A synthetic process for morpholinone derivatives

Abstract

The invention discloses a synthesis process of a morpholinone derivative, relating to the technical field of pharmaceutical production. The invention uses 4-benzyl-2-hydroxy-morpholin-3-one and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol as main raw materials, performs a dehydration reaction under the action of a catalyst, and induces chiral crystallization by adding a strong base to finally obtain a target compound (I), i.e., a morpholinone derivative. The reaction conditions of the synthesis process are mild and suitable for industrial-scale production. The reaction process of the catalyst and solvent combination is more stable. At the same time, the steps are simplified, the cumbersome intermediate processing operations are reduced, and the overall efficiency is improved. The invention also has a high atomic utilization rate, and the target compound is directly synthesized through dehydration and chiral crystallization, thereby improving resource utilization and reducing production costs. In addition, the main raw materials used, such as 4-benzyl-2-hydroxy-morpholin-3-one and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol, are widely available and moderately priced, thereby improving economic efficiency.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical production, in particular to a synthesis process of morpholinone derivatives. Background Art

[0002] Aprepitant and fosaprepitant dimeglumine are both receptor blockers of human substance P / neurokinin-1 (NK-1) and can be used to treat nausea and vomiting related to chemotherapy and radiotherapy in cancer patients. Fosaprepitant dimeglumine is a prodrug of aprepitant and is an injectable dosage form. After entering the human body, it can be rapidly converted into aprepitant. These two antiemetic drugs have comparable efficacy and complementary dosage forms. They are widely used in the field of adjuvant tumor treatment and have good market prospects.

[0003] Aprepitant's English name is Aprepitant, its Chinese chemical name is 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, its CAS registration number is 170729-80-3, and its English name is Fosaprepitant Dimeglumine umine, whose Chinese chemical name is 1-deoxy-1-(methylamino)-D-sorbitol [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphate (2:1), CAS registration number is 265121-04-8, and the chemical structures of the two are shown below.

[0004]

[0005] Compound (I) is a key intermediate in the synthesis of the antiemetic drugs aprepitant and fosaprepitant dimeglumine, and is a morpholinone derivative. The specific chemical structure is shown below.

[0006]

[0007] The currently disclosed methods for synthesizing compound (I) are mainly concentrated in the following synthetic routes. For example, the literature J.Org.Chem.2002,67,6743-6747 and J.Am.Chem.Soc.2003,125,2129-2135 and patents CN1182125C, CN103012305B, CN104447607B, CN106397349A, CN109694360A, CN114213355A and CN114805238A all disclose the use of 4-benzyl-2-hydroxy-morpholin-3-one and trifluoroacetic anhydride to obtain an activated hydroxyl intermediate, which is then further reacted with compound (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in the presence of a catalyst. In the presence of a reagent such as boron trifluoride etherate or (R)-2-methyl-CBS-oxazolidinone, condensation is performed to obtain a mixture of compound (I) containing diastereomers, which is then further crystallized using a strong base such as potassium tert-butoxide and / or potassium tetrahydrolinalool and / or potassium dihydroterpineol to obtain the target compound (I). Although this synthetic route has been widely reported, the synthetic process still has obvious shortcomings. The process route is long and the operation is cumbersome. Trifluoroacetic anhydride is first used to activate the raw material and then the activated group is removed in the condensation step, resulting in low atom utilization. The use of an organic liquid strong acid reagent causes serious corrosion to the equipment, and a large amount of waste acid is generated in the post-treatment, which is not environmentally friendly. The use of a low-boiling point boron trifluoride etherate solution poses a safety hazard. A large amount of mixed solvent is used in the crystal transformation step, which is difficult to recycle and produces a large amount of waste liquid, resulting in high process costs.

[0008]

[0009] In addition, the method for synthesizing compound (I) disclosed in patent CN109516964B has the following synthetic route: first, compound (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol is reacted with trifluoroacetic anhydride to obtain its hydroxyl-activated intermediate, which is then further reacted with compound 4-benzyl-2-hydroxy-morpholin-3-one in the presence of an organophosphorus reagent (triphenylphosphine) and a strong base (potassium tetrahydrolinalool) to obtain compound (I). This process route still does not overcome the shortcomings of existing processes, such as low atom utilization, cumbersome operation, and the use of organophosphorus reagents that are not environmentally friendly.

[0010]

[0011] In addition, the method for synthesizing compound (I) disclosed in patent CN106588809B has the following synthetic route, which uses the Mistunobu reaction. Although the steps are short, it requires the use of a high-purity compound (R)-4-benzyl-2-hydroxy-morpholin-3-one as a raw material. The commercial price of this raw material is expensive and difficult to obtain, making the synthesis process costly and not conducive to scale-up production. In addition, the process uses an organophosphorus reagent, and the post-processing will produce a large amount of organophosphorus waste liquid, which is not environmentally friendly. In addition, azo reagents are used, and the post-processing will produce hydrazine-type genotoxic impurities, which have the potential risk of being introduced into the finished drug.

[0012]

[0013] Therefore, scientific and technological personnel in this field are still carrying out various exploratory research and development work, hoping to have process routes and preparation methods with mild reaction conditions, simple operation, suitable for large-scale production, controllable costs, and green environmental protection. Summary of the Invention

[0014] In view of the above existing problems, the present invention is proposed.

[0015] The invention provides a synthesis process of morpholinone derivatives, which solves the problems of harsh reaction conditions, complex operation, low atom utilization and serious environmental pollution in the existing process.

[0016] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0017] The embodiment of the present invention provides a synthesis process of a morpholinone derivative, which comprises:

[0018] Step S1, dissolving 4-benzyl-2-hydroxy-morpholin-3-one and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in a reaction solvent to form a reaction system;

[0019] Step S2, adding a catalyst to the reaction system and performing a dehydration reaction under heating conditions;

[0020] Step S3, filtering to remove the catalyst in the reaction system, concentrating the filtrate, cooling it, and adding a strong base to induce chiral crystallization;

[0021] Step S4, washing the crystals by cooling, filtering and drying to obtain the target compound (I);

[0022] The target compound (I) is a morpholinone derivative, and its chemical structural formula is:

[0023]

[0024] The synthetic route of the target compound (I) is:

[0025]

[0026] As a preferred embodiment of the synthesis process of a morpholinone derivative described in the present invention, in step S1, the molar ratio of 4-benzyl-2-hydroxy-morpholin-3-one to (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol is 1.0:0.5 to 1.0:2.0.

[0027] As a preferred embodiment of the synthesis process of a morpholinone derivative described in the present invention, in step S1, the reaction solvent is a C1 to C10 linear and / or cyclic alkane, chlorinated hydrocarbon, aromatic hydrocarbon, ether, or nitrile solvent, preferably n-heptane, dichloroethane, toluene, ethylene glycol dimethyl ether, or a combination thereof, more preferably n-heptane, toluene, or a combination thereof.

[0028] As a preferred embodiment of the synthesis process of a morpholinone derivative according to the present invention, in step S2, the catalyst is an organic sulfonic acid or a solid superacid, preferably p-toluenesulfonic acid, camphorsulfonic acid, zirconium oxide, perfluorosulfonic acid resin or a combination thereof.

[0029] As a preferred embodiment of the synthesis process of a morpholinone derivative according to the present invention, in step S3, the strong base is potassium tert-butoxide, potassium tetrahydrolinalool or a combination thereof.

[0030] As a preferred solution of the synthesis process of a morpholinone derivative described in the present invention, the dehydration reaction in step S2 is carried out under nitrogen protection and heated under reflux for 12 hours.

[0031] As a preferred solution of the synthesis process of a morpholinone derivative described in the present invention, the crystallization operation in step S3 is carried out at a temperature within the range of -5°C to -10°C.

[0032] As a preferred embodiment of the synthesis process of a morpholinone derivative according to the present invention, the purity of the target compound (I) in step S4 is detected by high performance liquid chromatography.

[0033] As a preferred solution of the synthesis process of a morpholinone derivative described in the present invention, the by-products in step S2 and step S3 are washed with water and brine and then the solvent is recovered to improve the greenness and environmental friendliness of the process.

[0034] The present invention also discloses the application of the morpholinone derivatives, which are used as intermediates of the antiemetic drugs aprepitant and fosaprepitant dimeglumine to treat nausea and vomiting associated with radiotherapy and chemotherapy in tumor patients.

[0035] The beneficial effects of the present invention are:

[0036] The present invention has mild process reaction conditions, avoids extreme conditions such as high temperature and high pressure in traditional methods, greatly improves operational safety, and is suitable for industrial-scale production. The reaction process of the catalyst and solvent combination is more stable, and the steps are simplified, and tedious intermediate processing operations are reduced, thereby improving overall efficiency. The invention also has a high atom utilization rate, and the target compound is synthesized directly through dehydration and chiral crystallization, avoiding the waste of raw materials caused by the introduction and removal of activating groups in traditional routes, thereby improving resource utilization and reducing production costs. In addition, the main raw materials used, such as 4-benzyl-2-hydroxy-morpholin-3-one and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol, are widely available and moderately priced, thereby ensuring economy.

[0037] The present invention adopts the concept of green chemistry in the process, avoids the use of strong acids, strong bases, organophosphorus reagents and azo reagents, reduces the generation of corrosive substances and toxic by-products, and significantly reduces the discharge of waste liquid through the solvent recovery process, embodying green chemical industry; in addition, the purity of the target compound can reach more than 97% through high-performance liquid chromatography detection, meeting the high quality requirements of pharmaceutical synthesis and reducing the complexity of subsequent refining.

[0038] In summary, the present invention addresses the shortcomings and deficiencies of existing synthetic routes and process technologies and provides a process route and preparation method for a morpholinone derivative, namely compound (I). The method has mild reaction conditions, is simple to operate, can easily achieve large-scale production, has readily available raw materials, is cost-controllable, has good process reproducibility, and is environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0040] Figure 1 This is the H NMR spectrum of compound (1) of the present invention.

[0041] Figure 2 Schematic diagram of the synthesis process of the morpholinone derivatives of the present invention. DETAILED DESCRIPTION

[0042] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0043] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0044] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0045] The raw materials, reagents and solvents used in the present invention are not particularly limited, and commercially available conventional raw materials, reagents and solvents can be used.

[0046] Instruments and methods used to collect data:

[0047] The 1H NMR data were collected using a Bruker AVANCE III instrument with a resonance frequency of 400 MHz and deuterated chloroform as solvent.

[0048] Purity was tested by high performance liquid chromatography, and the chromatographic conditions were as follows:

[0049]

[0050]

[0051] The purity of the main peak was calculated using the principal component self-reference method.

[0052] It should be noted that the protection scope of the meaning or significance of the numerical values ​​or numerical endpoints involved in the technical solution of the present invention is not limited to the numbers themselves. Those skilled in the art will understand that they include those allowable error ranges that have been widely accepted in the art, such as experimental errors, measurement errors, statistical errors and random errors, etc., and these error ranges are all included in the scope of the present invention.

[0053] In order to further illustrate the present invention, specific examples will be given below. However, the following examples do not limit the scope of protection of the present invention.

[0054] Example 1

[0055] 4-Benzyl-2-hydroxy-morpholin-3-one (22.8 kg, 110 mol) and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (25.8 kg, 100 mol) were dissolved in 150 L of n-heptane, and 1.3 kg (5%) of solid superacid perfluorinated resin was added. The mixture was heated under reflux and dehydrated under nitrogen for 12 hours until anhydrous water was distilled off. The mixture was cooled and filtered to remove the catalyst. The mixture was concentrated to 80 L and tetrahydrolinalool (31.6 kg, 200 mol) was added. The mixture was cooled to -8°C in an ice-water bath. To -10 ° C, potassium tert-butoxide (23.2 kg, 0.2 mol) was added, and the reaction was carried out at 0 ° C for 6 hours. Acetic acid (24 kg, 400 mol) was added to quench the reaction, and then 30 L of (5%) sodium bicarbonate solution was added and the temperature was raised to room temperature for separation. The organic layer was washed with 30 L of water and 30 L of saturated brine. After the separation, 8 L of methyl tert-butyl ether was added and the temperature was cooled from -5 ° C to -10 ° C, stirred and crystallized. The filter cake was washed with 20 L of n-heptane and dried to obtain 33.5 kg of compound (I) with an HPLC purity of 98% and a yield of 75%.

[0056] The nuclear magnetic characterization data were analyzed as follows: 1H NMR: (400 MHz, CDCl3) δ7.98 (s, 2H), 7.84 (s, 1H), 7.33 (m, 5H), 5.06 (q, J = 6.6, 1H), 4.83 (s, 1H), 4.70 (d, J = 14.6, 1H), 4.59 (d, J = 14.6, 1H), 4.33 (m, 1H), 3.79 (m, 1H), 3.49 (m, 1H) 3.10 (m, 1H), 1.58 (d, J = 6.6, 3H), see for details. Figure 1 .

[0057] Example 2

[0058] 4-Benzyl-2-hydroxy-morpholin-3-one (22.78 g, 0.11 mol) and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (25.81 g, 0.10 mol) were added to 300 mL of toluene and dissolved, and p-toluenesulfonic acid (3.44 g, 0.02 mol) was added. The mixture was heated under reflux under nitrogen for 12 hours to remove water. After cooling, 30 mL of (5%) sodium bicarbonate solution was added and stirred for separation. The organic layer was diluted with 30 mL of water and 30 mL of saturated brine, and concentrated to 150 mL. Tetrahydrolinalool (31.6 g, 0 The mixture was refluxed and dehydrated to a concentration of less than 100 ppm, cooled to -8 to -10°C in an ice-water bath, potassium tert-butoxide (22.4 g, 0.2 mol) was added, and the mixture was reacted at 0°C for 6 hours. Acetic acid (24 g, 0.4 mol) was added to quench the reaction, and 30 mL of (5%) sodium bicarbonate solution was added. The mixture was warmed to room temperature for separation, and the organic layer was washed with 30 mL of water and 30 mL of saturated brine. The mixture was cooled to -5 to -10°C and stirred for crystallization. The mixture was filtered, and the filter cake was washed with 20 mL of n-heptane and dried to obtain 22.3 g of compound (I) with an HPLC purity of 97% and a yield of 50%.

[0059] Example 3

[0060] 4-Benzyl-2-hydroxy-morpholin-3-one (22.78 g, 0.11 mol) and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (25.81 g, 0.10 mol) were added to 300 mL of n-heptane to dissolve, and p-camphorsulfonic acid (2.32 g, 0.01 mol) was added. The mixture was heated under reflux under nitrogen for dehydration for 12 hours until anhydrous water was distilled out. After cooling, 30 mL of (5%) sodium bicarbonate solution was added and stirred for separation. The organic layer was diluted with 30 mL of water and 30 mL of saturated brine, concentrated to 150 mL, and tetrahydrolinalool (31.6 g, 0 The mixture was refluxed and dehydrated to a concentration of less than 100 ppm. The mixture was cooled to -8 to -10°C in an ice-water bath, potassium tert-butoxide (23.2 g, 0.2 mol) was added, and the mixture was reacted at 0°C for 6 hours. Acetic acid (24 g, 0.4 mol) was added to quench the reaction, and 30 mL of (5%) sodium bicarbonate solution was added and the temperature was raised to room temperature for separation. The organic layer was washed with 30 mL of water and 30 mL of saturated brine, and the mixture was cooled to -5 to -10°C and stirred for crystallization. The mixture was filtered, and the filter cake was washed with 20 mL of n-heptane and dried to obtain 24.5 g of compound (I) with an HPLC purity of 97% and a yield of 55%.

[0061] Example 4

[0062] 4-Benzyl-2-hydroxy-morpholin-3-one (22.78 g, 0.11 mol) and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (25.81 g, 0.10 mol) were added to 300 mL of n-heptane to dissolve, and then 2.2 g (10%) of solid superacid zirconium oxide was added. The mixture was heated under reflux under nitrogen protection for 12 hours to dehydrate until anhydrous water was distilled out. The catalyst was removed by cooling and filtration, and the mixture was concentrated to 150 mL. Tetrahydrolinalool (31.6 g, 0.20 mol) was added and the mixture was cooled to -8°C in an ice-water bath. To the reaction mixture, potassium tert-butoxide (23.2 g, 0.2 mol) was added at -10°C, and the reaction was carried out at 0°C for 6 hours. Acetic acid (24 g, 0.4 mol) was added to quench the reaction, and 30 mL of (5%) sodium bicarbonate solution was added and the temperature was raised to room temperature for separation. The organic layer was washed with 30 mL of water and 30 mL of saturated brine, and then 30 mL of methyl tert-butyl ether was added, cooled from -5°C to -10°C, stirred for crystallization, filtered, and the filter cake was washed with 20 mL of n-heptane. After drying, 31.3 g of compound (I) was obtained with an HPLC purity of 97% and a yield of 70%.

[0063] In summary, it can be seen that the process of the present invention has mild reaction conditions and is suitable for industrial-scale production. The reaction process of the catalyst and solvent combination is more stable, while simplifying the steps, reducing tedious intermediate processing operations, and improving overall efficiency. It also has a high atomic utilization rate, and the target compound is synthesized directly through dehydration and chiral crystallization, avoiding the waste of raw materials caused by the introduction and removal of activating groups in the traditional route, improving resource utilization and reducing production costs. In addition, the main raw materials used, such as 4-benzyl-2-hydroxy-morpholin-3-one and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol, are widely available and reasonably priced, ensuring economic efficiency. The process adopts the concept of green chemistry, avoids the use of strong acids, strong bases, organophosphorus reagents and azo reagents, reduces the production of corrosive substances and toxic byproducts, and significantly reduces the discharge of waste liquid through the solvent recovery process, reflecting green chemical industry. In addition, the purity of the target compound can reach more than 97% by high-performance liquid chromatography, meeting the high quality requirements of pharmaceutical synthesis and reducing the complexity of subsequent refining.

[0064] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A process for synthesizing a morpholinone derivative, characterized in that: The following steps are included: Step S1, dissolving 4-benzyl-2-hydroxy-morpholin-3-one and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in a reaction solvent to form a reaction system; Step S2, adding a catalyst to the reaction system and performing a dehydration reaction under heating conditions; Step S3, filtering to remove the catalyst in the reaction system, concentrating the filtrate, cooling it, and adding a strong base to induce chiral crystallization; Step S4, obtaining the target compound (I) by cooling, washing, filtering and drying; The target compound (I) is a morpholinone derivative with the chemical structural formula: ； The synthetic route of the target compound (I) is: ； In step S1, the reaction solvent is a C1 to C10 linear and / or cyclic alkane, chlorinated hydrocarbon, aromatic hydrocarbon, ether, or nitrile solvent; In step S2, the catalyst is an organic sulfonic acid or a solid super acid; In step S3, the strong base is potassium tert-butoxide, potassium tetrahydrolinalool or a combination thereof; The dehydration reaction in step S2 was carried out under nitrogen protection and heated under reflux for 12 hours; The crystallization operation in step S3 is performed at a temperature ranging from -5°C to -10°C.

2. The process for synthesizing a morpholinone derivative according to claim 1, wherein: In step S1, the molar ratio of 4-benzyl-2-hydroxy-morpholin-3-one to (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol is 1.0:0.5 to 1.0:2.

0.

3. The process for synthesizing a morpholinone derivative according to claim 2, wherein: The purity of the target compound (I) in step S4 is detected by high performance liquid chromatography.

4. The process for synthesizing a morpholinone derivative according to claim 3, wherein: The by-products in step S2 and step S3 are washed with water and brine and then the solvent is recovered.

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