A method for synthesizing an osimertinib intermediate

Abstract

The present invention discloses a method for synthesizing an osimertinib intermediate. Using 2-amino-5-fluoro-4-nitrophenol as a raw material, the target product is obtained through six steps of reaction, namely cyclization protection, substitution with N,N,N'-trimethylethylenediamine, nitro reduction, amidation, hydrolysis deprotection, and phenol hydroxyl methylation. In the cyclization protection and amidation reactions of the method of the present invention, a heteropolyacid-based ionic liquid catalyst is used, and the synthesis method is simple, highly active, can be recycled and reused multiple times, and is green and environmentally friendly; the hydrogen source used in the nitro reduction reaction step is cheap and easily available, the operation is convenient and safe; the hydrolysis deprotection reaction step is simple in operation and high in conversion rate, and at the same time, an allyl group is introduced, effectively avoiding side reactions caused by premature introduction of the allyl group; the entire process avoids the use of highly toxic chemicals, the process is simple, the conditions are easy to control, the reagents and intermediates have high stability, are convenient for transportation and storage, have less potential safety hazards, are easy to treat waste liquid, are green and environmentally friendly, and are convenient for large-scale industrial use.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis and pharmaceutical synthesis, and particularly relates to a method for synthesizing an osimertinib intermediate. Background Art

[0002] Osimertinib (or AZD9291) was developed by AstraZeneca UK and was approved by the FDA for early approval on November 13, 2015, under accelerated approval, with the trade name Tagrisso. Osimertinib is the first drug approved for the treatment of metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC). Due to the presence of multiple functional groups in its chemical structure, the synthesis of osimertinib has always been challenging and costly.

[0003] Currently, there are mainly three methods for the synthesis route of osimertinib.

[0004] Method 1 uses 1-methylindole, 2,4-dichloropyrimidine, and 4-fluoro-2-methoxyaniline as raw materials, and after 7 steps of reaction, osimertinib is obtained. The synthesis route is as follows. This route adopts a linear synthesis strategy, with more reaction steps and lower synthesis efficiency; mixed acid nitration is used, generating a large amount of three wastes; expensive 2-pentanol is required as a solvent; iron powder is used to reduce the nitro group on the benzene ring, with harsh reaction conditions and difficult treatment of iron mud after the reaction; finally, the amidation of acryloyl chloride requires two steps of reaction, with low efficiency, all of which are not conducive to large-scale industrial production.

[0005]

[0006] Method 2 is an improvement on Method 1. By introducing a Boc or Cbz protecting group on the amino group, intermediate 14 is obtained, and finally, it reacts with 3-(2-chloropyrimidin-4-yl)-1-methylindole 3 to prepare osimertinib. The synthesis route is as follows. In this method, the intermediates with Boc or Cbz protecting groups in the route are mostly oily substances and need to be purified by column chromatography, which is not conducive to industrial production.

[0007]

[0008] Method 3 uses 2-fluoro-4-methoxyaniline 15 as the raw material, and through 7 steps of reactions including amidation, substitution, nitration, reduction, guanidation of the amino group, and cyclization, osimertinib is obtained. The synthetic route is as follows. The starting material 2-fluoro-4-methoxyaniline 15 of this method is not easily available; introducing the acrylamide group in the first step reaction results in many by-products and a low overall yield in the whole synthetic route; it is necessary to use monocyanamide which is easy to decompose and not easy to transport and store; the last step of pyrimidine cyclization reaction has many side reactions and a low yield. Therefore, method 3 is not suitable for industrial production.

[0009]

[0010] Many deficiencies in the prior art have restricted the large-scale industrial production of osimertinib and the reduction of costs. Therefore, it is necessary to develop a synthetic method of osimertinib and its intermediates that is easy to control, safe and environmentally friendly, simple to operate, and has a high yield and is suitable for industrial production. Summary of the Invention

[0011] Aiming at the drawbacks of the prior art, the present invention provides a new method for preparing osimertinib intermediates. The raw materials used in this method are easily available, the operation steps are simple, the cost is low, the yield is high, it is economical and environmentally friendly, and it is conducive to realizing industrial production.

[0012] The technical solution of the present invention includes the following steps: A method for preparing osimertinib intermediate 14, including:

[0013] (1) A step of cyclizing 2-amino-5-fluoro-4-nitrophenol (5) as the raw material and R 1 CHO under the action of a catalyst to obtain compound 21,

[0014]

[0015] wherein, R 1 is any one of phenyl, p-methylphenyl, p-chlorophenyl, p-nitrophenyl, 1-naphthyl groups;

[0016] (2) A step of obtaining compound 22 by subjecting compound 21 and N,N,N'-trimethylethylenediamine to a substitution reaction,

[0017]

[0018] (3) A step of preparing compound 23 by subjecting compound 22 to a nitro reduction reaction under a reducing agent,

[0019]

[0020] (4) A step of obtaining compound 24 by subjecting compound 23 and an acyl compound to an amidation reaction under the action of a catalyst,

[0021]

[0022] Among them, is any one of methyl 3-chloropropionate, ethyl 3-chloropropionate, 3-chloropropionic acid, 3-chloropropionamide, and 3-chloropropionic anhydride;

[0023] (5) The step of obtaining compound 25 by subjecting compound 24 to a hydrolysis ring-opening reaction,

[0024]

[0025] (6) The step of obtaining the target product compound 14 by subjecting compound 25 to a phenolic hydroxyl methylation reaction,

[0026]

[0027] Preferably, in step (1), the catalyst is a heteropolyacid-based ionic liquid catalyst, and the heteropolyacid-based ionic liquid catalyst is selected from [MIMPS]3PW 12 O 40 , [MIMPS]3PMo 12 O 40 , [PyPS]3PW 12 O 40 , [PyPS]3PMo 12 O 40 , [TEAPS]3PW 12 O 40 , [TEAPS]3PMo 12 O 40 any one of them, and its chemical structure is:

[0028]

[0029] Preferably, in step (1), the molar ratio of 2-amino-5-fluoro-4-nitrophenol, R 1 CHO, and the catalyst is 1:1 to 2:0.01 to 0.05; the reaction temperature is 60 to 120 °C; the reaction time is 5 to 20 h.

[0030] Preferably, in step (2), the substitution reaction is carried out in the presence of a base, and the base is selected from any one of N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, triethylamine, sodium carbonate, and potassium carbonate; the reaction system uses an organic solvent as the solvent, and the organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, n-butanol, 1,4-dioxane, ethylene glycol dimethyl ether, and methyl tert-butyl ether.

[0031] Preferably, in step (2), the molar ratio of compound 21, N,N,N'-trimethylethylenediamine, and the base is 1:1 to 1.5:1.5 to 2; the reaction temperature is 60 to 120 °C; the reaction time is 4 to 12 h.

[0032] Preferably, in step (3), the reducing agent for the nitro reduction reaction is a hydrogen source, and the hydrogen source is selected from any one of ammonium formate and hydrazine hydrate; the nitro reduction reaction is carried out in the presence of a catalyst, and the catalyst is selected from any one of palladium on carbon (palladium content 1%-10 wt%), platinum on carbon (platinum content 1%-10 wt%), and Raney nickel; the reaction system uses an organic solvent as the solvent, and the organic solvent is selected from any one of methanol, ethanol, propanol, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, and dimethyl sulfoxide.

[0033] Preferably, in step (3), the mass ratio of compound 22 to the catalyst is 1:0.01 to 1; the molar ratio of compound 22 to the reducing agent is 1:2 to 10; the reaction temperature is 30 to 80 °C; the reaction time is 3 to 10 h.

[0034] Preferably, in step (4), the catalyst uses a heteropolyacid-based ionic liquid catalyst, and the heteropolyacid-based ionic liquid catalyst is selected from any one of [MIMPS]3PW 12 O 40 、[MIMPS]3PMo 12 O 40 、[PyPS]3PW 12 O 40 、[PyPS]3PMo 12 O 40 、[TEAPS]3PW 12 O 40 、[TEAPS]3PMo 12 O 40 among them.

[0035] Preferably, in step (4), the molar ratio of compound 23, the acyl compound to the catalyst is 1:1 to 2:0.01 to 0.05; the reaction temperature is 60 to 120 °C; the reaction time is 6 to 12 h.

[0036] Preferably, in step (5), the hydrolysis ring-opening reaction is carried out in the presence of a base, and the base is selected from any one of potassium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, and cesium carbonate.

[0037] Preferably, in step (5), the molar ratio of compound 24 to the base is 1:10 to 30; the reaction temperature is 60 to 100 °C; the reaction time is 4 to 10 h.

[0038] Preferably, in step (6), the methylation reagent for the methylation reaction is selected from any one of methyl iodide, dimethyl sulfate, and dimethyl carbonate; an organic solvent is used as the solvent in the reaction system, and the organic solvent is selected from any one of acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, and dimethyl sulfoxide; the methylation reaction is carried out in the presence of a base, and the base is selected from any one of potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0039] Preferably, in step (6), the molar ratio of compound 25, the methylation reagent, and the base is 1:1 to 1.5:1.5 to 4; the reaction temperature is 30 to 100 °C; the reaction time is 4 to 12 h.

[0040] The present invention uses 2-amino-5-fluoro-4-nitrophenol as a raw material and obtains the target product through six steps of reaction: cyclization protection, N,N,N'-trimethylethylenediamine substitution, nitro reduction, amidation, hydrolysis deprotection, and phenolic hydroxyl methylation. Compared with the prior art, the beneficial effects of the present invention are as follows: (1) In the two steps of cyclization protection and amidation, the use of heteropolyacid-based ionic liquid catalysts has a simple synthesis method, high activity, can be recycled and reused multiple times, and is green and environmentally friendly; the hydrogen source used in the nitro reduction reaction step is cheap and easily available, the operation is convenient and safe; the penultimate hydrolysis deprotection reaction step has a simple operation, high conversion rate, and simultaneously introduces an allyl group, effectively avoiding side reactions caused by premature introduction of the allyl group. (2) The whole process avoids the use of highly toxic chemicals, the process operation is simple, the conditions are easy to control, the reagents and intermediates have high stability, are convenient for transportation and storage, have less potential safety hazards, are easy to treat waste liquid, are green and environmentally friendly, and are convenient for large-scale industrial use. Description of the Drawings

[0041] Figure 1 The reaction yield data for the activity repeatability test of the heteropolyacid-based ionic liquid catalyst with the E group in Example 1 as the template reaction.

[0042] Figure 2 The reaction yield data for the activity repeatability test of the heteropolyacid-based ionic liquid catalyst with the C group in Example 9 as the template reaction. Detailed Description of the Invention

[0043] The present invention is further illustrated by the following examples, but the patent rights are not limited to these examples.

[0044] Through retrosynthetic analysis, it can be known that osimertinib can be split into 3-(2-chloropyrimidin-4-yl)-1-methylindole (3) and intermediate 14 (as shown in the following formula). Among them, the synthesis of 3-(2-chloropyrimidin-4-yl)-1-methylindole 3 is relatively mature and commercially available. Therefore, the key point lies in the synthesis of intermediate 14.

[0045]

[0046] The preparation method of the osimertinib intermediate 14 of the present invention uses 2-amino-5-fluoro-4-nitrophenol as a raw material, and obtains the target product through six steps of cyclization protection, N,N,N'-trimethylethylenediamine substitution, nitro reduction, amidation, hydrolysis deprotection, and phenolic hydroxyl methylation. The specific steps are as follows:

[0047] Step 1: Using 2-amino-5-fluoro-4-nitrophenol (5) as a raw material and R 1 CHO to obtain compound 21 through a cyclization reaction under the action of a catalyst.

[0048]

[0049] Under stirring conditions, 2-amino-5-fluoro-4-nitrophenol (5), R 1 CHO and a heteropolyacid-based ionic liquid catalyst are successively added to the reactor. After heating to the target reaction temperature, keep the temperature for a certain reaction time. After the reaction is completed, cool down to room temperature. Add an aprotic weakly polar solvent to the reactor, stir to dissolve the product, filter to recover the heteropolyacid-based ionic liquid catalyst, which can be recycled and reused. Concentrate the filtrate and further purify it by ethanol recrystallization or column chromatography to obtain compound 21.

[0050] Step 2: React compound 21 with N,N,N'-trimethylethylenediamine through a substitution reaction to obtain compound 22.

[0051]

[0052] Under stirring conditions, compound 21, N,N,N'-trimethylethylenediamine and a base are successively added to an organic solvent. After heating to the target reaction temperature, keep the temperature for a certain reaction time. After the reaction is completed, cool down to room temperature. Add water while stirring vigorously to crystallize. Filter and wash the filter cake with water. After obtaining the crude product, it can be further purified by ethanol recrystallization or column chromatography to obtain compound 22.

[0053] Step 3: Prepare compound 23 through a nitro reduction reaction of compound 22.

[0054]

[0055] Under stirring conditions, compound 22 and a catalyst are successively added to an organic solvent, and then a hydrogen source is slowly added. After heating to the target reaction temperature, keep the temperature for a certain reaction time. After the reaction is completed, cool down to room temperature. Filter to recover the catalyst for reuse. Concentrate the filtrate and further purify it by ethanol recrystallization or column chromatography to obtain compound 23.

[0056] Step 4: Compound 23 and an acyl compound are subjected to acrylamidation reaction under the action of a catalyst to obtain compound 24.

[0057]

[0058] Under stirring conditions, compound 23, the acyl compound and a heteropolyacid-based ionic liquid catalyst are successively added to a reactor. After heating to the target reaction temperature, the reaction is kept for a certain period of time. After the reaction is completed, the temperature is lowered to room temperature. A non-protic weakly polar solvent is added to the reactor. After stirring to dissolve the product, the heteropolyacid-based ionic liquid catalyst is recovered by filtration and can be recycled. The filtrate is concentrated and can be further purified by ethanol recrystallization or column chromatography to obtain compound 24.

[0059] Step 5: Compound 24 is subjected to hydrolysis ring-opening reaction to obtain compound 25.

[0060]

[0061] Under stirring conditions, compound 24 and a base are successively added to water. After heating to the target reaction temperature, the reaction is kept for a certain period of time. After the reaction is completed, the temperature is lowered to room temperature. Dilute hydrochloric acid is added to adjust the pH to acidic. The filter cake obtained by filtration can be further purified by ethanol recrystallization or column chromatography to obtain compound 25.

[0062] Step 6: Compound 25 is subjected to phenolic hydroxyl methylation reaction to obtain the target product compound 14.

[0063]

[0064] Under stirring conditions, compound 25, a methylation reagent and a base are successively added to an organic solvent. After heating to the target reaction temperature, the reaction is kept for a certain period of time. After the reaction is completed, the temperature is lowered to room temperature. Water is added while stirring vigorously to precipitate crystals. The filter cake is washed with water after filtration. After obtaining the crude product, it can be further purified by ethanol recrystallization or column chromatography to obtain compound 14.

[0065] The synthesis method of the osimertinib intermediate described in the present invention has the following total synthesis route:

[0066]

[0067] For the preparation method of the heteropolyacid-based ionic liquid catalyst used in the examples, refer to the relevant literature (An eco-benign and highly efficient procedure for N-acylation catalyzed by heteropolyanion-based ionic liquids using carboxylic acid under solvent-free conditions, Tetrahedron 70(2014)2237-2245.).

[0068] Example 1: Preparation of Compound 21a

[0069]

[0070] The experiment was divided into seven groups of comparative experiments, namely Group A - G. Each group either did not add a catalyst or added different types of heteropolyacid-based ionic liquid catalysts

[0071] Group A: No catalyst was added

[0072] Group B: [MIMPS]3PMo 12 O 40

[0073] Group C: [MIMPS]3PW 12 O 40

[0074] Group D: [PyPS]3PMo 12 O 40

[0075] Group E: [PyPS]3PW12O 40

[0076] Group F: [TEAPS]3PMo 12 O 40

[0077] Group G: [TEAPS]3PW 12 O 40

[0078] The specific experimental method is as follows:

[0079] Under stirring conditions, 3.5 g of 2-amino-5-fluoro-4-nitrophenol, 3.3 g of benzaldehyde and 0.20 mmol of catalysts in groups A - G were successively added into the reactor. After heating to 100 °C, the mixture was kept at this temperature for reaction for 10 h. After the reaction was completed, the temperature was lowered to room temperature. 100 ml of ethyl acetate was added into the reactor. After stirring to dissolve the product, the heteropolyacid-based ionic liquid catalyst was recovered by filtration and could be recycled. The filtrate was concentrated and could be further purified by ethanol recrystallization or column chromatography to obtain compound 21a. 1 HNMR(400MHz,CDCl3)δ8.22(d,J=8.0Hz,2H),7.78(s,1H),7.63 - 7.50(m,3H),7.20(d,J=7.8Hz,1H).

[0080] Table 1 Results of comparative experiments in groups A - G

[0081]

[0082]

[0083] From the data in Table 1, the following conclusions can be drawn: The experimental results without a catalyst (group A) are significantly worse than those with heteropolyacid-based ionic liquid catalysts (groups B - G); The catalytic activities of heteropolyacid-based ionic liquids containing MIMPS and PyPS are comparable and both are higher than those of heteropolyacid-based ionic liquids containing TEAPS; The catalytic activity of heteropolyacid-based ionic liquids containing PW 12 O 40 is higher than that of heteropolyacid-based ionic liquids containing PMo 12 O 40 ; The one with the highest catalytic activity in groups A - F is [PyPS]3PW 12 O 40 (group E).

[0084] Example 2: Recycling of the catalyst in the preparation of compound 21a

[0085] Using the reaction in group E in Example 1 as the template reaction, the activity repeatability test of the heteropolyacid-based ionic liquid catalyst was carried out, and the ionic liquid was reused 4 times. The yield data of the reaction are shown in Figure 1 .

[0086] From Figure 1 and the data, the following conclusion can be drawn: The yield of the heteropolyacid-based ionic liquid catalyst slightly decreases during the recycling process, but the decrease amplitude is small. Therefore, it can be proved that the heteropolyacid-based ionic liquid can be recycled.

[0087] Example 3: Preparation of compound 21b

[0088]

[0089] Under stirring conditions, 3.5 g of 2-amino-5-fluoro-4-nitrophenol, 3.8 g of 4-methylbenzaldehyde and [PyPS]3PW were successively added to the reactor. 12 O 40 1.4 g was added, and after the temperature was raised to 100 °C, the reaction was kept at this temperature for 10 h. After the reaction was completed, the temperature was lowered to room temperature. 100 ml of ethyl acetate was added to the reactor. After stirring to dissolve the product, the heteropolyacid-based ionic liquid catalyst was recovered by filtration and could be recycled. The filtrate was concentrated and could be further purified by ethanol recrystallization or column chromatography to obtain 5.0 g of compound 21b with a yield of 91%. 1 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.86 (s, 1H), 7.30 - 7.23 (m, 3H), 2.20 (s, 3H).

[0090] Example 4: Preparation of compound 21c

[0091]

[0092] Under stirring conditions, 3.5 g of 2-amino-5-fluoro-4-nitrophenol, 4.4 g of 4-chlorobenzaldehyde and [PyPS]3PW were successively added to the reactor. 12 O 40 1.6 g was added, and after the temperature was raised to 100 °C, the reaction was kept at this temperature for 12 h. After the reaction was completed, the temperature was lowered to room temperature. 100 ml of ethyl acetate was added to the reactor. After stirring to dissolve the product, the heteropolyacid-based ionic liquid catalyst was recovered by filtration and could be recycled. The filtrate was concentrated and could be further purified by ethanol recrystallization or column chromatography to obtain 5.2 g of compound 21c with a yield of 88%. 1 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.8 Hz, 1H).

[0093] Example 5: Preparation of compound 22a

[0094]

[0095] Under stirring conditions, 3.9 g of compound 21a, 1.9 g of N,N,N'-trimethylethylenediamine and 3.9 g of N,N-diisopropylethylamine were successively added to 40 ml of N,N-dimethylacetamide. After the temperature was raised to 90 °C, the reaction was kept at this temperature for 6 h. After the reaction was completed, the temperature was lowered to room temperature. Water was added while stirring vigorously to precipitate crystals. After filtration, the filter cake was washed with water. The crude product could be further purified by ethanol recrystallization or column chromatography to obtain 4.8 g of compound 22a with a yield of 93%.1 HNMR(400M Hz,CDCl3)δ7.88(s,1H),8.16(d,J=8.0Hz,2H),7.73 - 7.68(m,4H),7.05(s,1H),3.31(t,2H),2.93(s,3H),2.60(t,2H),2.29(s,6H).

[0096] Example 6: Preparation of Compound 22b

[0097]

[0098] Under stirring conditions, 4.1 g of Compound 21b, 2.2 g of N,N,N'-trimethylethylenediamine and 4.1 g of N,N-diisopropylethylamine were successively added to 40 ml of N,N-dimethylacetamide. After the temperature was raised to 80 °C, the reaction was kept at this temperature for 10 h. After the reaction was completed, the temperature was cooled to room temperature. Water was added while stirring vigorously to precipitate crystals. The filter cake was washed with water after filtration. After obtaining the crude product, it could be further purified by recrystallization from ethanol or column chromatography to obtain 4.7 g of Compound 22b, with a yield of 89%. 1 H NMR(400M Hz,CDCl3)δ8.02(d,J=8.0Hz,2H),7.64(s,1H),7.30(d,J=8.0Hz,2H),7.00(s,1H),3.30(t,2H),2.87(s,3H),2.55(t,2H),2.40(s,3H),2.23(s,6H).

[0099] Example 7: Preparation of Compound 23a

[0100]

[0101] Under stirring conditions, 10.2 g of Compound 22a and 1.0 g of 10 wt% palladium on carbon were successively added to 150 ml of methanol. Then 9.5 g of ammonium formate was slowly added. After the temperature was raised to 65 °C, the reaction was kept at this temperature for 8 h. After the reaction was completed, the temperature was cooled to room temperature. The catalyst was recovered by filtration and could be reused. After concentrating the filtrate, it could be further purified by recrystallization from ethanol or column chromatography to obtain 8.9 g of Compound 23a, with a yield of 96%. 1 H NMR(400M Hz,DMSO-d6)δ8.21(d,J=8.0Hz,2H),7.71 - 7.66(m,3H),6.71(s,1H),6.65(s,1H),4.66(brs,2H),2.90(t,2H),2.63(s,3H),2.38(t,2H),2.18(s,6H).

[0102] Example 8: Preparation of Compound 23b

[0103]

[0104] Under stirring conditions, 10.6 g of compound 22a and 1.1 g of 10 wt% palladium on carbon were successively added to 150 ml of 1,4-dioxane, and then 12.0 g of hydrazine hydrate was slowly added. After the temperature was raised to 100 °C, the mixture was kept warm and reacted for 6 h. After the reaction was completed, the temperature was lowered to room temperature. The catalyst was recovered by filtration and could be reused. After concentrating the filtrate, compound 23b (9.1 g, yield 93%) could be further purified by ethanol recrystallization or column chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 6.66 (s, 1H), 4.57 (brs, 2H), 2.88 (t, 2H), 2.61 (s, 3H), 2.37 (t, 2H), 2.24 (s, 3H), 2.18 (s, 6H).

[0105] Example 9: Preparation of compound 24a

[0106]

[0107] The experiment was divided into seven groups of comparative experiments, namely groups A - G. Each group either did not add a catalyst or added different kinds of heteropolyacid-based ionic liquid catalysts.

[0108] Group A: Without adding a catalyst

[0109] Group B: [MIMPS]3PMo 12 O 40

[0110] Group C: [MIMPS]3PW 12 O 40

[0111] Group D: [PyPS]3PMo 12 O 40

[0112] Group E: [PyPS]3PW12O 40

[0113] Group F: [TEAPS]3PMo 12 O 40

[0114] Group G: [TEAPS]3PW 12 O 40

[0115] The specific experimental method is as follows:

[0116] Under stirring conditions, 4.7 g of compound 23a, 2.4 g of 3-chloropropionic acid and 0.15 mmol of catalysts in groups A - G were successively added to the reactor. After heating to 100 °C, the reaction was kept at this temperature for 12 h. After the reaction was completed, the temperature was lowered to room temperature. 100 ml of ethyl acetate was added to the reactor. After stirring to dissolve the product, the heteropolyacid-based ionic liquid catalyst was recovered by filtration and could be recycled. The filtrate was concentrated and could be further purified by ethanol recrystallization or column chromatography to obtain compound 24a. 1 H NMR(400M Hz,DMSO-d6)δ10.00(s,1H),8.22(d,J=8.0Hz,2H),7.67 - 7.61(m,3H),7.43(s,1H),6.81(s,1H),3.85(t,2H),2.95(t,2H),2.85(t,2H),2.72(s,3H),2.25(t,2H),2.21(s,6H).

[0117] Table 2 Results of comparative experiments in groups A - G

[0118]

[0119]

[0120] From the data in Table 2, the following conclusions can be drawn: The experimental results without a catalyst (group A) are significantly worse than those with heteropolyacid-based ionic liquid catalysts (groups B - G); The catalytic activities of heteropolyacid-based ionic liquids containing MIMPS and PyPS are comparable and both are higher than those of heteropolyacid-based ionic liquids containing TEAPS; The catalytic activity of heteropolyacid-based ionic liquids containing PW 12 O 40 is higher than that of heteropolyacid-based ionic liquids containing PMo 12 O 40 ; The highest catalytic activity in groups A - F is [MIMPS]3PW 12 O 40 (group C).

[0121] Example 10: Recycling of the catalyst in the preparation of compound 24a

[0122] Using the reaction in group C of Example 9 as the template reaction, the activity repeatability test of the heteropolyacid-based ionic liquid catalyst was carried out, and the ionic liquid was reused 4 times. The yield data of the reaction are shown in Figure 2 .

[0123] From Figure 2 and the data, the following conclusion can be drawn: The yield of the heteropolyacid-based ionic liquid catalyst decreases slightly during the recycling process, but the decrease amplitude is small. Therefore, it can be proved that the heteropolyacid-based ionic liquid can be recycled.

[0124] Example 11: Preparation of Compound 24b

[0125]

[0126] Under stirring conditions, 4.9 g of Compound 23b, 3.8 g of ethyl acrylate and 1.0 g of [MIMPS]3PW were successively added to the reactor. After heating to 90 °C, the mixture was kept at this temperature for reaction for 12 h. After the reaction was completed, the temperature was cooled to room temperature. 100 ml of ethyl acetate was added to the reactor. After stirring to dissolve the product, the heteropolyacid-based ionic liquid catalyst was recovered by filtration and could be recycled. The filtrate was concentrated and further purified by ethanol recrystallization or column chromatography to obtain 5.5 g of Compound 24b with a yield of 87%. 12 O 40 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.81 (s, 1H), 3.84 (t, 2H), 2.95 (t, 2H), 2.85 (t, 2H), 2.72 (s, 3H), 2.32 (s, 3H), 2.28 (t, 2H), 2.21 (s, 6H). 1 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.81 (s, 1H), 3.84 (t, 2H), 2.95 (t, 2H), 2.85 (t, 2H), 2.72 (s, 3H), 2.32 (s, 3H), 2.28 (t, 2H), 2.21 (s, 6H).

[0127] Example 12: Preparation of Compound 25

[0128]

[0129] Under stirring conditions, 8.0 g of Compound 24a and 12.0 g of sodium hydroxide were successively added to 100 ml of water. After heating to 80 °C, the mixture was kept at this temperature for reaction for 8 h. After the reaction was completed, the temperature was cooled to room temperature. Dilute hydrochloric acid was added to adjust the pH to acidic. The filter cake obtained by filtration was further purified by ethanol recrystallization or column chromatography to obtain 4.8 g of Compound 25 with a yield of 86%. 1 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 6.61 (s, 1H), 6.44 (m, 1H), 6.38 (s, 1H), 6.16 (d, J = 15.7 Hz, 1H), 5.70 (d, J = 11.0 Hz, 1H), 5.02 (brs, 2H), 3.35 (t, 2H), 2.75 (s, 3H), 2.47 (t, 2H), 2.22 (s, 6H).

[0130] Example 13: Preparation of Compound 25

[0131]

[0132] Under stirring conditions, 8.3 g of compound 24b and 12.3 g of potassium hydroxide were successively added to 100 ml of water. After heating to 70 °C, the mixture was kept at this temperature for reaction for 10 h. After the reaction was completed, the temperature was lowered to room temperature, and dilute hydrochloric acid was added to adjust the pH to acidic. The filter cake obtained by filtration was further purified by recrystallization from ethanol or column chromatography to obtain 4.9 g of compound 25, with a yield of 88%. 1 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 6.61 (s, 1H), 6.44 (m, 1H), 6.38 (s, 1H), 6.16 (d, J = 15.7 Hz, 1H), 5.70 (d, J = 11.0 Hz, 1H), 5.02 (brs, 2H), 3.35 (t, 2H), 2.75 (s, 3H), 2.47 (t, 2H), 2.22 (s, 6H).

[0133] Example 14: Preparation of Compound 14

[0134]

[0135] Under stirring conditions, 8.4 g of compound 25, 5.1 g of methyl iodide and 12.4 g of potassium carbonate were successively added to 100 ml of acetonitrile. After heating to 80 °C, the mixture was kept at this temperature for reaction for 6 h. After the reaction was completed, the temperature was lowered to room temperature, water was added while stirring vigorously to precipitate crystals, and the filter cake was washed with water after filtration. The crude product obtained was further purified by recrystallization from ethanol or column chromatography to obtain 8.2 g of compound 14, with a yield of 93%. 1 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 6.71 (s, 1H), 6.46 (m, 1H), 6.30 (s, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.73 (d, J = 11.0 Hz, 1H), 4.95 (brs, 2H), 3.91 (s, 3H), 3.38 (t, 2H), 2.70 (s, 3H), 2.45 (t, 2H), 2.19 (s, 6H).

[0136] Example 15: Preparation of Compound 14

[0137]

[0138] Under stirring conditions, 8.4 g of compound 25, 4.7 g of methyl iodide and 24.4 g of cesium carbonate were successively added to 100 ml of acetone. After heating to 60 °C, the mixture was kept at this temperature for reaction for 10 h. After the reaction was completed, the temperature was lowered to room temperature, water was added while stirring vigorously to precipitate crystals, and the filter cake was washed with water after filtration. The crude product obtained was further purified by recrystallization from ethanol or column chromatography to obtain 7.9 g of compound 14, with a yield of 90%. 11H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 6.71 (s, 1H), 6.46 (m, 1H), 6.30 (s, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.73 (d, J = 11.0 Hz, 1H), 4.95 (brs, 2H), 3.91 (s, 3H), 3.38 (t, 2H), 2.70 (s, 3H), 2.45 (t, 2H), 2.19 (s, 6H).

Claims

1. A method for preparing osimertinib intermediate 14, characterized in that, Comprising: (1) A step of using 2-amino-5-fluoro-4-nitrophenol (5) as a raw material and R 1 CHO to obtain compound 21 through a cyclization reaction under the action of a catalyst, Among them, R 1 is any one of phenyl, p-methylphenyl, p-chlorophenyl, p-nitrophenyl, and 1-naphthyl groups; (2) A step of obtaining compound 22 by subjecting compound 21 and N,N,N'-trimethylethylenediamine to a substitution reaction in the presence of a base, (3) A step of preparing compound 23 by subjecting compound 22 to a nitro reduction reaction in the presence of a catalyst and a reducing agent, (4) The step of obtaining compound 24 by subjecting compound 23 and an acyl compound to an amidation reaction under the action of a catalyst, Among them, is any one of ethyl 3-chloropropionate and 3-chloropropionic acid; (5) A step of obtaining compound 25 by subjecting compound 24 to a hydrolysis ring-opening reaction in the presence of a base, (6) A step of obtaining the target product compound 14 by subjecting compound 25 to a phenolic hydroxyl methylation reaction in the presence of a base, Among them, in steps (1) and (4), the catalyst used is a heteropolyacid-based ionic liquid catalyst, and the heteropolyacid-based ionic liquid catalyst is selected from any one of [MIMPS]3PW 12 O 40 , [PyPS]3PW 12 O 40 .

2. The method according to claim 1, characterized in that, In step (1), the molar ratio of 2-amino-5-fluoro-4-nitrophenol, R 1 CHO, and the catalyst is 1:1 to 2:0.01 to 0.05; the reaction temperature is 60 to 120 °C; the reaction time is 5 to 20 h.

3. The method according to claim 1, characterized in that, In step (2), the base is selected from any one of N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, triethylamine, sodium carbonate, and potassium carbonate; the reaction system uses an organic solvent as the solvent, and the organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, n-butanol, 1,4-dioxane, ethylene glycol dimethyl ether, and methyl tert-butyl ether.

4. The method according to claim 1, wherein In step (2), the molar ratio of compound 21, N,N,N'-trimethylethylenediamine, and the base is 1:1 to 1.5:1.5 to 2; the reaction temperature is 60 to 120 °C; the reaction time is 4 to 12 h.

5. The method according to claim 1, characterized in that, In step (3), the reducing agent for the nitro reduction reaction is a hydrogen source, and the hydrogen source is selected from any one of ammonium formate and hydrazine hydrate; the catalyst is selected from any one of palladium carbon, platinum carbon, and Raney nickel; the reaction system uses an organic solvent as the solvent, and the organic solvent is selected from any one of methanol, ethanol, propanol, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, and dimethyl sulfoxide.

6. The method according to claim 1, wherein In step (3), the mass ratio of compound 22 to the catalyst is 1:0.01 to 1; the molar ratio of compound 22 to the reducing agent is 1:2 to 10; the reaction temperature is 30 to 80 °C; the reaction time is 3 to 10 h.

7. The method according to claim 1, wherein In step (4), the molar ratio of compound 23 to the acyl compound to the catalyst is 1:1 to 2:0.01 to 0.05; the reaction temperature is 60 to 120 °C; and the reaction time is 6 to 12 h.

8. The method according to claim 1, characterized in that, In step (5), the base is selected from any one of potassium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, and cesium carbonate; the molar ratio of compound 24 to the base is 1:10 to 30; the reaction temperature is 60 to 100 °C; the reaction time is 4 to 10 h.

9. The method according to claim 1, wherein In step (6), the methylation reagent for the methylation reaction is selected from any one of methyl iodide, dimethyl sulfate, and dimethyl carbonate; the reaction system uses an organic solvent as the solvent, and the organic solvent is selected from any one of acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, and dimethyl sulfoxide; the base is selected from any one of potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; the molar ratio of compound 25, the methylation reagent, and the base is 1:1 to 1.5:1.5 to 4; the reaction temperature is 30 to 100 °C; the reaction time is 4 to 12 h.

Images