Preparation method of camorelin

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of carmorelin. The method comprises the following steps: condensing pyrazolone-piperidine serving as a raw material with aminoisobutyryl-D-benzyloxyserine, selecting a phosphonium salt condensing agent, carrying out catalytic reaction by adopting inorganic alkali and a quaternary ammonium salt phase transfer catalyst, salifying with organic acid, recrystallizing and refining to remove epimers, and purifying to obtain the pyrazolone-D-benzyloxyserine. In the salifying process with L-(+)-tartaric acid, solid salt is directly separated out by adopting a mixed solvent. The method is high in purity and low in cost.

Description

Technical Field

[0001] The present application relates to the technical field of drug synthesis, and in particular to a method for preparing Camorellin. Background Art

[0002] Capromorelin is a growth hormone secretagogue that stimulates appetite by mimicking the structure of ghrelin and increasing the levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in plasma. The medicinal form of capromorelin is L-(+)-tartrate. The oral solution of capromorelin developed by Altana in the United States was approved by the FDA in May 2016 for the treatment of loss of appetite in dogs (trade name In 2019, Elantra acquired Altana and obtained the ownership of Camomorelin. In October 2020, the FDA approved Camomorelin oral solution for the treatment of weight loss caused by chronic kidney disease in cats (trade name Elura TM ). The chemical structures of Camorelin (CAS: 193273-66-4) and its pharmaceutical form Camorelin L-(+)-tartrate (CAS: 193273-69-7) are as follows:

[0003]

[0004] The structure of Camorelin is composed of two parts: a modified dipeptide (aminoisobutyryl-D-benzyloxyserine) and pyrazolone-piperidine, and there are two chiral centers in its structure. Through retrosynthetic analysis, it can be seen that the difficulty in preparing Camorelin is to maintain the configuration of the two chiral centers of the modified dipeptide and pyrazolone-piperidine during the condensation reaction.

[0005]

[0006] In view of this, this application is hereby filed. Summary of the invention

[0007] The purpose of the present application is to provide a method for preparing Camomorelin and its pharmaceutical form Camomorelin L-(+)-tartrate, so as to improve the preparation process and increase the reaction yield, which is suitable for industrialization.

[0008] In order to achieve the above purpose, this application adopts the following technical solutions:

[0009] A method for preparing Camorellin comprises the following steps:

[0010] (1) dissolving pyrazolone-piperidine and aminoisobutyryl-D-benzyloxyserine in a first organic solvent, cooling to 0-10° C., adding a phosphonium salt condensing agent, an inorganic base and a quaternary ammonium salt phase transfer catalyst, and reacting for 1-4 hours to obtain an intermediate Cap-1;

[0011] (2) dissolving the intermediate Cap-1 in a second organic solvent, adding an acid, and reacting at 20-25° C. for 1-6 hours to obtain a crude product of capmorelin;

[0012] (3) dissolving the crude product of Camorelin in a third organic solvent, adding an organic acid, reacting at 20-25° C. for 2-3 hours, filtering and drying the solid to obtain an organic acid salt of Camorelin;

[0013] (4) Add the organic acid salt of Camomorelin to the fourth organic solvent, reflux and dissolve, cool by 20-25° C. to precipitate a solid, filter by suction, add an alkaline aqueous solution and an extractant to the solid, separate the liquids, and evaporate the extractant to obtain Camomorelin.

[0014] In some embodiments, in step (1), the first organic solvent is an aprotic solvent, preferably at least one of dichloromethane, tetrahydrofuran or dioxane, more preferably dioxane;

[0015] Preferably, in step (1), the phosphonium salt condensing agent is benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate or (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate, preferably benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate;

[0016] Preferably, in step (1), the inorganic base is: K 2 CO 3 , Cs 2 CO 3 Or Na 2 CO 3 , preferably K 2 CO 3 ;

[0017] Preferably, in step (1), the quaternary ammonium salt phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium hydrogen sulfate, preferably tetrabutylammonium bromide.

[0018] In some embodiments, in step (2), the second organic solvent is methanol, ethanol, isopropanol, dichloromethane or tetrahydrofuran, preferably dichloromethane;

[0019] Preferably, in step (2), the acid is hydrochloric acid or trifluoroacetic acid, preferably trifluoroacetic acid.

[0020] In some embodiments, in step (3), the third organic solvent is at least one of ethyl acetate, acetone, methanol, ethanol and isopropanol.

[0021] In some embodiments, in step (3), the organic acid is citric acid, fumaric acid or maleic acid, preferably maleic acid.

[0022] In some embodiments, in step (4), the fourth organic solvent is at least one of methanol, ethanol, isopropanol, ethyl acetate, acetone and acetonitrile, preferably isopropanol and acetonitrile.

[0023] In some embodiments, in step (4), the alkaline aqueous solution is NaHCO 3 Aqueous solution, KHCO 3 Aqueous solution, K 2 CO 3 Aqueous solution, Cs 2 CO 3 Aqueous solution or Na 2 CO 3 Aqueous solution, preferably NaHCO 3 Aqueous solution;

[0024] Preferably, in step (4), the extractant is ethyl acetate, dichloromethane or toluene.

[0025] A method for preparing L-(+)-tartrate of Camorelin. Camorelin is prepared according to the above preparation method, and then the Camorelin is dissolved in a fifth organic solvent, L-(+)-tartaric acid is added, and the reaction is carried out at 20-25° C. for 1-12 hours to precipitate a solid, and the solid is filtered and dried to obtain L-(+)-tartrate of Camorelin, wherein the fifth organic solvent does not include methanol.

[0026] In some embodiments, the reaction time is 2 h.

[0027] In some embodiments, the fifth organic solvent is at least two of isopropanol, ethanol, methanol, ethyl acetate, acetone and acetonitrile, preferably acetone and isopropanol.

[0028] Compared with the prior art, the technical effects of this application are:

[0029] (1) The present application uses racemic pyrazolone-piperidine as a raw material for condensation with a modified dipeptide (aminoisobutyryl-D-benzyloxyserine), selects a phosphonium salt condensation agent, and uses an inorganic base and a quaternary ammonium salt phase transfer catalyst to catalyze the reaction, thereby avoiding the racemization of the chiral center during the condensation reaction, reducing the generation of isomeric impurities, and improving the reaction yield.

[0030] (2) The diastereomers in the crude product of Camorelin are removed by salting with an organic acid and then re-crystallizing and refining, thereby avoiding column chromatography operation, reducing the preparation cost, and being suitable for industrial production.

[0031] (3) The salt formation process of caberelin and L-(+)-tartaric acid uses a mixed solvent to react at room temperature for 2 hours to form a salt and precipitate a solid, avoiding complex processes such as reduced pressure distillation and reflux heating. The purity of the product reaches more than 99.5%, and the impurities of enantiomers and diastereomers are less than 0.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0033] Figure 1 This is the chiral purity result of Camorelin L-(+)-tartrate detected by HPLC in Comparative Example 1 of the present application;

[0034] Figure 2 This is the chiral purity result of Camorellin L-(+)-tartrate detected by HPLC in Comparative Example 2 of the present application;

[0035] Figure 3 The chiral purity result of HPLC test of the preparation of Camorelin L-(+)-tartrate in 1.5.1 of Example 1 of the present application;

[0036] Figure 4 This is the result of HPLC chiral purity test for preparing Camorelin L-(+)-tartrate in 1.5.2 of Example 1 of the present application. DETAILED DESCRIPTION

[0037] The technical solution of the present application will be described clearly and completely below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0038] The present application proposes a method for preparing Camorelin and its pharmaceutical form Camorelin L-(+)-tartrate. The process solves the problem of racemization of both raw materials using unstable organic bases in the prior art, reduces the generation of isomeric impurities, improves the reaction yield, and avoids procedures such as column chromatography, vacuum distillation, and reflux heating in the process, thereby reducing costs.

[0039] The preparation method of Camorellin comprises the following steps:

[0040] (1) Pyrazolone-piperidine and aminoisobutyryl-D-benzyloxyserine are dissolved in an organic solvent and cooled to 0-10°C. A phosphonium salt condensation agent, an inorganic base and a quaternary ammonium salt phase transfer catalyst are added and reacted for 1-4 hours to obtain the intermediate Cap-1.

[0041] In some embodiments, the organic solvent in step (1) is an aprotic solvent, preferably at least one of dichloromethane, tetrahydrofuran or dioxane, more preferably dioxane.

[0042] In some embodiments, the phosphonium salt condensing agent is one of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (PyAOP), etc., preferably benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP).

[0043] In some embodiments, the inorganic base is: K 2 CO 3 , Cs 2 CO 3 Or Na 2 CO 3 , preferably K 2 CO 3 .

[0044] In some embodiments, the quaternary ammonium salt phase transfer catalyst is one of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, etc., preferably tetrabutylammonium bromide (TBAB).

[0045] (2) The intermediate Cap-1 is dissolved in an organic solvent, an acid is added, and the mixture is reacted at 20-25° C. for 1-6 h to obtain a crude product of capmorelin.

[0046] In some embodiments, the organic solvent in step (2) is methanol, ethanol, isopropanol, dichloromethane or tetrahydrofuran, preferably dichloromethane.

[0047] In some embodiments, the acid is hydrochloric acid or trifluoroacetic acid, preferably trifluoroacetic acid.

[0048] (3) Dissolve the crude product of Camorelin in an organic solvent, add an organic acid, react at 20-25° C. for 2-3 h, filter and dry the solid to obtain an organic acid salt of Camorelin.

[0049] In some embodiments, the organic solvent in step (3) is at least one of ethyl acetate, acetone, methanol, ethanol and isopropanol.

[0050] In some embodiments, the organic acid is citric acid, fumaric acid or maleic acid, preferably maleic acid.

[0051] (4) Adding an organic acid salt of Camomorelin to an organic solvent, dissolving under reflux, cooling by 20 to 25° C. to precipitate a solid, filtering by suction, adding an alkaline aqueous solution and an extractant to the solid, separating the liquids, and evaporating the extractant to obtain Camomorelin.

[0052] In some embodiments, the organic solvent in step (4) is at least one of methanol, ethanol, isopropanol, ethyl acetate, acetone and acetonitrile, preferably isopropanol and acetonitrile.

[0053] In some embodiments, the alkaline aqueous solution is NaHCO 3 Aqueous solution, KHCO 3 Aqueous solution, K 2 CO 3 Aqueous solution, Cs 2 CO 3 Aqueous solution or Na 2 CO 3 Aqueous solution, preferably NaHCO 3 Aqueous solution.

[0054] In some embodiments, the extractant is ethyl acetate, dichloromethane, or toluene.

[0055] In order to prepare the pharmaceutical form of Camomorelin, Camomorelin L-(+)-tartrate, the following steps are also required:

[0056] (5) dissolving Camomorelin in an organic solvent, adding L-(+)-tartaric acid, reacting at 20-25° C. for 1-12 h, precipitating a solid, filtering the solid and drying it to obtain Camomorelin L-(+)-tartrate, wherein the organic solvent does not include methanol.

[0057] In some embodiments, the reaction time is 2 h.

[0058] In some embodiments, the organic solvent in this step is at least two of isopropanol, ethanol, methanol, ethyl acetate, acetone and acetonitrile, preferably acetone and isopropanol.

[0059] In one embodiment, the process route of Camorelin L-(+)-tartrate is as follows:

[0060] The present application is further described below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or purchased directly from the market.

[0061] Comparative Example 1 Preparation of Camorelin L-(+)-Tartrate

[0062] The preparation route of this comparative example 1 is as follows:

[0063] (1) Preparation of Cap-1, an intermediate of Capmorelin

[0064] Add 7.5g (0.031mol) of pyrazolone-piperidine to a 500ml three-necked flask, add 110ml of dichloromethane, stir to dissolve, cool to 0°C, add 18.0g (0.047mol) of modified dipeptide, 6.4g (0.047mol) of 1-hydroxybenzotriazole (HOBt), 9.1g (0.047mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and 6.5ml (0.047mol) of triethylamine (TEA), and heat to room temperature to react for 17h. After the reaction is completed, add 100ml of ethyl acetate to the reaction solution, wash the reaction solution with 100ml of 10% hydrochloric acid, 100ml of saturated NaHCO 3 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 The mixture was dried, filtered and evaporated to dryness to obtain the crude product of the capmorelin intermediate Cap-1.

[0065] The crude product was purified by column chromatography with an eluent of petroleum ether:ethyl acetate = 1:1 to obtain 7.1 g of the capmorelin intermediate Cap-1 with a yield of 37.8%.

[0066] (2) Preparation of Camorelin

[0067] Add 7.1 g (0.012 mol) of the intermediate Cap-1 to a 500 ml three-necked flask, add 80 ml of dichloromethane, stir and dissolve, cool to 0°C, add 25.0 ml of trifluoroacetic acid (TFA) dropwise, and heat to room temperature to react for 3 h. After the reaction is completed, remove the solvent under reduced pressure, add 200 ml of dichloromethane to dissolve the residue, and use 200 ml of saturated NaHCO 3 The dichloromethane phase was washed with aqueous solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dry the solvent to obtain 3.5 g of capmorelin with a yield of 59.1%.

[0068] (3) Preparation of Camorelin L-(+)-Tartrate

[0069] Add 3.5 g (0.007 mol) of Camomorelin to a 500 ml three-necked flask, add 35 ml of methanol and 1.05 g (0.007 mol) of L-(+)-tartaric acid and stir to dissolve at room temperature. Continue stirring to react for 17 h. Distill under reduced pressure to remove the solvent. Add 105 ml of ethyl acetate to the residue and reflux with stirring to react for 16 h. Cool to room temperature to precipitate solids. Filter the solids and dry them to obtain 2.3 g of Camomorelin L-(+)-tartrate with a yield of 50.5%.

[0070] Chiral purity detected by HPLC, Camorelin: enantiomer: epimer 1: epimer 2 = 63.31%: 34.65%: 0.74%: 0.71%. Figure 1 .

[0071] Conclusion: The preparation process provided in Comparative Example 1 has the following problems:

[0072] ① The epimers of the intermediate Cap-1 need to be purified by column chromatography. Since the polarity of the epimers is similar to that of the target product, column chromatography purification is difficult. By testing the chiral purity of the finished product Capmorelin L-(+)-tartrate, it is confirmed that the impurity contents of the two epimers are 0.74% and 0.71%, respectively. In addition, the column chromatography purification process is not suitable for industrial production.

[0073] ② The chiral purity test of L-(+)-tartrate of Camorelin showed that there were 34.65% enantiomers, indicating that the two chiral centers were racemized during the condensation of pyrazolone-piperidine and the modified dipeptide. The salt formation process of Camorelin and L-(+)-tartaric acid requires reduced pressure distillation, reflux heating and other steps, which is complicated.

[0074] Comparative Example 2 Preparation of Camorelin L-(+)-Tartrate

[0075] The preparation route of this comparative example is as follows:

[0076] (1) Preparation of single-configuration R-pyrazolone-piperidine L-(+)-tartrate

[0077] Add 5.0 g (0.021 mol) of pyrazolone-piperidine to a 500 ml three-necked flask, add 3.1 g (0.021 mol) of L-(+)-tartaric acid, 80 ml of acetone and 3.2 ml of purified water, heat to 50°C under nitrogen protection, stir and react for 70 h, cool to room temperature and filter, heat the solid under reflux with 30 ml of acetone and 10 ml of isopropanol to dissolve, cool to 0-5°C for crystallization for 2 h, filter and dry to obtain 2.8 g of R-pyrazolone-piperidine L-(+)-tartrate with a chiral purity of 98.2% and a yield of 34.7%.

[0078] (2) Preparation of Cap-1, an intermediate of Capmorelin

[0079] Add 2.8g (0.007mol) of R-pyrazolone-piperidine L-(+)-tartrate to a 500ml three-necked flask, add 30ml of dichloromethane, stir and cool to -10°C, add 2.8ml (0.02mol) of triethylamine (TEA) dropwise to the reaction solution and stir to react for 1.5h. Then add 4.4ml (0.032mol) of triethylamine (TEA) dropwise to the reaction solution, keep the reaction temperature at -5°C to -10°C, add 2.4g (0.0063mol) of modified dipeptide, 0.95g (0.007mol) of 1-hydroxybenzotriazole (HOBt), and 1.4g (0.007mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), keep the reaction at -5°C to -10°C for 1h, warm to room temperature and continue stirring to react for 16h. After the reaction was completed, the mother liquor was filtered and washed with 50 ml saturated NaHCO 3 The product was washed with aqueous solution, and the dichloromethane phase was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated to obtain 2.1 g of the capmorelin intermediate Cap-1 with a yield of 55.3%.

[0080] (3) Preparation of Camorelin

[0081] Add 2.1 g (0.0035 mol) of the intermediate Cap-1 to a 100 ml three-necked flask, add 21 ml of dichloromethane, stir and dissolve, cool to 0°C, add 7.5 ml of trifluoroacetic acid (TFA) dropwise, and warm to room temperature to react for 3 h. After the reaction, evaporate the solvent under reduced pressure, add 50 ml of dichloromethane to dissolve the residue, and then use 50 ml of saturated NaHCO 3 The dichloromethane phase was washed with aqueous solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dry the solvent to obtain 1.2 g of capmorelin with a yield of 67.8%.

[0082] (3) Preparation of Camorelin L-(+)-Tartrate

[0083] Add 1.2 g (0.0024 mol) of Camomorelin to a 100 ml three-necked flask, add 12 ml of methanol and 0.36 g (0.0024 mol) of L-(+)-tartaric acid and stir at room temperature to dissolve, continue stirring and reacting for 17 h, distill under reduced pressure to remove the solvent, add 36 ml of ethyl acetate to the residue and reflux and stir to react for 16 h, cool to room temperature to precipitate solid, filter and dry the solid to obtain 0.81 g of Camomorelin L-(+)-tartrate, with a yield of 51.9%.

[0084] HPLC detection of chiral purity, Camorelin: enantiomer: epimer 1: epimer 2 = 43.04%: 33.57%: 14.88%: 8.51%. See Figure 2 .

[0085] Conclusion: The preparation process provided in Comparative Example 2 was found to have the following problems:

[0086] ① The pyrazolone-piperidine structure is unstable and requires nitrogen protection. The chiral separation process requires heating reaction for more than 70 hours, the operation is complicated, and the chiral purity needs to be refined by recrystallization to reach more than 98%;

[0087] ② The chiral purity test of L-(+)-tartrate of Camorelin showed that there were 34.65% enantiomers and 23.39% diastereomers, indicating that the two chiral centers were racemized during the condensation of pyrazolone-piperidine and the modified dipeptide. The racemization of the chiral center during the condensation process resulted in the presence of diastereomers and enantiomeric impurities in the product Camorelin, which made purification difficult and reduced the reaction yield. The salt formation process of Camorelin and L-(+)-tartaric acid requires processes such as reduced pressure distillation and reflux heating, which is complicated to operate.

[0088] In order to solve the problem that the racemization of the chiral center of Camorelin and the purification of epimers by column chromatography are not suitable for industrial production, the specific implementation process provided in this application is as follows:

[0089] Example 1 Preparation of Camorelin L-(+)-Tartrate

[0090] (1) Preparation of Cap-1, an intermediate of Capmorelin

[0091] Scheme 1.1.1: Dichloromethane as solvent

[0092] Pyrazolone-piperidine 7.0g (0.029mol) was added to a 500ml three-necked flask, and 80ml of dichloromethane was added and stirred to dissolve. The temperature was lowered to 5-10°C, and the modified dipeptide 11.02g (0.029mol), PyBOP 16.6g (0.032mol), K 2 CO 3 4.4 g (0.032 mol), tetrabutylammonium bromide (TBAB) 0.93 g (0.0029 mol, add the mixture and react at room temperature for 1 h. After the reaction is complete, filter and wash the solid with 50 ml of dichloromethane, and the mother liquor with 50 ml of 10% hydrochloric acid, saturated NaHCO 3 The mixture was washed with aqueous solution, and the dichloromethane phase was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated to dryness to obtain 16.5 g of the capmorelin intermediate Cap-1 with a yield of 94.3%.

[0093] Scheme 1.1.2: Dioxane as solvent

[0094] Pyrazolone-piperidine 7.0g (0.029mol) was added to a 500ml three-necked flask, and 80ml of dioxane was added and stirred to dissolve. The temperature was lowered to 10°C, and the modified dipeptide 11.02g (0.029mol), PyBOP 16.6g (0.032mol), K 2 CO 3 4.4g (0.032mol), tetrabutylammonium bromide (TBAB) 0.93g (0.0029mol, after addition, keep the reaction at room temperature for 1h, the reaction is completed. Filter with suction, cool the mother liquor by 10℃, add 10% hydrochloric acid to adjust the pH to 3-4, then add 100ml purified water to precipitate a light yellow solid, filter and dry to obtain 17.0g of the capmorelin intermediate Cap-1, with a yield of 97.1%.

[0095] Conclusion: Schemes 1.1.1 and 1.1.2 can both obtain the target product in high yield. Scheme 1.1.2 uses dioxane as solvent for post-treatment and the product can be directly precipitated. The process is simple and reduces energy consumption. Considering the cost and yield, Scheme 1.1.2 is preferred.

[0096] (2) Preparation of crude capmorelin

[0097] Solution 1.2.1

[0098] Add 10.0 g (0.017 mol) of the intermediate Cap-1 to a 500 ml three-necked flask, add 100 ml of dichloromethane, stir and dissolve, cool to 0 °C, drop 35 ml of trifluoroacetic acid (TFA), and heat to room temperature for 2 h. After the reaction, drop 50 ml of saturated NaHCO 3 The pH of the aqueous solution was adjusted to about 8, and the liquids were separated. The aqueous phase was extracted with 100 ml of dichloromethane, and the dichloromethane phases were combined and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated to obtain 8.0 g of a crude product of Camorellin with a yield of 96.4%.

[0099] Solution 1.2.2

[0100] Add 10.0 g (0.017 mol) of the intermediate Cap-1 to a 500 ml three-necked flask, add 100 ml of ethanol and stir to dissolve, add 30 ml of concentrated hydrochloric acid dropwise, and heat to room temperature to react for 2 h. After the reaction is completed, add saturated NaHCO 3 The pH of the aqueous solution was adjusted to about 8, and dichloromethane was added for extraction three times (100 ml / time) to separate the liquids. The dichloromethane phases were combined and dried over anhydrous magnesium sulfate, and the solvent was filtered and evaporated to obtain 5.8 g of a crude product of Camorellin with a yield of 69.9%.

[0101] Conclusion: Both Schemes 1.2.1 and 1.2.2 can obtain the target product in high yield. Scheme 1.2.1 uses dichloromethane as solvent and the trifluoroacetic acid deprotection process is simple and has a higher yield. Considering the cost and yield, Scheme 1.2.1 is preferred.

[0102] (3) Preparation of organic acid salt of capmorelin

[0103] Scheme 1.3.1: Preparation of Camorelin Maleate

[0104] 5.0 g (0.01 mol) of Camomorelin was added to a 100 ml three-necked flask, and 50 ml of acetone and 1.16 g (0.01 mol) of maleic acid were added. The mixture was stirred at room temperature for 2 h to precipitate a solid. The solid was filtered and dried to obtain 5.8 g of Camomorelin maleate with a yield of 94.2%.

[0105] Scheme 1.3.2: Preparation of Capmorelin Fumarate

[0106] 5.0 g (0.01 mol) of Camorelin was added to a 100 ml three-necked flask, and 50 ml of isopropanol and 1.16 g (0.01 mol) of fumaric acid were added. The mixture was stirred at room temperature for 2 h to precipitate a solid. The solid was filtered and dried to obtain 5.2 g of Camorelin fumarate with a yield of 84.4%.

[0107] Protocol 1.3.3: Preparation of Camorelin Citrate

[0108] 5.0 g (0.01 mol) of Camomorelin was added to a 100 ml three-necked flask, and 50 ml of isopropanol and 1.92 g (0.01 mol) of citric acid were added. The mixture was stirred at room temperature for 2 h to precipitate a solid. The solid was filtered and dried to obtain 5.6 g of Camomorelin citrate with a yield of 80.9%.

[0109] Conclusion: Schemes 1.3.1, 1.3.2 and 1.3.3 can all obtain organic acid salts of capromorelin. Scheme 1.3.1 uses acetone as solvent and capromorelin reacts with maleic acid to form a salt. It is easy to operate and has a high yield, and is suitable for industrial production. Considering all factors, Scheme 1.3.1 is the preferred one.

[0110] (4) Preparation of Camorelin

[0111] Scheme 1.4.1: Recrystallization from isopropanol

[0112] Add 5.0 g (0.008 mol) of Camorelin maleate to a 100 ml three-necked flask, add 50 ml of isopropanol, heat to reflux and dissolve, cool to room temperature, stir and crystallize for 2 h, precipitate solid, filter the solid, add 100 ml of saturated NaHCO 3The aqueous solution was stirred with 100 ml of dichloromethane to dissolve the solid, the aqueous phase was extracted with 100 ml of dichloromethane, the dichloromethane was combined and dried over anhydrous magnesium sulfate, the solvent was filtered and evaporated to obtain 1.7 g of capmorelin with a yield of 42.1%.

[0113] Scheme 1.4.2: Recrystallization from acetonitrile

[0114] Add 5.0 g (0.008 mol) of Camorelin maleate to a 500 ml three-necked flask, add 200 ml of acetonitrile and heat to reflux to dissolve, cool to room temperature and stir to crystallize for 2 h, precipitate solid, filter the solid and add 100 ml of saturated K 2 CO 3 The aqueous solution was stirred with 100 ml of dichloromethane to dissolve the solid, the aqueous phase was extracted with 100 ml of dichloromethane, the dichloromethane was combined and dried over anhydrous magnesium sulfate, the solvent was filtered and evaporated to obtain 1.3 g of capmorelin with a yield of 32.2%.

[0115] Scheme 1.4.3: Recrystallization from a mixed solvent of isopropanol and acetonitrile

[0116] Add 5.0 g (0.008 mol) of Camorelin maleate to a 100 ml three-necked flask, add 30 ml of isopropanol and 30 ml of acetonitrile, heat to reflux and dissolve, cool to room temperature, stir and crystallize for 2 h, precipitate solid, filter the solid, add 100 ml of saturated NaHCO 3 The aqueous solution was adjusted and stirred with 100 ml of dichloromethane to dissolve the solid. The aqueous phase was extracted with 100 ml of dichloromethane, the dichloromethane was combined and dried over anhydrous magnesium sulfate, and the solvent was filtered and evaporated to obtain 1.9 g of Camorelin with a yield of 47.0%.

[0117] Conclusion: Schemes 1.4.1, 1.4.2 and 1.4.3 can all remove the diastereomers by recrystallization to obtain the target product. Scheme 1.4.3 uses mixed solvent recrystallization, has a higher yield, is easy to operate and is suitable for industrial production. Considering all factors, Scheme 1.4.3 is preferred.

[0118] (5) Preparation of Camorelin L-(+)-Tartrate

[0119] Scheme 1.5.1: Acetonitrile and isopropanol as solvents

[0120] 5.0 g (0.01 mol) of Camorelin was added to a 100 ml three-necked flask, 25 ml of acetonitrile and 25 ml of isopropanol were added and stirred at room temperature to dissolve, 1.5 g (0.01 mol) of L-(+)-tartaric acid was added, and the mixture was stirred at room temperature for 2 h to precipitate a white solid, which was filtered and dried to obtain 5.5 g of Camorelin L-(+)-tartrate, with a yield of 84.6%. The chiral purity was detected by HPLC, Camorelin: enantiomer = 97.04%: 2.96%. Figure 3 .

[0121] Scheme 1.5.2: Acetone and isopropanol as solvents

[0122] 5.0 g (0.01 mol) of Camorelin was added to a 100 ml three-necked flask, 25 ml of acetone and 25 ml of isopropanol were added and stirred at room temperature to dissolve, 1.5 g (0.01 mol) of L-(+)-tartaric acid was added, and the mixture was stirred at room temperature for 2 h to precipitate a white solid, which was filtered and dried to obtain 5.8 g of Camorelin L-(+)-tartrate, with a yield of 89.3%. The chiral purity was detected by HPLC, Camorelin: enantiomer = 99.54%: 0.46%. Figure 4 .

[0123] Conclusion: Both schemes can obtain high optical purity of caprelin L-(+)-tartrate. Scheme 1.5.2 uses acetone and isopropanol as mixed solvents, and the reaction yield and purity are better. Therefore, Scheme 1.5.2 is preferred.

[0124] Note that the above are only preferred embodiments of the present application and the technical principles used. Those skilled in the art will understand that the present application is not limited to the specific embodiments described herein, and that various obvious changes, readjustments and substitutions can be made by those skilled in the art without departing from the protection scope of the present application. Therefore, although the present application is described in more detail through the above embodiments, the present application is not limited to the above embodiments, and may also include more other equivalent embodiments without departing from the technical concept of the present application, all of which belong to the protection scope of the present application.

Claims

1. A method for preparing Camorellin, characterized in that: The following steps are involved: (1) dissolving pyrazolone-piperidine and aminoisobutyryl-D-benzyloxyserine in a first organic solvent, cooling to 0-10° C., adding a phosphonium salt condensing agent, an inorganic base and a quaternary ammonium salt phase transfer catalyst, and reacting for 1-4 hours to obtain an intermediate Cap-1; (2) dissolving the intermediate Cap-1 in a second organic solvent, adding an acid, and reacting at 20-25° C. for 1-6 hours to obtain a crude product of capmorelin; (3) dissolving the crude product of Camorelin in a third organic solvent, adding an organic acid, reacting at 20-25° C. for 2-3 hours, filtering and drying the solid to obtain an organic acid salt of Camorelin; (4) Add the organic acid salt of Camomorelin to the fourth organic solvent, reflux and dissolve, cool by 20-25° C. to precipitate a solid, filter by suction, add an alkaline aqueous solution and an extractant to the solid, separate the liquids, and evaporate the extractant to obtain Camomorelin.

2. The preparation method according to claim 1, characterized in that: In the step (1), the first organic solvent is an aprotic solvent, preferably at least one of dichloromethane, tetrahydrofuran or dioxane, more preferably dioxane; Preferably, in step (1), the phosphonium salt condensing agent is benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate or (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate, preferably benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate; Preferably, in step (1), the inorganic base is: K2CO3, Cs2CO3 or Na2CO3, preferably K2CO3; Preferably, in step (1), the quaternary ammonium salt phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium hydrogen sulfate, preferably tetrabutylammonium bromide.

3. The preparation method according to claim 1, characterized in that: In the step (2), the second organic solvent is methanol, ethanol, isopropanol, dichloromethane or tetrahydrofuran, preferably dichloromethane; Preferably, in step (2), the acid is hydrochloric acid or trifluoroacetic acid, preferably trifluoroacetic acid.

4. The preparation method according to claim 1, characterized in that: In the step (3), the third organic solvent is at least one of ethyl acetate, acetone, methanol, ethanol and isopropanol.

5. The preparation method according to claim 1, characterized in that: In the step (3), the organic acid is citric acid, fumaric acid or maleic acid, preferably maleic acid.

6. The preparation method according to claim 1, characterized in that: In the step (4), the fourth organic solvent is at least one of methanol, ethanol, isopropanol, ethyl acetate, acetone and acetonitrile, preferably isopropanol and acetonitrile.

7. The preparation method according to claim 1, characterized in that: In the step (4), the alkaline aqueous solution is a NaHCO3 aqueous solution, a KHCO3 aqueous solution, a K2CO3 aqueous solution, a Cs2CO3 aqueous solution or a Na2CO3 aqueous solution, preferably a NaHCO3 aqueous solution; Preferably, in step (4), the extractant is ethyl acetate, dichloromethane or toluene.

8. A method for preparing Camorellin L-(+)-tartrate, characterized in that: Camomorelin is prepared according to the preparation method according to any one of claims 1 to 7, and then the capomorelin is dissolved in a fifth organic solvent, L-(+)-tartaric acid is added, and the reaction is carried out at 20 to 25° C. for 1 to 12 hours, a solid is precipitated, and the solid is filtered and dried to obtain capomorelin L-(+)-tartrate, wherein the fifth organic solvent does not include methanol.

9. The preparation method according to claim 8, characterized in that: The reaction time is 2h.

10. The preparation method according to claim 8, characterized in that: The fifth organic solvent is at least two of isopropanol, ethanol, methanol, ethyl acetate, acetone and acetonitrile, preferably acetone and isopropanol.

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