Synthetic method of agomelatine

Abstract

The invention provides a synthesis method of agomelatine, which comprises the following step: in an inert atmosphere, reacting a compound shown as a formula (a), halogenated olefin shown as a formula (b), acetamide, a rhodium catalyst and alkali to obtain agomelatine. According to the method, the compound shown in the formula (a), halogenated olefin shown in the formula (b) and acetamide are used as raw materials and react in the inert atmosphere under the action of the rhodium catalyst and the alkali, the agomelatine can be prepared in one step, the synthesis steps and time are greatly shortened, the reaction raw materials are simple and easy to obtain, the feeding mode is simple, and the purity is high.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing agomelatine. Background Art

[0002] Agomelatine, whose chemical name is N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide and whose structural formula is shown in Formula I, is a new type of antidepressant drug mainly used to treat adult depression.

[0003] Formula I.

[0004] European patent EP0447285 reports that 7-methoxy-1-naphthyl ketone is used as the starting material, and 7-methoxy-1-naphthyl acetonitrile is obtained through condensation with ethyl bromoacetate, aromatization, ester hydrolysis, chlorination, amination, and dehydration, and then agomelatine is obtained through cyano reduction and acetylation. The synthetic route is as follows:

[0005]

[0006] This route has complicated reaction steps, is time-consuming and has low production efficiency. Summary of the invention

[0007] In view of this, the purpose of the present application is to provide a method for synthesizing agomelatine. The agomelatine provided in the present application can be prepared in one step, which greatly shortens the synthesis steps and time, saves costs, and improves production efficiency.

[0008] The present application provides a method for synthesizing agomelatine, comprising the following steps:

[0009] Under an inert atmosphere, the compound represented by formula (a), the halogenated olefin represented by formula (b), acetamide, a rhodium catalyst and a base react under an inert atmosphere to obtain agomelatine;

[0010] Formula (a);

[0011] Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to the naphthyl group;

[0012] Formula (b);

[0013] Wherein, X is a halogen.

[0014] The present application uses the compound represented by formula (a), the halogenated olefin represented by formula (b) and acetamide as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and agomelatine can be prepared in one step, which greatly shortens the synthesis steps and time, and has a higher yield and higher purity.

[0015] This application uses the compound represented by formula (a) as the raw material:

[0016] Formula (a);

[0017] Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to the naphthyl group, for example, it can be a boronic acid residue that has lost at least one hydroxyl group, a boric acid ester residue that has lost at least one hydroxyl group, or a borate residue that has lost at least one hydroxyl group, and optionally, the boric acid ester or borate can be substituted by a halogen. In the present application, the M group is used as a leaving group, and as long as the B atom is connected to the naphthyl group, it can be removed under the action of a catalyst and a base, so that the phenyl group reacts with the double bond of the halogenated olefin shown in formula (b). Therefore, the present application has no special restrictions on the boron-containing group.

[0018] In some specific implementations, the compound represented by formula (a) includes but is not limited to one or more of (7-methoxynaphthalene-1-yl)boric acid, (7-methoxynaphthalene-1-yl)potassium trifluoroborate (I), 2-(7-methoxynaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-(7-methoxynaphthalene-1-yl)-1,3,2-dioxaborolane, preferably (7-methoxynaphthalene-1-yl)boric acid and 2-(7-methoxynaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0019] This application uses the halogenated olefin represented by formula (b) as a raw material:

[0020] Formula (b);

[0021] Wherein, X is a halogen, preferably bromine. The present application has no special restrictions on the halogenated olefin represented by the formula (b), and it can be purchased on the market.

[0022] This application uses acetamide as raw material, and its structural formula is as follows:

[0023] .

[0024] In the preparation method provided by the present application, the solvent used in the reaction includes but is not limited to the solvent selected from water, deuterated water, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, ethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform, deuterated chloroform, tetrahydrofuran and one or more of 1,4-dioxane, preferably p-xylene, tetrahydrofuran, 1,4-dioxane or dimethyl sulfoxide.

[0025] The present application uses a rhodium-containing compound as a catalyst. In some specific implementations, the rhodium catalyst includes but is not limited to acetylacetonate bis(ethylene) rhodium (I), dicarbonyl acetylacetonate rhodium (I), (1,5-cyclooctadiene) chlororhodium (I) dimer, bis(1,5-cyclooctadiene)-trifluoromethanesulfonate rhodium, bis(1,5-cyclooctadiene) tetrafluoroborate rhodium, tri(triphenylphosphine) rhodium bromide (I), bis[(1,5-cyclooctadiene)(methoxy)rhodium], (1,5-cyclooctadiene) 2,4-pentanedione rhodium (I), chlorobis(ethylene) rhodium (I) dimer, dipolymerized hydroxy(1,5-cyclooctadiene) rhodium (I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane (1,5-cyclooctadiene) tetrafluoroborate rhodium (I), carbonyl bis(triphenylphosphino) rhodium chloride (I) , bis(1,5-cyclooctadiene)rhodium(I) hexafluoride antimony salt, tri(triphenylphosphine)carbonyl rhodium(I) hydride, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate or more, preferably bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, chlorobis(ethylene)rhodium(I) dimer, acetylacetonatobis(ethylene)rhodium(I) or tri(triphenylphosphine)rhodium(I) bromide.

[0026] The preparation method provided in the present application also includes a base, and the base includes but is not limited to lithium trimethylsilanolate, sodium trimethylsilanolate, potassium trimethylsilanolate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, lithium methoxide, potassium methoxide, sodium methoxide, lithium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium thiosulfate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium sulfate, potassium dihydrogen phosphate, potassium sulfate, potassium trihydrogen phosphate, calcium hydrogen phosphate, potassium tetrahydrogen phosphate, calcium tetrahydrogen phosphate, calcium dihydrogen phosphate, sodium phosphate, sodium trihydrogen phosphate, sodium dihydrogen phosphate, sodium tetrahydrogen phosphate, magnesium dihydrogen phosphate, magnesium phosphate, magnesium trihydrogen phosphate, aluminum dihydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum trihydrogen phosphate, copper phosphate, aluminum tetrahydrogen phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate and copper tetrahydrogen phosphate, preferably sodium carbonate, lithium tert-butoxide or cesium carbonate.

[0027] In the present application, the molar ratio of the compound represented by formula (a), the halogenated olefin represented by formula (b), and acetamide is 0.2~1:0.5~3:1~3, preferably 0.5~0.8:1~2.5:1.5~2.5. In some specific implementations, the molar ratio of the compound represented by formula (a), the base, and the rhodium catalyst is 1~3:1~3:0.01~1, preferably 1.5~2.5:1.5~2.5:0.05~0.8. In some specific implementations, the molar volume ratio of the compound represented by formula (a) and the reaction medium is 0.2mmol~1mmol:0.5mL~10mL, preferably 0.3mmol:2mL~6mL.

[0028] In the present application, the compound represented by formula (a), the halogenated olefin represented by formula (b), acetamide, a rhodium catalyst and a base are uniformly mixed in a reaction medium and reacted to obtain agomelatine. In some specific implementations, the reaction temperature is 0°C to 200°C, preferably 40°C to 150°C, more preferably 60°C to 120°C, more preferably 70°C to 100°C; the reaction time is 1h to 36h, preferably 5h to 30h, more preferably 6h to 24h. In some specific implementations, the reaction is preferably carried out in an oil bath.

[0029] After the reaction is completed, the reaction medium, ie, the solvent, is removed, and the obtained residue is eluted by silica gel column chromatography to obtain agomelatine.

[0030] The present application uses the compound represented by formula (a), the halogenated olefin represented by formula (b) and acetamide as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and agomelatine can be prepared in one step, which greatly shortens the synthesis steps and time. The reaction raw materials are simple and easy to obtain, the feeding method is simple, and the purity is relatively high. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the hydrogen spectrum of agomelatine provided in Example 1 of the present application;

[0032] Figure 2 This is the carbon spectrum of agomelatine provided in Example 1 of the present application. DETAILED DESCRIPTION

[0033] It should be understood that the expression "one or more of..." includes each of the items recited after the expression individually and in various different combinations of two or more of the recited items, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited items should be understood to have the same meaning, unless otherwise understood from the context.

[0034] The use of the terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, for example not excluding other unrecited elements or steps, unless otherwise specifically stated or otherwise understood from the context.

[0035] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0036] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0037] In addition, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0038] The present application provides a method for synthesizing agomelatine, comprising the following steps:

[0039] Under an inert atmosphere, the compound represented by formula (a), the halogenated olefin represented by formula (b), acetamide, a rhodium catalyst and a base react under an inert atmosphere to obtain agomelatine;

[0040] Formula (a);

[0041] Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to the naphthyl group;

[0042] Formula (b);

[0043] Wherein, X is a halogen.

[0044] The present application uses the compound represented by formula (a), the halogenated olefin represented by formula (b) and acetamide as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and can prepare agomelatine in one step, which greatly shortens the synthesis steps and time. The reaction raw materials are simple and easy to obtain, the feeding method is simple, and the yield and purity are high.

[0045] The synthesis method of agomelatine provided in the present application is further described below in conjunction with examples.

[0046] Example 1

[0047] Under the protection of an inert atmosphere, 0.3 mmol of (7-methoxynaphthalen-1-yl)boric acid, 1 mmol of vinyl bromide, 1.1 mmol of acetamide, 0.03 mmol of tris(triphenylphosphine)rhodium bromide (I) and 1.5 mmol of sodium carbonate were mixed, and 6 mL of p-xylene was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain agomelatine with a purity of 95% and a yield of 56%.

[0048] Example 2

[0049] Under the protection of an inert atmosphere, 0.3 mmol of (7-methoxynaphthalen-1-yl)boronic acid, 1 mmol of vinyl bromide, 1.1 mmol of acetamide, 0.03 mmol of acetylacetonatobis(vinyl)rhodium(I) and 1.5 mmol of cesium carbonate were mixed, 6 mL of toluene was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain agomelatine with a purity of 93% and a yield of 48%.

[0050] Example 3

[0051] Under the protection of inert atmosphere, 0.3 mmol of 2-(7-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 1 mmol of vinyl bromide, 1.1 mmol of acetamide, 0.03 mmol of di-hydroxy(1,5-cyclooctadiene)rhodium(I) and 1.5 mmol of sodium phosphate were mixed, and 6 mL of n-hexane was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain agomelatine with a purity of 94% and a yield of 52%.

[0052] Example 4

[0053] Under the protection of an inert atmosphere, 0.3 mmol of potassium (7-methoxynaphthalen-1-yl) trifluoroborate (I), 1 mmol of vinyl bromide, 1.1 mmol of acetamide, 0.03 mmol of bis(1,5-cyclooctadiene) tetrafluoroborate rhodium and 1.5 mmol of sodium carbonate were mixed, and 6 mL of dioxane was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain agomelatine with a purity of 94% and a yield of 38%.

[0054] The product prepared in Example 1 was subjected to NMR analysis, and the results are shown in Figure 1 and Figure 2 , Figure 1 This is the hydrogen spectrum of agomelatine provided in Example 1 of the present application, Figure 2 This is the carbon spectrum of agomelatine provided in Example 1 of the present application. Its nuclear magnetic resonance data are as follows:

[0055] 1 H NMR (500 MHz, Chloroform-d) δ 7.76 (d, J = 8.95 Hz, 1H), 7.68 (dd,J = 6.89, 2.49 Hz, 1H), 7.47 (d, J = 2.45 Hz, 1H), 7.31 – 7.24 (m, 2H), 7.17(dd, J = 8.95, 2.45 Hz, 1H), 5.60 (s, 1H), 3.99 (s, 3H), 3.62 (q, J = 6.66Hz, 2H), 3.25 (t, J = 7.23 Hz, 2H), 1.96 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 170.3, 158.0, 133.6, 133.2, 130.3, 129.3, 127.1, 127.1,123.2, 118.4, 102.4, 55.6, 40.1, 33.3, 23.5.

[0056] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing agomelatine, comprising the following steps: Under an inert atmosphere, the compound represented by formula (a), the halogenated olefin represented by formula (b), acetamide, a rhodium catalyst and a base react under an inert atmosphere to obtain agomelatine; Formula (a); Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to the naphthyl group; Formula (b); Wherein, X is a halogen.

2. The preparation method according to claim 1, characterized in that: The rhodium catalyst is selected from acetylacetonate bis(ethylene) rhodium (I), dicarbonyl acetylacetonate rhodium (I), (1,5-cyclooctadiene) chlororhodium (I) dimer, bis(1,5-cyclooctadiene)-trifluoromethanesulfonate rhodium, bis(1,5-cyclooctadiene) tetrafluoroborate rhodium, tri(triphenylphosphine) rhodium bromide (I), bis[(1,5-cyclooctadiene)(methoxy)rhodium], (1,5-cyclooctadiene) 2,4-pentanedione rhodium (I), chlorobis(ethylene) rhodium (I) dimer, dipolymerized hydroxy(1,5-cyclooctadiene) rhodium (I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane (1,5-cyclooctadiene) tetrafluoroborate rhodium (I), carbonyl bis(triphenylphosphino) rhodium chloride (I) , bis(1,5-cyclooctadiene)rhodium(I) antimony hexafluoride salt, tri(triphenylphosphine)carbonylrhodium(I) hydride, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate or one or more thereof.

3. The preparation method according to claim 1, characterized in that: The base is selected from lithium trimethylsilanolate, sodium trimethylsilanolate, potassium trimethylsilanolate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, lithium methoxide, potassium methoxide, sodium methoxide, lithium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium thiosulfate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium sulfate, potassium dihydrogen phosphate, potassium sulfate, potassium trihydrogen phosphate, calcium hydrogen phosphate, potassium tetrahydrogen phosphate, calcium tetrahydrogen phosphate, calcium dihydrogen phosphate, sodium phosphate, sodium trihydrogen phosphate, sodium dihydrogen phosphate, sodium tetrahydrogen phosphate, magnesium dihydrogen phosphate, magnesium phosphate, magnesium trihydrogen phosphate, aluminum dihydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum trihydrogen phosphate, copper phosphate, aluminum tetrahydrogen phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate and copper tetrahydrogen phosphate. One or more.

4. The preparation method according to claim 1, characterized in that: The solvent used in the reaction is selected from one or more of water, deuterated water, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, ethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform, deuterated chloroform, tetrahydrofuran and 1,4-dioxane.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the compound represented by formula (a), the halogenated olefin represented by formula (b), and acetamide is 0.2-1:0.5-3:1-3.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the compound represented by formula (a), the base and the rhodium catalyst is 1-3:1-3:0.01-1.

7. The preparation method according to claim 4, characterized in that: The reaction temperature is 0°C to 200°C, and the reaction time is 1 to 36 hours.

8. The preparation method according to claim 5, characterized in that: The compound represented by formula (a) is selected from one or more of (7-methoxynaphthalene-1-yl)boric acid, (7-methoxynaphthalene-1-yl)potassium trifluoroborate (I), 2-(7-methoxynaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-(7-methoxynaphthalene-1-yl)-1,3,2-dioxaborolane.

9. The preparation method according to claim 1, characterized in that: In the above formula (b), X is bromine.

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