Method for the synthesis of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline

Abstract

The application provides a synthesis method of 3-(5-fluoropyrimidin-2-yl)-2-methoxy aniline, and belongs to the technical field of chemical synthesis. The application first provides an intermediate for synthesizing 3-(5-fluoropyrimidin-2-yl)-2-methoxy aniline shown in formula I and formula II. The intermediate can be used to successfully prepare 3-(5-fluoropyrimidin-2-yl)-2-methoxy aniline. The synthesis method is simple in operation, high in product yield and purity. Meanwhile, in the key C-C bond coupling, a low-cost metal Ni catalyzed reductive coupling strategy is used to replace the traditional two-step Pd catalyzed coupling reaction, so that the material cost of the reaction is greatly reduced, and the problem of regioselectivity in the step of introducing a nitro group is avoided, and further purification is avoided. The synthesis method is simple and efficient, low in cost, and has a good industrialization prospect.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline. Background Technology

[0002] The kinase family (JAK) is a class of non-receptor tyrosine kinases, with four members identified: JAK1, JAK2, JAK3, and TYK2. Signal transduction and transcriptional activating proteins (STATs) are direct substrates of JAKs. Many cytokines and growth factors transduce signals through the JAK-STAT signaling pathway (J. Med. Chem. 2021, 64, 677-694, Discovery of BMS-986202: A clinical Tyk2 inhibitor that binds to Tyk2 JH2). BMS-986202 is a potent, selective, orally active Tyk2 inhibitor that binds to Tyk2 JH2, with an IC50 concentration of 100 mg / kg. 50 The concentration of β-carotene was 0.19 nM, and that of Ki was 0.02 nM. BMS-986202 exhibits high selectivity for other kinases, including members of the JAK family. BMS-986202 is also a weak inhibitor of CYP2C19, with an IC50 concentration of 0.19 nM and an IC50 concentration of 0.02 nM. 50 The concentration is 14 μM. BMS-986202 can be used for research in IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus.

[0003]

[0004] 3-(5-Fluoropyrimidin-2-yl)-2-methoxyaniline is an important intermediate in the synthesis of BMS-986202.

[0005]

[0006] Using 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline, the target product BMS-986202 can be synthesized via the following route (J.Med.Chem.2021,64,677-694,Discovery of BMS-986202:A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2):

[0007]

[0008] The reported synthetic route for 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline is as follows:

[0009] Route 1 (described in patent application publication number WO2021222153A1):

[0010]

[0011] In addition to requiring the synthesis of 2-chloro-5-fluoropyrimidine using Pd / C+H2, this synthetic route also requires the direct purchase or synthesis of 5-bromo-6-methoxyaniline and the use of two-step Pd catalysis (Step 3 and Step 4). The total yield of the two steps is 53%, which is relatively low. Furthermore, the Pd catalyst itself is expensive, resulting in relatively high material costs for the synthetic route.

[0012] Route 2 (described in patent application publication number WO2022117016A1):

[0013]

[0014] The synthetic route places the reduction of nitro to amino in the last step, but the construction of the compound still requires two Pd catalysis steps to complete the C-C bond coupling. The overall yield of the three steps is 31%, and the use of Pd catalyst also makes the route cost relatively high. Summary of the Invention

[0015] To address the above problems, this invention provides a method for synthesizing 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline.

[0016] This invention provides an intermediate for the synthesis of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline, the structure of which is shown in Formula I below:

[0017]

[0018] The present invention also provides a method for preparing the aforementioned intermediate, comprising the following steps:

[0019]

[0020] (1) Compound 1, Compound 2, nickel salt catalyst, 2,2'-bipyridine, zinc powder, magnesium chloride and sodium iodide are mixed in a solvent and reacted to obtain a reaction solution;

[0021] (2) After filtering the reaction solution, rinse it, collect the filtrate, concentrate it to dryness, and then purify it by column chromatography to obtain the compound described in Formula I.

[0022] Furthermore,

[0023] In step (1), the equivalent ratio of compound 1, compound 2, nickel salt catalyst, 2,2'-bipyridine, zinc powder, magnesium chloride and sodium iodide is 1:(1-3):(0.1-0.5):(0.1-0.5):(2-4):(2-4):(0.1-0.5);

[0024] And / or, in step (1), the volume-to-mass ratio of the solvent to compound 1 is (5-100) mL: 1 g;

[0025] And / or, in step (1), the reaction temperature is 100-120°C and the reaction time is 10-20 h;

[0026] And / or, in step (1), the nickel salt catalyst is nickel chloride hexahydrate, nickel bromide, nickel iodide, nickel bromide with ethylene glycol dimethyl ether, or nickel chloride with ethylene glycol dimethyl ether.

[0027] And / or, in step (1), the solvent is N-methylpyrrolidone, N,N'-dimethylformamide or N,N'-dimethylacetamide;

[0028] Preferably,

[0029] In step (1), the equivalent ratio of compound 1, compound 2, nickel salt catalyst, 2,2'-bipyridine, zinc powder, magnesium chloride and sodium iodide is 1:1:0.1:0.15:2:2:0.1;

[0030] And / or, in step (1), the volume-to-mass ratio of the solvent to compound 1 is 10 mL: 1 g;

[0031] And / or, in step (1), the nickel salt catalyst is nickel chloride hexahydrate or nickel iodide;

[0032] And / or, in step (1), the solvent is N-methylpyrrolidone;

[0033] And / or, in step (2), the reaction solution is cooled before filtration;

[0034] And / or, in step (2), the filtration of the reaction solution is performed using diatomaceous earth filtration;

[0035] And / or, in step (2), the rinsing is performed using ethyl acetate;

[0036] And / or, in step (2), the concentration to dryness is achieved by vacuum concentration to dryness at 60-70°C;

[0037] And / or, in step (2), the column purification is performed using 100-200 mesh silica gel, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1;

[0038] More preferably,

[0039] And / or, in step (1), the reaction is carried out in a sealed environment under a nitrogen atmosphere.

[0040] Furthermore, the preparation method of compound 1 includes the following steps:

[0041]

[0042] Step a: In a solvent, compound 1-1 reacts with concentrated sulfuric acid, then N-bromosuccinimide is added to react, and the reaction solution is purified to obtain compound 1-2;

[0043] Step b: After reacting compounds 1-2, potassium carbonate and dimethyl sulfate in a solvent, the reaction solution is purified to obtain compound 1;

[0044] Preferably,

[0045] In step a, the equivalent ratio of compound 1-1, concentrated sulfuric acid, and N-bromosuccinimide is 1:(1-3):(0.8-1);

[0046] And / or, in step a, the volume-to-mass ratio of the solvent to compound 1-1 is (5-10) mL: 1 g;

[0047] And / or, in step a, the reaction temperature of compound 1-1 and concentrated sulfuric acid is 20-30°C, and the reaction time is 10-30 min;

[0048] And / or, in step a, the temperature of the reaction involving the addition of N-bromosuccinimide is 25–30°C, and the reaction time is 5–10 h;

[0049] And / or, in step b, the equivalent ratio of compounds 1-2, potassium carbonate, and dimethyl sulfate is 1:(1-3):(1-3);

[0050] And / or, in step b, the volume-to-mass ratio of the solvent to compounds 1-2 is (5-10) mL: 1 g;

[0051] And / or, in step b, the reaction temperature is 50–70°C and the reaction time is 10–20 h;

[0052] More preferably,

[0053] In step a, the equivalent ratio of compound 1-1, concentrated sulfuric acid, and N-bromosuccinimide is 1:1.05:0.95;

[0054] And / or, in step a, the volume-to-mass ratio of the solvent to compound 1-1 is 6 mL: 1 g;

[0055] And / or, in step a, the solvent is acetonitrile;

[0056] And / or, in step a, the reaction time for adding N-bromosuccinimide is 6 hours;

[0057] And / or, in step a, the purification includes the following steps: concentrating the reaction solution to remove the solvent, adding saturated sodium carbonate solution to adjust the pH to >7; adding ethyl acetate for extraction, taking the organic phase, washing the organic phase with saturated brine and drying it with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness;

[0058] And / or, in step b, the equivalent ratio of compounds 1-2, potassium carbonate, and dimethyl sulfate is 1:1.5:1.5;

[0059] And / or, in step b, the volume-to-mass ratio of the solvent to compounds 1-2 is 6 mL: 1 g;

[0060] And / or, in step b, the solvent is acetone;

[0061] And / or, in step b, the purification includes the following steps: cooling the reaction solution and filtering and washing, concentrating the filtrate to dryness, adding water and ethyl acetate and stirring evenly, allowing it to stand and separating to collect the organic phase, washing the organic phase with saturated brine and drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness.

[0062] Furthermore, the preparation method of compound 2 includes the following steps:

[0063]

[0064] Step A: Compound 2-1, N,N-dimethylaniline, and phosphorus oxychloride are mixed thoroughly and reacted. After purification, compound 2-2 is obtained.

[0065] Step B: In a solvent, compound 2-2, sodium bicarbonate and 5% palladium on carbon are mixed evenly and reacted in a hydrogen atmosphere. After purification, compound 2 is obtained.

[0066] Preferably,

[0067] In step A, the equivalent ratio of compound 2-1, N,N-dimethylaniline, and phosphorus oxychloride is 1:(0.1-1):(2-5);

[0068] And / or, in step A, the reaction temperature is 100–120°C and the reaction time is 10–20 h;

[0069] And / or, in step B, the equivalent ratio of compound 2-2 to sodium bicarbonate is 1:(1-3);

[0070] And / or, in step B, the volume-to-mass ratio of the solvent to compound 2-2 is (5-10) mL: 1 g;

[0071] And / or, in step B, the mass ratio of compound 2-2 to 5% palladium on carbon is 1:(0.1-0.5);

[0072] And / or, in step B, the reaction pressure is 1-3 MPa, the reaction temperature is 30-40°C, and the reaction time is 10-20 h;

[0073] More preferably,

[0074] In step A, the equivalence ratio of compound 2-1, N,N-dimethylaniline, and phosphorus oxychloride is 1:0.5:2.3;

[0075] And / or, in step A, the purification method includes the following steps: cooling the reaction solution and adding ice to quench the reaction, then adding ethyl acetate for extraction, taking the organic phase and washing it with water, then washing the organic phase with saturated brine, then drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness;

[0076] And / or, in step B, the equivalent ratio of compound 2-2 to sodium bicarbonate is 1:1.2;

[0077] And / or, in step B, the volume-to-mass ratio of the solvent to compound 2-2 is 8 mL: 1 g;

[0078] And / or, in step B, the mass ratio of compound 2-2 and 5% palladium on carbon is 1:0.1;

[0079] And / or, in step B, the solvent is ethanol;

[0080] And / or, in step B, the purification method includes the following steps: depressurize after the reaction, filter the reaction solution onto diatomaceous earth, rinse with ethanol, collect the filtrate, and concentrate to dryness.

[0081] The present invention also provides an intermediate for the synthesis of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline, the structure of which is shown in Formula II below:

[0082]

[0083] The present invention also provides a method for preparing the aforementioned intermediate, comprising the following steps:

[0084] The intermediate with the aforementioned structure as shown in Formula I is dissolved in a solvent, and after adding concentrated sulfuric acid and fuming nitric acid, the reaction is carried out. The reaction solution is then purified to obtain the final product.

[0085] Preferably,

[0086] The equivalent ratio of the intermediate with the aforementioned structure as shown in Formula I, concentrated sulfuric acid, and fuming nitric acid is 1:(1-3):(1-3);

[0087] And / or, the mass-to-volume ratio of the intermediate with the structure shown in Formula I to the solvent is 1 g: (8-10) mL;

[0088] And / or, the reaction temperature is 20–30°C, and the reaction time is 10–20 h;

[0089] More preferably,

[0090] The equivalent ratio of the intermediate with the aforementioned structure as shown in Formula I, concentrated sulfuric acid, and fuming nitric acid is 1:1.6:2;

[0091] And / or, the mass-to-volume ratio of the intermediate with the structure shown in Formula I to the solvent is 1 g: 8 mL;

[0092] And / or, the solvent is concentrated sulfuric acid;

[0093] And / or, the temperature should be less than 20°C when adding concentrated sulfuric acid or fuming nitric acid;

[0094] And / or, the purification includes the following steps: quenching the reaction in ice, then extracting with dichloromethane, washing the organic phase with saturated sodium bicarbonate, washing the organic phase with saturated brine, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness.

[0095] The present invention also provides the use of the aforementioned intermediates for the synthesis of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline and / or the aforementioned intermediates for the synthesis of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline in the synthesis of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline.

[0096] The present invention also provides a method for synthesizing 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline, which includes the following steps:

[0097]

[0098] Step 1): Synthesize the compound shown in Formula I using the method described above;

[0099] Step 2): Synthesize the compound shown in Formula II using the method described above;

[0100] Step 3): The compound shown in Formula II, along with the catalyst and acid, reacts in a solvent under a hydrogen atmosphere, and after purification, 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline is obtained.

[0101] Furthermore,

[0102] In step 3), the equivalent ratio of the compound shown in formula II to the acid is 1:(2-5);

[0103] And / or, in step 3), the mass ratio of the compound shown in Formula II to the catalyst is 1:(1-5);

[0104] And / or, in step 3), the mass-to-volume ratio of the compound represented by formula II to the solvent is 1 g: (8-10) mL;

[0105] And / or, in step 3), the reaction pressure is 3-5 MPa, the reaction temperature is 80-100°C, and the reaction time is 10-20 h;

[0106] And / or, in step 3), the solvent is methanol;

[0107] And / or, in step 3), the catalyst is Raney Ni, Pd / C or Pt / C;

[0108] And / or, in step 3), the acid is concentrated hydrochloric acid;

[0109] Preferably,

[0110] In step 3), the equivalent ratio of the compound shown in Formula II to the acid is 1:2;

[0111] And / or, in step 3), the mass ratio of the compound shown in Formula II to the catalyst is 1:1;

[0112] And / or, in step 3), the mass-to-volume ratio of the compound represented by formula II to the solvent is 1 g: 8 mL;

[0113] And / or, in step 3), the catalyst is Raney Ni;

[0114] And / or, in step 3), the purification method includes the following steps: after the reaction, depressurize, filter the reaction solution onto diatomaceous earth, rinse with methanol, collect the filtrate, concentrate to dryness, and then purify by column chromatography; the column chromatography is performed using 100-200 mesh silica gel, and the eluent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 2:1.

[0115] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0116] (1) In the critical C-C bond coupling Step-5, a reduction coupling strategy catalyzed by inexpensive metal Ni is adopted to replace the traditional two-step Pd catalytic coupling reaction, which greatly reduces the material cost of the reaction.

[0117] (2) By occupying the para-Cl position in the substrate molecule in Step-6, the regioselectivity problem when introducing nitro groups is avoided;

[0118] (3) In Step-7, the catalytic hydrogenation strategy was used to achieve both nitro reduction and dechlorination, thus shortening the process steps.

[0119] In summary, this invention provides a method for synthesizing 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline. This method is simple to operate and yields high product purity. Furthermore, in the crucial C / C bond coupling, a low-cost Ni-catalyzed reductive coupling strategy replaces the traditional two-step Pd-catalyzed coupling reaction, significantly reducing material costs. Simultaneously, the regioselectivity problem is avoided in the nitro group introduction step, eliminating the need for further purification. This invention's synthetic method is simple, efficient, and low-cost, showing promising prospects for industrial application.

[0120] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0121] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0122] Figure 1 HPLC chromatogram in Step-1

[0123] Figure 2 This is the HPLC spectrum of the Step-1 product.

[0124] Figure 3 This is the TLC diagram for Step-2.

[0125] Figure 4 This is the HPLC spectrum of the Step-2 product.

[0126] Figure 5 This is the TLC diagram for Step-3.

[0127] Figure 6 This is the TLC diagram for Step-4.

[0128] Figure 7 This is the HPLC spectrum of the product from Step-4.

[0129] Figure 8 This is the TLC diagram for Step-5.

[0130] Figure 9 The HPLC spectrum of the product from Step-5 is shown.

[0131] Figure 10 This is a TLC diagram for the Step-6 control unit.

[0132] Figure 11 The HPLC spectrum of the Step-6 product is shown.

[0133] Figure 12 This is a TLC diagram for the Step-7 control system.

[0134] Figure 13 The HPLC purity of the Step-7 product is given.

[0135] Figure 14 Product of Step-7 1 H NMR spectrum. Detailed Implementation

[0136] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0137] The main synthetic route of this invention is as follows:

[0138]

[0139] Example 1: Synthesis of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline

[0140] Step 1:

[0141]

[0142] 1.1 Preparation method:

[0143] (1) Add acetonitrile (600.0 mL, 6.0 V) and p-chlorophenol (100.0 g, 777.87 mmol, 1.0 eq) to a 1000.0 mL three-necked flask and stir until completely clear, then cool to 10 °C;

[0144] (2) Slowly add concentrated sulfuric acid (81.74g, 816.76mmol, 1.05eq), control the temperature (T) <20℃, and after the addition is complete, keep the temperature at 20℃ for 10min.

[0145] (3) Add N-bromosuccinimide (131.52 g, 738.98 mmol, 0.95 eq), heat to 25 °C, and react for 6 h;

[0146] (4) After the reaction is complete, a sample is taken for HPLC control, such as... Figure 1 The sample showed <10% on HPLC, indicating that the reaction was complete. The next step is to proceed with purification. Figure 1This demonstrates that the HPLC central control method can centrally control this reaction, specifically 4-chlorophenol (tR = 3.293 min), 2-bromo-4-chlorophenol (tR = 4.316 min), and 2,6-dibromo-4-chlorophenol (tR = 5.245 min). Table 1 shows... Figure 1 The retention time and peak area of ​​the relevant peaks.

[0147] Table 1. Figure 1 Retention time and peak area of ​​related peaks

[0148] peak Retention time Peak area 1 3.293 7.36％ 2 4.316 86.9％ 3 5.245 3.21％

[0149] Following the above method, only the amount of N-bromosuccinimide (NBS) and the reaction time after adding NBS were changed. The contents of the raw material (4-chlorophenol), monosubstituted product (2-bromo-4-chlorophenol) and disubstituted product (2,6-dibromo-4-chlorophenol) in the reaction solution of step (3) were detected by HPLC. The results are shown in Table 2.

[0150] Table 2. Contents of the raw material 4-chlorophenol, the monosubstituted product 2-bromo-4-chlorophenol, and the disubstituted product 2,6-dibromo-4-chlorophenol in the reaction solution

[0151] NBS (equivalent) Time (hours) raw material Monosubstituted products Disubstituted products 0.95eq 6 7％ 87％ 3％ 1.0eq 6 6％ 80％ 10％ 1.05eq 6 3％ 75％ 18％ 0.95eq 10 3％ 81％ 10％

[0152] As shown in Table 2, the optimal reaction product was obtained when the NBS equivalent was 0.95 eq and the reaction time was 6 h, with the highest content of the monosubstituted product 2-bromo-4-chlorophenol required in this invention. Using other NBS equivalents or reaction times resulted in a decrease in the content of 2-bromo-4-chlorophenol in the reaction solution.

[0153] 1.2 Purification method:

[0154] (1) The reaction solution obtained in step (3) of 1.1 is concentrated under vacuum at 45°C to remove the solvent in the reaction solution, and a light yellow oily substance is obtained. The oily substance is added to a saturated sodium carbonate solution (500.0 mL, 5.0 V) (the operation should be slow, as a large amount of carbon dioxide gas will be generated) to make the pH > 7.

[0155] (2) Extract with ethyl acetate (200.0 mL, 2.0 V), allow to stand and separate to collect the organic phase, and extract the aqueous phase with ethyl acetate (200.0 mL, 2.0 V) again, allow to stand and separate to collect the organic phase;

[0156] (3) Combine the organic phases, wash with saturated saline solution (100.0 mL, 1.0 V), allow to stand, separate and collect the organic phases, add a small amount of anhydrous sodium sulfate to dry, filter, collect the filtrate, and concentrate to dryness under vacuum at 50 °C to obtain 175.42 g of 2-bromo-4-chlorophenol (yellow liquid), with a yield of 108.71% and a purity of 79.5%. Figure 2 This can be used directly in the next step.

[0157] Table 3. Figure 2 Retention time and peak area of ​​related peaks

[0158] peak Retention time Peak area 1 3.285 12.1％ 2 4.307 79.5％ 3 5.240 5.36％

[0159] Step 2:

[0160]

[0161] 2.1 Preparation method:

[0162] (1) Add acetone (960.0 mL, 6.0 V), 2-bromo-4-chlorophenol obtained in Step-1 (160.0 g, 771.26 mmol, 1.0 eq), and potassium carbonate (159.89 g, 1.16 mol, 1.5 eq) to a 2000.0 mL three-necked flask and stir until completely dispersed;

[0163] (2) Slowly add dimethyl sulfate (145.92g, 1.16mol, 1.5eq) and heat to 50℃, then keep the temperature for 10h.

[0164] (3) After the reaction is complete, the sampling point is taken in the center of the TLC plate (developing solvent: petroleum ether / ethyl acetate = 5 / 1, v / v), and the color is developed under ultraviolet light as follows. Figure 3 As shown, by Figure 3 Since the reaction is complete, purification procedures can be performed.

[0165] 2.2 Purification method:

[0166] (1)2.1 ​​After the reaction is completed, stop heating, cool the reaction solution to 20°C, filter and rinse with a small amount of acetone, collect the filtrate, concentrate it to dryness under vacuum at 50°C, and obtain a pink oily substance.

[0167] (2) Add water (320.0 mL, 2.0 V) and ethyl acetate (320.0 mL, 2.0 V), stir to dissolve, let stand and separate to collect the organic phase, add ethyl acetate (320.0 mL, 2.0 V) to the aqueous phase for extraction, let stand and separate to collect the organic phase;

[0168] (3) Combine the organic phases, wash with saturated brine (320.0 mL, 2.0 V), allow to stand, separate and collect the organic phases, add a small amount of anhydrous sodium sulfate to dry, filter, collect the filtrate, and concentrate to dryness under vacuum at 50 °C to obtain 183.01 g of 2-bromo-4-chloro-1-methoxybenzene (pink liquid), yield 90.00%, purity 80.3%. Figure 4 This can be used directly in the next step.

[0169] Table 4. Figure 4 Retention time and peak area of ​​related peaks

[0170] peak Retention time Peak area 1 0.924 4.61％ 2 3.280 3.97％ 3 4.987 5.62％ 4 5.705 80.36％ 5 6.699 4.37％

[0171] Step 3:

[0172]

[0173] 3.1 Preparation method:

[0174] (1) Add 5-fluorouracil (10.0 g, 76.88 mmol, 1.0 eq), N,N-dimethylaniline (4.66 g, 38.44 mmol, 0.5 eq), and phosphorus oxychloride (27.11 g, 176.82 mmol, 2.30 eq) to a 100.0 mL three-necked flask, stir and mix evenly, and heat to 110 °C and react for 10 h;

[0175] (2) After the reaction was complete, a sample was taken for TLC control (developing solvent: DCM / MeOH = 15 / 1, v / v), and the color was developed under a 254nm UV lamp as follows. Figure 5 As shown, by Figure 5 It is clear that the reaction has been completed and subsequent operations can proceed.

[0176] 3.2 Purification method:

[0177] (1) 3.1 After the reaction is completed, stop heating, cool the reaction solution to 20°C, and pour the reaction solution into ice (100.0g) to quench it;

[0178] (2) Then add ethyl acetate (50.0 mL, 5.0 V) for extraction, let stand and separate the organic phase, add water (20.0 mL, 2.0 V) for washing, let stand and separate the organic phase, add saturated saline (20.0 mL, 2.0 V) for washing, let stand and separate the organic phase;

[0179] (3) Add a small amount of anhydrous sodium sulfate to dry the organic phase, filter, collect the filtrate, and concentrate it to dryness under vacuum at 50°C to obtain 8.41 g of 2,4-dichloro-5-fluoropyrimidine (pale yellow liquid), with a yield of 65.00%.

[0180] Step 4:

[0181]

[0182] 4.1 Preparation method:

[0183] (1) Add ethanol (40.0 mL, 8.0 V), 2,4-dichloro-5-fluoropyrimidine (5.0 g, 29.95 mmol, 1.0 eq), sodium bicarbonate (3.02 g, 35.93 mmol, 1.2 eq), and 5% palladium on carbon (0.5 g) to a 100.0 mL autoclave and stir until well mixed.

[0184] (2) Seal, replace with nitrogen three times, pressurize with hydrogen at 1.0 MPa, and keep at 30°C for 10 hours;

[0185] (3) After the reaction is complete, the sampling point is taken and placed in the center of a TLC plate (developing solvent is PE / EA = 10 / 1, v / v). The result is displayed under a 254nm UV lamp as follows: Figure 6 As shown, by Figure 6 It can be seen that the reaction has been completed and subsequent operations can be carried out.

[0186] 4.2 Purification method:

[0187] 4.1 After the reaction in step (2) is completed, the pressure is released, the reaction liquid is filtered through diatomaceous earth, washed with a small amount of ethanol, the filtrate is collected, and concentrated to dryness under vacuum at 55°C to obtain 3.20 g of 2-chloro-5-fluoropyrimidine (pale yellow liquid), with a yield of 80.00% and a purity of 96.3%. Figure 7 This can be used directly in the next step.

[0188] Table 5. Figure 7 Retention time and peak area of ​​related peaks

[0189] peak Retention time Peak area 1 1.906 96.32％ 2 3.629 1.40％

[0190] Step 5:

[0191]

[0192] 5.1 Preparation method:

[0193] (1) Add N-methylpyrrolidone (100.0 mL, 10.0 V), 2-bromo-4-chloro-1-methoxybenzene (10.0 g, 45.15 mmol, 1.0 eq), 2-chloro-5-fluoropyrimidine (5.98 g, 45.15 mmol, 1.00 eq), nickel chloride hexahydrate (1.07 g, 4.52 mmol, 0.1 eq), 2,2'-bipyridine (1.06 g, 6.77 mmol, 0.15 eq), zinc powder (5.90 g, 90.30 mmol, 2.0 eq), magnesium chloride (8.60 g, 90.30 mmol, 2.0 eq), and sodium iodide (676.77 mg, 4.52 mmol, 0.1 eq) to a 150.0 mL sealed container and stir until completely dispersed. Purge with nitrogen for 20 min and maintain nitrogen protection.

[0194] (2) Seal the container, heat it to 100°C, and keep it at that temperature for 10 hours.

[0195] (3) After the reaction is complete, the sampling point is taken in the TLC plate (developing solvent: PE / EA = 3 / 1, v / v), and the result is displayed under a 254nm UV lamp as follows. Figure 8 As shown, by Figure 8 It can be seen that the reaction has been completed and the next step can be carried out.

[0196] 5.2 Purification Method:

[0197] (1) 5.1 After the reaction in step (3) is complete, stop heating, cool the reaction solution to 20°C, filter with diatomaceous earth, rinse with a small amount of ethyl acetate, collect the filtrate, concentrate it to dryness under vacuum at 65°C, and obtain a black oily substance.

[0198] (2) Purification was performed using a 100-200 mesh silica gel column (PE:EA = 3:1, v / v) to obtain 8.28 g of 2-(5-chloro-2-methoxyphenyl)-5-fluoropyrimidine (pale yellow solid), with a yield of 75% and a purity of 90.9%. Figure 9 It can be used directly in the next reaction.

[0199] Table 6. Figure 9 Retention time and peak area of ​​related peaks

[0200] peak Retention time Peak area 1 2.211 1.69％ 2 2.819 3.58％ 3 4.178 90.93％

[0201] The NMR characterization of 2-(5-chloro-2-methoxyphenyl)-5-fluoropyrimidine yielded the following results: 1 H NMR (400MHz, CDCl3) = 8.71 (s, 2H), 7.69 (d, J = 4.0Hz, 1H), 7.38 (dd, J = 8.0, 4.0Hz, 1H), 6.96 (d, J = 8.0Hz, 1H), 3.85 (s, 3H)

[0202] 5.3 Other conditions and results

[0203] Following the above preparation method, only the Ni salt (nickel chloride hexahydrate), ligand (2,2'-bipyridine, bipy), and solvent (N-methylpyrrolidone) were replaced according to the conditions shown in Table 7. After purification, the product 2-(5-chloro-2-methoxyphenyl)-5-fluoropyrimidine was obtained. The yield and purity of the product are shown in Table 7.

[0204] Table 7. Reaction conditions, product yield, and purity

[0205]

[0206]

[0207] As shown in Table 7, the product yield was higher when bipy (2,2'-bipyridine) was used as the ligand and N-methylpyrrolidone as the solvent. Based on this, the product yield and purity were the best when NiCl2·6H2O and NiI2 were used as Ni salts.

[0208] Step 6:

[0209]

[0210] 6.1 Preparation method:

[0211] (1) Add 2-(5-chloro-2-methoxyphenyl)-5-fluoropyrimidine (5.0 g, 20.95 mmol, 1.0 eq) and concentrated sulfuric acid (40.0 mL, 8.0 V) to a 100.0 mL three-necked flask, stir until completely dissolved, and cool to 10 °C;

[0212] (2) Add concentrated sulfuric acid (3.35g, 33.52mmol, 1.6eq) and fuming nitric acid (2.78g, 41.90mmol, 2.0eq) dropwise, keeping T < 20℃. After the addition is complete, raise the temperature to 25℃ and react for 10h.

[0213] (3) After the reaction is complete, the sampling point is taken and placed in the center of the TLC plate (developing solvent: PE / EA = 5 / 1, v / v). The result is displayed under a 254nm UV lamp as follows: Figure 10 As shown, the reaction has now completed, and the next stage of purification can proceed.

[0214] 6.2 Purification method:

[0215] (1) Slowly pour the reaction solution obtained in step (2) of 6.1 into ice (100.0g) to quench the reaction, and control the temperature of the mixture to be less than 20℃ throughout the process;

[0216] (2) Then add dichloromethane (25.0 mL, 5.0 V) for extraction, let stand and separate to collect the organic phase, add dichloromethane (25.0 mL, 5.0 V) to the aqueous phase for extraction, let stand and separate to collect the organic phase;

[0217] (3) Combine the organic phases, add saturated sodium bicarbonate (25.0 mL, 5.0 V) to wash, let stand and separate to collect the organic phases, add saturated saline (10.0 mL, 2.0 V) to wash, let stand and separate to collect the organic phases;

[0218] (4) Add a small amount of anhydrous sodium sulfate to dry the organic phase, filter, collect the filtrate, and concentrate it to dryness under vacuum at 40°C to obtain 4.87 g of 2-(5-chloro-2-methoxy-3-nitrophenyl)-5-fluoropyrimidine (yellow solid), with a yield of 80.00% and a purity of 84.5%. Figure 11 ).

[0219] Table 8. Figure 11 Retention time and peak area of ​​related peaks

[0220] peak Retention time Peak area 1 1.955 3.39％ 2 4.554 2.72％ 3 4.686 2.01％ 4 5.091 84.49％

[0221] The NMR characterization of 2-(5-chloro-2-methoxy-3-nitrophenyl)-5-fluoropyrimidine yielded the following results: 1 H NMR (400MHz, CDCl3) = 8.77 (s, 2H), 8.04 (d, J = 4.0Hz, 1H), 7.86 (d, J = 4.0Hz, 1H), 3.82 (s, 3H).

[0222] Step 7:

[0223]

[0224] 7.1 Preparation method:

[0225] (1) Add methanol (40.0 mL, 8.0 V), 2-(5-chloro-2-methoxy-3-nitrophenyl)-5-fluoropyrimidine (5.0 g, 17.63 mmol, 1.0 eq), concentrated hydrochloric acid (8.69 g, 88.14 mmol, 2.0 eq), and Raney Ni (5.0 g) to a 100.0 mL autoclave and stir until well mixed.

[0226] (2) Seal, replace with nitrogen three times, pressurize with hydrogen at 3.0 MPa, and heat to 80℃ for 10 h;

[0227] (3) After the reaction was completed, the sample point was taken and placed on a TLC plate (developing solvent: PE / EA = 5 / 1, v / v). Under a 254nm UV lamp, it was shown that the raw material reaction was complete, but some impurities were directly reduced to amino groups without dechlorination. Figure 12 ).

[0228] 7.2 Purification method:

[0229] (1) 7.1 Step (2) After the reaction is completed, release the pressure, filter the reaction liquid through diatomaceous earth, rinse with a small amount of methanol, collect the filtrate, and concentrate it to dryness under vacuum at 55°C, resulting in a yellow oily substance.

[0230] (2) Purification was performed using a 100-200 mesh silica gel column (PE:EA = 2:1, v / v) to obtain 3.0 g of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline (pale yellow solid), with a yield of 73.4% and a purity of 99.6%. Figure 13 ).

[0231] Table 9. Figure 13 Retention time and peak area of ​​related peaks

[0232]

[0233]

[0234] The NMR characterization of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline was performed, and the results are as follows: Figure 14 As shown, the NMR data are: 1 H NMR (400MHz, CDCl3) δ8.71 (s, 2H), 7.16 (dd, J = 8.0, 2.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.0, 2.0 Hz, 1H), 3.66 (s, 3H).

[0235] 7.3 Other conditions and results

[0236] Following the above preparation method, only the catalyst (Raney Ni) and additive (concentrated hydrochloric acid) were replaced according to the conditions shown in Table 10. After purification, the product 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline was obtained. The yield and purity of the product are shown in Table 10.

[0237] Table 10. Reaction conditions, product yield, and purity

[0238] sequence catalyst additive yield purity 1 Raney Ni HCl 73.4％ 99.6％ 2 Pd / C HCl 60％ 98.7％ 3 Pt / C HCl 30％ 98.5％ 4 Raney Ni NaOH 10％ 98.9％

[0239] Table 10 shows that the product yield obtained by reacting Raney Ni with HCl using catalyst is the highest.

[0240] Conclusion: The 2-chloro-5-fluoropyrimidine synthesized in Steps 3 and 4 of this invention is a commercially available product. Therefore, the overall yield calculated using Steps 1, 2, 5, 6, and 7 of this invention is 43.8%, and the purity of the obtained product is 99.6%. Furthermore, in existing technologies, the C / C bond construction step (corresponding to Step-5 of this invention) requires two Pd catalysis steps, with an overall yield of approximately 53%; while this invention, using inexpensive Ni, achieves a 75% synthesis yield in a single step. Therefore, compared with existing methods, the preparation method of this invention improves the yield and reduces the cost.

[0241] In summary, this invention provides a method for synthesizing 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline. This method is simple to operate and yields high product purity. Furthermore, in the crucial C / C bond coupling, a low-cost Ni-catalyzed reductive coupling strategy replaces the traditional two-step Pd-catalyzed coupling reaction, significantly reducing material costs. Simultaneously, the regioselectivity problem is avoided in the nitro group introduction step, eliminating the need for further purification. This invention's synthetic method is simple, efficient, and low-cost, showing promising prospects for industrial application.

Claims

1. A method for preparing an intermediate of 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline of Formula I, characterized in that: It includes the following steps: (1) Compound 1, compound 2, nickel salt catalyst, 2,2'-bipyridine, zinc powder, magnesium chloride and sodium iodide are mixed in a solvent and reacted to obtain a reaction solution; (2) After filtering the reaction solution, rinse it, collect the filtrate, concentrate it to dryness, and then purify it by column chromatography to obtain the compound described in Formula I.

2. The method according to claim 1, characterized in that: In step (1), the equivalent ratio of compound 1, compound 2, nickel salt catalyst, 2,2'-bipyridine, zinc powder, magnesium chloride and sodium iodide is 1:(1~3):(0.1~0.5):(0.1~0.5):(2~4):(2~4):(0.1~0.5); In step (1), the volume-to-mass ratio of the solvent to compound 1 is (5~100) mL: 1 g; In step (1), the reaction temperature is 100~120℃ and the reaction time is 10~20h; In step (1), the nickel salt catalyst is nickel chloride hexahydrate, nickel bromide, nickel iodide, nickel bromide with ethylene glycol dimethyl ether, or nickel chloride with ethylene glycol dimethyl ether. In step (1), the solvent is N-methylpyrrolidone, N,N'-dimethylformamide or N,N'-dimethylacetamide.

3. The method according to claim 2, characterized in that: In step (1), the equivalent ratio of compound 1, compound 2, nickel salt catalyst, 2,2'-bipyridine, zinc powder, magnesium chloride and sodium iodide is 1:1:0.1:0.15:2:2:0.1; In step (1), the volume-to-mass ratio of the solvent to compound 1 is 10 mL: 1 g; In step (1), the nickel salt catalyst is nickel chloride hexahydrate or nickel iodide; In step (1), the solvent is N-methylpyrrolidone; In step (2), the reaction solution is cooled before filtration; In step (2), the reaction solution is filtered using diatomaceous earth filtration; In step (2), the rinsing is performed using ethyl acetate; In step (2), the concentration to dryness is achieved by vacuum concentration to dryness at 60~70℃; In step (2), the column purification is performed using 100-200 mesh silica gel, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:

1.

4. The method according to claim 3, characterized in that: In step (1), the reaction is carried out in a sealed environment under a nitrogen atmosphere.

5. The method according to any one of claims 1 to 4, characterized in that: The preparation method of compound 1 includes the following steps: Step a: In a solvent, compound 1-1 reacts with concentrated sulfuric acid, then N-bromosuccinimide is added to react, and the reaction solution is purified to obtain compound 1-2; Step b: After reacting compounds 1-2, potassium carbonate and dimethyl sulfate in a solvent, the reaction solution is purified to obtain compound 1.

6. The method according to claim 5, characterized in that: In step a, the equivalent ratio of compound 1-1, concentrated sulfuric acid, and N-bromosuccinimide is 1:(1~3):(0.8~1); In step a, the volume-to-mass ratio of the solvent to compound 1-1 is (5~10) mL: 1 g; In step a, the reaction temperature of compound 1-1 and concentrated sulfuric acid is 20~30℃, and the reaction time is 10~30min; In step a, the reaction temperature for adding N-bromosuccinimide is 25~30℃, and the reaction time is 5~10h; In step b, the equivalent ratio of compounds 1-2, potassium carbonate, and dimethyl sulfate is 1:(1~3):(1~3); In step b, the volume-to-mass ratio of the solvent to compounds 1-2 is (5~10) mL: 1 g; In step b, the reaction temperature is 50~70℃ and the reaction time is 10~20h.

7. The method according to claim 6, characterized in that: In step a, the equivalent ratio of compound 1-1, concentrated sulfuric acid, and N-bromosuccinimide is 1:1.05:0.95; In step a, the volume-to-mass ratio of the solvent to compound 1-1 is 6 mL: 1 g; In step a, the solvent is acetonitrile; In step a, the reaction time for adding N-bromosuccinimide is 6 hours; In step a, the purification includes the following steps: concentrating the reaction solution to remove the solvent, adding saturated sodium carbonate solution to adjust the pH to >7; adding ethyl acetate for extraction, taking the organic phase, washing the organic phase with saturated brine and drying it with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness; In step b, the equivalent ratio of compounds 1-2, potassium carbonate, and dimethyl sulfate is 1:1.5:1.5; In step b, the volume-to-mass ratio of the solvent to compounds 1-2 is 6 mL: 1 g; In step b, the solvent is acetone; In step b, the purification includes the following steps: cooling the reaction solution and filtering and rinsing, concentrating the filtrate to dryness, adding water and ethyl acetate and stirring evenly, allowing it to stand and separating to collect the organic phase, washing the organic phase with saturated brine and drying it with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness.

8. The method according to any one of claims 1 to 4, characterized in that: The preparation method of compound 2 includes the following steps: Step A: Compound 2-1, N,N-dimethylaniline, and phosphorus oxychloride are mixed thoroughly and reacted. After purification, compound 2-2 is obtained. Step B: In a solvent, compound 2-2, sodium bicarbonate, and 5% palladium on carbon are mixed evenly and reacted under hydrogen atmosphere. After purification, compound 2 is obtained.

9. The method according to claim 8, characterized in that: In step A, the equivalent ratio of compound 2-1, N,N-dimethylaniline, and phosphorus oxychloride is 1:(0.1~1):(2~5); In step A, the reaction temperature is 100~120℃ and the reaction time is 10~20h; In step B, the equivalent ratio of compound 2-2 to sodium bicarbonate is 1:(1~3); In step B, the volume-to-mass ratio of the solvent to compound 2-2 is (5~10) mL: 1 g; In step B, the mass ratio of compound 2-2 to 5% palladium on carbon is 1:(0.1~0.5); In step B, the reaction pressure is 1~3MPa, the reaction temperature is 30~40℃, and the reaction time is 10~20h.

10. The method according to claim 9, characterized in that: In step A, the equivalence ratio of compound 2-1, N,N-dimethylaniline, and phosphorus oxychloride is 1:0.5:2.3; In step A, the purification method includes the following steps: after cooling the reaction solution, the reaction is quenched in ice, then ethyl acetate is added for extraction, the organic phase is washed with water, then the organic phase is washed again with saturated brine, then the organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness. In step B, the equivalent ratio of compound 2-2 to sodium bicarbonate is 1:1.2; In step B, the volume-to-mass ratio of the solvent to compound 2-2 is 8 mL: 1 g; In step B, the mass ratio of compound 2-2 to 5% palladium on carbon is 1:0.1; In step B, the solvent is ethanol; In step B, the purification method includes the following steps: after the reaction, depressurize, filter the reaction solution onto diatomaceous earth, rinse with ethanol, collect the filtrate, and concentrate it to dryness.

11. A method for synthesizing 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline, characterized in that: It includes the following steps: Step 1): Synthesize the compound of Formula I using the method described in any one of claims 2 to 5; Step 2): Dissolve the compound shown in Formula I in a solvent, add concentrated sulfuric acid and fuming nitric acid dropwise, react the solution, purify the reaction solution, and synthesize the compound shown in Formula II; Step 3): In a solvent, the compound shown in Formula II reacts with a catalyst and an acid under a hydrogen atmosphere, and after purification, 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline is obtained; In step 3), the catalyst is Raney Ni, Pd / C, or Pt / C; In step 3), the acid is concentrated hydrochloric acid.

12. The method according to claim 11, characterized in that: In step 3), the equivalent ratio of the compound shown in formula II to the acid is 1:(2~5); In step 3), the mass ratio of the compound shown in Formula II to the catalyst is 1:(1~5); In step 3), the mass-to-volume ratio of the compound shown in Formula II to the solvent is 1 g: (8~10) mL; In step 3), the reaction pressure is 3~5 MPa, the reaction temperature is 80~100℃, and the reaction time is 10~20 h; In step 3), the solvent is methanol.

13. The method according to claim 12, characterized in that: In step 3), the equivalent ratio of the compound shown in formula II to the acid is 1:2; In step 3), the mass ratio of the compound shown in Formula II to the catalyst is 1:1; In step 3), the mass-to-volume ratio of the compound shown in Formula II to the solvent is 1 g: 8 mL; In step 3), the catalyst is Raney Ni; In step 3), the purification method includes the following steps: after the reaction, the pressure is released, the reaction solution is filtered through diatomaceous earth, washed with methanol, the filtrate is collected, concentrated to dryness, and then purified by column chromatography; the column chromatography is performed using 100-200 mesh silica gel, and the eluent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 2:

1.

14. The method according to claim 11, characterized in that: In step 2), the equivalent ratio of the compound shown in Formula I, concentrated sulfuric acid, and fuming nitric acid is 1:(1~3):(1~3); The mass-to-volume ratio of the compound shown in Formula I to the solvent is 1 g : (8~10) mL; The reaction temperature is 20~30℃, and the reaction time is 10~20h.

15. The method according to claim 14, characterized in that: In step 2), the equivalent ratio of the compound shown in Formula I, concentrated sulfuric acid, and fuming nitric acid is 1:1.6:2; The mass-to-volume ratio of the compound shown in Formula I to the solvent is 1 g: 8 mL; The solvent is concentrated sulfuric acid; The temperature should be below 20℃ when adding concentrated sulfuric acid or fuming nitric acid dropwise. The purification process includes the following steps: quenching the reaction in ice, extracting with dichloromethane, washing the organic phase with saturated sodium bicarbonate, washing the organic phase with saturated brine, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness.

Images