Methods of making compounds
By using a synthetic route with catalysts such as pyridine hydrogen fluoride and cesium fluoride, the problems of high safety risks and high costs in the synthesis of orexin receptor antagonist intermediates have been solved, and the industrial production of 2,5-difluoropyridine with low cost and high yield has been realized.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- YANGTZE RIVER PHARM GRP CO LTD
- Filing Date
- 2022-03-29
- Publication Date
- 2026-06-09
AI Technical Summary
The key intermediates for synthesizing orexin receptor antagonists in existing technologies have high safety risks and high costs, making them difficult to apply to industrial production.
2,5-Difluoropyridine was prepared by contacting the compound with pyridine hydrogen fluoride as the first fluorinating agent in an acidic environment and in the presence of a diazotizing agent, followed by a second contact with cesium fluoride and a phase transfer catalyst at high temperature, combined with Raney nickel catalytic reduction.
It has achieved the synthesis of compounds with high safety and low cost, which are suitable for industrial production, and the yield of 2,5-difluoropyridine has been significantly improved.
Smart Images
Figure CN116924972B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis, and more specifically, to a method for preparing the compound shown in formula (I). Background Technology
[0002] Orexin is a hunger-regulating signal secreted by the hypothalamus, named for its strong appetite-stimulating effect. Orexin A and Orexin B are neuropeptides that act on G protein-coupled receptors, the orexin receptor OX1R and OX2R. OX1R binds to orexin A more strongly than orexin B, while OX2R binds to both orexin A and OX2R with similar binding affinity. Subsequent research found that dogs with narcolepsy had mutations in the gene expressing OX2R, leading to OX2R dysfunction. This research indicates that orexin not only affects feeding behavior but also participates in the regulation of the sleep-wake cycle. This has led to new insights into the etiology of insomnia, suggesting that insomnia may also be caused by inappropriate awakening. Considering the role of orexin in the sleep-wake cycle, Merck has been researching orexin receptor antagonists.
[0003] Currently, multiple patents have been filed for various types of orexin receptor antagonists, and the key intermediates for synthesizing orexin receptor antagonists... Existing technologies suffer from high safety risks and high costs; therefore, a technology suitable for large-scale industrial production is needed. The synthesis method is a key issue that needs to be solved. Summary of the Invention
[0004] The present invention aims to at least partially solve one of the technical problems in the related art.
[0005] In a first aspect, the present invention provides a method for preparing a compound of formula (I). According to an embodiment of the present invention, the method comprises: subjecting a compound of formula (II) to a first contact with a first fluorinating agent to obtain the compound of formula (I);
[0006]
[0007] Wherein, R1 is F, Cl, Br, or I, and the first fluorinating agent is selected from one or more of pyridine hydrogen fluoride, boron trifluoride ether, and fluoroboric acid.
[0008] The method according to embodiments of the present invention has low safety risks and low synthesis costs, and is suitable for industrial production.
[0009] According to embodiments of the present invention, the above method may further include at least one of the following additional technical features:
[0010] According to a specific embodiment of the present invention, the first fluorinating agent is pyridine hydrogen fluoride.
[0011] According to an embodiment of the present invention, the pyridine fluoride is provided in the form of a 50% to 80% (mass percentage) pyridine fluoride solution.
[0012] According to a specific embodiment of the present invention, the pyridine fluoride is provided in the form of a 70% (mass percentage) pyridine fluoride solution.
[0013] According to an embodiment of the present invention, the first contact is carried out in an acidic environment and in the presence of a diazotizing agent.
[0014] According to an embodiment of the present invention, the diazotizing agent is selected from at least one of sodium nitrite, isoamyl nitrite, and n-butyl nitrite.
[0015] According to a specific embodiment of the present invention, the acidic environment is provided by concentrated hydrochloric acid.
[0016] According to an embodiment of the present invention, the first contact is performed at -5 to 0°C for 25 to 35 minutes, and then at 75 to 85°C for 55 to 65 minutes.
[0017] According to an embodiment of the present invention, R1 is Cl, Br, or I, and further includes: making a second contact between the compound of formula (I) and a second fluorinating agent to obtain the compound of formula (1);
[0018]
[0019] According to embodiments of the present invention, the second fluorinating agent is selected from at least one of cesium fluoride and potassium fluoride, preferably, the second fluorinating agent is cesium fluoride. The inventors have found that selecting cesium fluoride as the fluorinating agent significantly increases the yield of 2,5-difluoropyridine and the conversion rate of the raw materials.
[0020] According to embodiments of the present invention, the second contact is carried out in the presence of an organic solvent, optionally selected from at least one of N,N-dimethylformamide (DMF) and sulfolane, preferably sulfolane. The inventors have found that using sulfolane as a reaction solvent results in fewer impurities in the reaction process, and the yield of 2,5-difluoropyridine can reach 85%.
[0021] According to an embodiment of the present invention, the second contact is carried out in the presence of a phase transfer catalyst. Since the second fluorinating agent is a salt and has low solubility in the reaction solvent, the addition of a phase transfer catalyst can greatly improve the solubility of the reactants and increase the reaction efficiency.
[0022] According to an embodiment of the present invention, the phase transfer catalyst is selected from at least one of 18-crown ether-6, tetramethylammonium chloride, tetrabutylammonium bromide, and 15-crown ether-5.
[0023] According to an embodiment of the present invention, the phase transfer catalyst comprises 18-crown ether-6 and tetramethylammonium chloride.
[0024] According to an embodiment of the present invention, the second contact is carried out at 165–175°C for 7.5–8.5 hours.
[0025] According to an embodiment of the present invention, the molar ratio of the compound shown in formula (I), the second fluorinating agent, 18-crown ether-6 and tetramethylammonium chloride is 1:3:(0.1-0.4):(0.1-0.4).
[0026] According to an embodiment of the present invention, the molar ratio of 18-crown ether-6 to tetramethylammonium chloride is 1:1.
[0027] According to embodiments of the present invention, the molar ratio of the compound of formula (I), the second fluorinating agent, 18-crown ether-6, and tetramethylammonium chloride is 1:3:0.4:0.4. The inventors have found that when the molar ratio of the compound of formula (I), the second fluorinating agent, 18-crown ether-6, and tetramethylammonium chloride is 1:3:0.4:0.4, the yield of 2,5-difluoropyridine is significantly higher.
[0028] According to an embodiment of the present invention, the compound represented by formula (II) is obtained by reducing the compound represented by formula (III) to obtain the compound represented by formula (II).
[0029]
[0030] According to an embodiment of the present invention, the reduction reaction is carried out in the presence of a catalyst, optionally comprising at least one selected from Raney nickel, palladium on carbon, titanium / magnesium tetrachloride, and zinc powder.
[0031] According to an embodiment of the present invention, the catalyst is Raney nickel. The inventors have found that, when Raney nickel is used to catalyze this reaction, the yield of the compound shown in formula (II) is significantly higher compared to reactions catalyzed by other catalysts.
[0032] According to an embodiment of the present invention, the reduction reaction is carried out in an alcohol solvent.
[0033] According to an embodiment of the present invention, the alcohol solvent is ethanol or methanol, preferably ethanol.
[0034] According to an embodiment of the present invention, the reduction reaction is carried out for 3.5 to 4.5 hours at a pressure of 0.1 to 0.2 MPa and a temperature of 23 to 27°C.
[0035] In a second aspect, the present invention provides a method for preparing the compound of formula I. According to an embodiment of the present invention, the method comprises: reducing the compound of formula (III) under Raney nickel catalysis to obtain the compound of formula (II), the reduction reaction being carried out for 3.5 to 4.5 hours in the presence of ethanol at a pressure of 0.1 to 0.2 MPa and a temperature of 23 to 27°C; and first contacting the compound of formula (II) with pyridine hydrogen fluoride to obtain the compound of formula (I), the first contact being carried out for 25 to 35 minutes in the presence of concentrated hydrochloric acid and a diazotizing agent at -5 to 0°C, followed by 55 to 65 minutes at 75 to 85°C.
[0036] When R1 is Cl, Br, or I, the process further includes: subjecting the compound of formula (I) to a second contact with cesium fluoride to obtain the compound of formula 1 (2,5-difluoropyridine), wherein the second contact is carried out for 7.5 to 8.5 h at 165–175 °C in the presence of sulfolane, 18-crown ether-6, and tetramethylammonium chloride, and the molar ratio of the compound of formula (I), the second fluorinating agent, 18-crown ether-6, and tetramethylammonium chloride is 1:3:0.4:0.4;
[0037]
[0038] Wherein, R1 is F, Cl, Br, or I.
[0039] The method for preparing the compound of Formula I according to the embodiments of the present invention has low synthesis cost, high safety, and high yield of 2,5-difluoropyridine, and is suitable for industrial production. Attached Figure Description
[0040] Figure 1 This is the hydrogen spectrum of the compound (2,5-difluoropyridine) of formula (1) prepared in Example 1.
[0041] Figure 2 This is the carbon spectrum of the compound (2,5-difluoropyridine) of formula (1) prepared in Example 1. Detailed Implementation
[0042] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.
[0043] This invention proposes and develops a route for synthesizing the compound (2,5-difluoropyridine) shown in Formula 1, and also develops a simple and easy-to-operate preparation process suitable for industrial scale-up.
[0044]
[0045] R1 = X(F,Cl,Br,I)
[0046] This synthetic route has low synthesis cost, is suitable for industrial scale-up, and yields 2,5-difluoropyridine of good quality.
[0047] Example 1
[0048] The following examples will use chlorine as an example to describe in detail the synthesis scheme of 2,5-difluoropyridine.
[0049] 1) Preparation of compound 2:
[0050] Add 10 g of 2-chloro-5-nitropyridine and 200 ml of ethanol to a three-necked reaction flask, purge with nitrogen three times, then add 10 g of Raney nickel (wet weight), pressurize with hydrogen to 0.1–0.2 MPa, react at room temperature for 4 hours, filter with diatomaceous earth after the reaction is complete, and concentrate to obtain intermediate 2 (8 g).
[0051]
[0052] 2) Preparation of compound 3
[0053] Add intermediate 2 (8.0 g), 50 ml of water, and 20 ml of concentrated hydrochloric acid to a three-necked fluorination reaction flask. Add 10 g of sodium nitrite in portions at -5 to 0 °C. After the addition is complete, maintain the temperature for 0.5 h. Then add 10 g of 70% pyridine hydrogen fluoride solution. After the addition is complete, react in an ice bath for half an hour, then slowly raise the temperature to 80 °C and react for 1 hour. After the reaction is complete, perform post-processing to obtain 3.8 g of intermediate 3 (yield approximately 46%).
[0054]
[0055] 3) Preparation of Compound 1
[0056] Under nitrogen protection, 3g of 2-chloro-5-fluoropyridine (intermediate 3) obtained in step 2), 30ml of sulfolane, 7g of cesium fluoride, 2.4g of 18-crown ether-6, and 1g of tetramethylammonium chloride were added to a three-necked flask, and the mixture was purged with nitrogen three times. The temperature was controlled at 170℃, and the reaction was carried out for 8 hours. After the reaction was completed, the reaction solution was filtered, and 2.2g (yield 83.8%) of compound 1 was obtained by vacuum distillation. Figure 1 The above is the 1H NMR spectrum of compound 1 obtained in Example 1. Figure 2 The image shows the carbon NMR spectrum of compound 1 obtained in Example 1.
[0057] 1H NMR (400MHz, CD3OD) δ 8.07 (dd, J = 3.0, 1.8 Hz, 1H), 7.74 (dddd, J = 9.1, 7.4, 6.0, 3.2 Hz, 1H), 7.08 (dt, J = 9.0, 3.3 Hz, 1H).
[0058] 13C NMR(101MHz,CD3OD)δ160.53,160.52,158.94,158.89,158.18,156.46,156.42,134.21,1 34.05,133.93,133.77,128.85,128.77,128.63,128.55,110.63,110.57,110.22,110.16.
[0059]
[0060] Example 2
[0061] The key parameters of step 3) in Example 1 will be examined below to determine the optimal preparation parameters for compound 1.
[0062] ① Solvent investigation
[0063] DMF and sulfolane were investigated separately. The results showed that sulfolane was a better solvent with fewer impurities, and the yield of 2,5-difluoropyridine reached 84.9%.
[0064]
[0065]
[0066] ② The fluorinating agents CsF and KF were investigated. The results showed that CsF, as a fluorinating agent, achieved a yield of 85.67% for 2,5-difluoropyridine.
[0067]
[0068] ③ The equivalent amounts of crown ether and tetramethylammonium chloride were investigated. The results showed that the equivalent amounts of crown ether and tetramethylammonium chloride were 0.4 eq, respectively. The yield of 2,5-difluoropyridine was high and the reaction was more rapid within the corresponding time.
[0069]
[0070]
[0071] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.
[0072] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.
Claims
1. A method for preparing the compound shown in formula (I), characterized in that, include: The compound of formula (II) is brought into a first contact with a first fluorinating agent to obtain the compound of formula (I); (AND), (II), Wherein, R1 is Cl, and the first fluorinating agent is selected from one or more of pyridine hydrogen fluoride, boron trifluoride ether, and fluoroboric acid; The first contact was carried out in an acidic environment and in the presence of a diazotizing agent; The diazotizing agent is selected from at least one of sodium nitrite, isoamyl nitrite, and n-butyl nitrite; The acidic environment is provided by concentrated hydrochloric acid; The compound shown in formula (I) is brought into a second contact with a second fluorinating agent to obtain the compound shown in formula (1); （1）； The second fluorinating agent is cesium fluoride; The second contact is carried out in the presence of a phase transfer catalyst, namely 18-crown ether-6 and tetramethylammonium chloride; The second contact is carried out in the presence of an organic solvent selected from at least one of N,N-dimethylformamide and sulfolane.
2. The method according to claim 1, characterized in that, The first fluorinating agent is pyridine hydrogen fluoride.
3. The method according to claim 2, characterized in that, The pyridine fluoride is provided in the form of a 50% to 80% pyridine fluoride solution.
4. The method according to claim 2, characterized in that, The pyridine fluoride is provided in the form of a 70% pyridine fluoride solution.
5. The method according to claim 1, characterized in that, The first contact was carried out at -5 to 0°C for 25 to 35 minutes, followed by a contact at 75 to 85°C for 55 to 65 minutes.
6. The method according to claim 1, characterized in that, The organic solvent is sulfolane.
7. The method according to claim 1, characterized in that, The second contact was carried out at 165~175℃ for 7.5~8.5 hours.
8. The method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I), the second fluorinating agent, 18-crown ether-6, and tetramethylammonium chloride is 1:3:(0.1~0.4):(0.1~0.4).
9. The method according to claim 8, characterized in that, The molar ratio of 18-crown ether-6 to tetramethylammonium chloride is 1:
1.
10. The method according to claim 8, characterized in that, The molar ratio of the compound shown in formula (I), the second fluorinating agent, 18-crown ether-6 and tetramethylammonium chloride is 1:3:0.4:0.
4.
11. The method according to claim 1, characterized in that, The compound represented by formula (II) is obtained by the following method: The compound shown in formula (III) is reduced to obtain the compound shown in formula (II). (III)。 12. The method according to claim 11, characterized in that, The reduction reaction is carried out in the presence of a catalyst selected from at least one of Raney nickel, palladium on carbon, titanium / magnesium tetrachloride, and zinc powder.
13. The method according to claim 12, characterized in that, The catalyst is Raney nickel.
14. The method according to claim 12, characterized in that, The reduction reaction is carried out in an alcohol solvent.
15. The method according to claim 12, characterized in that, The alcohol solvent is ethanol or methanol.
16. The method according to claim 12, characterized in that, The alcohol solvent is ethanol.
17. The method according to claim 12, characterized in that, The reduction reaction was carried out for 3.5 to 4.5 hours at a pressure of 0.1 to 0.2 MPa and a temperature of 23 to 27°C.
18. A method for preparing the compound shown in Formula I, characterized in that, include: The compound shown in formula (III) was reduced under Raney nickel catalysis to obtain the compound shown in formula (II). The reduction reaction was carried out in the presence of ethanol at a pressure of 0.1-0.2 MPa and a temperature of 23-27°C for 3.5-4.5 hours. The compound shown in formula (II) is first contacted with pyridine hydrogen fluoride to obtain the compound shown in formula (I). The first contact is carried out for 25 to 35 min at -5 to 0°C in the presence of concentrated hydrochloric acid and a diazotizing agent, followed by 55 to 65 min at 75 to 85°C. When R1 is Cl, the process further includes: subjecting the compound of formula (I) to a second contact with cesium fluoride to obtain the compound of formula (1), wherein the second contact is carried out for 7.5 to 8.5 h at 165 to 175 °C in the presence of sulfolane, 18-crown ether-6 and tetramethylammonium chloride, and the molar ratio of the compound of formula (I), the second fluorinating agent, 18-crown ether-6 and tetramethylammonium chloride is 1:3:0.4:0.4; (I), (II), (III), (1), Where R1 is Cl.