method for preparing the biotin intermediate as described in claim 1, characterized in that, It includes one or more of the following conditions: (a) The mass ratio of the (3aS,6aR)-biotin chiral lactone to the first solvent is 1:(1-5), for example 1:1, 1:2, 1:3, 1:3.1, 1:4, 1:4.6, 1:5 or 1:6.2; (b) The mass ratio of the reducing agent to the second solvent is 1:(4-20), for example, 1:5, 1:9, 1:10, 1:15 or 1:20; (c) The mass ratio of the (3aS,6aR)-biotin chiral lactone to the reducing agent is 1:(0.2-1), for example, 1:0.2, 1:0.3, 1:0.4, 1:0.6, 1:0.8 or 1:
1.
3. The method for preparing the biotin intermediate as described in claim 1, characterized in that, It includes one or more of the following conditions: (a) The first solvent and the second solvent are of the same type; (b) The first solvent comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; (c) The second solvent comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; (d) The reducing agent includes one or more of LiBH4, NaBH4, KBH4, Zn(BH4)2, Ca(BH4)2, NaBH(OAc)3 and NaBH3CN.
4. The method for preparing the biotin intermediate as described in claim 1, characterized in that, It includes one or more of the following conditions: (a) The temperature of the reduction reaction is 10-100°C, for example, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; (b) The reduction reaction takes 0.5-4 hours, for example, 0.5 hours, 1 hour, 2 hours, 3 hours or 4 hours; (c) In step S1, the solvent removal process is, for example, vacuum evaporation; The absolute pressure of the vacuum evaporation is 100-5000 Pa, for example, 100 Pa, 500 Pa, 1000 Pa, 2000 Pa, 2500 Pa, 3000 Pa, 4000 Pa or 5000 Pa. The temperature for vacuum drying is 20-50℃, for example, 20℃, 30℃, 35℃, 40℃ or 50℃; The time for vacuum evaporation is 0.5-2 hours, for example, 0.5 hours, 1 hour, 1.5 hours or 2 hours.
5. The method for preparing the biotin intermediate as described in claim 1, characterized in that, It includes one or more of the following conditions: (a) The extractant comprises a first extractant and a second extractant, wherein the first extractant and the second extractant are immiscible; Preferably, the first extractant is water and the second extractant is an organic solvent; Preferably, the organic solvent includes one or more of toluene, ethyl acetate, benzene, n-hexane, and n-butane; Preferably, the mass ratio of the second extractant to the (3aS,6aR)-biotin chiral lactone is 1:(0.1-1), for example, 0.2:1; Preferably, the mass ratio of the first extractant to the (3aS,6aR)-biotin chiral lactone is (1-10):1, for example, 5:1 or 8:1; (b) The extraction temperature is 20-60°C, for example, 20°C, 30°C, 40°C, 50°C or 60°C.
6. The method for preparing the biotin intermediate as described in claim 1, characterized in that, It includes one or more of the following conditions: (a) The settling time is 0.1-4h, for example 0.1h, 0.5h, 1h, 2h, 3h or 4h; (b) The settling temperature is 20-60°C, for example, 20°C, 30°C, 40°C, 50°C or 60°C; (c) In step S3, the solvent removal process is rotary evaporation; Preferably, the temperature of the rotary evaporation is 30-60°C, for example, 30°C, 40°C, 45°C, 50°C or 60°C; Preferably, the rotary evaporation time is 0.5-4 hours, for example, 0.1 hours, 1 hour, 2 hours, 3 hours or 4 hours; Preferably, the absolute pressure of the rotary evaporation is 100-5000 Pa, for example, 100 Pa, 500 Pa, 1000 Pa, 2000 Pa, 3000 Pa, 4000 Pa or 5000 Pa.
7. The method for preparing the biotin intermediate as described in claim 1, characterized in that, After the solvent removal process in step S3, the steps of washing and drying are also included in sequence. Preferably, the detergent used in the washing process includes one or more of toluene, ethyl acetate, benzene, n-hexane, and n-butane. Preferably, the mass ratio of the detergent used in the washing process to the (3aS,6aR)-biotin chiral lactone is (0.1-1):1, for example, 0.2:1 or 0.3:1; Preferably, the number of washes is 1-5 times, for example, 3 times; Preferably, the drying is oven drying; The drying process is carried out, for example, using an oven; Preferably, the drying temperature is 50-80°C, for example, 60°C or 70°C; Preferably, the drying time is 1-12 hours, for example, 4 hours, 5 hours or 6 hours.
8. A biotin intermediate substance prepared by a method according to any one of claims 1-7.
9. A standard product, characterized in that, It includes the biotin intermediate as described in claim 8; Preferably, the standard is composed of the biotin intermediate substance; Preferably, the purity of the biotin intermediate is 95.9% or higher, for example, 96.1%, 96.8%, 97.8%, 98.0%, 98.5%, 99.0% or 99.3%.
10. The application of the standard as described in claim 9 in the preparation of biotin.