Preparation method of drug intermediate difluoromethyl ether proline derivative without heavy metal participation

Abstract

The invention discloses a preparation method of a drug intermediate difluoromethyl ether proline derivative without participation of heavy metals, belongs to the technical field of organic synthesis, is suitable for industrial large-scale production, and completes difluoromethylation of the proline derivative by generating difluorocarbene by using cheap alkali without heavy metals as an additive. The important difluoromethyl ether proline derivative drug intermediate is obtained; compared with the existing synthesis method, the method has the advantages of mild reaction conditions, no need of heavy metal participation, large-scale preparation of fluorine-free products, cheap and easily available reagents and 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) are in urgent need of developing new compounds due to metabolic stability issues. Due to the efficacy and stability issues of the drug, major pharmaceutical companies are looking for compound molecules that are more metabolically stable and can be independently drugged. The proline subunit in existing antiviral drugs acts in the lipophilic binding pocket, and this subunit is an important part of the modification to improve the metabolic stability of the drug. Based on this study, proline fragment derivatives modified with difluoromethyl and trifluoromethyl ethers showed high efficiency and low clearance, and had good independent drug potential in simulations and experiments.

[0003] The kilogram-scale synthesis of difluoromethyl ether proline fragments is of great significance for supporting clinical research. Currently, there is only one kilogram-scale synthesis [Org. Process Res. Dev. 2024, 28, 1119−1128], but this kilogram-scale synthesis requires the use of heavy metals, and there are byproducts of difluoromethyl hydrolysis to carbonyl, which are difficult to separate and require further post-processing to successfully obtain the pure target product. Summary of the invention

[0004] 1. Technical problems to be solved: Based on the above background, the main technical problem solved by the present invention is to prepare a large amount of proline difluoromethyl ether derivatives by using the commercially available raw material N-Boc-trans-4-hydroxy-L-proline methyl ester, the industrially cheap reagent difluorocarbene reagent TMSCF2Br, and a cheap inorganic base that does not contain heavy metals as an initiator.

[0005] 2. Technical solution: To solve the above problems, the present invention adopts the following technical solutions:

[0006] 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, and more preferably acetonitrile (MeCN), N,N'-dimethylformamide (DMF) and a mixed solvent of dichloromethane (DCM), toluene and water.

[0007] Furthermore, the inorganic base added in 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).

[0008] Furthermore, the inorganic base used in the reaction will have a certain thermal effect when dissolved in water, and 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 amplifying the reaction.

[0009] Further, 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); Furthermore, the amount of reagent added to the reaction is 1-3 equivalents, preferably 1.5-2 equivalents, relative to the equivalent of (reaction substrate N-Boc-trans-4-hydroxy-L-proline methyl ester).

[0010] Furthermore, the inorganic base added to the reaction is 2-6 equivalents, preferably 3-5 equivalents, relative to the reaction substrate (N-Boc-trans-4-hydroxy-L-proline methyl ester).

[0011] Furthermore, the concentration of the reaction is 1-3 mol / L, preferably 2 mol / L.

[0012] 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.

[0013] The progress of the reaction can be tested using commonly used testing methods in the art (such as19 The end point of the reaction is usually when the starting material disappears or no longer reacts.

[0014] 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.

[0015] 3. Beneficial effects: Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects: The invention is reasonably designed, and uses the raw material N-Boc-trans-4-hydroxy-L-proline methyl ester, the common cheap and readily available reagent difluorobromomethyltrimethylsilane (TMSCF2Br), and the cheap inorganic base containing no heavy metals as an initiator to complete the mass preparation of proline difluoromethyl ether derivatives. Compared with the existing synthesis method, the method does not produce byproducts that are difficult to separate during the mass reaction process, uses cheap and readily available reagents, has a high yield, can be prepared in large quantities at the kilogram level, and provides strong support and a solid foundation for subsequent clinical trials of related drugs.

[0016] It should be noted that the structures not introduced in the present invention are the same as 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

[0017] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0018] In the present invention, the structure and purity of the compound are determined by nuclear magnetic resonance technology, high performance liquid chromatography and mass spectrometry. The reaction progress is determined by nuclear magnetic resonance fluorine spectrum ( 19 F-NMR) was used for the test, using a Bruker AVANCE 300 nuclear magnetic resonance spectrometer, and the solvent used in the reaction was the solvent used in the reaction.

[0019] Embodiment 1:

[0020] In a reaction kettle with mechanical stirring, 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) shown in formula (II) were weighed and added to the reaction kettle. After being fully stirred at 500 rpm, the reaction base and the substrate were fully mixed. At room temperature (25±5°C), dibromomethyltrimethylsilane (TMSCF2Br) (8 kg, 5.88 L, 2.5 equiv) was slowly added through a liquid phase injection tube under stirring. The addition time was 2 h. After the feeding was completed, the initial reaction temperature was maintained and stirring was continued for 4 hours. 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, which was then 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%).

[0021] Embodiment 2:

[0022] In a reactor with mechanical stirring, acetonitrile (MeCN) (30 L, 6 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) shown in formula (II) were weighed and added to the reactor. After being fully stirred by mechanical stirring at 500 rpm, the reaction base and the substrate were fully mixed. At room temperature (25±5°C), difluorobromomethyltrimethylsilane (TMSCF2Br) (10.78 kg, 8.25 L, 2.6 equiv) was slowly added through the liquid phase injection tube of the reactor under stirring, and the addition time was 3 h. After the feeding was completed, the initial reaction temperature was maintained and stirring was continued for 4 hours. 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, which was then 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%).

[0023] Embodiment 3:

[0024] In a reaction kettle with mechanical stirring, 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) shown in formula (II) were weighed and added to the reaction kettle. After being fully stirred at 500 rpm, the reaction base and the substrate were fully mixed in the solvent. At room temperature (25±5°C), dibromomethyltrimethylsilane (TMSCF2Br) (12.43 kg, 9.56 L, 3.0 equiv) was slowly added through a liquid phase injection tube under stirring. The addition time was 4 h. After the feeding was completed, the initial temperature was maintained and stirring was continued for 6 hours. After the reaction was completed by fluorine spectrum detection, the reaction system was directly filtered and concentrated under reduced pressure to obtain a crude reaction product, which was purified by column 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%).

[0025] Embodiment 4:

[0026] In a reaction kettle with mechanical stirring, 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) shown in formula (II) were weighed and added to the reaction kettle. At this time, deionized water (25 L, 5 L / kg) was added, and the reaction substrates were fully mixed after being fully stirred at 500 rpm. At room temperature (25±5°C), difluorobromomethyltrimethylsilane (TMSCF2Br) (9.53 kg, 7.33 L, 2.3 equiv) was slowly added through a liquid phase injection tube under stirring, and 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 organic phase was 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 (5.12 kg, yield 85%, purity: 98.4%).

[0027] Embodiment 5:

[0028] In a reactor with mechanical stirring, 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 returns to room temperature (25±5°C), it is added to the reactor through a reaction liquid phase tube. After being fully stirred at 500 rpm, the reaction substrate is fully mixed. At room temperature (25±5°C), difluorobromomethyltrimethylsilane (TMSCF2Br) (7.95 kg, 6.12 L, 2.4 equiv) is slowly added through a liquid phase injection tube under stirring. The addition time is 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 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%).

[0029] Embodiment 6:

[0030] In a reaction kettle with mechanical stirring, 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) shown in formula (II) were weighed and added to the reaction kettle. At this time, deionized water (25 L, 5 L / kg) was added, and the reaction substrate was fully mixed after being fully stirred at 500 rpm. At room temperature (25±5°C), difluorobromomethyltrimethylsilane (TMSCF2Br) (9.11 kg, 7.01 L, 2.2 equiv) was slowly added through a liquid phase injection tube while stirring, and 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 (20 L) was added to fully wash the reaction organic phase. The organic phase was separated, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. It was then purified by column 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%).

[0031] Embodiment 7:

[0032] In a reactor with mechanical stirring, 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) shown in 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 returns to room temperature (25±5°C), it is added to the reactor through a reaction liquid phase tube. After being fully stirred at 500 rpm, the reaction substrate is fully mixed. At room temperature (25±5°C), difluorobromomethyltrimethylsilane (TMSCF2Br) (6.83 kg, 5.25 L, 2.6 equiv) is slowly added through a liquid phase injection tube while stirring. The addition time is 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 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%).

[0033] Embodiment 8:

[0034] In a reactor with mechanical stirring, 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 returns to room temperature (25±5°C), it is added to the reactor through a reaction liquid phase tube. After being fully stirred at 500 rpm, the reaction substrate is fully mixed. At room temperature (25±5°C), difluorobromomethyltrimethylsilane (TMSCF2Br) (11.18 kg, 8.6 L, 2.7 equiv) is slowly added through a liquid phase injection tube under stirring. The addition time is 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%).

[0035] The final product spectrum and purification information are as follows: 19 F NMR (376 MHz, DMSO- d 6) d 80.9 (dd, J = 75.6, and12.9 Hz).

[0036] 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).

[0037] 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.

[0038] HRMS (ESI) m / z calcd. For C 12 H 19 F2NO5 [(M + H) + ] 296.1304, found,296.1307.

[0039] The above-described embodiments only express a certain implementation mode 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 modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope 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) is reacted with difluorobromomethyltrimethylsilane (TMSCF2Br) in a solvent, and an inorganic base free of heavy metals is added as an initiator to generate a difluoromethyl ether proline derivative represented by formula (I); The general formula of the reaction is: ； The solvent is selected from at least one of a dipolar aprotic solvent and a mixed solvent of a nonpolar solvent and water; the inorganic base is selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium acetate, ammonium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium fluoride, potassium bifluoride or potassium phosphate.

2. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: The dipolar aprotic solvent is selected from at least one of acetonitrile (MeCN), N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMAc); the mixed solvent of the non-polar solvent and water is selected from a mixture of at least one of dichloromethane (DCM), toluene, and cyclohexane and water.

3. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: The inorganic base is further preferably sodium hydroxide (NaOH), potassium carbonate (K2CO3) or potassium bifluoride (KHF2).

4. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: The reaction temperature is 0-100°C; when a dipolar aprotic solvent is used, the reaction temperature is 80-100°C; when a mixed solvent of a nonpolar solvent and water is used, the reaction temperature is 0-25°C.

5. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: The equivalent of the difluorobromomethyltrimethylsilane (TMSCF2Br) is 1-3 equivalents, and the equivalent of the inorganic base is 2-6 equivalents.

6. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: The concentration of the reaction is 1-3 mol / L.

7. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: The reaction is carried out under mechanical stirring at a speed of 300-600 rpm.

8. The method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to claim 1, characterized in that: The reaction progresses through 19 F-NMR monitoring was performed, and the end point was when the starting material disappeared or the reaction no longer proceeded.

9. 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 filtering, concentrating under reduced pressure, and purifying by column chromatography. The column chromatography purification uses a basic silica gel and an ethyl acetate / petroleum ether mixed solvent system.

10. A method for preparing a heavy metal-free pharmaceutical intermediate difluoromethyl ether proline derivative according to any one of claims 1 to 9, characterized in that: The method is suitable for kilogram-scale preparation, and the purity of the obtained product is ≥98%.

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