Purification preparation method of JM01
By replacing column chromatography with gradient cooling crystallization system and composite solvent system, the problem of efficient purification of enantiomer pure amine was solved, and efficient and low-cost purification effect was achieved, and environmentally friendly standards were met.
Patent Information
- Application Number
- CN202510403592.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-01
- Publication Date
- 2025-07-04
AI Technical Summary
In the prior art, column chromatography methods are cumbersome, time-consuming and costly, and have poor purification effects, making it difficult to achieve efficient separation and purification.
The gradient cooling crystal system was used to combine with the n-heptane-toluene composite solvent system to replace traditional column chromatography, and enantiomer purification was achieved by controlling the gradient temperature (-5°C to 45°C) and adding seeds.
Significantly shortens the process time, reduces solvent consumption, improves the crystallinity and chiral purity of the target product, improves the removal rate of impurities, reduces production costs, and complies with environmental protection standards.
Smart Images
Figure CN120247755A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of the preparation of enantiomerically pure amines, and particularly relates to a purification preparation method of JM01. Background Art
[0002] The purification and preparation of enantiomerically pure amines has always been an important challenge in the field of chemical synthesis. Especially in the process of drug research and development and manufacturing, the purity of enantiomers directly affects the activity, safety and effectiveness of drugs. In the prior art, for the purification of some enantiomerically pure amines that are easily soluble in most organic solvents, column chromatography is usually used.
[0003] However, the column chromatography method has obvious deficiencies. First of all, the column chromatography process is cumbersome and requires a lot of time and energy for operations such as column preparation, sample loading, elution and collection. Secondly, column chromatography requires the use of a large amount of organic solvents, which not only increases the cost but also burdens the environment. In addition, the separation efficiency of column chromatography is also affected by many factors, such as the selection of the column, the ratio of the eluent, the control of the flow rate, etc. These factors may lead to poor purification effects or even introduce new impurities.
[0004] Especially for some intermediates with special properties, such as enantiomerically pure amines that are easily soluble in most organic solvents, the purification effect of column chromatography is even more limited. Due to the high solubility of these intermediates in organic solvents, it is difficult to effectively separate and purify them during column chromatography. Therefore, there is an urgent need for a more efficient, simple and low-cost purification method to solve this problem.
[0005] In view of this, the inventor proposes a purification preparation method of JM01 to solve the above problems. Summary of the Invention
[0006] The purpose of the present invention is to provide a purification preparation method of JM01 to solve the problems raised in the above background art.
[0007] To achieve the above purpose, the present invention provides the following technical solutions:
[0008] A purification preparation method of JM01, comprising:
[0009] Reacting cyclohex-3-ene-1(R)-carboxylic acid, toluene, triethylamine, diphenylphosphoryl azide DPPA, tert-butanol and copper(I) chloride CuCl to prepare (R)-4-(BOC-amino)cyclohexene N-BOC;
[0010] React the N-BOC with meta-chloroperoxybenzoic acid (mCPBA) and dichloromethane to obtain tert-butyl ((1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-yl)carbamate (O-BOC).
[0011] React the O-BOC with tolyl thiobenzoate and tetrabutylammonium chloride monohydrate to obtain {(1R,2R,4R)-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclohexyl} phenyl thioester (JM01).
[0012] Preferably, the preparation steps of the N-BOC include:
[0013] Add 400.00 g of cyclohex-3-ene-1(R)-carboxylic acid and 4000 ml of toluene to the reaction kettle, dropwise add 352.96 g of triethylamine. After dropping, slowly add 872.66 g of DPPA while controlling the temperature not to exceed 95 °C.
[0014] Carry out a reflux reaction and monitor by HPLC until there is no remaining cyclohex-3-ene-1(R)-carboxylic acid.
[0015] Cool down to 80 °C, dropwise add 1175.17 g of tert-butanol. After dropping, add 10.05 g of CuCl, wash the kettle wall with 100 ml of toluene, and heat up to 100 °C for a reflux reaction for 1 h.
[0016] React for 3 h, cool down to 25 °C, add 2 L of saturated sodium bicarbonate aqueous solution, stir for 1 h, filter, wash the filter cake with 800 ml of toluene, and collect the filtrate.
[0017] Let the filtrate stand for liquid separation and collect the organic phase for standby.
[0018] Extract the aqueous phase with 1200 ml of toluene and combine the organic phases.
[0019] Wash the combined organic phases with 1200 ml of water.
[0020] Then concentrate under reduced pressure at 65 °C until there is no continuous dripping.
[0021] After the concentration is completed, a light brown solid is obtained with a purity of 71.15%
[0022] Add 1200 ml of n-heptane, heat up to 45 °C, stir for 0.5 h, and filter.
[0023] Naturally cool down to 15 °C ± 5 °C for crystallization. After the solid is precipitated, stir for 0.5 h, then cool down to -5 ± 5 °C for crystallization for 1 h, filter, wash with 200 ml of n-heptane pre-cooled at -5 ± 5 °C, collect the solid, and dry it in vacuo at 35 °C to obtain 418.82 g of N-BOC with a yield of 66.96% and a purity of 91.77%.
[0024] Preferably, the preparation steps of O-BOC include:
[0025] Add 493.97 g of 85% mCPBA and 3200 ml of dichloromethane into the reaction kettle. After stirring evenly;
[0026] Control the temperature not exceeding 25°C, and dropwise add the dichloromethane solution of N-BOC, which is prepared from 400.00 g of N-BOC and 600 ml of dichloromethane;
[0027] After dropping, control the temperature at 25°C and stir for reaction for 1 h;
[0028] Raise the temperature to reflux for reaction for 2 h, and take a sample for HPLC inspection until there is no remaining N-BOC;
[0029] Cool to -5°C and stir for 1 h, filter, and wash the filter cake with 200 ml of dichloromethane;
[0030] Wash the filtrate with 2 L of 10% aqueous sodium thiosulfate solution to remove peroxides, and use starch potassium iodide test paper to detect the removal degree of peroxides;
[0031] Then wash the filtrate with 2 L of 10% aqueous sodium bicarbonate solution;
[0032] Then wash the filtrate with 2 L of water;
[0033] Concentrate the organic phase under reduced pressure at 35°C until there is no continuous dripping, add 2 L of toluene, and concentrate the organic phase under reduced pressure at 45°C until there is no continuous dripping to obtain O-BOC.
[0034] Preferably, the preparation steps of JM01 include:
[0035] Add 340.00 g of O-BOC and 2040 ml of toluene into the reaction kettle, stir and cool down to 15°C ± 5°C, and introduce argon;
[0036] Control the temperature not exceeding 30°C and dropwise add the toluene solution of thiobenzoic acid. The toluene solution of thiobenzoic acid is prepared from 225.76 g of 90% thiobenzoic acid and 680 ml of toluene;
[0037] After dropping, add 11.56 g of tetrabutylammonium chloride hydrate;
[0038] After adding, under nitrogen protection, raise the temperature to 55°C ± 5°C and stir for reaction for 4 h, and monitor the reaction by HPLC during this period;
[0039] After the reaction is completed, cool down to 15°C ± 5°C, add 1.02 g of seed crystal and stir for crystallization. After the solid is precipitated, continue to stir for 0.5 h, and then cool down to 0°C ± 5°C and stir for crystallization for 1 h;
[0040] Filtration is carried out by rinsing with a toluene - n - heptane solution, and the toluene - n - heptane solution is prepared by mixing 85 ml of toluene and 85 ml of n - heptane;
[0041] Soaking and washing is carried out with a toluene - n - heptane solution for 5 min, and it is prepared by mixing 170 ml of toluene and 170 ml of n - heptane;
[0042] Filtration is carried out by rinsing with a toluene - n - heptane solution, which is prepared by mixing 85 ml of toluene and 85 ml of n - heptane;
[0043] Soaking and washing is carried out with a toluene - n - heptane solution for 5 min, and it is prepared by using 170 ml of toluene and 170 ml of n - heptane;
[0044] Filtration is carried out by rinsing with 170 ml of n - heptane. After filtration, vacuum drying is carried out at 35 °C for 4 h to obtain 125 g of a white solid, JM01 with a purity of 99.26%.
[0045] The chemical equation for preparing (R)-4-(BOC - amino)cyclohexene N - BOC from cyclohex - 3 - ene - 1(R)-carboxylic acid is:
[0046]
[0047] The chemical equation for preparing JM01 from N - BOC is:
[0048]
[0049] The chemical equation for preparing JM01 from cyclohex - 3 - ene - 1(R)-carboxylic acid is:
[0050] .
[0051] Compared with the prior art, the beneficial effects of the present invention are:
[0052] (1) The present invention adopts column chromatography alternative technology. In view of the characteristic that the intermediate is easily soluble in organic solvents, a gradient cooling crystallization system (-5 °C to 45 °C dynamic control) is developed and combined with a n - heptane - toluene composite solvent system to successfully achieve the high - efficiency purification of difficult - to - crystallize compounds. Compared with traditional column chromatography, the process time is significantly shortened and the solvent consumption is reduced.
[0053] (2) The present invention establishes a four - stage precise temperature control system (15 °C → 0 °C → -5 °C gradient crystallization), combined with the seed induction technology (0.3% seed addition amount), to increase the crystallinity of the target product to 98.5%. Among the key quality indicators, the chiral purity remains >99.9% and the isomer residue <0.1%. Description of the Drawings
[0054] Figure 1 It is the chromatogram of the crude N - BOC prepared by the present invention;
[0055] Figure 2 Chromatogram of refined N-BOC prepared for the present invention;
[0056] Figure 3 Chromatogram of JM01 prepared for the present invention;
[0057] Figure 4 Overall chemical equation for preparing JM01 from cyclohex-3-ene-1(R)-carboxylic acid of the present invention;
[0058] Figure 5 Chemical equation for preparing N-BOC from cyclohex-3-ene-1(R)-carboxylic acid of the present invention;
[0059] Figure 6 Chemical equation for preparing JM01 from N-BOC of the present invention. Detailed implementation manners
[0060] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
[0061] Example 1:
[0062] As Figures 1 to 6 shown, a method for purifying and preparing JM01 includes:
[0063] Add 400.00 g of cyclohex-3-ene-1(R)-carboxylic acid and 4000 ml of toluene to the reaction kettle, dropwise add 352.96 g of triethylamine. After dropping, slowly dropwise add 872.66 g of DPPA, and control the temperature not exceeding 95 °C;
[0064] Carry out reflux reaction and monitor by HPLC until there is no remaining cyclohex-3-ene-1(R)-carboxylic acid;
[0065] Cool down to 80 °C, dropwise add 1175.17 g of tert-butanol. After dropping, add 10.05 g of CuCl, wash the kettle wall with 100 ml of toluene, and heat up to 100 °C for reflux reaction for 1 h;
[0066] React for 3 h, cool down to 25 °C, add 2 L of saturated sodium bicarbonate aqueous solution, stir for 1 h, filter, wash the filter cake with 800 ml of toluene, and collect the filtrate;
[0067] Let the filtrate stand for liquid separation, and collect the organic phase for standby;
[0068] Extract the aqueous phase with 1200 ml of toluene, and combine the organic phases:
[0069] The combined organic phase was washed with 1200 ml of water;
[0070] Then, it was concentrated under reduced pressure at 65 °C until there was no continuous dripping;
[0071] The concentration was completed to obtain a light brown solid with a purity of 71.15%;
[0072] 1200 ml (3V) of n-heptane was added, the temperature was raised to 45 °C, and it was stirred for 0.5 h, then filtered;
[0073] It was naturally cooled to 15 °C ± 5 °C for crystallization. After the solid was precipitated, it was stirred for 0.5 h, then cooled to -5 ± 5 °C for crystallization for 1 h, filtered, and washed with 200 ml of n-heptane pre-cooled at -5 ± 5 °C. The solid was collected and dried in vacuo at 35 °C to obtain 418.82 g of N-BOC with a yield of 66.96% and a purity of 91.77%.
[0074] Figure 1 and Figure 2 are the chromatograms of crude N-BOC and refined N-BOC respectively. Table 1 is Figure 1 the explanatory notes;
[0075] Table 1
[0076]
[0077]
[0078] Table 2 is Figure 2 the explanatory notes;
[0079] Table 2
[0080]
[0081]
[0082] 493.97 g of 85% mCPBA and 3200 ml of dichloromethane were added to the reaction kettle. After stirring evenly;
[0083] The temperature was controlled not to exceed 25 °C, and the dichloromethane solution of N-BOC was added dropwise, which was prepared from 400.00 g of N-BOC and 600 ml of dichloromethane;
[0084] After the dropping was completed, it was stirred at 25 °C for 1 h;
[0085] The temperature was raised to reflux for 2 h, and a sample was taken for HPLC inspection until there was no remaining N-BOC;
[0086] It was cooled to -5 °C and stirred for 1 h, then filtered, and the filter cake was washed with 200 ml of dichloromethane;
[0087] The filtrate was washed with 2 L of 10% aqueous sodium thiosulfate solution to remove peroxides, and the degree of peroxide removal was detected using starch potassium iodide test paper;
[0088] The filtrate was then washed with 2 L of 10% aqueous sodium bicarbonate solution;
[0089] Then the filtrate was washed with 2 L of water;
[0090] The organic phase was concentrated under reduced pressure at 35 °C until there was no continuous dripping, and 2 L of toluene was added. The organic phase was concentrated under reduced pressure at 45 °C until there was no continuous dripping to obtain O-BOC.
[0091] The preparation steps of the said JM01 include:
[0092] 340.00 g of O-BOC and 2040 ml of toluene were added to the reaction kettle, stirred and cooled to 15 °C ± 5 °C, and argon was introduced;
[0093] While controlling the temperature not exceeding 30 °C, a toluene solution of thiobenzoic acid was added dropwise. The toluene solution of thiobenzoic acid was prepared with 225.76 g of 90% thiobenzoic acid and 680 ml of toluene;
[0094] After the addition was completed, 11.56 g of tetrabutylammonium chloride hydrate was added;
[0095] After the addition was completed, under nitrogen protection, the temperature was raised to 55 °C ± 5 °C and stirred for reaction for 4 h. During this period, the reaction was monitored by HPLC;
[0096] After the reaction was completed, the temperature was cooled to 15 °C ± 5 °C, 1.02 g of seed crystal was added and stirred for crystallization. After the solid was precipitated, it was continuously stirred for 0.5 h, and then cooled to 0 °C ± 5 °C and stirred for crystallization for 1 h;
[0097] Filtered, and washed with a toluene - n - heptane solution. The toluene - n - heptane solution was prepared with 85 ml of toluene and 85 ml of n - heptane;
[0098] Washed by soaking with a toluene - n - heptane solution for 5 min. The toluene - n - heptane solution was prepared with 170 ml of toluene and 170 ml of n - heptane;
[0099] Filtered, and washed with a toluene - n - heptane solution. The toluene - n - heptane solution was prepared with 85 ml of toluene and 85 ml of n - heptane;
[0100] Washed by soaking with a toluene - n - heptane solution for 5 min. The toluene - n - heptane solution was prepared with 170 ml of toluene and 170 ml of n - heptane;
[0101] Filtered, washed with 170 ml of n - heptane, filtered, and dried in vacuo at 35 °C for 4 h to obtain 125 g of white solid, JM01 with a purity of 99.26%.
[0102] Table 3 is Figure 3 Partial parameter annotations of
[0103] Table 3
[0104] PDA Ch3 240nm
[0105]
[0106]
[0107] As can be seen from the above, the present invention adopts a column chromatography replacement technology. In view of the characteristic that the intermediate is easily soluble in organic solvents, a gradient cooling crystallization system (-5°C to 45°C dynamic control) is developed and combined with a n-heptane-toluene composite solvent system to successfully achieve the high-efficiency purification of difficult-to-crystallize compounds. Compared with traditional column chromatography, the process time is shortened and the solvent consumption is reduced.
[0108] The crystallization process parameters are optimized, a four-stage precise temperature control system (gradient crystallization of 15°C → 0°C → -5°C) is established, and combined with the seed induction technology (seed addition amount of 0.3%), the crystallinity of the target product is increased to 98.5%. Among the key quality indicators, the chiral purity remains >99.9% and the isomer residue <0.1%.
[0109] The solvent system is innovatively designed, a toluene / n-heptane composite solvent system (V / V = 1:1 to 1:3) is developed, and through the solubility difference amplification effect (ΔS = 28.5 g / L), the impurity clearance rate is increased to 99.2%. The specially designed gradient elution scheme (three alternating washes) enables the purity of the final product to exceed 99.26%, an 8 percentage point increase compared to the original process.
[0110] The production cost is significantly reduced. The material cost analysis shows that the production cost per kilogram of the product has decreased by 42% (from 1,250 to 725), among which the proportion of the solvent cost has decreased from 35% to 12% and the labor cost has decreased by 58%. The equipment investment return period is shortened to 1 / 3 of the original process, suitable for tonnage-scale production.
[0111] The green process is improved, the solvent recovery rate reaches 91% (68% in the original process), and the VOC emissions are reduced by 64%. The generation amount of hazardous waste has decreased from 3.2 kg / kg of product to 0.8 kg, and the process safety index (PI value) has been optimized from 7.2 to 4.5, meeting the ICH Q3C Class 3 standard.
[0112] The quality controllability is improved, an online HPLC monitoring system (automatic sampling every 30 minutes) is established, the number of key intermediate quality control points has increased from 3 to 7, and the process robustness index (Cpk) has increased from 1.2 to 1.8. The batch-to-batch RSD has been narrowed from ±5.7% to ±1.2%, meeting the requirements of the FDA process validation guidelines.
[0113] In the description of this specification, the descriptions referring to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.
[0114] In the drawings of the disclosed embodiments of the present invention, only the structures related to the disclosed embodiments are involved, and other structures can refer to the general design. Without conflict, the same embodiment and different embodiments of the present invention can be combined with each other.
[0115] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. A method for purifying and preparing JM01, characterized in that, The steps include: React cyclohex-3-ene-1(R)-carboxylic acid, toluene, triethylamine, diphenylphosphoryl azide (DPPA), tert-butanol and copper(I) chloride (CuCl) to obtain (R)-4-(BOC-amino)cyclohexene (N-BOC); React the N-BOC with meta-chloroperoxybenzoic acid (mCPBA) and dichloromethane to obtain tert-butyl ((1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-yl)carbamate (O-BOC); React the O-BOC with thiotoluic acid and tetrabutylammonium chloride monohydrate to obtain {(1R,2R,4R)-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclohexyl} phenyl thioester (JM01).
2. The JM01 purification preparation method according to claim 1, wherein The preparation steps of the N-BOC include: Add 400.00 g of cyclohex-3-ene-1(R)-carboxylic acid and 4000 ml of toluene into the reaction kettle, dropwise add 352.96 g of triethylamine. After dropping, slowly dropwise add 872.66 g of DPPA, and control the temperature not exceeding 95 °C; Carry out reflux reaction and monitor by HPLC until there is no remaining cyclohex-3-ene-1(R)-carboxylic acid; Cool down to 80 °C, dropwise add 1175.17 g of tert-butanol. After dropping, add 10.05 g of CuCl, wash the kettle wall with 100 ml of toluene, and heat up to 100 °C for reflux reaction for 1 h; React for 3 h, cool down to 25 °C, add 2 L of saturated sodium bicarbonate aqueous solution, stir for 1 h, filter, wash the filter cake with 800 ml of toluene, and collect the filtrate; Let the filtrate stand for liquid separation, and collect the organic phase for standby; Extract the aqueous phase with 1200 ml of toluene, and combine the organic phases; Wash the combined organic phase with 1200 ml of water; Then concentrate under reduced pressure at 65 °C until there is no continuous dripping; After concentration is completed, obtain a light brown solid with a purity of 71.15%; Add 1200 ml of n-heptane, heat up to 45 °C, stir for 0.5 h, and filter; Cool naturally to 15 °C ± 5 °C for crystallization. After the solid is precipitated, stir for 0.5 h, cool to -5 ± 5 °C for crystallization for 1 h, filter, wash with 200 ml of n-heptane precooled at -5 ± 5 °C, collect the solid, and dry in vacuum at 35 °C to obtain 418.82 g of N-BOC with a yield of 66.96% and a purity of 91.77%.
3. The JM01 purification and preparation method according to claim 1, characterized in that, The preparation steps of the O-BOC include: Add 493.97 g of 85% mCPBA and 3200 ml of dichloromethane into the reaction kettle, and stir evenly; Control the temperature not exceeding 25 °C, and dropwise add the dichloromethane solution of N-BOC, which is prepared from 400.00 g of N-BOC and 600 ml of dichloromethane; After dropping, control the temperature at 25 °C and stir for reaction for 1 h; Heat up to reflux for reaction for 2 h, take a sample and send it for HPLC inspection until there is no remaining N-BOC; Cool to -5 °C and stir for 1 h, filter, and wash the filter cake with 200 ml of dichloromethane; Wash the filtrate with 2 L of 10% sodium thiosulfate aqueous solution to remove peroxides, and use starch potassium iodide test paper to detect the removal degree of peroxides; Then wash the filtrate with 2 L of 10% sodium bicarbonate aqueous solution; Then wash the filtrate with 2 L of water; The organic phase was concentrated under reduced pressure at 35 °C until there was no continuous dripping, and 2 L of toluene was added. The organic phase was concentrated under reduced pressure at 45 °C until there was no continuous dripping to obtain O-BOC.
4. A purification and preparation method of JM01 according to claim 1, characterized in that, The preparation steps of the said JM01 include: 340.00 g of O-BOC and 2040 ml of toluene were added to the reaction kettle, and the temperature was lowered to 15 °C ± 5 °C with stirring, and argon was introduced. The toluene solution of thiobenzoic acid was added dropwise while controlling the temperature not exceeding 30 °C. The toluene solution of thiobenzoic acid was prepared with 225.76 g of 90% thiobenzoic acid and 680 ml of toluene. After the dropping was completed, 11.56 g of tetrabutylammonium chloride hydrate was added. After the addition was completed, under nitrogen protection, the temperature was raised to 55 °C ± 5 °C and stirred for 4 h, and the reaction was monitored by HPLC during this period. After the reaction was completed, the temperature was lowered to 15 °C ± 5 °C, 1.02 g of seed crystal was added and stirred for crystallization. After the solid was precipitated, stirring was continued for 0.5 h, and then the temperature was lowered to 0 °C ± 5 °C and stirred for crystallization for 1 h. Filter, and wash with a toluene-n-heptane solution. The toluene-n-heptane solution was prepared with 85 ml of toluene and 85 ml of n-heptane. Wash with a toluene-n-heptane solution for 5 min, prepared with 170 ml of toluene and 170 ml of n-heptane. Filter, and wash with a toluene-n-heptane solution, prepared with 85 ml of toluene and 85 ml of n-heptane. Wash with a toluene-n-heptane solution for 5 min, prepared with 170 ml of toluene and 170 ml of n-heptane. Filter, wash with 170 ml of n-heptane, filter, and dry in vacuo at 35 °C for 4 h to obtain 125 g of a white solid, JM01 with a purity of 99.26%.
5. A method for purifying and preparing JM01 according to claim 1, characterized in that, The chemical equation for preparing (R)-4-(BOC-amino)cyclohexene N-BOC from cyclohex-3-ene-1(R)-carboxylic acid is:
6. The JM01 purification preparation method according to claim 1, characterized in that, The chemical equation for preparing JM01 from N-BOC is:
7. A method for purifying and preparing JM01 according to claim 1, characterized in that, The chemical equation for preparing JM01 from cyclohex-3-ene-1(R)-carboxylic acid is: