Synthetic method for preparing fluazinone precursor and similar derivatives thereof

Abstract

The invention discloses a synthesis method for preparing a fluazinone precursor and similar derivatives thereof, and belongs to the technical field of organic chemistry, the synthesis method comprises the following steps: (1) preparing a corresponding substituted ketone compound III from a compound I and different Grignard reagents; (2) carrying out bromination reaction on the compound III to obtain an alpha carbonyl brominated compound IV; (3) hydrolyzing the compound IV to obtain an alpha hydroxy ketone compound V; (4) carrying out methylamination on the compound V to obtain a corresponding fluazinone precursor compound VI; the invention provides the synthesis method of the fluazinone precursor and the derivative thereof, the reaction post-treatment is simple, the purity of a target key intermediate can reach 95% without column purification and liquid phase preparation, and a reliable synthesis method is provided for subsequent research based on fluazinone and the derivative thereof.

Description

Technical Field

[0001] The invention discloses a synthetic method for preparing a fluamine precursor and similar derivatives thereof, belonging to the technical field of organic chemistry, and in particular relates to a synthetic route and method for preparing a fluamine precursor and similar derivatives thereof. Background Art

[0002] Ketamine is a short-acting anesthetic. It was approved for clinical use in 1970. In addition to being used as a short-acting anesthetic, it also has good effects in the treatment of some neuropathic pain, and also has a certain auxiliary effect on postoperative analgesia. However, subsequent studies have found that it has some disadvantages, such as being addictive and dependent on it, and causing certain damage to the human spirit. In order to reduce its addictiveness, it is structurally modified to reduce side effects. The chlorine on the benzene ring is replaced with a fluorine element. Fluamine is used as an anesthetic instead of ketamine. The patent of this invention reports on the synthesis method of fluamine precursor and its similar derivatives.

[0003] At present, the synthetic route of fluramine is reported in Synthetic Communications, 2014, 44 (14): 2021-2028. The synthetic route is shown in the following formula. This synthetic route is based on the synthetic method of ketamine. Different from the synthetic raw material of ketamine, it uses o-fluorobenzonitrile as the starting material. This route has short linear synthesis steps and high total yield. However, the reaction conditions for synthesizing the key precursor 4 require the use of methylamine liquid, and the boiling point of methylamine is -6°C. At the same time, the reaction temperature of this step reported in the literature is -40°C. Another patent WO 2021 / 134086A1 reports that the reaction conditions of this step are also methylamine liquid reaction, and the reaction temperature is -78 to -6°C. Such harsh conditions have led to certain restrictions on large-scale industrial production, so it is particularly important to develop a route that is more conducive to industrial production.

[0004]

[0005] Refer to other synthetic routes for ketamine, Organic letters, 2019, 21(16): 6575-6578. The synthetic route is as follows. It can be seen that compared with the direct synthesis from o-fluorobenzonitrile as the starting material, the linear steps of this synthesis are long, and it requires multiple steps such as coupling, reduction, oxidation, etc., which have high requirements on reaction conditions. At the same time, it is still unknown whether the fluorinated substrate can obtain the corresponding fluramine product according to the following synthetic route. Therefore, this route is not suitable for large-scale industrial synthesis.

[0006]

[0007] In summary, the reaction conditions reported in the existing literature do not have a good synthesis method suitable for large-scale industrial production. Based on this, the inventors provide a synthesis method for synthesizing fluamine precursors and similar derivatives thereof. The method is simple and efficient, and does not require additional liquid phase separation preparation to obtain a target precursor product with a purity of 95%. And this synthesis strategy can complete the synthesis of most fluamine-like derivative precursors, thereby meeting the needs of various studies based on fluamine modified derivatives. Summary of the invention

[0008] The purpose of the present invention is to provide an efficient method for synthesizing a fluamine precursor and similar derivatives thereof. The synthetic method is simple to operate, has a short synthesis step, and has strong substrate applicability. It can synthesize most fluamine-like derivative precursors. The synthetic method is simple to purify, and does not require column purification and liquid phase separation. A purity of 95% can be achieved through simple column purification, which provides great help for the needs of research on fluamine modified derivatives.

[0009] The technical solution adopted by the present invention is as follows:

[0010] 1 To achieve the above object, the present invention provides a method for synthesizing a fluamine precursor and similar derivatives thereof, characterized in that it comprises the following steps:

[0011] (1) Compound I is dissolved in an organic solvent, added to the Grignard reagent corresponding to compound II, and a copper catalyst is added to stir the reaction. After the reaction is completed, a crude product is treated and concentrated by distillation to obtain compound III. The structural formulas of compounds I, II, and III are:

[0012]

[0013] (2) dissolving compound III in an organic solvent, and brominating by adding a brominating agent to obtain compound IV; the structural formula of compound IV is:

[0014]

[0015] (3) dissolving compound IV in an organic solvent, adding a base to carry out a hydrolysis reaction, and obtaining compound V after the reaction. The structural formula of compound V is:

[0016]

[0017] (4) dissolving compound VI in an organic solvent, and reacting compound V with methylamine solution under the protection of an inert gas to obtain compound VI: the structural formula of the compound VI is:

[0018]

[0019] Preferably, the reaction copper catalyst in step (1) is one of cuprous bromide, cuprous chloride, cuprous iodide, and cuprous bromide dimethyl sulfide, the reaction solvent is one of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, and the reaction temperature is 50-70°C.

[0020] Preferably, the bromination reagent in step (2) is one of copper bromide, bromine, hydrobromic acid and hydrogen peroxide system, and the solvent used is one of dichloromethane, dichloroethane, tetrahydrofuran, ethanol, methanol, n-hexane and n-heptane.

[0021] Preferably, the base in step (3) is one of triethylamine, tetrahydropyrrole, diethylamine, dimethylamine, potassium hydroxide, lithium hydroxide, sodium hydroxide, sodium formate, sodium acetate, and ammonia water, and the reaction solvent is one of methanol, ethanol, dioxane and water, tetrahydrofuran and water, methanol and water, and ethanol and water.

[0022] Preferably, the methylamination reagent in step (4) is one of methylamine liquid, methylamine aqueous solution, methylamine methanol solution, methylamine ethanol solution and methylamine tetrahydrofuran solution.

[0023] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0024] The present invention provides a method for synthesizing a fluamine precursor and similar derivatives thereof. The method is simple and efficient to operate, and the product is easy to purify. A product purity of 95% can be obtained without column purification or liquid phase preparation. At the same time, since the reaction conditions are mostly mild, it is suitable for industrial-scale production. Since there has been no literature previously reporting the route for synthesizing a fluamine precursor and similar derivatives thereof, the present invention is the first to propose the use of a key intermediate α-hydroxyketone compound to synthesize a fluamine precursor and similar derivatives thereof, and does not adopt a strategy of synthesizing a traditional α-carbonyl bromide compound, making the process possible for large-scale industrial production. At the same time, the convergent synthesis method greatly broadens the applicability of the substrate, which can almost meet the synthesis of most amine precursors and similar derivatives thereof, and provides a reliable synthesis method for the subsequent synthesis of fluamine and similar derivatives thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The present invention will now be described by way of example with reference to the accompanying drawings, in which:

[0026] Figure 1 is the synthesis route diagram of the present invention;

[0027] Figure 2 It is the 1H-NMR spectrum and mass spectrum of the product in the implementation case of the product of the present invention;

[0028] Figure 3 It is the 1H-NMR spectrum of the product of implementation cases 1 and 2;

[0029] Figure 4 This is the 1H-NMR spectrum of the product of implementation case 3;

[0030] Figure 5 This is the mass spectrum of the product of implementation case 3. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention, and all experimental methods used in the following embodiments are conventional methods unless otherwise specified.

[0032] Example 1

[0033] This embodiment provides a method for synthesizing an amine ketone precursor, the synthetic route is as follows Figure 1 As shown, the specific steps include:

[0034] Preparation of compound III

[0035] 0.5 mol of cyclopentylmagnesium bromide was added to a 2L three-necked flask, and compound I (50.0 g, 413.2 mmol) was dissolved in 400 mL of tetrahydrofuran and added dropwise to the reaction flask. After the addition was complete, copper catalyst was added, the temperature was raised to 55°C, and the reaction was allowed to proceed overnight. After the reaction was complete, n-hexane was added for extraction, and the organic phase was dried and concentrated to obtain 76.1 g of crude compound III with a yield of 95.8%.

[0036] Preparation of Compound IV

[0037] In a 100mL single-mouth bottle, compound III (40.0g, 208.2mmoL) was dissolved in 320mL of tetrahydrofuran, and an ice-water bath was added to cool it down. After cooling, an aqueous solution of hydrobromic acid (38.6mL, 229.0mmoL) was added. After stirring for 5 minutes, hydrogen peroxide (47.2mL, 416.4mmoL) was slowly added dropwise. After the addition was completed, the temperature was raised to 70°C and reacted for 1h. After the reaction was complete, n-hexane was added for extraction, and the mixture was dried and concentrated to obtain compound IV (57.3g) with a crude yield of 102%.

[0038] Preparation of Compound Ⅴ

[0039] Under argon protection, compound IV (10.0 g, 37.04 mmol) was dissolved in 100 mL of methanol in a 100 mL single-mouth bottle. After cooling to 0°C, sodium hydroxide (4.44 g, 111.1 mmol) was added and the reaction was allowed to proceed overnight. After the reaction was complete, aqueous hydrochloric acid was slowly added to quench the reaction while cooling. After adjusting to neutrality, ethyl acetate was added for extraction to obtain compound V (7.7 g) with a yield of 100%.

[0040] Preparation of Compound VI

[0041] Compound V (7.7 g, 37.04 mmol) was dissolved in 20 mL of anhydrous ethanol in a 100 mL single-necked bottle, and methylamine ethanol solution (7.66 g, 74.08 mmol) was added. The reaction was stirred overnight. After the reaction was complete, the organic phase was concentrated and recrystallized from n-hexane to obtain compound VI (6.65 g) with a yield of 80.1%.

[0042] In this example, compound I is used as a raw material, and the target compound VI is obtained through 4 steps of reaction. In addition, in this example, R is o-fluorobenzene, n=3, so the conversion structure of the series of compounds in this example is as follows:

[0043]

[0044] Example 2

[0045] This embodiment provides a method for synthesizing an amine ketone precursor, the synthetic route is as follows Figure 1 As shown, the specific steps include:

[0046] Preparation of compound III

[0047] Add magnesium chips (4.96g, 20.67mmol) to a 1L three-necked flask, add 100mL tetrahydrofuran, replace with nitrogen three times, start stirring and add 1-2 iodine, dissolve cyclopentyl bromide (26.88g, 18.04mmoL) in 100mL tetrahydrofuran, slowly drop it into the reaction flask, the temperature rises rapidly with micro-reflux, react at 60℃ for 3h after the addition is completed, then drop it to 35℃ and add compound I (17.86g, 14.74mmoL) dissolved in 60mL tetrahydrofuran into the reaction flask, add copper catalyst after the addition is complete, heat to 55℃, and react overnight. After the reaction is complete, extract with n-hexane, dry and concentrate the organic phase to obtain 26.33g of crude compound III with a yield of 93.0%.

[0048] Preparation of Compound IV

[0049] In a 100mL single-necked bottle, compound III (26.3g, 13.69mmol) was dissolved in 120mL of dichloromethane. Bromine (22.99g, 14.37mmol) was weighed and dissolved in 100mL of dichloromethane. The mixture was placed in a constant pressure dropping funnel and bromine was added dropwise. A large amount of acid gas was released during the process. After the addition was completed, the reaction was allowed to proceed overnight. After the reaction was complete, the mixture was concentrated by distillation to obtain compound IV (37.3g) with a crude yield of 101%.

[0050] Preparation of Compound Ⅴ

[0051] Under nitrogen protection, compound IV (10.0 g, 37.04 mmol) was dissolved in 100 mL of ethanol in a 100 mL single-mouth bottle. After cooling to 0°C, sodium hydroxide (4.44 g, 111.1 mmol) was added and the reaction was allowed to proceed overnight. After the reaction was complete, aqueous hydrochloric acid was slowly added to quench the reaction while cooling. After adjusting to neutrality, ethyl acetate was added for extraction to obtain compound V (6.8 g) with a yield of 88.3%.

[0052] Preparation of Compound VI

[0053] Compound V (6.8 g, 32.69 mmol) was dissolved in 20 mL of anhydrous ethanol in a 100 mL single-mouth bottle, and methylamine ethanol solution (6.76 g, 65.38 mmol) was added. The reaction was stirred overnight. After the reaction was complete, the organic phase was concentrated and recrystallized from n-hexane to obtain compound VI (5.35 g) with a yield of 74%.

[0054] In this example, compound I is used as a raw material, and the target compound VI is obtained through 4 steps of reaction. In addition, in this example, R is o-fluorobenzene, n=3, so the conversion structure of the series of compounds in this example is as follows:

[0055]

[0056] Example 3

[0057] This embodiment provides a method for synthesizing an amine ketone derivative precursor. The synthetic route is as follows: Figure 1 As shown, the specific steps include:

[0058] Preparation of compound III

[0059] Add magnesium chips (4.96g, 20.67mmol) to a 1L three-necked flask, add 100mL tetrahydrofuran, replace with nitrogen three times, start stirring and add 1-2 iodine, dissolve cyclohexyl bromide (29.22g, 18.04mmoL) in 100mL tetrahydrofuran, slowly drop it into the reaction flask, the temperature rises rapidly with micro-reflux, react at 60℃ for 3h after the addition is completed, then drop it to 35℃ and add compound I (17.86g, 14.74mmoL) dissolved in 60mL tetrahydrofuran into the reaction flask, add copper catalyst after the addition is complete, heat to 55℃, and react overnight. After the reaction is complete, extract with n-hexane, dry and concentrate the organic phase to obtain 27.02g of crude compound III with a yield of 89.0%.

[0060] Preparation of Compound IV

[0061] In a 100mL single-necked bottle, compound III (27.02g, 13.12mmol) was dissolved in 120mL of dichloromethane. Bromine (22.04g, 13.78mmol) was weighed and dissolved in 100mL of dichloromethane. The mixture was placed in a constant pressure dropping funnel and bromine was added dropwise. A large amount of acid gas was released during the process. After the addition was completed, the reaction was allowed to proceed overnight. After the reaction was complete, the mixture was concentrated by distillation to obtain compound IV (36.51g) with a yield of 98%.

[0062] Preparation of Compound Ⅴ

[0063] Under nitrogen protection, compound IV (10.0 g, 35.21 mmol) was dissolved in 100 mL of ethanol in a 100 mL single-mouth bottle. After cooling to 0°C, sodium hydroxide (4.23 g, 105.63 mmol) was added and the reaction was allowed to proceed overnight. After the reaction was complete, aqueous hydrochloric acid was slowly added to quench the reaction while cooling. After adjusting to neutrality, ethyl acetate was added for extraction to obtain compound V (5.86 g) with a yield of 75.0%.

[0064] Preparation of Compound VI

[0065] Compound V (5.86 g, 26.40 mmol) was dissolved in 20 mL of anhydrous ethanol in a 100 mL single-necked bottle, and methylamine ethanol solution (5.46 g, 52.80 mmol) was added. The reaction was stirred overnight. After the reaction was complete, the organic phase was concentrated and recrystallized from n-hexane to obtain compound VI (5.37 g) with a yield of 86.1%.

[0066] In this example, compound I is used as a raw material, and the target compound VI is obtained through 4 steps of reaction. In addition, in this example, R is o-fluorobenzene, n=4, so the conversion structure of the series of compounds in this example is as follows:

[0067]

[0068] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. These modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and specification of the present invention.

Claims

1. A method for synthesizing a fluamine precursor and similar derivatives thereof, characterized in that: The following steps are involved: (1) Compound I is dissolved in an organic solvent, added to the Grignard reagent corresponding to compound II, and a copper catalyst is added to stir the reaction. After the reaction is completed, a crude product is treated to obtain compound III. The structural formulas of compounds I, II, and III are: (2) dissolving compound III in an organic solvent, adding a bromination reagent to obtain compound IV; the structural formula of compound IV is: (3) dissolving compound IV in an organic solvent, adding a base to carry out a hydrolysis reaction, and obtaining compound V after the reaction. The structural formula of compound V is: (4) dissolving compound VI in an organic solvent, and reacting compound V with methylamine solution under the protection of an inert gas to obtain compound VI: the structural formula of the compound VI is:

2. The method for synthesizing the fluamine precursor and its similar derivatives according to claim 1, characterized in that: The R is one of the following structures:

3. The method for synthesizing the fluamine precursor and its similar derivatives according to claim 1, characterized in that: When n in the structural formula is 1, 3, or 4, the corresponding structure is as follows:

4. The method for synthesizing the fluamine precursor and its similar derivatives according to claim 1, characterized in that: The copper catalyst in step (1) is one of cuprous bromide, cuprous chloride, cuprous iodide, and cuprous bromide dimethyl sulfide, and the reaction solvent used is one of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

5. The method for synthesizing the fluamine precursor and its similar derivatives according to claim 1, characterized in that: The bromination reagent in step (2) is one of copper bromide, bromine, hydrobromic acid and hydrogen peroxide system, and the solvent used is one of dichloromethane, dichloroethane, tetrahydrofuran, ethanol, methanol, n-hexane and n-heptane.

6. The method for synthesizing the fluamine precursor and its similar derivatives according to claim 1, characterized in that: The base in step (3) is one of triethylamine, tetrahydropyrrole, diethylamine, dimethylamine, potassium hydroxide, lithium hydroxide, sodium hydroxide, sodium formate, sodium acetate, and ammonia water; and the reaction solvent is one of methanol, ethanol, dioxane and water, tetrahydrofuran and water, methanol and water, and ethanol and water.

7. The method for synthesizing the fluamine precursor and its similar derivatives according to claim 1, characterized in that: In the step (4), the methylamination reagent is one of methylamine liquid, methylamine aqueous solution, methylamine methanol solution, methylamine ethanol solution, and methylamine tetrahydrofuran solution.

Images