Preparation method of carprorelin intermediate based on catalytic oxidation of yeast alcohol dehydrogenase

Abstract

The invention discloses a preparation method of a carptorelin intermediate based on catalytic oxidation of yeast alcohol dehydrogenase, which comprises the following operation steps of: generating an intermediate product 1 from N-Boc-4-piperidinol by adopting a method of catalytic oxidation of yeast alcohol dehydrogenase oxidase, purifying, adding semicarbazide, and reacting to obtain the carptorelin intermediate. The preparation method comprises the following steps: reacting at least one of tert-butyloxycarboryl hydrazine or methyl carbazate with alkali to generate an intermediate product 2, adding DMF-DMA to react with alkali to generate an intermediate product 3, adding benzyl bromide to react with basic salt to generate an intermediate product 4, and adding acid to react to generate the carprorelin intermediate. According to the method, a brand new synthesis route is used, the semicarbazide which is low in price and easy to obtain is adopted in the new process route, hydrazine hydrate which seriously pollutes a water body is prevented from being used, highly toxic methylhydrazine is prevented from being used, a shrinkage process and a micro-channel continuous flow process can be adopted in the synthesis steps, and the method is simple in process, high in yield, good in safety and high in product quality.

Description

Technical Field

[0001] The invention relates to the field of synthesis of caprorelin intermediates, and in particular to a method for preparing a caprorelin intermediate based on yeast alcohol dehydrogenase-catalyzed oxidation. Background Art

[0002] As a growth hormone releasing peptide agonist, caprorelin can be used to induce hunger, increase appetite, treat long-term loss of appetite, anorexia, and alleviate the phenomenon of long-term weight loss in mammals due to drug treatment. The existing preparation methods of caprorelin intermediates mostly adopt the following methods: Figure 1 The process route for preparation uses expensive raw materials, and in the synthesis step, methylhydrazine needs to be used, which is highly toxic and explosive, resulting in high cost of the existing preparation method, environmental pollution, and safety hazards in the production process.

[0003] On this basis, the inventors developed Figure 2 The process route is to first use hydrazine hydrate in the synthesis process, and then methylate to avoid the use of methylhydrazine, but the hydrazine hydrate used in the above steps will also pollute the water body, and the product yield is low; on this basis, the inventors developed the synthesis method of the present invention, such as Figure 3 The process route is used to prepare caprelin intermediates. The new process route avoids the use of hydrazine hydrate that seriously pollutes water bodies, avoids the use of highly toxic methylhydrazine, and uses cheap and easily available aminourea. In addition, the intermediate steps can use a telescopic process and a microchannel continuous flow process. The process is simple, the yield is high, the safety is good, and the product quality is high. Summary of the invention

[0004] Based on the above research results, the present invention discloses a method for preparing a caprorelin intermediate based on yeast alcohol dehydrogenase catalytic oxidation, comprising the following steps: N-Boc-4-piperidinol is subjected to yeast alcohol dehydrogenase oxidase catalytic oxidation to generate intermediate 1, after purification, at least one of semicarbazide, tert-butyloxycarbonylhydrazine or methyl carbazate and a base are added to generate intermediate 2, then DMF-DMA and a base are added to generate intermediate 3, then benzyl bromide and a basic salt are added to generate intermediate 4, and then an acid is added to generate a caprorelin intermediate. The present invention uses a completely new synthesis route, and the new process route avoids the use of hydrazine hydrate that seriously pollutes water bodies, avoids the use of highly toxic methylhydrazine, and uses cheap and readily available semicarbazide, and the intermediate steps can use a telescoping process and a microchannel continuous flow process, with a simple process, high yield, good safety, and high product quality.

[0005] Specifically, the present invention provides a method for preparing a caprelin intermediate based on yeast alcohol dehydrogenase-catalyzed oxidation, see Figure 3 As shown, the following steps are included:

[0006] S1: adding N-Boc-4-piperidinol to an organic solvent, adding oxidized coenzyme nicotinamide adenine dinucleotide and yeast alcohol dehydrogenase, and reacting to obtain an intermediate product 1, wherein the structural formula of the N-Boc-4-piperidinol is shown in a1, and the structural formula of the intermediate product 1 is shown in a2;

[0007]

[0008] S2: adding the intermediate product 1 to deionized water, adding raw material a and a base, and reacting to obtain the intermediate product 2, wherein the structural formula of the intermediate product 2 is shown in a5; the raw material a is selected from semicarbazide, tert-butyloxycarbonylhydrazine or methyl carbazate;

[0009]

[0010] S3: mixing the intermediate product 2, N,N-dimethylformamide dimethyl acetal, i.e., DMF-DMA, and a base to react to obtain an intermediate product 3, the structural formula of the intermediate product 3 is shown in a6;

[0011]

[0012] S4: adding the intermediate product 3, benzyl bromide and basic salt to an organic solvent to react to obtain an intermediate product 4, the structural formula of the intermediate product 4 is shown in a7;

[0013]

[0014] S5: adding the intermediate product 4 and the acid to an organic solvent to react to obtain a caprorelin intermediate, the structure of which is shown in a8;

[0015]

[0016] Furthermore, in step S1, the solvent is selected from dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, and n-heptane; the molar concentration of the oxidized coenzyme nicotinamide adenine dinucleotide in the solution is above 10 mM, the mass ratio of the yeast alcohol dehydrogenase to N-Boc-4-piperidinol is not less than 0.1:50, the enzyme activity of the yeast alcohol dehydrogenase is 1.8 u / mg, the reaction temperature is 15-40°C, and the reaction time is 8-16 h.

[0017] Furthermore, in step S1, the solvent is dichloromethane, the reaction temperature is 25° C., and the reaction time is 12 h.

[0018] Furthermore, in step S2, the molar ratio of the intermediate product 1, the raw material a and the base is 1:1.5-3:3-6, the reaction temperature is 55-80°C, and the reaction time is 8-16h.

[0019] Furthermore, in step S2, the raw material a is semicarbazide, the base is sodium hydroxide, the molar ratio of the intermediate product 1, semicarbazide and NaOH is 1:2:4, the reaction temperature is 75°C, and the reaction time is 12h.

[0020] Furthermore, in step S3, the molar ratio of the intermediate product 2, DMF-DMA and the base is 1:2-4:4-8, the reaction temperature is 60-90°C, and the reaction time is 8-16h.

[0021] Furthermore, in step S3, the base is sodium hydroxide, the molar ratio of the intermediate product 2, DMF-DMA and NaOH is 1:3:6, the reaction temperature is 85° C., and the reaction time is 10 h.

[0022] Furthermore, in step S4, the solvent is selected from DMF or tetrahydrofuran, the basic salt is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the molar ratio of the intermediate product 3, benzyl bromide and the base is 1:1.2-1.5:1-1.5; the reaction temperature is 15-40°C, and the reaction time is 16-48h.

[0023] Furthermore, in step S5, the solvent is selected from dichloromethane or ethyl acetate; the acid is selected from hydrochloric acid and trifluoroacetic acid; the molar ratio of the intermediate product 4 to the acid is 1:3-5, the reaction temperature is 25-40°C, and the reaction time is 2-4h.

[0024] Furthermore, in step S4, the solvent is selected from DMF, the base is selected from potassium carbonate; the molar ratio of the intermediate product 3, benzyl bromide and potassium carbonate is 1:1.35:1.25; the reaction temperature is 25°C, and the reaction time is 48h;

[0025] Furthermore, in step S5, the solvent is selected from ethyl acetate; the molar ratio of the intermediate product 4 to the acid is 1:4, the reaction temperature is 25° C., and the reaction time is 2 h.

[0026] Beneficial technical effects

[0027] Compared with the prior art, the present invention provides a new process route for preparing a caprelin intermediate, which avoids the use of hydrazine hydrate that seriously pollutes water bodies, avoids the use of highly toxic methylhydrazine, and adopts cheap and readily available semicarbazide, and the intermediate steps can adopt a telescoping process and a microchannel continuous flow process, and the process is simple, the yield is high, the safety is good, and the product quality is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a synthetic process route map in the prior art.

[0029] Figure 2This is the improved synthetic process route for the intermediate.

[0030] Figure 3 The synthetic process route diagram of the present invention is shown in FIG.

[0031] Figure 4 The NMR spectrum of the intermediate product 4 of the present invention is DETAILED DESCRIPTION

[0032] The technical scheme of the present invention will be clearly and completely described below in conjunction with the accompanying drawings and specific embodiments, but it will be understood by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. If specific conditions are not specified in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0033] See also Figure 3 As shown, the structural formula of N-Boc-4-piperidinol in the present invention is shown as a1, the structural formula of intermediate product 1 is shown as a2; the structural formula of intermediate product 2 is shown as a5; the structural formula of intermediate product 3 is shown as a6, the structural formula of intermediate product 4 is shown as a7, and the structural formula of caprorelin intermediate is shown as a8;

[0034] Embodiment 1:

[0035] S1: Add 50g N-Boc-4-piperidinol to 75g dichloromethane, add oxidized coenzyme nicotinamide adenine dinucleotide until the molar concentration in the solution reaches 10mM, stir at 15℃ for 10min, add 0.1g yeast alcohol dehydrogenase, the enzyme activity is 1.8u / mg, keep at 15℃ for 16h, after the reaction is completed, add water, desolventize, white solid precipitates, wash the filter cake with appropriate amount of water, dry to obtain intermediate 1, yield: 94.5%, purity: 98.5%;

[0036] S2: 50g of intermediate product 1 was added to 100g of deionized water, and then 28.26g of semicarbazide and 30.11g of NaOH were added, wherein the molar ratio of intermediate product 1, semicarbazide and NaOH was 1:1.5:3, and the mixture was stirred and heated to 55°C for reaction for 16h. After the reaction was completed, the mixture was cooled to room temperature, and a white solid was precipitated. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 2; yield: 90.3%, purity: 98.7%;

[0037] S3: 50 g of intermediate product 2, 49.83 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) and 33.43 g of NaOH were mixed, wherein the molar ratio of the intermediate product 2, DMF-DMA and NaOH was 1:2:4, and the mixture was stirred and heated to 60°C for reaction for 16 h. After the reaction, intermediate product 3 was obtained; yield: 85.3%, purity: 99.5%;

[0038] S4: Add 50g of intermediate product 3 to 100g of DMF, add 66.94g of benzyl bromide and 27.27g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.2:1; keep at 15°C for 48h, after the reaction is completed, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 96.3%, purity: 98.5%;

[0039] S5: Add 50 g of the intermediate product 4 to 100 g of ethyl acetate, add 45.50 g of 36 wt% hydrochloric acid, the molar ratio of the intermediate product 4 to the hydrochloric acid is 1:3, stir and react at 25°C for 4 h. After the reaction is completed, desolventize, adjust the pH to 7, wash the filter cake with an appropriate amount of water to obtain the caprelin intermediate, with a yield of 98.0% and a purity of 99.0%.

[0040] Embodiment 2:

[0041] S1: Add 50g N-Boc-4-piperidinol to 75g dichloromethane, add oxidized coenzyme nicotinamide adenine dinucleotide until the molar concentration in the solution reaches 10mM, stir at 40℃ for 10min, add 0.1g yeast alcohol dehydrogenase, the enzyme activity is 1.8u / mg, keep at 40℃ for 8h, after the reaction is completed, add water, desolventize, white solid precipitates, wash the filter cake with appropriate amount of water, dry to obtain intermediate 1, yield: 95.0%, purity: 97.5%;

[0042] S2: 50g of intermediate product 1 was added to 100g of deionized water, and then 56.52g of semicarbazide and 60.23g of NaOH were added, wherein the molar ratio of intermediate product 1, semicarbazide and NaOH was 1:3:6, and the mixture was stirred and heated to 80°C for reaction for 8h. After the reaction was completed, the mixture was cooled to room temperature, and a white solid was precipitated. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 2; yield: 90.5%, purity: 98.0%;

[0043] S3: 50 g of intermediate product 2, 99.65 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) and 66.87 g of NaOH were mixed, wherein the molar ratio of the intermediate product 2, DMF-DMA and NaOH was 1:4:8, and the mixture was stirred and heated to 90°C for reaction for 8 h. After the reaction, intermediate product 3 was obtained; yield: 85.5%, purity: 99.0%;

[0044] S4: Add 50g of intermediate product 3 to 100g of DMF, add 83.68g of benzyl bromide and 40.91g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.5:1.5; keep warm at 40°C for 16h, after the reaction is completed, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 96.5%, purity: 98.2%;

[0045] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 75.83g of 36wt% hydrochloric acid, the molar ratio of the intermediate product 4 to the hydrochloric acid is 1:5, stir and react at 40°C for 2h. After the reaction is completed, desolventize, adjust the pH to 7, wash the filter cake with appropriate amount of water to obtain caprelin intermediate, yield: 97.8%, purity: 99.2%.

[0046] Embodiment 3:

[0047] S1: Add 50g N-Boc-4-piperidinol to 75g dichloromethane, add oxidized coenzyme nicotinamide adenine dinucleotide until the molar concentration in the solution reaches 10mM, stir at 25℃ for 10min, add 0.1g yeast alcohol dehydrogenase, the enzyme activity is 1.8u / mg, keep at 25℃ for 12h, after the reaction is completed, add water, desolventize, white solid precipitates, wash the filter cake with appropriate amount of water, dry to obtain intermediate 1, yield: 97.3%, purity: 98.5%;

[0048] S2: 50g of intermediate product 1 was added to 100g of deionized water, and then 37.68g of semicarbazide and 40.15g of NaOH were added, wherein the molar ratio of intermediate product 1, semicarbazide and NaOH was 1:2:4, and the mixture was stirred and heated to 75°C for 12h. After the reaction was completed, the mixture was cooled to room temperature, and a white solid was precipitated. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 2; yield: 92.5%, purity: 98.7%;

[0049] S3: 50 g of intermediate product 2, 74.74 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) and 50.15 g of NaOH were mixed, wherein the molar ratio of the intermediate product 2, DMF-DMA and NaOH was 1:3:6, and the mixture was stirred and heated to 85°C for 10 h. After the reaction, intermediate product 3 was obtained; yield: 87.3%, purity: 99.5%;

[0050] S4: Add 50g of intermediate product 3 to 100g of DMF, add 75.31g of benzyl bromide and 34.09g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.35:1.25; keep warm at 25°C for 48h, after the reaction is completed, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 97.3%, purity: 98.5%;

[0051] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 60.66g of 36wt% hydrochloric acid, the molar ratio of the intermediate product 4 to the hydrochloric acid is 1:4, stir and react at 25°C for 2h. After the reaction is completed, desolventize, adjust the pH to 7, wash the filter cake with appropriate amount of water to obtain caprelin intermediate, yield: 98.5%, purity: 99.5%.

[0052] Embodiment 4:

[0053] S1: Add 50g N-Boc-4-piperidinol to 75g toluene, add oxidized coenzyme nicotinamide adenine dinucleotide until the molar concentration in the solution reaches 10mM, stir at 25℃ for 10min, add 0.1g yeast alcohol dehydrogenase, the enzyme activity is 1.8u / mg, keep at 25℃ for 12h, after the reaction is completed, add water, desolventize, white solid precipitates, wash the filter cake with appropriate amount of water, dry to obtain intermediate 1, yield: 97.0%, purity: 98.2%;

[0054] S2: 50g of intermediate product 1 was added to 100g of deionized water, and then 37.68g of semicarbazide and 40.15g of NaOH were added, wherein the molar ratio of intermediate product 1, semicarbazide and NaOH was 1:2:4, and the mixture was stirred and heated to 75°C for 12h. After the reaction was completed, the mixture was cooled to room temperature, and a white solid was precipitated. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 2; yield: 92.5%, purity: 98.7%;

[0055] S3: 50 g of intermediate product 2, 74.74 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) and 50.15 g of NaOH were mixed, wherein the molar ratio of the intermediate product 2, DMF-DMA and NaOH was 1:3:6, and the mixture was stirred and heated to 85°C for 10 h. After the reaction, intermediate product 3 was obtained; yield: 87.3%, purity: 99.5%;

[0056] S4: Add 50g of intermediate product 3 to 100g of tetrahydrofuran, add 75.31g of benzyl bromide and 34.09g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.35:1.25; keep warm at 25°C for 48h, after the reaction is completed, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 97.2%, purity: 98.2%;

[0057] S5: Add 50g of the intermediate product 4 to 100g of dichloromethane, add 60.66g of 36wt% hydrochloric acid, the molar ratio of the intermediate product 4 to the hydrochloric acid is 1:4, stir and react at 25°C for 2h. After the reaction is completed, desolventize, adjust the pH to 7, wash the filter cake with an appropriate amount of water to obtain the caprelin intermediate, with a yield of 98.4% and a purity of 99.3%.

[0058] Embodiment 5:

[0059] S1: Add 50g N-Boc-4-piperidinol to 75g dichloromethane, add oxidized coenzyme nicotinamide adenine dinucleotide until the molar concentration in the solution reaches 10mM, stir at 20℃ for 10min, add 0.1g yeast alcohol dehydrogenase, the enzyme activity is 1.8u / mg, keep at 20℃ for 12h, after the reaction is completed, add water, desolventize, white solid precipitates, wash the filter cake with appropriate amount of water, dry to obtain intermediate 1, yield: 96.0%, purity: 97.8%;

[0060] S2: 50g of intermediate product 1 was added to 100g of deionized water, and then 47.1g of semicarbazide and 50.19g of NaOH were added, wherein the molar ratio of intermediate product 1, semicarbazide and NaOH was 1:2.5:5, and the mixture was stirred and heated to 60°C for 10h. After the reaction was completed, the mixture was cooled to room temperature, and a white solid was precipitated. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 2; the yield was 92.2%, and the purity was 98.0%;

[0061] S3: 50 g of intermediate product 2, 74.74 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) and 41.79 g of NaOH were mixed, wherein the molar ratio of the intermediate product 2, DMF-DMA and NaOH was 1:3:5, and the mixture was stirred and heated to 70°C for reaction for 15 h. After the reaction, intermediate product 3 was obtained; yield: 86.2%, purity: 98.8%;

[0062] S4: Add 50g of intermediate product 3 to 100g of DMF, add 78.10g of benzyl bromide and 32.73g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.4:1.2; keep warm at 30°C for 32h, after the reaction is completed, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 98.2%, purity: 98.3%;

[0063] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 53.08g of 36wt% hydrochloric acid, the molar ratio of the intermediate product 4 to the hydrochloric acid is 1:3.5, stir and react at 40°C for 3h. After the reaction is completed, desolventize, adjust the pH to 7, wash the filter cake with appropriate amount of water to obtain caprelin intermediate, yield: 98.3%, purity: 99.4%.

[0064] Embodiment 6:

[0065] S1: Add 50g N-Boc-4-piperidinol to 75g dichloromethane, add oxidized coenzyme nicotinamide adenine dinucleotide until the molar concentration in the solution reaches 10mM, stir at 35℃ for 10min, add 0.1g yeast alcohol dehydrogenase, the enzyme activity is 1.8u / mg, keep at 35℃ for 10h, after the reaction, add water, desolventize, white solid precipitates, wash the filter cake with appropriate amount of water, dry to obtain intermediate 1, yield: 96.5%, purity: 98.1%;

[0066] S2: 50g of intermediate product 1 was added to 100g of deionized water, and then 47.1g of semicarbazide and 40.15g of NaOH were added, wherein the molar ratio of intermediate product 1, semicarbazide and NaOH was 1:2.5:4, and the mixture was stirred and heated to 65°C for 12h. After the reaction was completed, the mixture was cooled to room temperature, and a white solid was precipitated. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 2; yield: 91.5%, purity: 98.2%;

[0067] S3: 50 g of intermediate product 2, 99.65 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) and 50.15 g of NaOH were mixed, wherein the molar ratio of the intermediate product 2, DMF-DMA and NaOH was 1:4:6, and the mixture was stirred and heated to 75°C for reaction for 12 h. After the reaction, intermediate product 3 was obtained; yield: 87.0%, purity: 99.2%;

[0068] S4: Add 50g of intermediate product 3 to 100g of DMF, add 83.68g of benzyl bromide and 34.09g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.5:1.25; keep warm at 20°C for 36h, after the reaction is completed, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 98.2%, purity: 98.3%;

[0069] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 60.66g of 36wt% hydrochloric acid, the molar ratio of the intermediate product 4 to the hydrochloric acid is 1:4, stir and react at 40°C for 2h. After the reaction is completed, desolventize, adjust the pH to 7, wash the filter cake with appropriate amount of water to obtain caprelin intermediate, yield: 98.5%, purity: 99.2%.

[0070] like Figure 4 It can be seen that the synthesis process of the present invention has successfully synthesized the intermediate product 4. It can be seen from Examples 1-6 of the present invention that the caprelin intermediate is successfully prepared through the new process route. The new process route avoids the use of hydrazine hydrate that seriously pollutes water bodies, avoids the use of highly toxic methylhydrazine, and adopts cheap and readily available aminourea. In addition, the yield and purity of the intermediate steps are relatively high. Except for the yield of step 3 being more than 85%, the yields of other steps are all above 94%, and the purity is all above 97%. Example 3 of the present invention is the optimal embodiment, and its yield and purity basically reach the highest values. Since the yield and purity of the process steps of the present invention are relatively high, the intermediate steps can adopt the telescopic process and the microchannel continuous flow process, which can be continuously produced and the process is simplified.

[0071] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A method for preparing a caprelin intermediate based on yeast alcohol dehydrogenase-catalyzed oxidation, characterized in that: The following steps are involved: S1: adding N-Boc-4-piperidinol to an organic solvent, adding oxidized coenzyme nicotinamide adenine dinucleotide and yeast alcohol dehydrogenase, and reacting to obtain an intermediate product 1, wherein the structural formula of the N-Boc-4-piperidinol is shown in a1, and the structural formula of the intermediate product 1 is shown in a2; S2: adding the intermediate product 1 to deionized water, adding raw material a and a base, and reacting to obtain the intermediate product 2, wherein the structural formula of the intermediate product 2 is shown in a5; the raw material a is selected from semicarbazide, tert-butyloxycarbonylhydrazine or methyl carbazate; S3: mixing the intermediate product 2, N,N-dimethylformamide dimethyl acetal, i.e., DMF-DMA, and a base to react to obtain an intermediate product 3, the structural formula of the intermediate product 3 is shown in a6; S4: adding the intermediate product 3, benzyl bromide and basic salt to an organic solvent to react to obtain an intermediate product 4, the structural formula of the intermediate product 4 is shown in a7; S5: adding the intermediate product 4 and the acid to an organic solvent to react to obtain a caprorelin intermediate, the structure of which is shown in a8; 2. The preparation method according to claim 1, characterized in that: In step S1, the solvent is selected from dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, and n-heptane; the molar concentration of the oxidized coenzyme nicotinamide adenine dinucleotide in the solution is above 10 mM, the mass ratio of the yeast alcohol dehydrogenase to N-Boc-4-piperidinol is not less than 0.1:50, the enzyme activity of the yeast alcohol dehydrogenase is 1.8 u / mg, the reaction temperature is 15-40°C, and the reaction time is 8-16 h.

3. The preparation method according to claim 2, characterized in that: In step S1, the solvent is dichloromethane, the reaction temperature is 25° C., and the reaction time is 12 h.

4. The preparation method according to claim 1, characterized in that: In step S2, the molar ratio of the intermediate product 1, the raw material a and the base is 1:1.5-3:3-6, the reaction temperature is 55-80°C, and the reaction time is 8-16h.

5. The preparation method according to claim 4, characterized in that: In step S2, the raw material a is semicarbazide, the base is sodium hydroxide, the molar ratio of the intermediate product 1, semicarbazide and NaOH is 1:2:4, the reaction temperature is 75° C., and the reaction time is 12 h.

6. The preparation method according to claim 1, characterized in that: In step S3, the molar ratio of the intermediate product 2, DMF-DMA and the base is 1:2-4:4-8, the reaction temperature is 60-90°C, and the reaction time is 8-16h.

7. The preparation method according to claim 1, characterized in that: In step S3, the base is sodium hydroxide, the molar ratio of the intermediate product 2, DMF-DMA and NaOH is 1:3:6, the reaction temperature is 85° C., and the reaction time is 10 h.

8. The preparation method according to claim 1, characterized in that: In step S4, the solvent is selected from DMF or tetrahydrofuran, the basic salt is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the molar ratio of the intermediate product 3, benzyl bromide and the base is 1:1.2-1.5:1-1.5; the reaction temperature is 15-40°C, and the reaction time is 16-48h.

9. The preparation method according to claim 1, characterized in that: In step S5, the solvent is selected from dichloromethane or ethyl acetate; the acid is selected from hydrochloric acid and trifluoroacetic acid; the molar ratio of the intermediate product 4 to the acid is 1:3-5, the reaction temperature is 25-40°C, and the reaction time is 2-4h.

10. The preparation method according to claim 8 or 9, characterized in that: In step S4, the solvent is selected from DMF, and the base is selected from potassium carbonate; the molar ratio of the intermediate product 3, benzyl bromide and potassium carbonate is 1:1.35:1.25; the reaction temperature is 25°C, and the reaction time is 48h; in step S5, the solvent is selected from ethyl acetate; the molar ratio of the intermediate product 4 to the acid is 1:4, the reaction temperature is 25°C, and the reaction time is 2h.

Images