A method for preparing (1R,2S)-2,6-dimethyl-1-indeneamine using a chiral amino acid resolving agent

Abstract

This invention discloses a chiral amino acid resolving agent for the preparation of trans-chiral indeneamine. Specifically, it provides a chiral amino acid derivative as a resolving agent for the resolution of trans-2,6-dimethyl-1-indeneamine to prepare (1R,2S)-2,6-dimethyl-1-indeneamine. The resolution process is conducted under mild conditions, using a widely available and inexpensive general-purpose solvent. (1R,2S)-2,6-dimethyl-1-indeneamine was obtained with high yield and high optical purity. The beneficial effects of this invention are: obtaining (1R,2S)-2,6-dimethyl-1-indeneamine with an ee value greater than 97% and a resolution yield greater than 95%. Due to the poor hydrophilicity of the resolving agent, it can be recycled with high recovery rate, the process has high repeatability, and it is easy to achieve industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a chiral amino acid resolving agent for the preparation of 2,6-dimethyl-1-indeneamine. Background Technology

[0002] The latest triazine herbicide to be marketed is indaziflam (trade name Specticle), development code BCS-AA10717, launched by Bayer in 2011. Indaziflam is a new compound obtained by structural modification at several sites in the triazine-fluorinate molecule, resulting in significantly enhanced herbicidal activity. Its chemical structure differs considerably from previously marketed triazine herbicides, being more novel and complex, and exhibiting superior performance. The structure is shown in Formula 1 below.

[0003]

[0004] Currently, the synthesis of indazine-flufenoxam involves two fragments: the 1-aminodihydroindazine fragment and the triazine fragment. As shown in Formula 1, the 1-aminodihydroindazine fragment is (1R,2S)-2,6-dimethyl-1-indazine. Its synthesis methods mainly fall into two categories. One method involves enantiomeric resolution of indazine. Reports indicate that a suspension of L(+)-aspartic acid is formed in boiling methanol. A methanol solution of 1-aminoindazine is added to the boiling suspension, and the mixture is stirred at 50°C for 6 hours. The mixture is then stirred to room temperature and kept overnight. The precipitate is filtered and dried to obtain (R)-1-aminoindazine L(+)-aspartic acid salt, with a yield of 66% and an optical purity of 91.9%. Alternatively, the racemic 1-aminoindane can be dissolved in methanol, stirred and heated to 50°C, and an L(-)-malic acid methanol solution can be added. The reactants are cooled to 35°C, seeded, and the temperature is lowered to 20°C after 2 hours. This temperature is maintained for 3 hours, and the precipitate is filtered, washed with methanol, and dried to obtain (R)-1-aminoindane L(-)-malate, with a yield of 47% and an optical purity of 99.75% (WO2012116752). There are also reports using D-mandelic acid as a chiral resolving agent, and a mixture of alcohol and water... Using a solvent, racemic 1-aminoindane is added dropwise under reflux. 1-Aminoindane reacts with D-mandelic acid to form an enantiomeric salt. Based on the different solubilities of the enantiomers, D-mandelic acid salts of SI-aminoindane are crystallized and separated. After purification and alkalization, (S)-1-aminoindane is obtained with a yield of 34% and an optical purity of 99.2% (CN105061219A). Alternatively, lipases using biocatalysts, such as *Pseudomonas cepacia*, *Candida cylindracea*, or *Candida antarcticus*, or the commercially available lipase "Novozym435," can be used to obtain (1R,2S)-indane (CN1747939). Another suitable method is that established by J. M. Assaletta, involving dynamic kinetic resolution followed by nucleophilic substitution to obtain chiral indane. The method consists of two steps: In the first step, indanone is hydrogenated to the corresponding indanol using a ruthenium-based Noyori / Ikariya catalyst. The reducing agent enters from the less sterically hindered side, opposite the methyl group, forming cis-indanone. Under the chiral induction of the ruthenium catalyst, only (2S)-indanone is reduced, while the remaining (2R)-indanone undergoes an equilibrium reaction under the reaction conditions to yield (2R / S)-indanone. Therefore, the racemic indanone is completely converted to (1S,2S)-indanol, exhibiting high diastereomeric and enantiomeric selectivity. In the second step, the hydroxyl group is substituted with an azide group (through conversion with diphenylphosphine-phosphated azide), achieving complete configuration inversion. Subsequently, a stoein reduction is performed with triphenylphosphine to obtain the desired (1R,2S)-indanamine.Although this method has high stereoselectivity, the two-step yield is only 50%, and a large amount of azide compounds and triphenylphosphine are required in the intermediate alcohol to amine process. In industrial production, the process technology is difficult to implement and is not economical, making it difficult to mass-produce on a large scale (Tetrahedron (2007), 63 (29), 6755-6763). Summary of the Invention

[0005] This invention provides a method for resolving racemic trans-2,6-dimethyl-1-indane using a chiral amino acid derivative as a resolving agent to prepare (1R,2S)-2,6-dimethyl-1-indane. The advantages of this invention are: obtaining (1R,2S)-2,6-dimethyl-1-indane with an ee value greater than 97%, a resolution yield greater than 95%, recyclability of both the resolving agent and solvent, mild resolving conditions, and the use of widely available and inexpensive general-purpose solvents, resulting in minimal waste pollution.

[0006] This invention provides a chiral amino acid resolving agent for preparing trans-chiral indeneamine. The chiral amino acid resolving agent has the following general structural formula (Formula 1):

[0007]

[0008] The R group can be methyl, ethyl, n-propyl, isopropyl, phenyl, or benzyl.

[0009] (1R,2S)-2,6-dimethyl-1-indeneamine, with the structural formula shown in Formula 2:

[0010]

[0011] Specific separation steps: Add the chiral amino acid derivative to the solvent, stir and heat until dissolved and clear, then slowly add an ethyl acetate solution of trans-2,6-dimethyl-1-indane. After the addition is complete, stop heating and precipitate 2,6-dimethyl-1-indane salt. Add sodium hydroxide solution to the ammonium salt precipitate obtained by filtration, extract with methyl tert-butyl ether, dry with anhydrous sodium sulfate, and concentrate to obtain trans-chiral indane.

[0012] The solvent mentioned in the steps is methanol, ethanol, toluene, petroleum ether, ethyl acetate or water.

[0013] The mass ratio of the chiral amino acid derivative to the solvent in the steps is 1:1-20, preferably 1:2-8.

[0014] The mass ratio of the bio-trans-2,6-dimethyl-1-indoleamine to the solvent in the steps is 1:1-20, preferably 1:2-8.

[0015] The molar ratio of trans-2,6-dimethyl-1-indoleamine to the chiral amino acid derivative in the steps is 1:0.1-2, preferably 1:0.5-2.

[0016] The temperature of the reaction system described in the steps is 0-160℃, preferably 20-100℃.

[0017] The concentration of the sodium hydroxide solution mentioned in the steps is 5-50%, preferably 10-30%.

[0018] The mass ratio of ammonium salt to sodium hydroxide solution used in the steps is 1:1-20, preferably 1:5-10.

[0019] The pH value of the system after adding alkali in the step is 8-13, preferably 9-12.

[0020] This invention provides a chiral amino acid derivative as a resolving agent for the resolution of trans-2,6-dimethyl-1-indane to prepare (1R,2S)-2,6-dimethyl-1-indane. The resolution process is conducted under mild conditions, using a widely available and inexpensive general-purpose solvent. (1R,2S)-2,6-dimethyl-1-indane was obtained in high yield and with high optical purity. The advantages of this invention are: obtaining (1R,2S)-2,6-dimethyl-1-indane with an ee value greater than 97% and a resolution yield greater than 95%. Due to the poor hydrophilicity of the resolving agent, it can be recycled with high recovery rates, resulting in high process repeatability and easy industrial-scale production. Attached image description:

[0021] Figure 1 The gas chromatogram of (1R,2S)-2,6-dimethyl-1-indeneamine obtained in Example 1;

[0022] Figure 2 The liquid chromatogram of the (1R,2S)-2,6-dimethyl-1-indeneamine derivative obtained in Example 1;

[0023] Figure 3 The 1H NMR spectrum of chiral (1R,2S)-2,6-dimethyl-1-indeneamine obtained in Example 1; Detailed Implementation

[0024] The following examples will further illustrate the present invention, but are not intended to limit the invention. In the examples, the NMR of the products was determined using a Bruker 400M NMR spectrometer. The cis-trans ratio analysis of (1R,2S)-2,6-dimethyl-1-indane was performed using an Agilent 7890 series gas chromatograph under the following conditions: column: PEG20M: 30m*320μm*0.25μm, column inlet pressure: 9.8764mp (flow rate 1.5ml / min), injection port temperature: 250°C, detector temperature: 250°C, column temperature: 50°C, hold time: 2 minutes, ramp rate: 10°C / min, stop temperature: 280°C, hold time: 5 minutes. The ee value of (1R,2S)-2,6-dimethyl-1-indane was determined by liquid chromatography after product derivatization under the following conditions: column: CHIRALPAK AD-H isopropanol / water = 97 / 3, 254 nm, 0.8 ml / min, column temperature 40 °C.

[0025] In the examples below, the raw material trans-2,6-dimethyl-1-indane, namely trans-2,6-dimethyl-1-aminoindane, was prepared using Examples 1 and 5 reported in patent CN108794339A.

[0026] Example 1

[0027]

[0028] 15.7 g of N-isopropyl-L-proline and 80 g of anhydrous ethanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to 65 °C until dissolved and transparent. Then, an ethyl acetate solution of trans-2,6-dimethyl-1-indeneamine (16.1 g indeneamine and 80 g ethyl acetate) was added dropwise over 30 minutes. After the addition was complete, the system was slowly cooled. After 3 hours, it was cooled to room temperature and maintained for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum. It was then added to 50 g of 15% sodium hydroxide aqueous solution and extracted with 60 g of methyl tert-butyl ether. The organic phase was dried over anhydrous sodium sulfate, concentrated, and analyzed by gas chromatography to obtain 7.9 g of (1R,2S)-2,6-dimethyl-1-indeneamine, with a resolution of 98.1%. The 1H NMR data are as follows:

[0029] 1 H NMR (400MHz, DMSO) δ7.10 (s, 1H), 7.00 (d, J = 7.6Hz, 1H), 6.96-

[0030] 6.87(m,1H),3.56(d,J=8.6Hz,1H),2.86(dd,J=15.1,7.5Hz,1H),2.36-

[0031] 2.28(m,1H),2.27(s,3H),1.90-1.83(m,1H),1.18(d,J=6.7Hz,3H).

[0032] Derivatization reaction conditions (the methods in the following examples are the same as those here):

[0033] Take 0.5g of the product and add it to 10ml of dichloromethane. Add 0.33g of triethylamine and stir at 0-5℃. Add 0.43g of benzoyl chloride and keep the reaction at room temperature for 1 hour. Column chromatography (ethyl acetate / petroleum ether = 1:5, volume ratio) yields the derivatized product. NMR confirms the result, and HPLC analysis shows 97.8% ee.

[0034] Resolving agent recovery scheme (the methods in the following examples are the same as those described here):

[0035] The filtrate after separation and the aqueous phase after alkaline hydrolysis of ammonium salt were combined, concentrated to remove organic matter, and 6N hydrochloric acid was added to neutralize the pH of the system to 5-6. Methyl tert-butyl ether was added for extraction (i.e., extraction), and the solution was dried and concentrated with anhydrous sodium sulfate to obtain 15.2 g of N-isopropyl-L-proline with a recovery rate of 96.8%.

[0036] Example 2

[0037]

[0038] 12.9 g of N-methyl-L-proline and 65 g of anhydrous ethanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to 75 °C until it dissolved and became transparent. Then, an ethyl acetate solution of trans-2,6-dimethyl-1-indeneamine (16.1 g of indeneamine and 85 g of ethyl acetate) was added dropwise over 30 minutes. After the addition was completed, the system was slowly cooled. After 3 hours, the mixture was cooled to room temperature and kept for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum. It was then added to 50 g of 20% sodium hydroxide aqueous solution and extracted with 50 g of methyl tert-butyl ether. After drying with anhydrous sodium sulfate, the extract was concentrated to obtain 7.88 g of (1R,2S)-2,6-dimethyl-1-indeneamine, with a resolution of 97.9%. After derivatization, liquid chromatography analysis showed a purity of 98.4% ee.

[0039] Example 3

[0040]

[0041] 19.1 g of N-phenyl-L-proline and 120 g of anhydrous ethanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to 60 °C until dissolved and transparent. Then, an ethyl acetate solution of trans-2,6-dimethyl-1-indeneamine (16.1 g of indeneamine and 85 g of ethyl acetate) was added dropwise over 30 minutes. After the addition was complete, the system was slowly cooled. After 3 hours, the mixture was cooled to room temperature and kept at that temperature for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum. It was then added to 70 g of 15% sodium hydroxide aqueous solution and extracted with 50 g of methyl tert-butyl ether. After drying with anhydrous sodium sulfate, the extract was concentrated to obtain 7.95 g of (1R,2S)-2,6-dimethyl-1-indeneamine, with a resolution of 98.7%. After derivatization, liquid chromatography analysis showed a purity of 98.6% ee.

[0042] Example 4

[0043]

[0044] 14.3 g of N-ethyl-L-proline and 70 g of anhydrous ethanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to 65 °C until dissolved and transparent. Then, an ethyl acetate solution of trans-2,6-dimethyl-1-indeneamine (16.1 g of indeneamine and 80 g of ethyl acetate) was added dropwise over 30 minutes. After the addition was complete, the system was slowly cooled. After 3 hours, the mixture was cooled to room temperature and kept at that temperature for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum. It was then added to 50 g of 15% sodium hydroxide aqueous solution and extracted with 50 g of methyl tert-butyl ether. After drying with anhydrous sodium sulfate, the extract was concentrated to obtain 7.92 g of (1R,2S)-2,6-dimethyl-1-indeneamine, with a resolution of 98.4%. After derivatization, liquid chromatography analysis showed a purity of 98.7% ee.

[0045] Example 5

[0046]

[0047] 20.5 g of N-benzyl-L-proline and 160 g of anhydrous ethanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to 80 °C until dissolved and transparent. Then, an ethyl acetate solution of trans-2,6-dimethyl-1-indeneamine (16.1 g indeneamine and 80 g ethyl acetate) was added dropwise over 30 minutes. After the addition was complete, the system was slowly cooled. After 3 hours, the mixture was cooled to room temperature and maintained for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum. It was then added to 90 g of 20% sodium hydroxide aqueous solution and extracted with 50 g of methyl tert-butyl ether. After drying with anhydrous sodium sulfate, the extract was concentrated to obtain 7.85 g of (1R,2S)-2,6-dimethyl-1-indeneamine, with a resolution of 97.5%. After derivatization, liquid chromatography analysis showed a purity of 98.1% ee.

[0048] Example 6

[0049]

[0050] 15.7 g of N-propyl-L-proline and 75 g of anhydrous ethanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to 60 °C until dissolved and transparent. Then, an ethyl acetate solution of trans-2,6-dimethyl-1-indeneamine (16.1 g indeneamine and 85 g ethyl acetate) was added dropwise over 30 minutes. After the addition was complete, the system was slowly cooled. After 3 hours, the mixture was cooled to room temperature and maintained for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum. It was then added to 60 g of 10% sodium hydroxide aqueous solution and extracted with 50 g of methyl tert-butyl ether. After drying with anhydrous sodium sulfate, the extract was concentrated to obtain 7.7 g of (1R,2S)-2,6-dimethyl-1-indeneamine, with a resolution of 95.6%. After derivatization, liquid chromatography analysis showed a purity of 97.1% ee.

Claims

1. A method for preparing a trans-chiral indenylamine using a chiral amino acid resolving agent, characterized by: The chiral amino acid resolving agent has the following formula 1 structure general formula: Formula 1, wherein the R group is one of methyl, ethyl, n-propyl, isopropyl, phenyl or benzyl; the resolving agent is used to resolve the racemic trans-2,6-dimethyl-1-indenamine to prepare (1R,2S)-2,6-dimethyl-1-indenamine; the chiral amino acid resolving agent is added into a solvent, stirred and heated to 40-120℃ until dissolved and clear, then the ethyl acetate solution of trans-2,6-dimethyl-1-indenamine is added dropwise, after the dropwise addition is completed, the heating is stopped and the temperature is lowered to room temperature, the 2,6-dimethyl-1-indenamine salt is precipitated, the obtained amine salt is added into a sodium hydroxide solution, methyl tert-butyl ether is used for extraction, the organic phase is dried with anhydrous sodium sulfate and then concentrated to obtain the trans-body chiral indenamine, i.e. (1R,2S)-2,6-dimethyl-1-indenamine, and its structural formula is shown in formula 2: Formula 2.

2. The method of claim 1, wherein: The solvent is one or more of methanol, ethanol, toluene, petroleum ether, ethyl acetate or water.

3. The method of claim 1, wherein: The mass ratio of the chiral amino acid resolving agent to the solvent is 1:1-20.

4. The method of claim 3, wherein: The mass ratio of the chiral amino acid resolving agent to the solvent is 1:2-8.

5. The method of claim 1, wherein: The mass ratio of trans-2,6-dimethyl-1-indanamine to ethyl acetate is 1:1-20.

6. The method of claim 5, wherein: The mass ratio of trans-2,6-dimethyl-1-indanamine to ethyl acetate is 1:2-8.

7. The method of claim 1, wherein: The molar ratio of trans-2,6-dimethyl-1-indanamine to the chiral amino acid resolving agent is 1:0.1-2.

8. The method of claim 7, wherein: The molar ratio of trans-2,6-dimethyl-1-indanamine to the chiral amino acid resolving agent is 1:0.5-1.

9. The method of claim 1, wherein: The temperature of the reaction system is 40-120℃.

10. The method of claim 9, wherein: The temperature of the reaction system is 50-100℃.

11. The method of claim 1, wherein: The mass concentration of the sodium hydroxide solution is 5-50%, and the mass ratio of the amine salt to the sodium hydroxide solution is 1:1-20.

12. The method of claim 11, wherein: The mass concentration of the sodium hydroxide solution is 10-30%, and the mass ratio of the amine salt to the sodium hydroxide solution is 1:5-10.

13. The method of claim 1, wherein: The resolving agent can be recycled.

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