Synthesis method of 3-bromo-5-fluoro-2, 4-dimethylaniline and intermediate compound of 3-bromo-5-fluoro-2, 4-dimethylaniline

Abstract

The invention belongs to the technical field of medicine synthesis, and provides a synthesis method of 3-bromo-5-fluoro-2, 4-dimethylaniline and an intermediate compound of the 3-bromo-5-fluoro-2, 4-dimethylaniline. The method comprises the following steps: by taking 2, 4, 5-trifluoronitrobenzene as a raw material, carrying out substitution reaction with malonic acid diester to obtain a compound shown as a formula II, then carrying out decarboxylation under high-temperature reaction to obtain a compound shown as a formula III, carrying out bromination reaction to obtain a compound shown as a formula IV, and finally carrying out nitro reduction reaction to obtain a target compound 3-bromo-5-fluoro-2, 4-dimethylaniline (shown as a formula V). The method has the advantages of simple synthesis steps, convenient process, simple and easily available raw materials, low cost, convenient operation method and high overall yield, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a synthesis method of 3-bromo-5-fluoro-2,4-dimethylaniline and an intermediate compound thereof. Background Art

[0002] The compound 3-bromo-5-fluoro-2,4-dimethylaniline (Formula V) is an important synthetic intermediate of compound 14-2 in the patent WO2022083569A1 disclosed by Amgen, and the related example compound is an inhibitor of KRAS with G12C mutation, which can be used to treat various tumors with KRAS G12C mutation. The structure of compound 14-2 is as follows:

[0003]

[0004] For the synthesis route of 3-bromo-5-fluoro-2,4-dimethylaniline, the disclosed prior art is as follows:

[0005] (1) The synthesis route disclosed in patent WO2022083569A1 is:

[0006]

[0007] (2) The synthetic routes disclosed in patent CN117865812A and Journal of the American Chemical Society, 1932, vol.54, 2973-2976 are:

[0008]

[0009] The above-mentioned prior arts all have various deficiencies, such as: WO2022083569A1 uses the compound of formula III as the raw material, adds 1.6 equivalents of N-bromosuccinimide (NBS), and reacts at a temperature of 50°C to produce a large amount of dibromo compounds. The nitro reduction is carried out using ferric acetate reduction, which is difficult to handle, and the product needs to be purified by column chromatography; and the compound of formula III is both expensive and not available in large quantities.

[0010] The synthetic route disclosed in patent CN117865812A and the preparation of compound III reported in Journal of the American Chemical Society, 1932, vol. 54, 2973-2976 both use 2,4-dimethyl-5-nitroaniline as the raw material. This raw material is not only expensive, but also dangerous to prepare the intermediate diazonium salt.

[0011] Although the document Synthesis, 2000, No. 12, 165-1661 reports a method for preparing 5-chloro-2,4-dimethylnitrobenzene from 5-chloro-2,4-difluoronitrobenzene, its product contains precursor impurities that are not completely deethoxycarbonylated and require column chromatography separation. In addition, the document does not report the preparation of 5-fluoro-2,4-dimethylnitrobenzene.

[0012] As far as we know, intermediate compounds Ⅱ-a and Ⅱ-b have not been reported so far.

[0013] Summary of the invention

[0014] In view of the above technical problems, the present invention provides a method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline and an intermediate compound thereof, the purpose of which is to solve the defects of the existing synthesis of 3-bromo-5-fluoro-2,4-dimethylaniline compounds, such as high cost, complicated operation, and unsuitability for industrial production.

[0015] To achieve this object, the present invention adopts the following technical solutions:

[0016] In a first aspect, the present invention provides a method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline, comprising the following steps:

[0017] Step S1, the compound of formula I reacts with a malonic acid diester under alkaline conditions to generate a compound of formula II;

[0018] Step S2, heating the compound of formula II in the presence of a high boiling point polar solvent and a salt hydrate to perform a decarboxylation reaction to generate a compound of formula III;

[0019] Step S3, the compound of formula III undergoes a bromination reaction with a brominating agent under acidic conditions to generate a compound of formula IV;

[0020] Step S4, reducing the nitro group of the compound of formula IV in a solvent to generate the compound of formula V;

[0021] The specific synthetic route of this synthetic method is as follows:

[0022]

[0023] Preferably, R is a C1 to C10 hydrocarbon group.

[0024] Preferably, in step S1, the molar ratio of the compound of formula I to the malonic acid diester is 3-6.

[0025] Preferably, in step S1, the diester of malonate is dimethyl malonate, and the compound of formula I reacts with it under alkaline conditions to generate the compound of formula II, where R = Me, i.e., the compound of formula II-a;

[0026] Preferably, in step S1, when the diester of malonate is diethyl malonate, the compound of formula I reacts with it under alkaline conditions to generate a compound of formula II, where R=Et, i.e., a compound of formula II-b.

[0027] Preferably, in step S1, the alkaline condition is formed by adding potassium carbonate, sodium carbonate, sodium hydrogen, sodium tert-butoxide or potassium tert-butoxide, more preferably sodium hydrogen.

[0028] Preferably, in step S1, the solvent is DMF, DMSO or acetonitrile, more preferably DMF; the reaction temperature is 100°C to 150°C, more preferably 130°C.

[0029] Preferably, in step S1, the molar ratio of the malonic acid diester to the compound of formula I is 2 to 5:1, more preferably 3:1.

[0030] Preferably, in step S1, the molar ratio of the base to the compound of formula I is 2 to 5:1, more preferably 3:1.

[0031] Preferably, in step S1, the volume ratio of the reaction solvent to the compound of formula I is 5 to 15:1, more preferably 10:1.

[0032] Preferably, in step S2, the hydrate of the salt is magnesium chloride hexahydrate; the salt is lithium chloride, sodium bromide, sodium chloride, sodium cyanide, potassium chloride, magnesium chloride, sodium sulfate or magnesium sulfate.

[0033] Preferably, in step S2, the high boiling point polar solvent is DMF, DMSO, DMAC, NMP or HMPA.

[0034] In step S2, the reaction temperature is 120°C to 180°C, more preferably 150°C to 160°C.

[0035] Preferably, in step S2, the molar ratio of the salt hydrate to the compound of formula II is 3 to 6:1, more preferably 4:1.

[0036] Preferably, in step S2, the volume ratio of the high boiling point polar solvent to the compound of formula II is 3 to 8:1, more preferably 5:1.

[0037] Preferably, in step S3, the acidic condition is trifluoroacetic acid or sulfuric acid.

[0038] Preferably, in step S3, the brominating agent is NBS, bromine, dibromohydantoin or tribromopyridinium salt (PyHBr3).

[0039] Preferably, in step S3, the molar ratio of the bromination reagent to the compound of formula III is 1.0 to 2.5:1, more preferably 1.15:1.

[0040] Preferably, in step S3, the molar ratio of sulfuric acid to the compound of formula III is 2 to 5:1, more preferably 3.6:1.

[0041] Preferably, in step S3, the volume ratio of trifluoroacetic acid to the compound of formula III is 4 to 6:1, more preferably 5:1.

[0042] Preferably, in step S3, the reaction temperature is 20°C to 60°C, more preferably 30°C to 40°C.

[0043] Preferably, in step S4, the reducing agent is selected from iron-ammonium chloride, zinc-ammonium chloride, zinc-acetic acid, zinc-hydrazine hydrate-formic acid, ferric chloride-activated carbon-hydrazine hydrate; more preferably ferric chloride-activated carbon-hydrazine hydrate, that is, hydrazine hydrate reduces the nitro group under the catalysis of activated carbon and ferric chloride.

[0044] Preferably, in step S4, the solvent is methanol, ethanol, isopropanol, etc., more preferably ethanol; and the reaction is preferably carried out under reflux.

[0045] Preferably, in step S4, the molar ratio of hydrazine hydrate to the compound of formula IV is 2 to 5:1, preferably 4:1;

[0046] Preferably, in step S4, the volume ratio of the solvent to the compound of formula IV is 4 to 6:1, more preferably 5:1.

[0047] In the first aspect, the present invention provides an unreported intermediate compound, namely, a compound of formula II, wherein R is a C1-C10 hydrocarbon group; more preferably, R is a methyl group or an ethyl group, namely, compounds II-a and II-b, whose structural formulas are as follows:

[0048]

[0049] The present invention uses 2,4,5-trifluoronitrobenzene as a raw material, undergoes a substitution reaction with a malonic acid diester to obtain a compound of formula II, undergoes a high temperature reaction to remove an alkyloxycarbonyl group to obtain a compound of formula III, then undergoes a bromination reaction to obtain a compound of formula IV, and then undergoes a nitro reduction to obtain a compound of formula V, 3-bromo-5-fluoro-2,4-dimethylaniline. Compared with the prior art, the present invention has at least the following beneficial effects:

[0050] 1. The synthesis steps of the present invention are simple, the process is simple, the raw materials are easy to obtain, the cost is low, the operation method is convenient, and it is suitable for industrial scale-up production.

[0051] 2. The raw material cost is low and the output is large, the yield of each step is high, the overall yield is high, and it is economical, safe and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 is the NMR image of the compound of formula II-a in Example 1 of the present invention;

[0053] Figure 2 is the NMR image of the compound of formula III in Example 1 of the present invention;

[0054] Figure 3 is the NMR image of the compound of formula II-b in Example 2 of the present invention;

[0055] Figure 4 is the NMR image of the compound of formula III in Example 2 of the present invention;

[0056] Figure 5 is the NMR image of the compound of formula IV in Example 2 of the present invention;

[0057] Figure 6 is the NMR image of the compound of formula V in Example 2 of the present invention;

[0058] Figure 7 This is the GC chart of the compound of formula V in Example 2 of the present invention. DETAILED DESCRIPTION

[0059] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0060] Unless otherwise specified, the raw materials and materials used in the examples of the present invention are purchased through general commercial channels.

[0061] The sources of the raw materials, materials and instruments involved in the following examples or comparative examples are as follows:

[0062] Raw material information:

[0063]

[0064]

[0065] Instrument information:

[0066] Name Model

[0067] Gas chromatograph, Thermo TRACEAC UCTRA;

[0068] Outsourcing testing: Nuclear magnetic resonance H 1 -NMR, Ausun (Shanghai) Testing Technology Co., Ltd.

[0069] <Example 1>

[0070] This embodiment prepares 3-bromo-5-fluoro-2,4-dimethylaniline, comprising the following steps:

[0071] Step S1-a, synthesizing the compound of formula II-a from the compound of formula I according to the following synthetic route,

[0072]

[0073] The specific operations are:

[0074] Add 200ml N,N-dimethylformamide (DMF) to a 1L reactor, add 13.7g sodium hydrogen with stirring, cool down and control the temperature to 0-10℃, add 54.2g dimethyl malonate dropwise, stir for 1h after the addition is complete, control the temperature to 0-10℃ and add 20g 2,4,5-trifluoronitrobenzene (compound of formula I), raise the temperature to 130℃ and react for 4h after the addition is complete, and the reaction is basically complete. Cool down to room temperature, add 100ml saturated aqueous ammonium chloride solution, 500ml water and 300ml ethyl acetate, stir and stand for separation. The aqueous phase is extracted once with 300ml ethyl acetate, and the organic phases are combined; wash once with water, spin dry, and obtain 62.3g of crude oil of compound of formula II-a. Take 5g of the crude product and purify it through a column to obtain 2.9g of pure compound of formula II-a, and the nuclear magnetic spectrum is shown in Figure 1 . 1 H NMR (400MHz, Chloroform-d) δ7.83 (dd, J = 8.6, 6.1 Hz, 1H), 7.57 (dd, J = 10.9, 5.7 Hz, 1H), 5.03 (s, 1H), 3.89–3.67 (m, 12H), 3.39 (s, 1H). The mass analysis of the pure compound of formula II-a was performed using liquid chromatography-mass spectrometry, and MS (ESI + ,m / z):[M+H] + =402.34.

[0075] Step S2-a, synthesizing the compound of formula III from the compound of formula II-a according to the following synthetic route,

[0076]

[0077] The specific operations are:

[0078] Add 57.3 g of crude oil of compound of formula II-a to a 1L reaction bottle, add 300 ml of N,N-dimethylacetamide, 91.8 g of magnesium chloride hexahydrate, stir and heat to 150°C, react for 12 hours, and the reaction is complete. Cool to room temperature, add 500 ml of water, extract with 300 ml of ethyl acetate, extract 3 times in total, and combine the organic phases. Wash the organic phase with saturated brine, spin dry, and obtain 21 g of crude oil. Distill under reduced pressure, distill at 93°C to obtain 10 g of compound of formula III, and the NMR is shown in Figure 2 . 1H NMR (400MHz, Chloroform-d) δ7.71 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 2.56 (s, 3H), 2.32 (d, J = 2.0 Hz, 3H). The mass spectrometer was used to analyze the compound of formula III, MS: [M+H] + =170.22, and the molar yield of the two steps (S1-a and S2-a) based on 2,4,5-trifluoronitrobenzene is 52.3%.

[0079] <Example 2>

[0080] This embodiment prepares 3-bromo-5-fluoro-2,4-dimethylaniline, comprising the following steps:

[0081] Step S1-b, synthesizing the compound of formula II-b from the compound of formula I according to the following synthetic route,

[0082]

[0083] The specific operations are:

[0084] Add 16L N,N-dimethylformamide to a 50L reactor, add 1119g sodium hydrogen with stirring, cool down and control the temperature to 0-10℃, add 3729g diethyl malonate dropwise, stir for 1h after the addition, control the temperature to 0-10℃, add 1650g 2,4,5-trifluoronitrobenzene dropwise, heat to 130℃ and react for 4h after the addition, and the reaction is basically complete. Cool down to room temperature, add 5L saturated ammonium chloride aqueous solution, 20L water and 10L ethyl acetate, stir and stand to separate to obtain organic phase and aqueous phase, extract the aqueous phase with 10L ethyl acetate once to obtain organic phase, combine with the above organic phase, wash the combined organic phase with water once, spin dry, and obtain 5.8kg crude oil of compound of formula II, take 5g crude product and further purify by column to obtain 3.3g pure compound of formula II-b, NMR is shown in Figure 3 . 1 HNMR (400MHz, Chloroform-d) δ7.97–7.81 (m, 1H), 7.72 (d, J = 6.8 Hz, 1H), 5.25 (s, 1H), 4.98 (s, 1H), 4.41–4.17 (m, 8H), 1.28 (td, J = 7.1, 1.6 Hz, 12H). The mass analysis of the pure compound of formula II was performed using liquid chromatography-mass spectrometry, and MS (ESI + ,m / z):[M+H] + =458.52.

[0085] Step S2-b, synthesizing the compound of formula III from the compound of formula II-b according to the following synthetic route,

[0086]

[0087] The specific operations are:

[0088] Add 5.8 kg of crude oil of compound of formula II-b into a 100L reactor, add 21L N,N-dimethylacetamide (DMAC), 7.6 kg of magnesium chloride hexahydrate, stir and heat to 150°C, react for 12 hours, and the reaction is complete. Cool to room temperature, add 20L of water, extract with 8L of ethyl acetate, extract 3 times in total, and combine the organic phases. Wash the organic phase with 8L of saturated brine; spin dry to obtain 1.8 kg of crude oil, distill under reduced pressure, and distill at a fraction temperature of 93°C to obtain 1 kg of compound of formula III, with NMR as shown in Figure 4 . 1 H NMR (400MHz, Chloroform-d) δ7.71 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 2.56 (s, 3H), 2.32 (d, J = 2.0 Hz, 3H). The mass spectrometer was used to analyze the compound of formula III, MS: [M+H] + =170.22, and the molar yield of the two steps (S1-b and S2-b) is 63.4% based on 2,4,5-trifluoronitrobenzene. The results all show that its structure is consistent with the compound of formula III prepared from the compound of formula II-a in Example 1.

[0089] Step S3, synthesizing the compound of formula IV from the compound of formula III according to the following synthetic route,

[0090]

[0091] The specific operations are:

[0092] Add 5L trifluoroacetic acid to a 10L three-necked flask, stir and cool, control the temperature at 0-10°C and add 1.1L sulfuric acid dropwise, add 1000g crude product of compound III after the addition is complete, add 1.2kg N-bromosuccinimide (NBS), after the addition is complete, heat to 35°C and react for 16h, the reaction is complete. Cool to room temperature, pour the reaction solution into 8kg ice water to precipitate solid, filter out the solid, and dry to obtain 1.2kg crude product of compound IV, the NMR of which is shown in Figure 5 . 1 H NMR (400 MHz, Chloroform-d) δ7.50 (d, J = 8.6 Hz, 1H), 2.55 (s, 3H), 2.41 (d, J = 2.6 Hz, 3H). The mass spectrometer was used to analyze the compound of formula IV, MS: [M+H] + =247.98 / 249.98(1:1).

[0093] Step S4, synthesizing the compound of formula V from the compound of formula IV according to the following synthetic route,

[0094]

[0095] The specific operations are:

[0096] 1.2 kg of crude compound of formula IV was added to a 20L three-necked flask, followed by 6L of ethanol, 240g of activated carbon and 121g of ferric chloride, heated to reflux, and then 1.2 kg of hydrazine hydrate was added dropwise. After the addition was complete, the reaction was continued for 2 hours. The temperature was cooled to room temperature, the solution was filtered out, and 1 kg of crude product was obtained by spin drying. The crude product was subjected to vacuum distillation at a fraction temperature of 124°C to obtain 600 g of compound of formula V. The molar yield of compound of formula V was 46.5% based on compound of formula III. The NMR showed Figure 6 . 1 H NMR (400 MHz, Chloroform-d) δ 6.38 (d, J = 10.8 Hz, 1H), 2.24 (t, J = 2.0 Hz, 6H). The mass spectrometer was used to analyze the compound of formula V. MS: [M+H] + =217.98 / 219.98(1:1). GC chart Figure 7 .Depend on Figure 7 It can be seen that the retention time of the compound of formula V is 11.467 min and the purity is 99.37%.

[0097] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention are within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline, characterized in that: The following steps are involved: Step S1, the compound of formula I reacts with a malonic acid diester under alkaline conditions to generate a compound of formula II; Step S2, the compound of formula II is heated in the presence of a high boiling point polar solvent and a salt hydrate to undergo a decarboxylation reaction to generate a compound of formula III; Step S3, the compound of formula III undergoes a bromination reaction with a brominating agent under acidic conditions to generate a compound of formula IV; Step S4, reducing the nitro group of the compound of formula IV in a solvent to generate a compound of formula V; The specific synthetic route of this synthetic method is as follows:

2. The method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline according to claim 1, characterized in that: R is a C1-C10 hydrocarbon group.

3. The method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline according to claim 1, characterized in that: In step S1, when the diester of malonate is dimethyl malonate, R in the compound of formula II is methyl; when the diester of malonate is diethyl malonate, R in the compound of formula II is ethyl.

4. The method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline according to claim 1, characterized in that: In step S1, the alkaline condition is formed by adding a base, the base is any one of potassium carbonate, sodium carbonate, sodium hydrogen, sodium tert-butoxide or potassium tert-butoxide, the solvent is any one of DMF, DMSO or acetonitrile, and the reaction temperature is 100° C. to 150° C.

5. The method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline according to claim 4, characterized in that: In step S1, the molar ratio of the malonic acid diester to the compound of formula I is 2 to 5:1; the molar ratio of the base to the compound of formula I is 2 to 5:1; and the volume ratio of the reaction solvent to the compound of formula I is 5 to 15:

1.

6. The method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline according to claim 1, characterized in that: In step S2, the salt is any one of lithium chloride, sodium bromide, sodium chloride, sodium cyanide, potassium chloride, magnesium chloride, sodium sulfate or magnesium sulfate, and the hydrate of the salt is magnesium chloride hexahydrate; in step S2, the high boiling point polar solvent is any one of DMF, DMSO, DMAC, NMP or HMPA; in step S2, the reaction temperature is 120°C to 180°C; in step S2, the molar ratio of the hydrate of the salt to the compound of formula II is 3 to 6:1, and the volume ratio of the high boiling point polar solvent to the compound of formula II is 3 to 8:

1.

7. The method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline according to claim 1, characterized in that: In step S3, the acidic condition is formed by adding trifluoroacetic acid or sulfuric acid, the molar ratio of the sulfuric acid to the compound of formula III is 2 to 5:1, and the volume ratio of the trifluoroacetic acid to the compound of formula III is 4 to 6:1; In step S3, the brominating agent is any one of NBS, bromine, dibromohydantoin or tribromopyridinium salt, and the molar ratio of the brominating agent to the compound of formula III is 1.0 to 2.5:1; In step S3, the reaction temperature is 20°C to 150°C.

8. The method for synthesizing 3-bromo-5-fluoro-2,4-dimethylaniline according to claim 1, characterized in that: In step S4, the reducing agent is any one of iron-ammonium chloride, zinc-ammonium chloride, zinc-acetic acid, zinc-hydrazine hydrate-formic acid or iron chloride-activated carbon-hydrazine hydrate, and the molar ratio of hydrazine hydrate to the compound of formula IV is 2 to 5:1; In step S4, the solvent is any one of methanol, ethanol or isopropanol, and the volume ratio of the solvent to the compound of formula IV is 4 to 6:1; In step S4, the reaction is carried out under reflux.

9. An intermediate compound that can be used in the synthesis method according to any one of claims 1 to 8, characterized in that: The structure of the intermediate compound is shown in Formula II: Wherein, R is a C1-10 hydrocarbon group.

10. The intermediate compound according to claim 9, characterized in that R is methyl or ethyl.

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