Method for splitting trans-2, 6-dimethyl-1-indene amine

Abstract

The invention relates to the field of organic synthesis, relates to a method for splitting trans-2, 6-dimethyl-1-indene amine, and in particular relates to a method for obtaining (1R, 2S)-2, 6-dimethyl-1-indene amine by splitting trans-2, 6-dimethyl-1-indene amine by utilizing a chiral inulin compound. The method comprises the following steps: reacting a chiral inulin compound with trans-2, 6-dimethyl-1-indene amine under a heating condition to generate salt, cooling and crystallizing, and hydrolyzing the obtained solid under an alkaline condition to obtain (1R, 2S)-2, 6-dimethyl-1-indene amine. The chiral chrysanthemic acid compound is adopted as a resolving agent, a traditional amino acid derivative resolving agent is replaced, good durability and stability are achieved, and by optimizing resolving conditions and technological parameters, a universal solvent which is widely applied in the market, low in price and easy to obtain serves as a solvent system, and the resolution efficiency is improved. The resolution with high yield (greater than 97%) and high optical purity (ee value greater than 98%) is realized.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and to a method for resolving trans-2,6-dimethyl-1-indane, specifically to a method for resolving trans-2,6-dimethyl-1-indane using chiral chrysanthemic acid compounds to obtain (1R,2S)-2,6-dimethyl-1-indane. Background Technology

[0002] (1R,2S)-2,6-dimethyl-1-indeneamine is an important pesticide intermediate. It has two chiral carbons on a five-membered ring. Its unique configuration, after a series of chemical synthesis, yields triazine pesticides with excellent herbicidal activity.

[0003] The difficulty in synthesizing (1R,2S)-2,6-dimethyl-1-indane lies in the resolution method, and current resolution methods still have some shortcomings. Traditional resolution methods, such as crystallization resolution, chromatography, biological resolution, and chemical resolution, all face certain challenges in industrial application. For example, chiral resolution by chromatography is not conducive to industrial application and is costly. In addition, some resolution methods yield products with low optical purity, which is difficult to meet the requirements of high-purity drug production. For example, the authorized patent CN201710298389.6 of Shanghai Puyi Chemical Technology Co., Ltd. (a subsidiary of Yaben Chemical) reports that using R-mandelic acid for resolution yields 99.8% of the enantiomers, but secondary crystallization is required, and the yield is low at only 31.7%. Mandelic acid is used in large quantities and is expensive, making it uneconomical for industrial production. Patent CN119661374 A applied for by the Dalian Institute of Chemical Physics reports the use of chiral amino acids as resolution reagents. High-optical-purity chiral amino acids are expensive, and the recovery process is cumbersome and has a low yield, resulting in high separation costs and making them unsuitable for large-scale industrial production.

[0004] Therefore, developing an efficient, economical, and environmentally friendly resolution method, especially one capable of preparing high-purity trans-chiral indeneamine, is of great significance for advancing drug research and development and production. The resolution method not only needs to address the problems of low yield, poor stereoselectivity, and difficulties in process implementation in existing technologies, but also needs to consider factors such as the stability, recyclability, and reusability of the resolving agent to achieve industrial-scale production. Summary of the Invention

[0005] The purpose of this invention is to provide a method for resolving trans-2,6-dimethyl-1-indane using chiral chrysanthemic acid compounds to obtain (1R,2S)-2,6-dimethyl-1-indane. The method involves resolving the racemic trans-chiral indane to prepare (1R,2S)-2,6-dimethyl-1-indane.

[0006] To solve the above-mentioned technical problems and achieve the above-mentioned objectives, the present invention adopts the following technical solution: Under heating conditions, chiral chrysanthemic acid compounds react with trans-2,6-dimethyl-1-indane to form a salt. Upon cooling, crystals are precipitated. The resulting solid is hydrolyzed under alkaline conditions to yield (1R,2S)-2,6-dimethyl-1-indane. The structure of the chiral chrysanthemic acid compound is shown in general formula (I):

[0007] (I) R1 is hydrogen or methyl, R2 is methyl or CH=CR 21 R 22 , where R 21 R 22 Each can be an independent hydrogen, methyl, propyl, phenyl, or halogen.

[0008] Furthermore, the general formula (I) is:

[0009] Under heating conditions, an alcoholic solution of trans-2,6-dimethyl-1-indane is added to an alcoholic solution of chiral chrysanthemic acid compounds and reacted for 0.5-3 hours to form a salt. After cooling and crystallization, the solid obtained by filtration is subjected to hydrolysis with alkali for 0.5-3 hours. Then, an aprotic solvent is added for extraction, and the oil layer is desolventized to obtain (1R,2S)-2,6-dimethyl-1-indane. In general formula (I), R1 is hydrogen or methyl, and R2 is CH=CR 21 R 22 , where R 21 R 22 Each of these can be an independent hydrogen, methyl, propyl, phenyl, or halogen, wherein the halogen is F, Cl, Br, or I.

[0010] The alcoholic solution of the chiral chrysanthemic acid compound is prepared by adding the chiral chrysanthemic acid compound to an alcoholic solvent, heating to 40-80 ℃ and stirring to dissolve it. The alcoholic solution of trans-2,6-dimethyl-1-indane is prepared by adding trans-2,6-dimethyl-1-indane to an alcoholic solvent and heating to 40-80 °C while stirring to dissolve. The alcohol solvent is one or more of methanol, ethanol, n-butanol or propanol; The mass ratio of trans-2,6-dimethyl-1-indoleamine to alcohol solvent is 1:1-10, preferably 1:2-5; The mass ratio of the chiral chrysanthemic acid compound to the alcohol solvent is 1:1-10, preferably 1:2-5; The molar ratio of trans-2,6-dimethyl-1-indoleamine to chiral chrysanthemic acid compounds is 1:0.4-1, preferably 1:0.5-0.8.

[0011] The chiral chrysanthemic acid compound is trans-dextral DV chrysanthemic acid or levorotatory trans-dextral DV chrysanthemic acid.

[0012] The heating conditions are at a temperature of 40-80℃, preferably 50-70℃; The cooling and crystallization temperature is 5-30℃, preferably 10-25℃.

[0013] The solid obtained by filtration is dispersed by adding water and stirring. Then, alkali is added to adjust the pH to 10-12, and hydrolysis is carried out at 30-60℃ for 0.5-3 hours. Then, aprotic solvent is added for extraction. The oil layer is washed with water, dried, and desolventized to obtain (1R,2S)-2,6-dimethyl-1-indeneamine. The mass ratio of water to solid is 2-6:1, preferably 3-5:1.

[0014] The filtrate obtained by filtration was adjusted to pH 10-12 with alkali and subjected to hydrolysis at 30-60℃ for 0.5-3 hours. After desolvation, it was extracted with an aprotic solvent and the oil layer was desolvated to obtain (1S,2R)-2,6-dimethyl-1-indeneamine. The preferred hydrolysis reaction temperature is 40-55℃; The alkali is a sodium hydroxide or potassium hydroxide solution with a mass concentration of 5-50%, preferably 10-30%.

[0015] The aprotic solvent is one or more of toluene, xylene, n-hexane, cyclohexane, dichloroethane, and chloroform.

[0016] After extraction, the aqueous layer was added with an aprotic solvent, and then acidified at 20-50℃ to adjust the pH to 0.5-2. After standing and separating, the oil layer was washed with water, dried, and desolventized to recover chiral chrysanthemic acid compounds for reuse. The acid is one or more of sulfuric acid, hydrochloric acid, and phosphoric acid; The aprotic solvent is one or more of toluene, xylene, n-hexane, cyclohexane, dichloroethane, and chloroform.

[0017] The preferred acidification temperature is 25-40℃; The beneficial effects of this invention are: This invention provides a chiral chrysanthemic acid resolving agent for resolving racemic trans-2,6-dimethyl-1-indaneamine to prepare (1R,2S)-2,6-dimethyl-1-indaneamine. The advantages of this invention lie in using chiral chrysanthemic acid compounds as the resolving agent, replacing traditional amino acid derivative resolving agents. This results in better durability and stability. By optimizing the resolving conditions and process parameters, and using widely available and inexpensive general-purpose solvents, high yields (greater than 97%) and high optical purity (ee value greater than 98%) are achieved. The chiral chrysanthemic acid resolving agent has low solubility in water, allowing for a recovery rate of over 99% through solvent extraction and reuse, effectively reducing resource consumption and production costs, and improving process repeatability and the feasibility of industrial production. The resolving method is mild, simple to operate, and easy to implement for industrial production. Chiral chrysanthemic acid compounds, as resolving agents for trans-2,6-dimethyl-1-indaneamine, have significant practical value and promising application prospects. Attached Figure Description

[0018] Figure 1 The image shows the liquid phase chiral column chromatogram of trans-2,6-dimethyl-1-indeneamine, the raw material in Example 1.

[0019] Figure 2 The image shows the liquid phase chiral column chromatogram of (1R,2S)2,6-dimethyl-1-indeneamine obtained in Example 1. Detailed Implementation

[0020] The following embodiments will further illustrate the present invention, but are not intended to limit the invention.

[0021] Example 1 Preparation of (1R,2S)2,6-dimethyl-1-indeneamine dextrorotatory trans-chrysanthemate trans-2,6-dimethyl-1-indoleamine ( Figure 1 5 g of trans-2,6-dimethyl-1-indoleamine was added to 25 g of methanol and stirred and heated to 40 °C to dissolve. 4.1 g of trans-dextral chrysanthemic acid was added to 20 g of methanol and stirred and heated to 40 °C to dissolve. Then the temperature was raised to 70 °C. The methanol solution of trans-2,6-dimethyl-1-indoleamine was added dropwise to the trans-dextral chrysanthemic acid resolving agent solution over 2 minutes, maintaining the temperature at 70 °C. After the addition was completed, the temperature was maintained for 1 hour, then heating was stopped and the temperature was lowered to 25 °C. The reaction mixture was filtered to obtain 4.98 g of (1R,2S)-2,6-dimethyl-1-indoleamine dextro-trans-chrysanthemic acid salt; ee value 98.6. Preparation of (1R,2S)-2,6-dimethyl-1-indeneamine Solid-liquid separation yielded 4.98 g of solid (1R,2S)-2,6-dimethyl-1-indeneamine dextrorotatory trans-chrysanthemate. 24.9 g of water was added, and the mixture was stirred and dispersed. The pH was adjusted to 12 by dropwise addition of 15% sodium hydroxide aqueous solution. Hydrolysis was then carried out at 50°C for 1 hour. After hydrolysis, the mixture was extracted with 12.2 g of toluene. The oil layer was washed with water, dried, and desolventized to obtain 2.44 g of pure (1R,2S)-2,6-dimethyl-1-indeneamine, with a resolution of 97.6%. The liquid chromatogram is shown below. Figure 2 As shown.

[0022] Dextrorotatory trans-chrysanthemic acid recovery 49.1 g of the filtrate obtained from solid-liquid separation was adjusted to pH 12 by adding 15% sodium hydroxide aqueous solution, and the mixture was heated to 50°C for hydrolysis and maintained at this temperature for 30 minutes. After the hydrolysis was completed, the solvent was removed at atmospheric pressure and heated to 100°C to recover methanol. 12 g of toluene was added to the remaining material for extraction, and the oil layer was further removed to obtain 2.51 g of (1S,2R)-2,6-dimethyl-1-indeneamine. The aqueous layer after extraction and the aqueous layer after toluene extraction in the previous step of (1R,2S)-2,6-dimethyl-1-indane preparation were combined. 12g of toluene was added, and 30% hydrochloric acid was added dropwise at 25℃ to adjust the pH to 1. After standing for 45 minutes, the layers separated. The oil layer was washed with water, dried and desolventized to obtain 4g of dextrorotatory trans-chrysanthemic acid, which was reused for the next batch of separation.

[0023] Example 2 Preparation of (1R,2S)2,6-dimethyl-1-indanamine dextrorotatory trans-DV chrysanthemate 5 g of trans-2,6-dimethyl-1-indoleamine was added to 25 g of methanol and stirred and heated to 40 °C to dissolve. 4.5 g of trans-dextral DV chrysanthemic acid was added to 21 g of methanol and stirred and heated to 40 °C to dissolve. Then the mixture was heated to 70 °C. The methanol solution of trans-2,6-dimethyl-1-indoleamine was added dropwise to the trans-dextral chrysanthemic acid resolving agent solution over 2 minutes, maintaining the temperature at 70 °C. After the addition was completed, the mixture was kept at this temperature for another hour before heating was stopped. The temperature was then lowered to 25 °C, and the reaction mixture was filtered to obtain 5.56 g of (1R,2S)-2,6-dimethyl-1-indoleamine dextrorotatory trans-chrysanthemic acid salt; ee value 98.8. Preparation of (1R,2S)-2,6-dimethyl-1-indeneamine The preparation method was the same as in Example 1, yielding 2.42 g of pure (1R,2S)-2,6-dimethyl-1-indoleamine with a resolution efficiency of 97.1%.

[0024] Dextrorotatory trans-chrysanthemic acid recovery The preparation method was the same as in Example 1, and 4.46 g of dextrorotatory trans-DV chrysanthemic acid was recovered and reused for the next batch resolution. 2.56 g of (1S,2R)-2,6-dimethyl-1-indeneamine was obtained.

[0025] Example 3 Preparation of (1R,2S)2,6-dimethyl-1-indeneamine levorotatory trans-DV chrysanthemate 5 g of trans-2,6-dimethyl-1-indeneamine was added to 25 g of methanol and stirred and heated to 40 °C to dissolve. 4.5 g of levorotatory trans-DV chrysanthemic acid was added to 21 g of methanol and stirred and heated to 40 °C to dissolve. The methanol solution of trans-2,6-dimethyl-1-indeneamine was added dropwise to the solution of trans-dextral chrysanthemic acid resolving agent over 2 minutes, maintaining the temperature at 70 °C. After the addition was completed, the temperature was maintained for 1 hour, then heating was stopped, and the temperature was lowered to 25 °C. The reaction mixture was filtered to obtain 5.56 g of (1R,2S)-2,6-dimethyl-1-indeneamine levorotatory trans-chrysanthemic acid salt; ee value 98.7. Preparation of (1R,2S)-2,6-dimethyl-1-indeneamine The preparation method was the same as in Example 1, yielding 2.43 g of pure (1R,2S)-2,6-dimethyl-1-indoleamine with a resolution efficiency of 97.3%.

[0026] L-trans-chrysanthemic acid recovery The preparation method was the same as in Example 1, and 4.45 g of levorotatory trans-DV chrysanthemic acid was recovered and reused for the next batch resolution. 2.55 g of (1S,2R)-2,6-dimethyl-1-indeneamine was obtained.

[0027] Example 4 Preparation of (1R,2S)2,6-dimethyl-1-indeneamine levorotatory trans-DV chrysanthemate 5 g of trans-2,6-dimethyl-1-indeneamine was added to 25 g of methanol and stirred and heated to 40 °C to dissolve. 4.5 g of levorotatory trans-DV chrysanthemic acid was added to 21 g of methanol and stirred and heated to 40 °C to dissolve. Then, the temperature was raised to 70 °C. The methanol solution of trans-2,6-dimethyl-1-indeneamine was added dropwise to the solution of trans-dextral chrysanthemic acid resolving agent over 2 minutes, maintaining the temperature at 70 °C. After the addition was completed, the temperature was maintained for 1 hour, then heating was stopped, and the temperature was lowered to 25 °C. The reaction mixture was filtered to obtain 5.54 g of (1R,2S)-2,6-dimethyl-1-indeneamine levorotatory trans-chrysanthemic acid salt; ee value 98.5. Preparation of (1R,2S)-2,6-dimethyl-1-indeneamine The preparation method was the same as in Example 1, using cyclohexane as the extraction solvent. The final product (1R,2S)-2,6-dimethyl-1-indoleamine 2.42 g was obtained with a resolution efficiency of 97.1%.

[0028] L-trans-chrysanthemic acid recovery The preparation method was the same as in Example 1, and 4.43 g of levorotatory trans-DV chrysanthemic acid was recovered and reused for the next batch resolution. 2.56 g of (1S,2R)-2,6-dimethyl-1-indeneamine was obtained.

[0029] Comparative Example Preparation of (1R,2S)2,6-dimethyl-1-indeneamine mandelate 5 g of trans-2,6-dimethyl-1-indoleamine was added to 25 g of methanol and stirred and heated to 40 °C to dissolve. 4.3 g of R-mandelic acid was added to 14.3 g of methanol and stirred and heated to 40 °C until completely dissolved. This solution was then added dropwise to the methanol solution of 2,6-dimethyl-1-indoleamine and refluxed for 2 hours. After the reaction was completed, heating was stopped, and the temperature was lowered to 25 °C. The reaction mixture was filtered to obtain 5.8 g of (1R,2S)-2,6-dimethyl-1-indoleamine mandelic acid salt with an ee value of 90. 17.4 g of methanol was added to the 5.8 g of (1R,2S)-2,6-dimethyl-1-indoleamine mandelic acid salt, and the mixture was heated to reflux and held at that temperature for 1 hour. The temperature was then lowered to 25 °C and filtered to obtain 3.4 g of the solution with an ee value of 99.7.

[0030] Preparation of (1R,2S)-2,6-dimethyl-1-indeneamine The preparation method was the same as in Example 1, using cyclohexane as the extraction solvent. The final product (1R,2S)-2,6-dimethyl-1-indoleamine 1.75g ​​was obtained with a resolution efficiency of 75%.

[0031] R-mandelic acid recovery The filtrate containing mandelic acid salts and the aqueous layer after toluene extraction in the previous step of (1R,2S)-2,6-dimethyl-1-indane preparation were mixed with 12g of toluene, and 30% hydrochloric acid was added dropwise to adjust the pH to 1. The mixture was allowed to stand and separate into layers. The oil layer was washed with water, dried and desolventized to obtain 4.1g of R-mandelic acid.

[0032] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for resolving trans-2,6-dimethyl-1-indoleamine, characterized in that: Under heating conditions, chiral chrysanthemic acid compounds react with trans-2,6-dimethyl-1-indane to form a salt. Upon cooling, crystals are precipitated. The resulting solid is hydrolyzed under alkaline conditions to yield (1R,2S)-2,6-dimethyl-1-indane. The structure of the chiral chrysanthemic acid compound is shown in general formula (I): （I） R1 is hydrogen or methyl, R2 is methyl or CH=CR 21 R 22 , where R 21 R 22 Each can be an independent hydrogen, methyl, propyl, phenyl, or halogen.

2. The method according to claim 1, characterized in that: Under heating conditions, an alcoholic solution of trans-2,6-dimethyl-1-indane is added to an alcoholic solution of chiral chrysanthemic acid compounds and reacted for 0.5-3 hours to form a salt. After cooling and crystallization, the solid obtained by filtration is subjected to hydrolysis with alkali for 0.5-3 hours. Then, an aprotic solvent is added for extraction, and the oil layer is desolventized to obtain (1R,2S)-2,6-dimethyl-1-indane. In general formula (I), R1 is hydrogen or methyl, and R2 is CH=CR 21 R 22 , where R 21 R 22 Each of these can be an independent hydrogen, methyl, propyl, phenyl, or halogen, wherein the halogen is F, Cl, Br, or I.

3. The method according to claim 2, characterized in that: The alcoholic solution of the chiral chrysanthemic acid compound is prepared by adding the chiral chrysanthemic acid compound to an alcoholic solvent, heating to 40-80 ℃ and stirring to dissolve it. The alcoholic solution of trans-2,6-dimethyl-1-indane is prepared by adding trans-2,6-dimethyl-1-indane to an alcoholic solvent and heating to 40-80 °C while stirring to dissolve. The alcohol solvent is one or more of methanol, ethanol, n-butanol or propanol; The mass ratio of trans-2,6-dimethyl-1-indoleamine to the alcohol solvent is 1:1-10; The mass ratio of the chiral chrysanthemic acid compound to the alcohol solvent is 1:1-10; The molar ratio of trans-2,6-dimethyl-1-indoleamine to chiral chrysanthemic acid compounds is 1:0.4-1; The chiral chrysanthemic acid compound is trans-dextral DV chrysanthemic acid or levorotatory trans-dextral DV chrysanthemic acid.

4. The method according to claim 1 or 2, characterized in that: The heating temperature is 40-80℃; the cooling and crystallization temperature is 5-30℃.

5. The method according to claim 2, characterized in that: The solid obtained by filtration is dispersed by adding water and stirring. Then, alkali is added to adjust the pH to 10-12, and hydrolysis is carried out at 30-60℃ for 0.5-3 hours. Then, aprotic solvent is added for extraction. The oil layer is washed with water, dried, and desolventized to obtain (1R,2S)-2,6-dimethyl-1-indoleamine. The mass ratio of water to solid is 2-6:

1.

6. The method according to claim 2, characterized in that: The filtrate was adjusted to pH 10-12 with alkali and subjected to hydrolysis at 30-60℃ for 0.5-3 hours. After desolvation, it was extracted with an aprotic solvent and the oil layer was desolvated to obtain (1S,2R)-2,6-dimethyl-1-indane.

7. The method according to any one of claims 5 or 6, characterized in that: The alkali is a sodium hydroxide or potassium hydroxide solution with a mass concentration of 5-50%; the aprotic solvent is one or more of toluene, xylene, n-hexane, cyclohexane, dichloroethane, and chloroform.

8. The method according to claim 5 or 6, characterized in that: After extraction, the aqueous layer was added with an aprotic solvent, and then acidified at 20-50℃ to adjust the pH to 0.5-2. After standing and separating, the oil layer was washed with water, dried, and desolventized to recover chiral chrysanthemic acid compounds for reuse. The aprotic solvent is one or more of toluene, xylene, n-hexane, cyclohexane, dichloroethane, and chloroform; the acid is one or more of sulfuric acid, hydrochloric acid, and phosphoric acid.

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