A method for preparing an anti-irritant hair dye intermediate and its application

Abstract

This invention discloses a method for preparing an anti-irritant hair dye intermediate and its application. The method uses 1-isochromone-6-carboxylic acid as the starting material, undergoing saponification and ammoniation reactions, followed by reaction with 1-p-methylbenzenesulfonylimidazole in the presence of triethylamine. The reaction is then followed by Hoffmann degradation and salt formation with concentrated sulfuric acid to obtain the target product, the anti-irritant hair dye intermediate, namely 2,5-diaminophenylethanol sulfate. The obtained dye intermediate is used to prepare anti-irritant hair dyes. The preparation method specified in this invention avoids nitration, catalytic hydrogenation, and high-temperature, high-pressure reaction conditions, offering advantages such as mild reaction conditions, simple operation, and high yield. In use, by adjusting the component ratio of the dye intermediate, the resulting hair dye can achieve different color effects with good coloring properties, and is mild and low in irritation.

Description

Technical Field

[0001] This invention relates to a method for preparing an anti-irritant hair dye intermediate and its application. Background Technology

[0002] Currently, the most widely used type of permanent hair dye on the market is the oxidative type, which has advantages such as good coloring effect, wide range of color changes, and long duration. Most oxidative hair dyes on the market use phenylenediamine compounds as dye intermediates. These dyes are toxic and irritating to the skin and eyes, often causing severe allergic reactions and other adverse effects, and may even have mutagenic, carcinogenic, and nephritis and leukemia-inducing potential effects. It has been reported that introducing a large substituent at the ortho-amino position of p-phenylenediamine, or introducing a large alkyl or alkoxy group into its structural unit, can weaken or eliminate its mutagenic activity. 2,5-Diaminophenylethanol is a hair dye intermediate developed based on this principle, and it generally exists in the form of hydrochloride or sulfate.

[0003] Currently, according to domestic and international literature, the synthesis methods of 2,5-diaminophenylethanol or its salts are generally as follows, depending on the starting materials: (1) Using o-chlorophenylacetic acid as the starting material (JP11012238; JP11012239; CN103242177). The starting materials for this type of synthesis route are inexpensive and readily available, but the synthesis steps are numerous, and there are problems such as low yield of sodium borohydride reduction of acetic acid (ester) group and easy condensation of 2-amino-5-nitrobenzeneacetic acid, resulting in low actual yield. (2) Using o-aminophenylethanol as the starting material (WO8602829; CN101717342). The starting materials for this synthesis route are relatively expensive, and the nitration process is prone to side reactions, resulting in low reaction yield, which limits the industrial application of this route. (3) Using 3-fluorophenylacetic acid as the starting material (Chemical Industry Progress, 2007, 26(03):438-441). Although the synthetic route is relatively short, the starting materials are expensive, and both ammonolysis and catalytic hydrogenation require high pressure conditions, which is not conducive to industrial production. (4) Using o-nitrotoluene as the starting material (CN101698647). Although the starting material o-nitrotoluene is cheaper, the process route is long and the operation steps are complicated, which is not conducive to industrial production. (5) Using 2-hydroxyphenylacetic acid as the starting material (CN10789256). Although this route has fewer steps and higher yield, it requires a mixture of cerium chloride, lanthanum chloride and zinc powder as a catalyst, which is expensive and difficult to recover. The process routes reported in the above literature all involve nitration and catalytic hydrogenation reactions, which are highly dangerous and limit their industrial production. (6) Patent CN111440077 discloses a new method for synthesizing 2,5-diaminophenylethanol and its sulfate. Although this route avoids nitration and catalytic hydrogenation, and is relatively mild and simple to operate, the amination step still has some problems, such as: 1) In 4-chloro-2-(2-hydroxyethyl)benzoic acid, nucleophilic amination is difficult due to the p-π conjugation effect between the chlorine atom and the benzene ring, and it needs to be carried out under high temperature and high pressure conditions; 2) The amino group in 4-amino-2-(2-hydroxyethyl)benzamide is easily oxidized in subsequent reactions, resulting in many impurities in the product and difficulty in purification. Due to the above reasons, the yield of the amination step and the product are not as high as reported in actual operation. Therefore, it is necessary to continue to explore a synthetic route for 2,5-diaminophenylethanol and its salt with mild process conditions and high product yield. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention aims to provide a method for preparing an anti-irritant hair dye intermediate and its application.

[0005] This invention defines a method for preparing an intermediate for anti-irritant hair dyeing, specifically: using 1-isochromone-6-carboxylic acid as shown in formula (I) as the starting material, after saponification and acidification, 2-(2-hydroxyethyl) terephthalic acid as shown in formula (II) is obtained. The 2-(2-hydroxyethyl) terephthalic acid as shown in formula (II) is reacted with ammonia to obtain ammonium 2-(2-hydroxyethyl) terephthalate as shown in formula (III). The ammonium 2-(2-hydroxyethyl) terephthalate as shown in formula (III) is reacted with 1-p-methylbenzenesulfonylimidazole in the presence of triethylamine to generate 2-(2-hydroxyethyl) terephthalamide as shown in formula (IV). The 2-(2-hydroxyethyl) terephthalamide as shown in formula (IV) is subjected to Hoffmann degradation and salt formation with concentrated sulfuric acid to obtain the target product 2,5-diaminophenylethanol sulfate as shown in formula (V). The reaction equation is as follows:

[0006]

[0007] This invention provides a detailed description of each step, as follows:

[0008] 1) Synthesis of 2-(2-hydroxyethyl) terephthalic acid as shown in formula (II)

[0009] 1-Isochromone-6-carboxylic acid (I) and sodium hydroxide were added to a mixed solvent of methanol and water. After the addition was complete, the mixture was heated to reflux and stirred for 1.0–4.0 h. After the reaction was completed, an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise until the pH was 2–3. A solid was precipitated, filtered, washed with water, and dried to obtain a white solid 2-(2-hydroxyethyl) terephthalic acid (II).

[0010] 2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate as shown in formula (III)

[0011] The 2-(2-hydroxyethyl) terephthalic acid obtained in step 1) was dissolved in methanol, and the resulting solution was added dropwise to 20-30 wt.% ammonia water. The mixture was stirred at room temperature for 2-3 h, and the solution was removed and dried under vacuum to obtain a white solid of ammonium 2-(2-hydroxyethyl) terephthalate as shown in formula (III).

[0012] 3) Synthesis of 2-(2-hydroxyethyl)terephthalamide as shown in formula (IV)

[0013] The 2-(2-hydroxyethyl) terephthalate ammonium obtained in step 2) was dissolved in N,N-dimethylformamide, 1-p-methylbenzenesulfonyl imidazole was added, and the mixture was heated to 100-120°C for 1-2 h. Triethylamine was then added and the reaction was continued for 3-5 h. After the reaction was completed, water was added and stirred. The mixture was then filtered, washed with water, and dried to obtain a white solid 2-(2-hydroxyethyl) terephthalate as shown in formula (IV).

[0014] 4) Synthesis of the target product 2,5-diaminophenylethanol sulfate as shown in formula (V)

[0015] The 2-(2-hydroxyethyl) terephthalamide and sodium hydroxide obtained in step 3) were dissolved in acetonitrile and water, cooled to below 0°C, and then added to a suspension of trichloroisocyanuric acid (TCCA) and water. The mixture was stirred and reacted under freezing conditions for 1-2 hours, then heated to reflux and reacted for another 0.5-1 hour. The reaction solution turned reddish-brown. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was extracted with dichloromethane 3-5 times. The combined organic layers were cooled in an ice-water bath and concentrated sulfuric acid was added dropwise to form a salt. The mixture was filtered, washed with anhydrous methanol, and dried under vacuum to obtain the target product 2,5-diaminophenylethanol sulfate as shown in formula (V).

[0016] Furthermore, the present invention further specifies the reaction conditions for step 1): the molar ratio of 1-isochromone-6-carboxylic acid (I) to sodium hydroxide is 1:2.0 to 6.0, preferably 1:3.0 to 5.0; in the mixed solvent of methanol and water, the amount of methanol used is 0.3 to 1.5 mL / mmol, preferably 0.5 to 1.0 mL / mmol, and the amount of water used is 0.5 to 2.0 mL / mmol, preferably 0.8 to 1.5 mL / mmol, based on the amount of 1-isochromone-6-carboxylic acid; the molar ratio of 1-isochromone-6-carboxylic acid to sodium hydroxide is 1:2.0 to 6.0, preferably 1:3.0 to 5.0.

[0017] Furthermore, the present invention further limits the reaction conditions in step 2): the molar ratio of 2-(2-hydroxyethyl) terephthalic acid to ammonia is 1:4.0 to 20.0, preferably 1:8.0 to 16.0; the amount of methanol used is 0.5 to 1.0 mL / mmol based on the amount of 2-(2-hydroxyethyl) terephthalic acid.

[0018] Furthermore, the present invention further specifies the reaction conditions for step 3): the molar ratio of 2-(2-hydroxyethyl) terephthalate to 1-p-methylbenzenesulfonylimidazole and triethylamine is 1:2.0-4.0:2.0-4.0, preferably 1:2.4-3.2:2.4-3.6; the amount of N,N-dimethylformamide, based on the amount of 2-(2-hydroxyethyl) terephthalate, is 1.0-3.0 mL / mmol, preferably 1.2-1.8 mL / mmol; after the reaction in step 3) is completed, water is added and stirred, wherein the amount of water, based on the amount of 2-(2-hydroxyethyl) terephthalate (III), is 1.0-1.5 mL / mmol;

[0019] Furthermore, the present invention further specifies the reaction conditions for step 4): the molar ratio of 2-(2-hydroxyethyl) terephthalamide, sodium hydroxide, and trichloroisocyanuric acid in step 4) is 1:10.0–13.0:0.67–0.8, preferably 1:11.0–12.0:0.7–0.77; in the acetonitrile and water mixed solvent, the amount of acetonitrile, based on the molar amount of 2-(2-hydroxyethyl) terephthalamide (IV), is 1.0–2.0 mL / mmol, preferably 1.2–1.6 mL / mmol, and the amount of water is 0.5–1.5 mL / mmol, preferably... 0.75–1.2 mL / mmol; in the suspension of trichloroisocyanuric acid and water, the amount of water used is 0.5–1.0 mL / mmol, preferably 0.6–0.8 mL / mmol, based on the amount of 2-(2-hydroxyethyl)-terephthalamide (IV); the amount of dichloromethane used in each extraction is 1.0–1.6 mL / mmol, based on the amount of 2-(2-hydroxyethyl)-terephthalamide (IV); the concentrated sulfuric acid used has a mass concentration of 98%, and the molar ratio of 2-(2-hydroxyethyl)-terephthalamide (IV) to sulfuric acid is 1:1.0–2.0, preferably 1:1.2–1.6.

[0020] The present invention also specifies the use of the obtained dye intermediate in the preparation of an anti-irritant hair dye, wherein the anti-irritant hair dye comprises a dyeing agent (hereinafter referred to as Agent 1) and an oxidizing agent (hereinafter referred to as Agent 2).

[0021] Based on a total dyeing agent volume of 100%, the names, mass percentage concentrations, and functions of each component are listed in Table 1:

[0022] Table 1. Components of the dye (1 agent)

[0023]

[0024]

[0025] Note: All extracts in Table 1 were obtained using conventional methods.

[0026] The preparation method of a single-dose staining agent includes the following steps:

[0027] 1) Mix the A phase components thoroughly and heat to about 85℃;

[0028] 2) Mix the B phase components thoroughly and heat to about 85℃;

[0029] 3) Add phase A to phase B, emulsify and stir;

[0030] 4) Cool down to about 45℃ and add the pre-stirred C phase;

[0031] 5) Cool down to below 35℃ before discharging and filling.

[0032] The 2,5-diaminophenylethanol sulfate obtained by the synthesis method defined in this invention is one of the main components of the dye intermediate in phase C of the table above. It can be used in combination with dye components such as phenylmethylpyrazolone, resorcinol, m-aminophenol, N,N-bis(2-hydroxyethyl)p-phenylenediamine sulfate, 4-amino-2-hydroxytoluene, and p-aminophenol. Different combinations can achieve different hair dyeing effects.

[0033] Based on a total oxidant content of 100%, the names, mass percentage concentrations, and functions of each component are listed in Table 2:

[0034] Table 2. List of Components of Oxidizing Agent (2 Agents)

[0035]

[0036] The preparation method of the two oxidants is as follows: heat phase A and phase B to about 85°C respectively; then add phase A to phase B, emulsify and stir, cool to about 38°C and add hydrogen peroxide (phase C), stir evenly, cool to below 35°C and discharge for filling.

[0037] When using the mild hair dye of the present invention, mix the dye agent (1 part) and oxidant (2 parts) in a 1:1 mass ratio, apply the mixture to the hair, wait 20-30 minutes, and then wash off the excess dye.

[0038] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0039] 1) This invention provides a method for synthesizing dye intermediates for anti-irritant hair dyeing, which avoids the nitration and catalytic hydrogenation reactions in the traditional route, as well as the high temperature and high pressure reaction conditions; at the same time, two amino groups are introduced in the last step of the reaction route to avoid the oxidation of amino groups during the reaction; this route has the advantages of mild reaction conditions, simple operation and high yield.

[0040] 2) This invention also provides the application of 2,5-diaminophenylethanol sulfate, an anti-irritant hair dye intermediate obtained by a defined method, as a dye intermediate component in an anti-irritant hair dye. Experimental results show that this hair dye allows for the adjustment of the dye intermediate component ratio to obtain different hair colors, with good coloring effect. Animal acute skin irritation tests and human skin patch tests show that the above-mentioned hair dye is non-irritating to the skin and has no adverse skin reactions, making it a mild hair dye. Attached Figure Description

[0041] Figure 1The image shows the dyeing effect of a hair dye made using 2,5-diaminophenylethanol sulfate prepared according to this invention as a dye intermediate. Detailed Implementation

[0042] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0043] This invention first provides an example of the synthesis of 2,5-diaminophenylethanol sulfate, an intermediate for anti-irritant hair dyeing.

[0044] Example 1: Synthesis of 2,5-diaminophenylethanol sulfate, an intermediate for anti-irritant hair dyeing

[0045] (1) Synthesis of 2-(2-hydroxyethyl)terephthalic acid (II)

[0046] 1-Isochromone-6-carboxylic acid (I) (100 mmol, 19.2 g) and sodium hydroxide (300 mmol, 12.0 g) were added to a mixed solvent of 50 mL methanol and 150 mL water. After the addition was complete, the mixture was heated to reflux and stirred for 4.0 h. After the reaction was completed, an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise to pH 2-3, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain 19.2 g of white solid, namely 2-(2-hydroxyethyl)terephthalic acid (II), with a yield of 91.3%.

[0047] (2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate (III)

[0048] The 2-(2-hydroxyethyl) terephthalic acid (II) (90 mmol, 18.9 g) obtained in step (1) was dissolved in 90 mL of methanol. The resulting solution was added dropwise to 30% ammonia water (1.44 mol, 81.6 g). The mixture was stirred at room temperature for 2 h. After solvent removal and vacuum drying, 21.3 g of white solid, namely ammonium 2-(2-hydroxyethyl) terephthalate (III), was obtained, with a yield of 96.9%.

[0049] (3) Synthesis of 2-(2-hydroxyethyl)-terephthalamide (IV)

[0050] The 2-(2-hydroxyethyl) terephthalate ammonium (III) (80 mmol, 19.6 g) obtained in step (2) was dissolved in 144 mL of N,N-dimethylformamide, and 1-p-methylbenzenesulfonylimidazole (256 mmol, 56.9 g) was added. The mixture was heated to 110 °C and reacted for 1.5 h. Triethylamine (240 mmol, 24.3 g) was then added and the reaction was continued for 5 h. After the reaction was completed, 120 mL of water was added and stirred. The mixture was filtered, washed with water, and dried to obtain 15.6 g of a white solid, namely 2-(2-hydroxyethyl) terephthalamide (IV), with a yield of 93.7%.

[0051] (4) Synthesis of the target product 2,5-diaminophenylethanol sulfate (V)

[0052] The 2-(2-hydroxyethyl) terephthalamide (IV) (70 mmol, 14.6 g) and sodium hydroxide (805 mmol, 32.2 g) obtained in step (3) were dissolved in a mixed solvent of 100 mL acetonitrile and 70 mL water. The solution was cooled to below 0 °C and then added to a suspension of trichloroisocyanuric acid (52.5 mmol, 12.2 g) and 50 mL water. The mixture was stirred under freezing conditions for 1.5 h, then heated to reflux and the reaction was continued for 45 min. The reaction solution turned reddish-brown. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was extracted three times with dichloromethane (3 × 90 mL). The organic layers were combined, and 98% concentrated sulfuric acid (84 mmol, 8.4 g) was added dropwise under ice-water bath cooling to form a salt. The solution was filtered, washed with anhydrous methanol, and dried under vacuum to give 16.4 g of white solid, which is the sulfate (V) of the target product 2,5-diaminophenylethanol, with a yield of 93.6% and a purity of 99.2%; mp: 223–225 °C. 1 H NMR(500MHz,D2O)δ:7.36(d,J=8.5Hz,1H),7.31(d,J=2.5Hz,1H),7.25(dd,J=8.5,2.5Hz,1H),3.74(t,J=6.0Hz,2H),2.83(t,J=6.0Hz,2H); HRMS(ESI)calcd C8H 13 N₂O[M+H] + 153.0950, found 153.0954.

[0053] Example 2: Synthesis of 2,5-Diaminophenylethanol Sulfate, an intermediate for anti-irritant hair dyeing

[0054] 1) Synthesis of 2-(2-hydroxyethyl)terephthalic acid (II)

[0055] 1-Isochromone-6-carboxylic acid (I) (100 mmol, 19.2 g) and sodium hydroxide (400 mmol, 16.0 g) were added to a mixed solvent of 100 mL methanol and 80 mL water. After the addition was complete, the mixture was heated to reflux and stirred for 2.5 h. After the reaction was completed, an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise to pH 2-3, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain 19.0 g of white solid, namely 2-(2-hydroxyethyl)terephthalic acid (II), with a yield of 90.4%.

[0056] (2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate (III)

[0057] The 2-(2-hydroxyethyl) terephthalic acid (II) (90 mmol, 18.9 g) obtained in step (1) was dissolved in 50 mL of methanol. The resulting solution was added dropwise to 20% ammonia water (1.08 mol, 91.8 g). The mixture was stirred at room temperature for 3 h. After solvent removal and vacuum drying, 21.4 g of white solid, namely ammonium 2-(2-hydroxyethyl) terephthalate (III), was obtained, with a yield of 97.4%.

[0058] (3) Synthesis of 2-(2-hydroxyethyl)-terephthalamide (IV)

[0059] The 2-(2-hydroxyethyl) terephthalate ammonium (III) (80 mmol, 19.6 g) obtained in step (2) was dissolved in 120 mL of N,N-dimethylformamide, and 1-p-methylbenzenesulfonylimidazole (224 mmol, 49.8 g) was added. The mixture was heated to 100 °C and reacted for 2 h. Triethylamine (288 mmol, 29.2 g) was then added and the reaction was continued for 4 h. After the reaction was completed, 100 mL of water was added and stirred. The mixture was then filtered, washed with water, and dried to obtain 15.4 g of a white solid, namely 2-(2-hydroxyethyl) terephthalamide (IV), with a yield of 92.5%.

[0060] (4) Synthesis of the target product 2,5-diaminophenylethanol sulfate (V)

[0061] The 2-(2-hydroxyethyl)terephthalamide (IV) (70 mmol, 14.6 g) obtained in step (3) and sodium hydroxide (770 mmol, 30.8 g) were dissolved in a mixed solvent of 84 mL acetonitrile and 84 mL water. The solution was cooled to below 0 °C and then added to a suspension of trichloroisocyanuric acid (53.9 mmol, 12.5 g) and 42 mL water. The mixture was stirred for 1 h under freezing conditions, then heated to reflux and reacted for another 1 h until the reaction solution turned reddish-brown. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was extracted three times with dichloromethane (3 × 70 mL). The organic layers were combined, and 98% concentrated sulfuric acid (98 mmol, 9.8 g) was added dropwise under ice-water bath cooling to form a salt. The solution was filtered, washed with anhydrous methanol, and dried under vacuum to obtain 16.6 g of white solid, which is the sulfate (V) of the target product 2,5-diaminophenylethanol, with a yield of 94.8% and a purity of 99.15%.

[0062] Example 3: Synthesis of 2,5-diaminophenylethanol sulfate, an intermediate for anti-irritant hair dyeing

[0063] (1) Synthesis of 2-(2-hydroxyethyl)terephthalic acid (II)

[0064] 1-Isochromone-6-carboxylic acid (I) (100 mmol, 19.2 g) and sodium hydroxide (500 mmol, 20.0 g) were added to a mixed solvent of 80 mL methanol and 100 mL water. After the addition was complete, the mixture was heated to reflux and stirred for 1.0 h. The reaction was completed, and an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise to pH 2-3, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain 18.8 g of white solid, namely 2-(2-hydroxyethyl)terephthalic acid (II), with a yield of 89.4%.

[0065] (2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate (III)

[0066] The 2-(2-hydroxyethyl) terephthalic acid (II) (85 mmol, 17.9 g) obtained in step (1) was dissolved in 80 mL of methanol. The resulting solution was added dropwise to 25% ammonia water (0.68 mol, 46.3 g). The mixture was stirred at room temperature for 2.5 h. After solvent removal and vacuum drying, 20.3 g of white solid, namely ammonium 2-(2-hydroxyethyl) terephthalate (III), was obtained, with a yield of 97.8%.

[0067] (3) Synthesis of 2-(2-hydroxyethyl)-terephthalamide (IV)

[0068] The 2-(2-hydroxyethyl) terephthalate ammonium (III) (80 mmol, 19.6 g) obtained in step (2) was dissolved in 96 mL of N,N-dimethylformamide, and 1-p-methylbenzenesulfonylimidazole (192 mmol, 42.7 g) was added. The mixture was heated to 120 °C and reacted for 1 h. Triethylamine (192 mmol, 19.5 g) was then added and the reaction was continued for 3 h. After the reaction was completed, 80 mL of water was added and stirred. The mixture was then filtered, washed with water, and dried to obtain 15.5 g of a white solid, namely 2-(2-hydroxyethyl) terephthalamide (IV), with a yield of 93.1%.

[0069] (4) Synthesis of the target product 2,5-diaminophenylethanol sulfate (V)

[0070] The 2-(2-hydroxyethyl) terephthalamide (IV) (70 mmol, 14.6 g) and sodium hydroxide (840 mmol, 33.6 g) obtained in step (3) were dissolved in a mixed solvent of 112.0 mL acetonitrile and 53.0 mL water. The solution was cooled to below 0 °C and then added to a suspension of trichloroisocyanuric acid (49.0 mmol, 11.39 g) and 56 mL water. The solution was stirred and reacted under freezing conditions for 2 h, then heated to reflux and reacted for another 30 minutes. The reaction solution turned reddish-brown. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was extracted three times with dichloromethane (3 × 112 mL). The organic layers were combined, and 98% concentrated sulfuric acid (112 mmol, 11.2 g) was added dropwise under ice-water bath cooling to form a salt. The solution was filtered, washed with anhydrous methanol, and dried under vacuum to give 16.2 g of white solid, which is the sulfate (V) of the target product 2,5-diaminophenylethanol, with a yield of 92.5% and a purity of 99.3%.

[0071] Example 4: Synthesis of 2,5-diaminophenylethanol sulfate, an intermediate for anti-irritant hair dyeing

[0072] (1) Synthesis of 2-(2-hydroxyethyl)terephthalic acid (II)

[0073] 1-Isochromone-6-carboxylic acid (I) (100 mmol, 19.2 g) and sodium hydroxide (180 mmol, 12.0 g) were added to a mixed solvent of 25 mL methanol and 220 mL water. After the addition was complete, the mixture was heated to reflux and stirred for 45 min. After the reaction was completed, an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise to pH 2-3, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain 11.5 g of white solid, namely 2-(2-hydroxyethyl)terephthalic acid (II), with a yield of 54.7%.

[0074] (2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate (III)

[0075] The 2-(2-hydroxyethyl) terephthalic acid (II) (50 mmol, 10.5 g) obtained in step (1) was dissolved in 60 mL of methanol. The resulting solution was added dropwise to 30% ammonia water (180 mmol, 10.2 g). The mixture was stirred at room temperature for 3 h. After desolventizing and vacuum drying, 10.3 g of white solid, namely 2-(2-hydroxyethyl) ammonium terephthalate (III), was obtained, with a yield of 84.3%.

[0076] (3) Synthesis of 2-(2-hydroxyethyl)-terephthalamide (IV)

[0077] The 2-(2-hydroxyethyl) terephthalate ammonium (III) (40 mmol, 9.8 g) obtained in step (2) was dissolved in 130 mL of N,N-dimethylformamide, and 1-p-methylbenzenesulfonyl imidazole (72 mmol, 16.0 g) was added. The mixture was heated to 110 °C and reacted for 1.5 h. Triethylamine (72 mmol, 7.3 g) was added and the reaction was continued for 5 h. After the reaction was completed, 70 mL of water was added and stirred. The mixture was filtered, washed with water, and dried to obtain 5.9 g of white solid, namely 2-(2-hydroxyethyl) terephthalamide (IV), with a yield of 70.8%.

[0078] (4) Synthesis of the target product 2,5-diaminophenylethanol sulfate (V)

[0079] The 2-(2-hydroxyethyl)terephthalamide (IV) (25 mmol, 5.2 g) obtained in step (3) and sodium hydroxide (200 mmol, 8.0 g) were dissolved in a mixed solvent of 60 mL acetonitrile and 40 mL water. The solution was cooled to below 0 °C and then added to a suspension of trichloroisocyanuric acid (15 mmol, 3.5 g) and 30 mL water. The mixture was stirred under freezing conditions for 2.0 h, then heated to reflux and reacted for another 50 minutes until the reaction solution turned reddish-brown. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was extracted three times with dichloromethane (3 × 45 mL). The organic layers were combined, and 98% concentrated sulfuric acid (25 mmol, 2.5 g) was added dropwise under ice-water bath cooling to form a salt. The solution was filtered, washed with anhydrous methanol, and dried under vacuum to obtain 4.5 g of white solid, which is the sulfate (V) of the target product 2,5-diaminophenylethanol, with a yield of 71.9% and a purity of 99.15%.

[0080] Application Example: Hair Dyeing Effect Test

[0081] Using the 2,5-diaminophenylethanol sulfate obtained in Example 1 of this invention as a dye intermediate component, the corresponding dyeing agent (referred to as Agent 1) and oxidizing agent (referred to as Agent 2) were prepared according to the formula shown in Table 3 and the aforementioned method. Agent 1 and Agent 2 were mixed in a 1:1 mass ratio and applied to the hair. After waiting for 25 minutes, excess dye was rinsed off with water. The hair color after dyeing was observed and the colorfastness was evaluated. The colorfastness was scored from 1 to 5 points, with a higher score indicating more obvious coloring.

[0082] Table 3 Examples of several representative hair dyes and their dyeing effects

[0083]

[0084]

[0085] As can be seen from Table 3, the formulated hair dyes listed in Examples 5 to 8 can dye white hair into natural black, brown, gorgeous purple and chestnut brown respectively. It can be seen that using 2,5-diaminophenylethanol sulfate as the main component of the dye intermediate can be used in combination with other dye intermediates such as phenylmethylpyrazolone, resorcinol, metaphenol, N,N-bis(2-hydroxyethyl)p-phenylenediamine sulfate, 4-amino-2-hydroxytoluene, p-aminophenol, etc., to obtain different color hair dyeing effects; generally speaking, the higher the content of 2,5-diaminophenylethanol sulfate, the darker the dyeing color and the better the coloring effect. The specific dyeing situation is as shown in the appendix Figure 1 As shown, the blank in the figure is the white hair sample before dyeing.

[0086] In this example, using the 2,5-diaminophenylethanol sulfate prepared in Examples 2-4 as the dye intermediate to replace the 2,5-diaminophenylethanol sulfate in Example 1 can achieve the same technical effect. Examples 1-4 only change the preparation parameters and do not affect the performance of their products.

[0087] Example 9 Acute Skin Irritation Test

[0088] Entrusted Suzhou Huabo Bio-detection Co., Ltd. to conduct an acute skin irritation test on the hair dyes prepared in Examples 5 to 8 in accordance with the "Cosmetics Safety and Technology Specifications" (2015 Edition).

[0089] I. Materials and Methods

[0090] 1. Test Substances

[0091] The dyes and oxidants listed in Examples 5 to 8 were mixed in a 1:1 ratio and tested as原样.

[0092] 2. Experimental Animals and Rearing Environment

[0093] 2.1 Information of Experimental Animals \

[0094] Species: Rabbit;

[0095] Strain: New Zealand rabbit;

[0096] Level: Ordinary level;

[0097] Number of animals: 4, female animals were selected as non-pregnant and non-littering;

[0098] Body weight: 2.4 - 2.6 kg;

[0099] Source: Suzhou Huqiao Biotechnology Co., Ltd.;

[0100] Production License Number of Experimental Animals: SCXK(SU)2K20 - 0001;

[0101] Quality Certificate Number: No.202308074.

[0102] 2.2 Information on the Rearing Environment

[0103] Temperature: 19.3 - २३.८ °C;

[0104] Relative Humidity: 59.6% - 64.8%;

[0105] Experimental Animal Environment Use Permit Number: SYXK (Su) 2019 - 0032.

[0106] 2.3 Feed Information

[0107] Feed Source: Suzhou Anmufei Biotechnology Co., Ltd.;

[0108] Feed Qualification Certificate: R02 - 20221230007.

[0109] 3. Test Methods

[0110] Before the test, the animals were acclimated in the experimental animal house environment for 3 days. Approximately 24 hours before the test, the hair on both sides of the spine on the back of the experimental animals was shaved off, and the hair removal area was about 3 cm × 3 cm on each side of the left and right. During the test, 0.5 mL of the test substance was applied to the left skin, and the application area was about 2.5 cm × 2.5 cm. Then, it was covered with two layers of gauze and one layer of cellophane, and fixed with non - irritating adhesive tape. The right skin was used as a control. A closed - test was adopted. After 2 hours of application, the residual test substance was removed with warm water. The skin reactions at the application site were observed at 1, 24, 48, and 72 hours after removing the test substance. The skin reactions were scored according to Table 1 of the Skin Irritation / Corrosion Test in Chapter 6 of the "Cosmetics Safety Technical Specifications" (2015 Edition). The comprehensive evaluation was carried out based on the average value of the scores of the experimental animals. According to the highest average score at each observation time point of 24, 48, and 72 hours, the skin irritation intensity was determined according to Table 2.

[0111] II. Test Results

[0112] Table 4 Results of the Acute Skin Irritation Test of the Test Substance on Rabbits

[0113]

[0114]

[0115] From the results of the acute skin irritation test in Table 4, it can be seen that no erythema and edema occurred after 1 hour, 24 hours, 48 hours, and 72 hours of applying the hair dye samples of Examples 5 - 8 to the rabbit skin, that is, there is no skin irritation. This shows that the hair dye prepared with 2,5 - diaminophenylethanol sulfate as the main component of the dye intermediate in the present invention is a mild hair dye.

[0116] It should be noted that in the above translation, for the Chinese characters and symbols that cannot be directly translated in a specific context, they are retained in Chinese. If there are specific requirements for further processing these special characters, please let me know. Also, the "२३.८" in the temperature expression is a way to represent the number in a form that can be recognized during the translation process. If it needs to be in a more standard form, it can be adjusted according to actual needs.Example 10 Human Skin Patch Test

[0117] Suzhou Huabo Biotechnology Testing Co., Ltd. was commissioned to conduct human skin patch tests on the hair dyes prepared in Examples 5-8 in accordance with the "Cosmetic Safety Technical Specifications" (2015 edition).

[0118] I. Materials and Methods

[0119] 1. Test substance:

[0120] The dyes and oxidants listed in Examples 5-8 were prepared in a 1:1 ratio and then diluted with experimental water to a concentration of 1%.

[0121] 2. Negative control: Water used in the experiment. Positive control: Replace 2,5-diaminophenylethanol sulfate in Example 5 of Table 3 with an equal mass percentage of p-phenylenediamine, while keeping other components and contents unchanged.

[0122] 3. Subjects: A total of 30 subjects, including 5 males and 25 females, aged 23 to 59 years, with a mean age of 44.2 ± 11.3 years, who met the subject voluntary inclusion criteria.

[0123] 4. Patch Test Method: Select qualified patch test equipment and use the closed patch test method. Place approximately 0.020–0.025 mL (liquid) of the test substance into the patch test device, apply it to the back of the subject with hypoallergenic adhesive tape, remove the test substance after 24 hours, and observe the skin reaction at 0.5, 24, and 48 hours after removal. Record the results according to the skin reaction grading standard in the "Cosmetic Safety Technical Specifications" (2015 edition).

[0124] II. Test Results

[0125] Table 5 Results of human skin patch test

[0126]

[0127]

[0128] Table 5 shows the results of human skin patch tests on hair dye samples from Examples 5-8. None of the 30 subjects experienced adverse skin reactions. However, the positive control results indicate that when 2,5-diaminophenylethanol sulfate in Example 5 was replaced with an equal percentage of p-phenylenediamine, 24 hours after the patch test, one person showed a weak positive reaction (erythema), three people showed a questionable reaction (only slight erythema), and 48 hours later, three people showed a weak positive reaction (erythema), and four people showed a questionable reaction (only slight erythema). Therefore, compared to the traditional dye intermediate p-phenylenediamine, 2,5-diaminophenylethanol sulfate effectively reduces skin irritation. The hair dye of this invention, with 2,5-diaminophenylethanol sulfate as the main dye intermediate, is a mild hair dye.

[0129] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept. The scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments. The scope of protection of this invention is also limited to the equivalent technical means that can be conceived by those skilled in the art based on the inventive concept.

Claims

1. A method for preparing an anti-irritant hair dye intermediate, characterized in that... Includes the following steps: (1) Synthesis of 2-(2-hydroxyethyl)terephthalic acid (II) 100 mmol of 1-isochromone-6-carboxylic acid (I) and 300 mmol of sodium hydroxide were added to a mixed solvent of 50 mL of methanol and 150 mL of water. After the addition was complete, the mixture was heated to reflux and stirred for 4.0 h. After the reaction was completed, an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise to pH 2-3, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain 19.2 g of a white solid, namely 2-(2-hydroxyethyl)terephthalic acid (II), with a yield of 91.3%. (2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate (III) 90 mmol of 2-(2-hydroxyethyl) terephthalic acid (II) obtained in step (1) was dissolved in 90 mL of methanol. The resulting solution was added dropwise to 1.44 mol of 30% ammonia water. The mixture was stirred at room temperature for 2 h. After solvent removal and vacuum drying, 21.3 g of white solid, namely ammonium 2-(2-hydroxyethyl) terephthalate (III), was obtained, with a yield of 96.9%. (3) Synthesis of 2-(2-hydroxyethyl)terephthalamide (IV) 80 mmol of 2-(2-hydroxyethyl) terephthalic acid ammonium (III) obtained in step (2) was dissolved in 144 mL of N,N-dimethylformamide, and 256 mmol of 1-p-methylbenzenesulfonyl imidazole was added. The mixture was heated to 110 °C and reacted for 1.5 h. 240 mmol of triethylamine was added and the reaction was continued for 5 h. After the reaction was completed, 120 mL of water was added and stirred. The mixture was filtered, washed with water, and dried to obtain 15.6 g of white solid, namely 2-(2-hydroxyethyl) terephthalic acid amide (IV), with a yield of 93.7%. (4) Synthesis of the target product 2,5-diaminophenylethanol sulfate (V) 70 mmol of 2-(2-hydroxyethyl) terephthalamide (IV) and 805 mmol of sodium hydroxide obtained in step (3) were dissolved in a mixed solvent of 100 mL acetonitrile and 70 mL water. The solution was cooled to below 0 °C and then added to a suspension of 52.5 mmol of trichloroisocyanuric acid and 50 mL of water. The mixture was stirred for 1.5 h under freezing conditions, then heated to reflux and continued to react for 45 minutes. The reaction solution turned reddish-brown and the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the filtrate was extracted three times with dichloromethane (3 × 90 mL). The organic layers were combined and 84 mmol of 98% concentrated sulfuric acid was added dropwise under ice-water bath cooling to form a salt. The solution was filtered, washed with anhydrous methanol, and dried under vacuum to obtain 16.4 g of white solid, which is the sulfate (V) of the target product 2,5-diaminophenylethanol, with a yield of 93.6% and a purity of 99.2%.

2. A method for preparing an anti-irritant hair dye intermediate, characterized in that... Includes the following steps: (1) Synthesis of 2-(2-hydroxyethyl)terephthalic acid (II) 100 mmol of 1-isochromone-6-carboxylic acid (I) and 400 mmol of sodium hydroxide were added to a mixed solvent of 100 mL methanol and 80 mL water. After the addition was complete, the mixture was heated to reflux and stirred for 2.5 h. After the reaction was completed, an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise to pH 2-3, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain 19.0 g of a white solid, namely 2-(2-hydroxyethyl)terephthalic acid (II), with a yield of 90.4%. (2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate (III) 90 mmol of 2-(2-hydroxyethyl) terephthalic acid (II) obtained in step (1) was dissolved in 50 mL of methanol. The resulting solution was added dropwise to 1.08 mol of 20% ammonia water. The mixture was stirred at room temperature for 3 h. After solvent removal and vacuum drying, 21.4 g of white solid, namely ammonium 2-(2-hydroxyethyl) terephthalate (III), was obtained, with a yield of 97.4%. (3) Synthesis of 2-(2-hydroxyethyl)terephthalamide (IV) 80 mmol of 2-(2-hydroxyethyl) terephthalic acid ammonium (III) obtained in step (2) was dissolved in 120 mL of N,N-dimethylformamide, and 224 mmol of 1-p-methylbenzenesulfonyl imidazole was added. The mixture was heated to 100 °C and reacted for 2 h. 288 mmol of triethylamine was added and the reaction was continued for 4 h. After the reaction was completed, 100 mL of water was added and stirred. The mixture was filtered, washed with water, and dried to obtain 15.4 g of white solid, namely 2-(2-hydroxyethyl) terephthalic acid amide (IV), with a yield of 92.5%. (4) Synthesis of the target product 2,5-diaminophenylethanol sulfate (V) Dissolve 70 mmol of 2-(2-hydroxyethyl)terephthalamide (IV) and 770 mmol of sodium hydroxide obtained in step (3) in a mixed solvent of 84 mL acetonitrile and 84 mL water. Cool to below 0 °C and add to a suspension of 53.9 mmol of trichloroisocyanuric acid and 42 mL of water. Stir the reaction under freezing conditions for 1 h, then heat to reflux and continue the reaction for 1 h. When the reaction solution turns reddish-brown, the reaction is complete. Cool the reaction solution to room temperature, filter, and extract the filtrate three times with dichloromethane (3 × 70 mL). Combine the organic layers, add 98 mmol of 98% concentrated sulfuric acid dropwise under ice-water bath cooling to form a salt, filter, wash with anhydrous methanol, and vacuum dry. 16.6 g of white solid was obtained by drying, which is the sulfate (V) of the target product 2,5-diaminophenylethanol, with a yield of 94.8% and a purity of 99.15%.

3. A method for preparing an anti-irritant hair dye intermediate, characterized in that... Includes the following steps: (1) Synthesis of 2-(2-hydroxyethyl)terephthalic acid (II) 100 mmol of 1-isochromone-6-carboxylic acid (I) and 500 mmol of sodium hydroxide were added to a mixed solvent of 80 mL of methanol and 100 mL of water. After the addition was complete, the mixture was heated to reflux and stirred for 1.0 h. The reaction was completed, and an orange-red reaction solution was obtained. The solution was cooled to room temperature and acidified with 36% hydrochloric acid dropwise to pH 2-3, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain 18.8 g of a white solid, namely 2-(2-hydroxyethyl)terephthalic acid (II), with a yield of 89.4%. (2) Synthesis of 2-(2-hydroxyethyl)ammonium terephthalate (III) 85 mmol of 2-(2-hydroxyethyl) terephthalic acid (II) obtained in step (1) was dissolved in 80 mL of methanol. The resulting solution was added dropwise to 0.68 mol of 25% ammonia water. The mixture was stirred at room temperature for 2.5 h. After solvent removal and vacuum drying, 20.3 g of white solid, namely ammonium 2-(2-hydroxyethyl) terephthalate (III), was obtained, with a yield of 97.8%. (3) Synthesis of 2-(2-hydroxyethyl)terephthalamide (IV) 80 mmol of 2-(2-hydroxyethyl) terephthalate (III) obtained in step (2) was dissolved in 96 mL of N,N-dimethylformamide, and 192 mmol of 1-p-methylbenzenesulfonylimidazole was added. The mixture was heated to 120 °C and reacted for 1 h. 192 mmol of triethylamine was added and the reaction was continued for 3 h. After the reaction was completed, 80 mL of water was added and stirred. The mixture was filtered, washed with water, and dried to obtain 15.5 g of white solid, namely 2-(2-hydroxyethyl) terephthalamide (IV), with a yield of 93.1%. (4) Synthesis of the target product 2,5-diaminophenylethanol sulfate (V) 70 mmol of 2-(2-hydroxyethyl) terephthalamide (IV) and 840 mmol of sodium hydroxide obtained in step (3) were dissolved in a mixed solvent of 112.0 mL acetonitrile and 53.0 mL water. The solution was cooled to below 0 °C and then added to a suspension of 49.0 mmol of trichloroisocyanuric acid and 56 mL of water. The mixture was stirred for 2 h under freezing conditions, then heated to reflux and continued to react for 30 minutes. The reaction solution turned reddish-brown and the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the filtrate was extracted three times with dichloromethane (3 × 112 mL). The organic layers were combined and 112 mmol of 98% concentrated sulfuric acid was added dropwise under ice-water bath cooling to form a salt. The solution was filtered, washed with anhydrous methanol, and dried under vacuum to obtain 16.2 g of white solid, which is the sulfate (V) of the target product 2,5-diaminophenylethanol, with a yield of 92.5% and a purity of 99.3%.

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