A method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative

Abstract

The invention discloses a method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative, which belongs to the technical field of organic synthesis and is suitable for industrial large-scale production. Difluorocarbene is produced by using a cheap base free of heavy metals as an additive, and the difluoromethylation of the proline derivative is completed to obtain an important difluoromethyl ether proline derivative pharmaceutical intermediate. Compared with existing synthesis methods, the method has mild reaction conditions, does not require the participation of heavy metals, can produce a large amount of fluorine-free products, uses inexpensive and readily available reagents, and has a high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative, which is suitable for industrial large-scale production. Background Art

[0002] Existing antiviral drugs, such as the combination of namatevir and ritonavir, face metabolic stability issues, necessitating the development of novel compounds. Due to these drug efficacy and stability issues, major pharmaceutical companies are searching for compounds with enhanced metabolic stability and potential for standalone drug development. The proline subunits in existing antiviral drugs act within the lipophilic binding pocket, making them a crucial component for drug modification to enhance metabolic stability. Based on this research, proline fragment derivatives modified with difluoromethyl and trifluoromethyl ethers have demonstrated high efficacy and low clearance, demonstrating promising standalone drug development potential in both simulations and experiments.

[0003] The kilogram-scale synthesis of difluoromethyl ether proline fragments is crucial for supporting clinical research. Currently, only one kilogram-scale synthesis has been achieved [Org. Process Res. Dev. 2024, 28, 1119−1128]. However, this kilogram-scale synthesis requires the use of heavy metals and produces a byproduct of hydrolysis of the difluoromethyl group to a carbonyl group, which is difficult to separate and requires further post-processing to obtain the pure target product. Summary of the Invention

[0004] 1. Technical problems to be solved:

[0005] Based on the above background, the main technical problem solved by the present invention is to complete the large-scale preparation of proline difluoromethyl ether derivatives by using the commercially available raw material N-Boc-trans-4-hydroxy-L-proline methyl ester, the industrially inexpensive reagent difluorocarbene reagent TMSCF2Br, and a cheap inorganic base that does not contain heavy metals as an initiator.

[0006] 2. Technical solution:

[0007] In order to solve the above problems, the present invention adopts the following technical solutions:

[0008]

[0009] In the method for preparing the compound of formula (I), the solvent is a dipolar aprotic solvent such as a nitrile solvent, an amide solvent, and a mixed solvent of a non-polar solvent and water, such as a halogenated hydrocarbon solvent and a mixed solvent of a hydrocarbon solvent and water, preferably acetonitrile (MeCN), N,N'-dimethylacetamide (DMAc), N,N'-dimethylformamide (DMF), dichloromethane (DCM), toluene, cyclohexane (hexane) solvent, more preferably acetonitrile (MeCN), N,N'-dimethylformamide (DMF) and a mixed solvent of dichloromethane (DCM), toluene and water.

[0010] Furthermore, the inorganic base added to the fluoroalkylation reaction is at least one of sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), potassium acetate (KOAc), sodium acetate (NaOAc), ammonium acetate (NH4OAc), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), potassium fluoride (KF), potassium bifluoride (KHF2), and potassium phosphate (K3PO4), preferably sodium hydroxide (NaOH), potassium carbonate (K2CO3), and potassium bifluoride (KHF2).

[0011] Furthermore, the inorganic base used in the reaction will have a certain thermal effect when dissolved in water, so it can be dissolved in water in advance. Direct use of the inorganic base solution has the same effect, and this operation is more suitable for amplified reactions.

[0012] Furthermore, the reaction temperature is 0-100°C; when a dipolar aprotic solvent is used, the preferred temperature is 80-100°C; when a non-polar solvent and water are used as a mixed solvent, the preferred reaction temperature is 0-25°C (room temperature);

[0013] Furthermore, the amount of the reagent added to the reaction is 1-3 equivalents relative to the reaction substrate N-Boc-trans-4-hydroxy-L-proline methyl ester, preferably 1.5-2 equivalents.

[0014] Furthermore, the amount of the inorganic base added to the reaction is 2-6 equivalents, preferably 3-5 equivalents, relative to the amount of the reaction substrate (N-Boc-trans-4-hydroxy-L-proline methyl ester).

[0015] Furthermore, the concentration of the reaction is 1-3 mol / L, preferably 2 mol / L.

[0016] Furthermore, the reaction is carried out under mechanical stirring to ensure that the reaction substrates are fully mixed, preferably at 300-600 revolutions per minute.

[0017] The progress of the reaction can be monitored using commonly used testing methods in the art (e.g. 19 The reaction is usually monitored by F-NMR, and the disappearance of the starting material or its end point is generally regarded as the end point of the reaction.

[0018] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0019] 3. Beneficial effects:

[0020] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects:

[0021] This method is rationally designed to prepare large quantities of proline difluoromethyl ether derivatives using the common, inexpensive, and readily available reagent, difluorobromomethyltrimethylsilane (TMSCF2Br), as the raw material, N-Boc-trans-4-hydroxy-L-proline methyl ester, and an inexpensive, heavy-metal-free inorganic base as an initiator. Compared to existing synthetic methods, this method avoids the production of difficult-to-isolate byproducts during the large-scale reaction, utilizes inexpensive, readily available reagents, and offers high yields. It can be prepared in large quantities, often in kilogram quantities, providing strong support and a solid foundation for subsequent clinical trials of related drugs.

[0022] It should be noted that the structures not introduced in the present invention are the same as those in the prior art or can be implemented by using the prior art, and are not described in detail here because they do not involve the design points and improvement directions of the present invention. DETAILED DESCRIPTION

[0023] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0024] The structure and purity of the compounds in the present invention were determined by nuclear magnetic resonance (NMR), high performance liquid chromatography (HPLC), and mass spectrometry. 19 F-NMR) was performed using a Bruker AVANCE 300 nuclear magnetic resonance spectrometer, and the solvent used in the reaction was used.

[0025] Example 1:

[0026]

[0027] In a mechanically stirred reactor, N,N'-dimethylformamide (DMF) (32 L, 8 L / kg) was added, and the raw materials N-Boc-trans-4-hydroxy-L-proline methyl ester (4 kg, 1 equiv) and potassium carbonate (K2CO3) (4.51 kg, 2.0 equiv) represented by formula (II) were weighed and added to the reactor. After being fully stirred at 500 rpm, the reaction base and substrate were fully mixed. At room temperature (25±5°C), difluoromethylbromotrimethylsilane (TMSCF2Br) (8 kg, 5.88 L, 2.5 equiv) was slowly added through a liquid phase injection tube with stirring. The addition time was 2 h. After the feeding was completed, the initial reaction temperature was maintained and stirring was continued for 4 h. After the reaction was complete as detected by fluorine spectrum, the reaction system was directly filtered and concentrated under reduced pressure to obtain a crude reaction product. The crude product was purified by column purification using alkaline silica gel and eluted with ethyl acetate and petroleum ether (EA:PE=1:6) to obtain a colorless oily product (3.84 kg, yield: 79.2%, purity: 98.3%).

[0028] Example 2:

[0029]

[0030] Acetonitrile (MeCN) (30 L, 6 L / kg) was added to a reactor with mechanical stirring. The raw materials N-Boc-trans-4-hydroxy-L-proline methyl ester (5 kg, 1 equiv) and potassium bifluoride (KHF2) (3.51 kg, 2.2 equiv) represented by formula (II) were weighed and added to the reactor. After being fully stirred by mechanical stirring at 500 rpm to allow the reaction base and substrate to be fully mixed, difluoromethylbromotrimethylsilane (TMSCF2Br) (10.78 kg, 8.25 L, 2.6 equiv) was slowly added through the liquid phase injection tube of the reactor under stirring at room temperature (25±5°C). The addition time was 3 h. After the feeding was completed, the initial reaction temperature was maintained and stirring was continued for 4 h. After the reaction was complete as detected by fluorine spectrum, the reaction system was directly filtered and concentrated under reduced pressure to obtain a crude reaction product. The crude product was purified by column purification using alkaline silica gel and eluted with ethyl acetate and petroleum ether (EA:PE=1:6) to obtain a colorless oily product (4.88 kg, yield 81.4%, purity 98.5%).

[0031] Example 3:

[0032]

[0033] In a mechanically stirred reactor, N,N'-dimethylformamide (DMF) (40 L, 8 L / kg) was added, and the raw materials N-Boc-trans-4-hydroxy-L-proline methyl ester (5 kg, 1 equiv) and sodium acetate (NaOAc) (5.02 kg, 3.0 equiv) represented by formula (II) were weighed and added to the reactor. After being fully stirred at 500 rpm, the reaction base and substrate were fully mixed in the solvent. At room temperature (25±5°C), difluoromethylbromotrimethylsilane (TMSCF2Br) (12.43 kg, 9.56 L, 3.0 equiv) was slowly added through a liquid phase injection tube with stirring. The addition time was 4 h. After the feeding was completed, the initial temperature was maintained and stirring was continued for 6 h. After the reaction was complete as detected by fluorine spectrum, the reaction system was directly filtered and concentrated under reduced pressure to obtain a crude reaction product. The crude product was purified by column purification using alkaline silica gel and eluted with ethyl acetate petroleum ether system (EA:PE=1:6) to obtain a colorless oily product (4.47 kg, yield: 77%, purity: 98.1%).

[0034] Example 4:

[0035]

[0036] In a mechanically stirred reactor, dichloromethane (DCM) (25 L, 5 L / kg) was added, and the raw materials N-Boc-trans-4-hydroxy-L-proline methyl ester (5 kg, 1 equiv) and potassium bifluoride (KHF2) (3.51 kg, 2.2 equiv) represented by formula (II) were weighed and added to the reactor. At this time, deionized water (25 L, 5 L / kg) was added. After being thoroughly stirred at 500 rpm, the reaction substrates were fully mixed. At room temperature (25±5°C), difluoromethylbromotrimethylsilane (TMSCF2Br) (9.53 kg, 7.33 L, 2.3 equiv) was slowly added through a liquid phase injection tube with stirring. The addition time was 2 h. After the feeding was completed, the initial temperature was maintained and stirring was continued for 10 hours. After the reaction was complete as detected by fluorine spectrum, dichloromethane (30 L) was added to the reaction system to dilute the reaction solution, and deionized water (20 L) was added to fully wash the reaction organic phase. The liquids were separated, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column purification using alkaline silica gel and eluted with ethyl acetate petroleum ether system (EA:PE=1:6) to obtain a colorless oily product (5.12 kg, yield 85%, purity: 98.4%).

[0037] Example 5:

[0038]

[0039] In a mechanically stirred reactor, dichloromethane (DCM) (20 L, 5 L / kg) was added, and the raw material N-Boc-trans-4-hydroxy-L-proline methyl ester (4 kg, 1 equiv) represented by formula (II) was weighed and added to the reactor. At this time, sodium hydroxide (NaOH) (1.7 kg, 2.6 equiv) was weighed and dissolved in deionized water (25 L). The dissolution will release heat. After the solution temperature returned to room temperature (25±5°C), it was added to the reactor through a reaction liquid phase tube. After being fully stirred at 500 rpm, the reaction substrate was fully mixed. At room temperature (25±5°C), difluoromethylbromotrimethylsilane (TMSCF2Br) (7.95 kg, 6.12 L, 2.4 equiv) was slowly added through a liquid phase injection tube with stirring. The addition time was 2 h. After the feeding was completed, the initial temperature was maintained and stirring was continued for 12 hours. After the reaction was complete as detected by fluorine spectrum, dichloromethane (20 L) was added to the reaction system to dilute the reaction solution, and deionized water (15 L) was added to fully wash the reaction organic phase. The liquids were separated, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column purification using alkaline silica gel and eluted with ethyl acetate petroleum ether system (EA:PE=1:6) to obtain a colorless oily product (4.14 kg, yield 86%, purity: 98.6%).

[0040] Example 6:

[0041]

[0042] In a mechanically stirred reactor, dichloromethane (DCM) (25 L, 5 L / kg) was added, and the raw materials N-Boc-trans-4-hydroxy-L-proline methyl ester (5 kg, 1 equiv) and sodium carbonate (Na2CO3) (4.54 kg, 2.1 equiv) represented by formula (II) were weighed and added to the reactor. At this time, deionized water (25 L, 5 L / kg) was added. After being thoroughly stirred at 500 rpm, the reaction substrates were fully mixed. At room temperature (25±5°C), difluoromethylbromotrimethylsilane (TMSCF2Br) (9.11 kg, 7.01 L, 2.2 equiv) was slowly added through a liquid phase injection tube with stirring. The addition time was 2 h. After the feeding was completed, the initial temperature was maintained and stirring was continued for 12 h. After the reaction was complete as detected by fluorine spectrum, dichloromethane (20 L) was added to the reaction system to dilute the reaction solution, and deionized water (20 L) was added to fully wash the reaction organic phase. The liquids were separated, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column purification using alkaline silica gel and eluted with ethyl acetate petroleum ether system (EA:PE=1:6) to obtain a colorless oily product (4.94 kg, yield 82.3%, purity: 98.3%).

[0043] Example 7:

[0044]

[0045] In a mechanically stirred reactor, dichloromethane (DCM) (20 L, 5 L / kg) was added, and the raw material N-Boc-trans-4-hydroxy-L-proline methyl ester (4 kg, 1 equiv) represented by formula (II) was weighed and added to the reactor. At this time, sodium hydroxide (KOH) (3.02 kg, 3.3 equiv) was weighed and dissolved in deionized water (25 L). The dissolution will release heat. After the solution temperature returned to room temperature (25±5°C), it was added to the reactor through a reaction liquid phase tube. After being fully stirred at 500 rpm, the reaction substrate was fully mixed. At room temperature (25±5°C), difluoromethylbromotrimethylsilane (TMSCF2Br) (6.83 kg, 5.25 L, 2.6 equiv) was slowly added through a liquid phase injection tube with stirring. The addition time was 2 h. After the feeding was completed, the initial temperature was maintained and stirring was continued for 10 hours. After the reaction was complete as detected by fluorine spectrum, dichloromethane (20 L) was added to the reaction system to dilute the reaction solution, and deionized water (20 L) was added to fully wash the reaction organic phase. The liquids were separated, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column purification using alkaline silica gel and eluted with ethyl acetate petroleum ether system (EA:PE=1:6) to obtain a colorless oily product (4.05 kg, yield 84.3%, purity: 98.6%).

[0046] Example 8:

[0047]

[0048] In a mechanically stirred reactor, dichloromethane (DCM) (25 L, 5 L / kg) was added, and the raw material N-Boc-trans-4-hydroxy-L-proline methyl ester (5 kg, 1 equiv) represented by formula (II) was weighed and added to the reactor. At this time, sodium hydroxide (NaOH) (2.7 kg, 3.3 equiv) was weighed and dissolved in deionized water (25 L). The dissolution will release heat. After the solution temperature returned to room temperature (25±5°C), it was added to the reactor through a reaction liquid phase tube. After being fully stirred at 500 rpm, the reaction substrate was fully mixed. At room temperature (25±5°C), difluoromethylbromotrimethylsilane (TMSCF2Br) (11.18 kg, 8.6 L, 2.7 equiv) was slowly added through a liquid phase injection tube with stirring. The addition time was 4 h. After the feeding was completed, the initial temperature was maintained and stirring was continued for 12 hours. After the reaction was complete as detected by fluorine spectrum, dichloromethane (25 L) was added to the reaction system to dilute the reaction solution, and deionized water (25 L) was added to fully wash the reaction organic phase. The liquids were separated, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The product was then purified by column purification using alkaline silica gel and eluted with ethyl acetate petroleum ether system (EA:PE=1:6) to obtain a colorless oily product (5.06 kg, yield 84.2%, purity: 98.3%).

[0049] The final product spectrum and purification information are as follows:

[0050] 19 F NMR (376 MHz, DMSO- d 6) d 80.9 (dd, J = 75.6, and12.9 Hz).

[0051] 1 H NMR (400 MHz, DMSO- d 6) d 6.75 (t, J = 75.4 Hz, 1H),4.83-4.79 (m,1H), 4.27-4.19 (m, 1H), 3.68-3.65 (m, 3H),3.59-3.45 (m, 2H), 2.46-2.32 (m,1H), 2.21-2.07 (m, 1H),1.39-1.34 (m, 9H).

[0052] 13 C NMR (101 MHz, DMSO- d 6) d 173.4, 173.0, 154.2,153.5, 117.7 (t,J =255.8 Hz), 74.6 (t, J = 3.9 Hz), 74.0 (t, J =3.9 Hz), 58.0, 57.6, 53.0, 52.8,52.8, 52.7, 37.0, 36.1, 28.8, 28.7,28.6, 28.6, 28.5.

[0053] HRMS (ESI) m / z calcd. For C 12 H 19 F2NO5 [(M + H) + ] 296.1304, found,296.1307.

[0054] The above-mentioned embodiments only express a certain implementation method of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the patent scope of the present invention. It should be pointed out that for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent of the present invention shall be based on the attached claims.

Claims

1. A method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative, characterized in that: The following steps are involved: The N-Boc-trans-4-hydroxy-L-proline methyl ester represented by formula (II) and an inorganic base initiator free of heavy metals are fully mixed in a solvent, and a difluorocarbene reagent difluorobromomethyltrimethylsilane (TMSCF2Br) is slowly added to generate a difluoromethyl ether proline derivative represented by formula (I); The general formula of the reaction is: ； Wherein, the solvent is a mixture of acetonitrile (MeCN), N,N-dimethylformamide (DMF) or dichloromethane (DCM) and water; The inorganic base is sodium hydroxide (NaOH), potassium carbonate (K2CO3) or potassium bifluoride (KHF2); The reaction temperature is 25 ± 5 ° C; The equivalent weight of the difluoromethylbromotrimethylsilane (TMSCF2Br) is 1.5-2.0 equivalents, and the equivalent weight of the inorganic base is 3.0-5.0 equivalents; The reaction was stirred and difluoromethylbromotrimethylsilane (TMSCF2Br) was slowly added through a liquid phase injection tube; The method is suitable for kilogram-scale preparation, and the purity of the obtained product is ≥98%.

2. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: After the reaction is completed, the target product is obtained by filtration, concentration under reduced pressure, and purification by column chromatography. The column chromatography purification uses a basic silica gel and an ethyl acetate / petroleum ether mixed solvent system.

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