A process for the synthesis of racemic 2,6-dimethyl-2,3-dihydro-1h-inden-1-amine

Abstract

The present application relates to the technical field of drug synthesis, and in particular to a synthesis method of racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine, which introduces amino through a conjugate addition reaction and a nucleophilic substitution reaction under the catalysis of cuprous iodide and other copper reagents by using N-acetyl-N-1-propenylacetamide and 2-fluoro-1,4-dimethylbenzene, and then hydrolyzes under alkaline conditions to obtain the racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine conveniently; the present application provides a more efficient, safe and economic solution for related synthesis reactions, has a wide application prospect, provides a new idea and method for the synthesis of such compounds, and improves the synthesis efficiency and quality of drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine. Background Technology

[0002] Racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is an important intermediate used in the synthesis of active ingredients for fine chemicals and agrochemicals. Currently reported synthetic methods mainly involve the conversion of 2,6-dimethylindene to racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine. The synthesis of 2,6-dimethylindene is complex and requires large amounts of Lewis acids such as aluminum trichloride for cyclization. The conversion from 2,6-dimethylindene to racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine requires reductive ammoniation or hydrogenation reduction, which necessitates the use of hazardous, flammable, and explosive chemicals such as palladium on carbon or sodium borohydride as catalysts. Furthermore, this synthetic method involves a long route, cumbersome steps, high cost, and low yield. Therefore, developing a new process that is low-cost, has a short route, high yield, and simple operation is urgently needed.

[0003] In view of the above-mentioned defects, the inventors of this invention have finally obtained this invention after a long period of research and practice. Summary of the Invention

[0004] The purpose of this invention is to solve the problems of long, complicated, costly and low-yield synthetic methods for racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine, and to provide a synthetic method for racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine.

[0005] To achieve the above objectives, this invention discloses a method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine, comprising the following steps:

[0006] S1, after stirring the solvent, 2-fluoro-1,4-dimethylbenzene, alkaline substance and catalyst at room temperature for 30 min, add N-acetyl-N-1-propenylacetamide, stir and heat to 60-65℃, keep the temperature for 8 h, after the reaction is complete, extract and separate to obtain intermediate I.

[0007] S2, the solvent, water, intermediate I, and alkaline substance are mixed and heated to 75-85℃ while stirring. The mixture is kept at this temperature for 8-10 hours. After the reaction is completed, the temperature is lowered to 20-25℃ and extracted to obtain racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine.

[0008] In step S1, the solvent is any one or a combination of tetrahydrofuran, N,N-dimethylformamide (DMF), N-methylpyrrolidone, acetonitrile, and 2-methyltetrahydrofuran.

[0009] In step S1, the catalyst is any one or a combination of cuprous iodide, cuprous bromide, cuprous chloride, cuprous chloride, copper iodide, and copper bromide.

[0010] In step S1, the specific process of extracting and separating intermediate I is as follows: After the reaction is complete, the temperature is lowered to room temperature, the reaction solution is concentrated, ethyl acetate and water are added for extraction and separation, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are washed once with saturated brine, the organic phase is dried with anhydrous sodium sulfate and then concentrated to obtain intermediate I.

[0011] In step S2, the solvent is any one or a combination of tetrahydrofuran, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran, and dimethyl sulfoxide (DMSO).

[0012] In step S2, the alkaline substance is any one or more combinations of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

[0013] In step S2, the specific process of extracting and separating racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is as follows: After the reaction is complete, the temperature is lowered to 20-25℃, most of the solvent is removed under reduced pressure, ethyl acetate is added, and water is used for extraction and separation. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed once with saturated brine. After separation, the organic phase is dried with anhydrous sodium sulfate and concentrated to obtain the crude product. Then, the crude product is added to isopropanol, and hydrochloric acid is added dropwise. After the addition is complete, the temperature is raised to reflux and kept at that temperature for 1 hour. The temperature is then lowered to room temperature and filtered to obtain racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine hydrochloride. Then, after freeing and evaporating under reduced pressure, racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is obtained.

[0014] Reaction mechanism of intermediate I:

[0015] 1. Cuprous iodide complexation and deprotonation of methyl α-H (initiation step):

[0016] Cuprous iodide (CuI) first complexes with the diacetylimine allyl compound in the substrate. Through the coordination of Cu(I) with the olefin double bond, imine nitrogen and carbonyl group, it activates the β-carbon of the olefin, making it more susceptible to nucleophilic attack.

[0017] A base (such as sodium tert-butoxide) removes the α-H from the ortho-methyl group of the fluorine atom in 2-fluoro-1,4-dimethylbenzene (the electron-withdrawing effect of fluorine enhances the acidity of the CH bond of the methyl group), generating a benzyl carbanion intermediate.

[0018] 2. Conjugate-like addition (nucleophilic addition step):

[0019] The benzyl carbanion acts as a nucleophile, performing a conjugated addition to the double bond of the olefin activated by CuI complexation, attacking the β-carbon of the olefin to generate an alkyl carbanion intermediate. At this point, the double bond of the olefin is converted into a single bond, and the diacetyl group on the imine nitrogen remains in a complexed state, completing the carbon chain extension.

[0020] 3. Nucleophilic fluorine substitution of aromatic rings (ring-closing step):

[0021] The alkyl carbanion generated by the addition reaction undergoes an intramolecular nucleophilic attack on the fluorinated carbon of 2-fluoro-1,4-dimethylbenzene. The fluorine atom acts as a leaving group (the CF bond on the aromatic ring is easily attacked by nucleophiles due to the electron-withdrawing effect of fluorine, and the complexation of CuI with the fluorine atom assists the leaving reaction), resulting in an aromatic ring nucleophilic substitution reaction (SNAr) to generate a dihydroindene ring skeleton.

[0022] 4. Catalyst complexation cycle:

[0023] In the reaction, CuI continuously complexes with the olefin double bond, imine nitrogen, carbonyl group and fluorine atom of the substrate, thereby reducing the activation energy of the reaction. After the reaction is completed, it dissociates in the form of CuI and can participate in complexation catalysis again to achieve recycling.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] 1. This invention utilizes N-acetyl-N-1-propenylacetamide and 2-fluoro-1,4-dimethylbenzene under the catalysis of copper reagents such as cuprous iodide to cleverly introduce an amino group through a conjugate-like addition reaction and a nucleophilic substitution reaction. Subsequently, hydrolysis under alkaline conditions readily yields racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine.

[0026] 2. This invention innovatively utilizes a conjugate-like addition reaction and an intramolecular nucleophilic substitution reaction to achieve one-step tandem ring closure under the catalysis of copper reagents such as cuprous iodide. This high degree of selectivity and directionality is difficult to achieve in traditional synthesis methods, and greatly improves the atom utilization rate.

[0027] 3. Through its unique design and ingenious reaction strategy, this invention significantly shortens the reaction route compared to existing technologies. It is low-cost, simple to operate, and has mild reaction conditions, making it more suitable for industrial scale-up. It avoids the use of dangerous reagents such as palladium on carbon and sodium borohydride, greatly shortens the reaction route, and significantly improves the efficiency and yield of the reaction.

[0028] 4. This invention provides a more efficient, safe, and economical solution for related synthetic reactions, with broad application prospects. It offers new ideas and methods for the synthesis of such compounds, improving the efficiency and quality of drug synthesis. Attached Figure Description

[0029] Figure 1 The NMR spectrum of racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine;

[0030] Figure 2 The liquid phase spectrum of racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine (the two main peaks in the spectrum are the product peaks, representing the cis and trans products of the product, respectively). Detailed Implementation

[0031] The above-mentioned and other technical features and advantages of the present invention will be described in more detail below with reference to the accompanying drawings.

[0032] All raw materials and reagents used in this invention were commercially available or prepared experimentally. N-acetyl-N-1-propenylacetamide (CAS: 65693-80-3) and 2-fluoro-1,4-dimethylbenzene (CAS: 696-01-5) were custom-made by Anhui Leyong Biotechnology Co., Ltd., and the remaining reagents and equipment were purchased from Sigma.

[0033] Example 1

[0034] The synthesis route in this embodiment is as follows:

[0035]

[0036] (1) Synthesis of intermediate I:

[0037] In a 500 mL three-necked flask, add 100 mL of tetrahydrofuran, 12.42 g (0.1 mol) of 2-fluoro-1,4-dimethylbenzene, 11.53 g (0.12 mol) of sodium tert-butoxide, and 1.9 g (0.01 mol) of cuprous iodide. After stirring at room temperature for 30 min, add 15.53 g (0.11 mol) of N-acetyl-N-1-propenylacetamide. After the addition is complete, stir and heat to 65 °C, and maintain the reaction temperature for 8 h. The 2-fluoro-1,4-dimethylbenzene raw material was almost completely eliminated during sampling. After cooling to room temperature, the reaction solution was concentrated, and 500 mL of ethyl acetate and 300 mL of water were added for extraction and separation. The aqueous phase was extracted twice with 100 mL of ethyl acetate (100 mL x 2). The combined organic phases were washed once with 300 mL of saturated saline solution. After separation, the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain intermediate I 22.32 g, with a yield of 91% and an HPLC purity of 98.1%.

[0038] (2) Synthesis of racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine:

[0039] Add 30 mL of tetrahydrofuran, 100 mL of water, intermediate I (22.32 g, 0.091 mol), and sodium hydroxide (21.84 g, 0.546 mol) to a three-necked flask. Heat to 80 °C with stirring and maintain the reaction temperature for 8-10 hours. When intermediate I has largely disappeared, stop the reaction and cool to 20 °C. Remove most of the solvent by evaporation under reduced pressure. Add 500 mL of ethyl acetate and 300 mL of water to extract and separate the layers. Extract the aqueous phase twice with 100 mL of ethyl acetate (100 mL x 2). Combine the organic phases and wash once with 300 mL of saturated saline solution. After separation, add anhydrous sodium sulfate to the organic phase. After drying and concentration, 14.38 g of crude product was obtained. This crude product was then added to 120 mL of isopropanol, followed by dropwise addition of 15 g of hydrochloric acid. After the addition was complete, the mixture was heated to reflux and maintained at this temperature for 1 hour. The mixture was then cooled to room temperature and filtered to obtain 17 g of racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine hydrochloride. This was then purified by free radical scavenging and vacuum distillation to obtain 13.6 g of racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine, with a yield of 93%. The two main peaks in the HPLC (high performance liquid chromatography) chromatogram were both product peaks, representing the cis and trans forms of the product, respectively. The HPLC purity was 99.94%. Figure 2 As shown. The NMR spectrum is as follows. Figure 1 As shown, 1 H NMR (300 MHz, Chloroform-d) δ 7.16(dt, J = 7.8, 0.9 Hz, 1H), 7.13 – 7.09 (m, 1H), 7.01 – 6.95 (m, 1H), 4.11(ddd, J = 5.5, 2.1, 1.1 Hz, 1H), 2.94 (ddd, J = 14.6, 5.2, 0.7 Hz, 1H), 2.69 (ddd, J = 14.8, 5.3, 0.9 Hz, 1H), 2.33 (s, 3H), 2.26 (dt, J = 10.9, 5.4 Hz, 1H), 0.96 (dd, J = 5.7, 1.5 Hz, 3H).

[0040] Example 2

[0041] The difference between this embodiment and Example 1 is that the solvent tetrahydrofuran in the synthesis of intermediate I is replaced with DMF (N,N-dimethylformamide), while other process conditions are the same. The yield of intermediate I is 90.2%, and the HPLC purity is 97.5%.

[0042] Example 3

[0043] In this embodiment, different bases were used to synthesize intermediate I. The reaction conditions and results are shown in Table 1 below:

[0044] Table 1 Effect of different bases on the reaction

[0045]

[0046] As shown in Table 1, when sodium tert-butoxide or potassium tert-butoxide is used as the base, the yield of intermediate I is relatively high. When the base is reduced, the yield of intermediate I decreases significantly, and the lower the base, the lower the yield of intermediate I.

[0047] Example 4

[0048] In this embodiment, intermediate I was synthesized using different equivalents of tert-butanol. The reaction conditions and results are shown in Table 2 below.

[0049] Table 2 Effect of different equivalents of sodium tert-butoxide on the reaction

[0050]

[0051] As shown in Table 2, the yield is highest when the sodium tert-butoxide equivalent is 1.2. When the alkali equivalent decreases or increases, the yield of intermediate I decreases, and the lower the equivalent, the lower the yield of intermediate I.

[0052] Example 5

[0053] In this embodiment, different copper catalysts were used to synthesize intermediate I. The reaction conditions and results are shown in Table 3 below.

[0054] Table 3 Effect of different copper catalysts on the reaction

[0055]

[0056] Table 3 shows that the yield of intermediate I is highest (91%) when cuprous iodide is used as the catalyst. The yield of intermediate I decreases significantly when cuprous bromide, cuprous chloride, or cuprous bromide are used as catalysts, with the lowest yield observed when cuprous chloride or cuprous bromide is used. However, the yield of intermediate I is significantly improved when cuprous bromide or cuprous chloride is used in combination with potassium iodide.

[0057] The good direct reaction efficiency of cuprous iodide is due to the large radius of the iodide ion, which facilitates the deformation of its outer electron cloud and results in high polarizability. This characteristic gives the copper-iodine bond in cuprous iodide a certain degree of covalentity, while the iodide ion exhibits strong nucleophilicity. In the reaction, it rapidly forms a transition state with the substrate, thereby promoting the reaction. The copper ion in cuprous iodide can act as a catalytic active center, coordinating with reactant molecules, activating chemical bonds in the reactant molecules, and lowering the activation energy of the reaction.

[0058] Cuprous bromide exhibits low catalytic yields. Due to differences in ionic properties, the bromide ion has a smaller radius than the iodide ion, relatively lower polarizability, and is less nucleophilic. Therefore, the copper-bromine bond in cuprous bromide has relatively weak reactivity, and the bromide ion's ability to attack reactant molecules is limited, resulting in a slow reaction rate. Although the copper ion in cuprous bromide can also serve as a catalytic active center, the presence of the bromide ion may affect the coordination environment and electron cloud distribution of the copper ion, making its activation effect on reactant molecules less pronounced than in cuprous iodide, thus affecting the reaction's progress.

[0059] The synergistic reaction between cuprous bromide and potassium iodide is favorable because the addition of potassium iodide introduces iodide ions into the solution. These iodide ions can undergo a halide exchange reaction with cuprous bromide to form cuprous iodide. Since cuprous iodide exhibits superior reactivity, it accelerates the reaction.

[0060] Furthermore, even if halide ion exchange does not occur completely, iodide ions and cuprous bromide may still have a synergistic effect. The high nucleophilicity of iodide ions can assist the copper ions in cuprous bromide in activating reactant molecules, accelerating the formation and transformation of reaction intermediates, and increasing the reaction rate.

[0061] The slow reaction of cuprous chloride is due to the influence of its ionic properties. Chloride ions have a smaller radius, lower polarizability, and significantly weaker nucleophilicity than iodide and bromide ions. The copper-chlorine bond in cuprous chloride is relatively stable, making it difficult for chloride ions to launch an effective attack on reactant molecules, thus hindering the rapid initiation of the reaction. Chloride ions significantly affect the electron cloud distribution of copper ions, preventing the catalytic activity of copper ions from being fully realized. In the reaction, the coordination between copper ions and reactant molecules is limited, failing to effectively lower the activation energy of the reaction, thereby resulting in a slow reaction rate.

[0062] The combined addition of cuprous chloride and potassium iodide is still not ideal because, although the addition of potassium iodide may lead to halide ion exchange, the copper-chlorine bond in cuprous chloride is relatively stable, resulting in a limited extent of halide ion exchange and making it difficult to generate a large quantity of highly reactive cuprous iodide. Therefore, even if a small amount of cuprous iodide is generated, the abundant chloride ions in the reaction system may interfere with the reaction. Chloride ions may react with reaction intermediates or other reactants, or affect the reaction equilibrium, hindering the reaction from proceeding towards the formation of the target product, thus leading to poor reaction results.

[0063] Example 6

[0064] In this embodiment, intermediate I was synthesized using different equivalents of cuprous iodide. The reaction conditions and results are shown in Table 4 below.

[0065] Table 4 Effect of different equivalents of cuprous iodide on the reaction

[0066]

[0067] Table 4 shows that the yield of intermediate I is relatively high when the cuprous iodide equivalent is 0.01 and 0.03. However, when the cuprous iodide equivalent is 0.03, a large amount of brown viscous substance appears in the reaction system, making the post-processing more complicated. As the cuprous iodide equivalent decreases, the yield decreases significantly, and the reaction does not occur without the addition of cuprous iodide. During the reaction, CuI lowers the activation energy through continuous complexation with the alkene double bond, imine nitrogen, carbonyl group, and fluorine atom of the substrate, making the reaction easier to occur.

[0068] Example 7

[0069] In this embodiment, intermediate I was synthesized using different reaction temperatures. The reaction conditions and results are shown in Table 5 below.

[0070] Table 5. Effect of different reaction temperatures on the reaction

[0071]

[0072] As shown in Table 5, the yield of intermediate I was the highest when the reaction temperature was 65℃. As the temperature decreased, the yield of intermediate I decreased significantly.

[0073] Example 8

[0074] The difference between this embodiment and Example 1 is that the solvent tetrahydrofuran in the synthesis of racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is replaced with methanol. Other process conditions are the same as in Example 1. The yield of racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is 89%, and the HPLC purity is 99.25%.

[0075] Example 9

[0076] The difference between this embodiment and Example 1 is that sodium hydroxide, the basic substance in the synthesis of racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine, is replaced with potassium hydroxide. Other process conditions are the same as in Example 1. The yield of racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is 91%, and the HPLC purity is 99.34%.

[0077] The above description is merely a preferred embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalents can be made within the spirit and scope defined by the claims of the present invention, all of which will fall within the protection scope of the present invention.

Claims

1. A method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine, characterized in that, Includes the following steps: S1, after stirring the solvent, 2-fluoro-1,4-dimethylbenzene, alkaline substance and catalyst at room temperature for 30 min, add N-acetyl-N-1-propenylacetamide, stir and heat to 60-65℃, keep the temperature for 8 h, after the reaction is complete, extract and separate to obtain intermediate I. S2, the solvent, water, intermediate I and alkaline substance are mixed and heated to 75-85℃ while stirring. The reaction is maintained at this temperature for 8-10 hours. After the reaction is completed, the temperature is lowered to 20-25℃ and extracted to obtain racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine. In step S1, the alkaline substance is sodium tert-butoxide or potassium tert-butoxide; the catalyst is cuprous iodide or cuprous bromide + potassium iodide.

2. The method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine as described in claim 1, characterized in that, In step S1, the solvent is any one or a combination of tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, and 2-methyltetrahydrofuran.

3. The method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine as described in claim 1, characterized in that, In step S1, the specific process of extracting and separating intermediate I is as follows: After the reaction is complete, the temperature is lowered to room temperature, the reaction solution is concentrated, ethyl acetate and water are added for extraction and separation, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are washed once with saturated brine, the organic phase is dried with anhydrous sodium sulfate and then concentrated to obtain intermediate I.

4. The method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine as described in claim 1, characterized in that, In step S2, the solvent is any one or a combination of tetrahydrofuran, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran, and dimethyl sulfoxide.

5. The method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine as described in claim 1, characterized in that, In step S2, the alkaline substance is any one or more combinations of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

6. The method for synthesizing racemic 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine as described in claim 1, characterized in that, In step S2, the specific process for extracting and separating racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is as follows: After the reaction is complete, the temperature is lowered to 20-25℃, the solvent is removed under reduced pressure, ethyl acetate is added, and water is used for extraction and separation. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed once with saturated brine. After separation, the organic phase is dried with anhydrous sodium sulfate and concentrated to obtain the crude product. Then, the crude product is added to isopropanol, and hydrochloric acid is added dropwise. After the addition is complete, the temperature is raised to reflux and kept at that temperature for 1 hour. The temperature is then lowered to room temperature and filtered to obtain racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine hydrochloride. Then, after freeing and evaporating under reduced pressure, racemic 2,6-dimethyl-2,3-dihydro-1H-indene-1-amine is obtained.

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