Preparation method of adapalene raw material

Abstract

The invention relates to the technical field of adapalene production, and discloses an adapalene raw material preparation method which comprises the following steps: (1) adding a basic salt reagent into an alcohol solvent, and stirring until the basic salt reagent is dissolved; (2) adding 6-bromo-2-naphthoic acid into the alkaline alcohol solution in the step (1) under the protection of nitrogen, and uniformly stirring to obtain a mixed suspension; (3) stirring and heating the mixed turbid liquid in the step (2) under a nitrogen protection condition, and stirring and cooling to 10-30 DEG C; and (4) carrying out suction filtration, pulping and suction filtration on the mixed suspension cooled to 10-30 DEG C in the step (3), collecting a filter cake, and carrying out forced air drying to obtain the 6-bromo-2-sodium naphthoate. The invention provides a preparation process of 6-substituted-2-sodium naphthoate, which is simple, low in cost and suitable for industrialization, and is applied to synthesis of adapalene.

Description

Technical Field

[0001] The invention relates to the technical field of adapalene production, in particular to a method for preparing adapalene raw materials. Background Art

[0002] Adapalene, chemically known as 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, is a third-generation polyaromatic retinoid. It specifically binds to the retinoid receptor RARγ on epidermal cells, effectively inhibiting the keratinization process of keratinocytes. It also has immune-regulating, sebum-suppressing, and anti-inflammatory effects. It is primarily used clinically to treat acne, keratotic diseases, psoriasis, and photodermatoses.

[0003] 6-Bromo-2-naphthoic acid is an intermediate in the synthesis of the dermatological drug adapalene. Existing adapalene synthesis processes (e.g., WO0156563A; Bioorg. Chem., 2011, 39, 151; US7345189; CN104003838A) require esterification of the carboxyl group of 6-bromo-2-naphthoic acid to ensure the intermediate's reactivity, inevitably increasing the hydrolysis step and the presence of impurities. To address this issue, we developed an efficient and low-cost method for preparing 6-substituted 2-naphthoic acid salts. Summary of the Invention

[0004] (1) Technical problems solved

[0005] In view of the shortcomings of the existing technology, the present invention provides a method for preparing adapalene raw materials, which solves the problem that in the preparation process of 6-bromo-2-naphthoic acid in the prior art, the reaction activity of the intermediate is ensured by esterification of the carboxyl group, which inevitably increases the hydrolysis reaction step and increases related impurities.

[0006] (2) Technical solution

[0007] To achieve the above objectives, the present invention is implemented through the following technical solutions: A method for preparing adapalene raw materials, comprising the following steps:

[0008] (1) Add the alkaline salt reagent to the alcohol solvent and stir until dissolved;

[0009] (2) under nitrogen protection, adding 6-bromo-2-naphthoic acid to the alkaline alcohol solution in step (1), stirring evenly to obtain a mixed suspension;

[0010] (3) Under nitrogen protection, the mixed suspension in step (2) was stirred and heated, and then stirred and cooled to 10-30°C;

[0011] (4) The mixed suspension cooled to 10-30° C. in step (3) is filtered, beaten, filtered, and the filter cake is collected and dried with air to obtain sodium 6-bromo-2-naphthoate.

[0012] Preferably, the salt in step (1) is one or more of sodium hydroxide, sodium carbonate, sodium hydride, and sodium alkoxide.

[0013] Preferably, the sodium hydroxide is 2 to 5 molar equivalents of 6-bromo-2-naphthoic acid, and the mass ratio of the alcohol solvent to 6-bromo-2-naphthoic acid is 5 to 10:1.

[0014] Preferably, the stirring speed is 60-120 r / min, and the stirring time is 20-40 min.

[0015] Preferably, in step (3), the heating temperature is 40-100° C. and the heating time is 20-50 min, and the blast drying temperature is 60-100° C. and the drying time is more than 5 hours.

[0016] Preferably, the alcohol solvent in step (1) is one or more of methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, ethylene glycol, and polyethylene glycol.

[0017] (3) Beneficial effects

[0018] The present invention has the following beneficial effects:

[0019] The present invention provides a method for preparing an adapalene raw material, which provides a method for preparing 6-bromo-2-sodium formate, an adapalene intermediate. The method has simple operation, mild conditions, high yield of the target product, and low preparation cost. Furthermore, under nitrogen protection conditions, the purity of the prepared 6-bromo-2-sodium formate is effectively improved. DETAILED DESCRIPTION

[0020] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0021] The present invention provides a technical solution:

[0022] A method for preparing adapalene raw materials comprises the following steps:

[0023] (1) Add the alkaline salt reagent to the alcohol solvent and stir until dissolved;

[0024] (2) under nitrogen protection, adding 6-bromo-2-naphthoic acid to the alkaline alcohol solution in step (1), stirring evenly to obtain a mixed suspension;

[0025] (3) Under nitrogen protection, the mixed suspension in step (2) was stirred and heated, and then stirred and cooled to 10-30°C;

[0026] (4) The mixed suspension cooled to 10-30° C. in step (3) is filtered, beaten, filtered, and the filter cake is collected and dried with air to obtain sodium 6-bromo-2-naphthoate.

[0027] The present invention aims to provide a method for preparing 6-bromo-2-sodium formate, an intermediate of adapalene, which is simple to operate, requires mild conditions, has a high yield of the target product, and has a low preparation cost. Furthermore, under nitrogen protection, the purity of the prepared 6-bromo-2-sodium formate can be effectively improved.

[0028] In this embodiment, the salt described in step (1) is one or more of sodium hydroxide, sodium carbonate, sodium hydride, and sodium alcoholate (such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, etc.).

[0029] In this embodiment, the sodium hydroxide is 2 to 5 molar equivalents of 6-bromo-2-naphthoic acid, and the mass ratio of the alcohol solvent to 6-bromo-2-naphthoic acid is 5 to 10:1.

[0030] In this embodiment, in step (2), the stirring speed is 60 to 120 r / min, and the stirring time is 20 to 40 min.

[0031] In this embodiment, in step (3), the heating temperature is 40-100° C. and the heating time is 20-50 min, and the blast drying temperature is 60-100° C. and the drying time is more than 5 hours.

[0032] In this embodiment, the alcohol solvent described in step (1) is one or more of methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, ethylene glycol, and polyethylene glycol.

[0033] Example 1

[0034] A method for preparing an adapalene raw material comprises the following steps:

[0035] Add ethanol (180 g) and sodium hydroxide (8 g, 200 mmol) to a 500 mL reaction bottle and stir for 30 min until completely dissolved;

[0036] Under nitrogen protection, 6-substituted-2-naphthoic acid (20 g, 79 mmol) was added to the alkaline alcohol solution in step (1) and stirred for 40 min to obtain a mixed suspension;

[0037] Under nitrogen protection, the mixed suspension in step (2) was heated to 75-80°C with stirring, and then cooled to 25-30°C with stirring.

[0038] The mixed suspension cooled to 25-30°C in step (3) was filtered with suction, and the filter cake was slurried with 40 g of ethanol, filtered, and the filter cake was collected and air-dried (65°C, 6 h) to obtain 22.7 g of an off-white powder (sodium 6-bromo-2-naphthoate), with a yield of 96%. 1H NMR (500 MHz, DMSO) δ 8.41 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.7, 1.8 Hz, 1H).

[0039] Example 2

[0040] A method for preparing an adapalene raw material comprises the following steps:

[0041] Methanol (180 g) and sodium hydroxide (8 g, 200 mmol) were added to a 500 mL reaction bottle and stirred for 30 min until completely dissolved.

[0042] Under nitrogen protection, 6-substituted-2-naphthoic acid (20 g, 79 mmol) was added to the alkaline alcohol solution in step (1) and stirred for 40 min to obtain a mixed suspension;

[0043] Under nitrogen protection, the mixed suspension in step (2) was heated to 60-70°C with stirring, and then cooled to 25-30°C with stirring.

[0044] (4) The mixed suspension cooled to 25-30°C in step (3) was filtered by suction, and the filter cake was slurried with 40g of ethanol, filtered, collected, and air-dried (65°C, 6h). 19.2g of an off-white powder (sodium 6-bromo-2-naphthoate) was obtained, with a yield of 81%. 1H NMR (500MHz, DMSO) δ 8.41 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.7, 1.8 Hz, 1H).

[0045] Example 3

[0046] A method for preparing an adapalene raw material comprises the following steps:

[0047] Add ethanol (180 g) and sodium ethoxide (6 g, 88 mmol) to a 500 mL reaction bottle and stir for 30 min until completely dissolved;

[0048] Under nitrogen protection, 6-substituted-2-naphthoic acid (20 g, 79 mmol) was added to the alkaline alcohol solution in step (1) and stirred for 40 min to obtain a mixed suspension;

[0049] Under nitrogen protection, the mixed suspension in step (2) was heated to 75-80°C with stirring, and then cooled to 25-30°C with stirring.

[0050] (4) The mixed suspension cooled to 25-30°C in step (3) was filtered by suction, and the filter cake was slurried with 40g of ethanol, filtered, and the filter cake was collected and air-dried (65°C, 6h). 20.5g of off-white powder (sodium 6-bromo-2-naphthoate) was obtained, with a yield of 87%. 1H NMR (500MHz, DMSO) δ8.41(s,1H),8.16(s,1H),8.08(s,1H),7.92(d,J=8.8Hz,1H),7.78(d,J=8.4Hz,1H),7.58(dd,J=8.7,1.8Hz,1H).

[0051] Preparation of adapalene using sodium 6-bromo-2-naphthoate:

[0052] (1) Under nitrogen atmosphere, magnesium chips (0.45 g, 18.6 mmol), iodoethane (0.24 g, 1.6 mmol), 2-(1-adamantane)-4-bromoanisole (1.0 g, 3.1 mmol) and reaction solvent were added to a three-necked flask. The bottom of the flask was heated to initiate the reaction, and a tetrahydrofuran solution of 2-(1-adamantane)-4-bromoanisole (4.0 g, 12.5 mmol) was added dropwise. The temperature was controlled at 60-65°C for 5 h, and then the temperature was lowered to room temperature to obtain the Grignard reagent.

[0053] (2) Under nitrogen atmosphere, anhydrous zinc chloride (2.2 g, 15.6 mmol) was added at 25°C and the reaction was continued for 1 h. Sodium 6-bromo-2-naphthoate (2.6 g, 10.9 mmol) and 1,2-(bis(diphenylphosphine))nickel chloride (0.08 g, 0.16 mmol) were added and the reaction was continued for 8 h. The pH value of the reaction system was adjusted to 4 with hydrochloric acid, and the solid was precipitated by stirring. The solid was filtered and washed with water until neutral. The white solid was collected and recrystallized with 20 g of tetrahydrofuran solvent and dried to obtain 1.9 g (yield 42%) of adapalene. 1H NMR (500MHz, DMSO) δ13.04(s,1H),8.61(s,1H),8.24(s,1H),8.16(d,J=8.6Hz,1H),8.08(d,J=8.6Hz,1H),7.98(dd,J=8.5,1.4Hz, 1H), 7.90 (d, J = 8.7Hz, 1H), 7.66 (dd, J = 8.4, 1.9Hz, 1H), 7.59 (d, J = 2.1Hz, 1H), 3.88 (s, 3H), 2.15 (s, 7H), 2.08 (s, 3H), 1.77 (s, 6H). .

[0054] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "include," "comprise," or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article, or device that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or device. In the absence of further limitations. The phrase "includes an element defined by..." does not exclude the presence of other identical elements in the process, method, article, or device that includes the element.

[0055] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing adapalene raw materials, characterized in that, The following steps are involved: (1) Add the alkaline salt reagent to the alcohol solvent and stir until dissolved; (2) under nitrogen protection, adding 6-bromo-2-naphthoic acid to the alkaline alcohol solution in step (1), stirring evenly to obtain a mixed suspension; (3) Under nitrogen protection, the mixed suspension in step (2) was stirred and heated, and then stirred and cooled to 10-30°C; (4) The mixed suspension cooled to 10-30° C. in step (3) is filtered, beaten, filtered, and the filter cake is collected and dried with air to obtain sodium 6-bromo-2-naphthoate.

2. A method for preparing adapalene raw materials according to claim 1, characterized in that: The salt in step (1) is one or more of sodium hydroxide, sodium carbonate, sodium hydride and sodium alkoxide.

3. A method for preparing adapalene raw materials according to claim 1, characterized in that: The sodium hydroxide is 2 to 5 molar equivalents of 6-bromo-2-naphthoic acid, and the mass ratio of the alcohol solvent to the 6-bromo-2-naphthoic acid is 5 to 10:

1.

4. A method for preparing adapalene raw materials according to claim 1, characterized in that: In step (2), the stirring speed is 60 to 120 r / min, and the stirring time is 20 to 40 min.

5. A method for preparing adapalene raw materials according to claim 1, characterized in that: In step (3), the heating temperature is 40-100° C. and the heating time is 20-50 min. The blast drying temperature is 60-100° C. and the drying time is more than 5 hours.

6. A method for preparing adapalene raw materials according to claim 1, characterized in that: The alcohol solvent in step (1) is one or more of methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, ethylene glycol, and polyethylene glycol.