Method for preparing (1R, 2S)-2, 6-dimethyl-1-indene amine by adopting chiral amino acid resolving agent

Abstract

The invention discloses a chiral amino acid resolving agent for preparing trans chiral indene amine, and particularly provides a chiral amino acid derivative which is used as a resolving agent for resolving trans-2, 6-dimethyl-1-indene amine and preparing (1R, 2S)-2, 6-dimethyl-1-indene amine. According to the method, the conditions of the resolution process are mild, the used solvent is a general solvent which is widely applied in the market, low in price and easy to obtain, and the (1R, 2S)-2, 6-dimethyl-1-indene amine is obtained with high yield and high optical purity. The method has the beneficial effects that (1R, 2S)-2, 6-dimethyl-1-indene amine is obtained, the ee value of the (1R, 2S)-2, 6-dimethyl-1-indene amine is greater than 97%, and the resolution yield is greater than 95%. As the resolving agent is poor in hydrophilicity, the resolving agent can be recycled at a high recovery rate, the process repeatability is high, and industrial production is easy to realize.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a chiral amino acid splitting agent for preparing 2,6-dimethyl-1-indenamine. Background Art

[0002] The latest triazine herbicide to be launched is indaziflam (trade name Specticle), developed under the code name BCS-AA10717 and launched by Bayer in 2011. Indaziflam is a new compound obtained by structural modification of several sites in the triazine molecule, and its herbicidal activity is significantly improved. Its chemical structure is quite different from that of previously launched triazine herbicides, with a more novel and complex structure and better performance. The structure is shown in Formula 1 below.

[0003]

[0004] At present, the synthesis of indazine fluazifop is divided into two fragments, namely, 1-aminodihydroindenyl fragment and triazine fragment. As shown in Formula 1, the 1-aminodihydroindenyl fragment is (1R, 2S)-2,6-dimethyl-1-indenamine, and its synthesis method is mainly divided into two methods. One method is to separate the enantiomers of indenamine. It is reported that L(+)-aspartic acid is used to form a suspension in boiling methanol, and a methanol solution of 1-aminoindane is added to the boiling suspension, stirred at 50°C for 6 hours, and then the mixture is stirred to room temperature overnight. After filtering and drying the precipitate, (R)-1-aminoindane L(+)-aspartate is obtained, with a yield of 66% and an optical purity of 91.9%. Alternatively, the racemic 1-aminoindan is dissolved in methanol, stirred and heated to 50°C, and L(-)-malic acid methanol solution is added thereto, the reactant is cooled to 35°C, and the temperature is lowered to 20°C 2 hours after the addition of the seed crystals, and maintained for 3 hours. The precipitate is filtered, washed with methanol, and dried to obtain (R)-1-aminoindan L(-)-malate, with a yield of 47% and an optical purity of 99.75% (WO2012116752); there are also reports on the use of D-mandelic acid as a chiral resolving agent, a mixture of alcohol and water The solution is used as a solvent, racemic 1-aminoindan is added dropwise under heating and reflux conditions, 1-aminoindan reacts with D-mandelic acid to form enantiomeric salts, and then the D-mandelic acid salt of SI-aminoindan is crystallized and separated according to the different solubility of the enantiomeric salts, and then purified and alkalized to obtain (S)-1-aminoindan with a yield of 34% and an optical purity of 99.2% (CN105061219A); there are also lipases using biocatalysts, such as Pseudomonas cepacia, Candida cylindracea or Candida antarctica, or commercially available lipase "Novozym435", to obtain (1R, 2S)-indeneamine (CN1747939). Another suitable method is established by JM Lassaletta, which involves dynamic kinetic resolution, followed by nucleophilic substitution to obtain chiral indeneamine. The method consists of two steps: in the first step, indanone is hydrogenated to the corresponding indanol in the presence of a ruthenium-based Noyori / Ikariya-type catalyst. The reducing agent enters from the less sterically hindered side, opposite the methyl group, to form the cis-indene. Under the chiral induction of the ruthenium catalyst, only the (2S)-indanone is reduced, and the remaining (2R)-indanone undergoes an equilibrium reaction under the reaction conditions to give the (2R / S)-indanone. Therefore, the racemic indanone is completely converted to the (1S,2S)-indanol with high diastereomeric and enantiomeric selectivity. In the second step, the hydroxyl group is replaced by an azido group (by conversion with diphenylphosphorylated azide), achieving complete configuration inversion. Subsequently, a Stoine-type reduction with triphenylphosphine is performed to give the desired (1R,2S)-indamine.Although this method has high stereoselectivity, the two-step yield is only 50%, and a large amount of azide compounds and triphenylphosphine are used in the process from intermediate alcohol to amine. In industrial production, the process technology is difficult to implement, uneconomical, and difficult to mass produce (Tetrahedron (2007), 63 (29), 6755-6763). Summary of the invention

[0005] The present invention provides a method for preparing (1R, 2S)-2,6-dimethyl-1-indenamine by splitting racemic trans-2,6-dimethyl-1-indenamine using a chiral amino acid derivative as a splitting agent. The present invention has the advantages of obtaining (1R, 2S)-2,6-dimethyl-1-indenamine with an ee value greater than 97% and a splitting yield greater than 95%, the splitting agent and the solvent can be recycled, the splitting process conditions are mild, the solvent used is a general solvent that is widely used in the market and is cheap and easily available, and the three wastes pollution is small.

[0006] The present invention provides a chiral amino acid resolving agent for preparing trans-isomer chiral indaneamine, wherein the chiral amino acid resolving agent has the following general structural formula (Formula 1):

[0007]

[0008] Among them, the R group is methyl, ethyl, n-propyl, isopropyl, phenyl, benzyl.

[0009] (1R,2S)-2,6-dimethyl-1-indenylamine, its structural formula is shown in (Formula 2):

[0010]

[0011] Specific separation steps: add the chiral amino acid derivative into the solvent, stir and heat until dissolved and clarified, slowly add the ethyl acetate solution of trans-2,6-dimethyl-1-indenylamine, stop heating after the addition is completed, precipitate 2,6-dimethyl-1-indenylamine 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 the trans-isomer chiral indenylamine.

[0012] The solvent in the step 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 step is 1:1-20, preferably 1:2-8.

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

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

[0016] The temperature of the reaction system in the step is 0-160°C, preferably 20-100°C.

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

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

[0019] After the alkali is added in the step and released, the pH value of the system is 8-13, preferably 9-12.

[0020] The present invention provides a chiral amino acid derivative as a resolving agent for resolving trans-2,6-dimethyl-1-indenamine to prepare (1R,2S)-2,6-dimethyl-1-indenamine. The conditions of the resolving process are mild, and the solvent used is a general solvent that is widely used in the market and is cheap and easily available. (1R,2S)-2,6-dimethyl-1-indenamine is obtained with high yield and high optical purity. The beneficial effects of the present invention are: (1R,2S)-2,6-dimethyl-1-indenamine is obtained, and its ee value is greater than 97%, and the resolving yield is greater than 95%. Since the resolving agent has poor hydrophilicity, it can be recycled with a high recovery rate, the process has high repeatability, and it is easy to realize industrial production. Description of the drawings:

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

[0022] Figure 2 This is the liquid chromatography spectrum of the (1R, 2S)-2,6-dimethyl-1-indenylamine derivative obtained in Example 1;

[0023] Figure 3 This is the H NMR spectrum of chiral (1R,2S)-2,6-dimethyl-1-indenylamine obtained in Example 1; DETAILED DESCRIPTION

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

[0025] The raw material trans-2,6-dimethyl-1-indenylamine in the following examples is trans-2,6-dimethyl-1-aminoindan, which is prepared by Example 1 and Example 5 reported in patent CN108794339A.

[0026] Example 1

[0027]

[0028] Add 15.7g of N-isopropyl-L-proline and 80g of anhydrous ethanol to a 500ml four-necked bottle, stir and heat to 65°C, dissolve and become transparent, then drop ethyl acetate solution of trans-2,6-dimethyl-1-indenamine (16.1g indenamine and 80g ethyl acetate), add dropwise after the dropwise addition is completed in 30 minutes, slowly cool the system to room temperature after 3 hours, keep for 1 hour, filter, wash the filter cake with ethyl acetate and drain, add to 50g of 15% sodium hydroxide aqueous solution, extract with 60g of methyl tert-butyl ether (i.e., extract), dry the organic phase with anhydrous sodium sulfate, concentrate and analyze by gas chromatography to obtain 7.9g of (1R,2S)-2,6-dimethyl-1-indenamine, with a resolution yield of 98.1%. The H-NMR spectrum 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 following examples are the same as here):

[0033] Take 0.5 g of the product and add 10 ml of dichloromethane, add 0.33 g of triethylamine, add 0.43 g of benzoyl chloride under stirring at 0-5°C, keep the reaction at room temperature for 1 hour, and obtain the derivatized product by column chromatography (ethyl acetate / petroleum ether=1:5, volume ratio) for NMR confirmation and HPLC analysis of 97.8% ee.

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

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

[0036] Example 2

[0037]

[0038] Add 12.9 g of N-methyl-L-proline and 65 g of anhydrous ethanol to a 500 ml four-necked bottle, stir and heat to 75°C, and after dissolving and becoming transparent, add dropwise a solution of trans-2,6-dimethyl-1-indenamine in ethyl acetate (16.1 g indenamine and 85 g ethyl acetate). After the addition is completed in 30 minutes, the system is slowly cooled down to room temperature after 3 hours, maintained for 1 hour, filtered, the filter cake is washed with ethyl acetate and then dried, added to 50 g of 20% sodium hydroxide aqueous solution, extracted with 50 g of methyl tert-butyl ether, dried over anhydrous sodium sulfate, and concentrated to obtain 7.88 g of (1R, 2S)-2,6-dimethyl-1-indenamine, with a resolution yield of 97.9%. After derivatization, liquid chromatography analysis yielded 98.4% ee.

[0039] Example 3

[0040]

[0041] Add 19.1g of N-phenyl-L-proline and 120g of anhydrous ethanol to a 500ml four-necked bottle, stir and heat to 60°C, and after dissolving and becoming transparent, add dropwise a solution of trans-2,6-dimethyl-1-indenylamine in ethyl acetate (16.1g indenylamine and 85g ethyl acetate). After the addition is completed in 30 minutes, the system is slowly cooled down, and after 3 hours, it is cooled to room temperature, maintained for 1 hour, filtered, the filter cake is washed with ethyl acetate and then dried, added to 70g of 15% sodium hydroxide aqueous solution, extracted with 50g of methyl tert-butyl ether, dried with anhydrous sodium sulfate, and concentrated to obtain 7.95g of (1R,2S)-2,6-dimethyl-1-indenylamine, with a resolution yield of 98.7%. After derivatization, liquid chromatography analysis yields 98.6% ee.

[0042] Example 4

[0043]

[0044] Add 14.3g of N-ethyl-L-proline and 70g of anhydrous ethanol to a 500ml four-necked bottle, stir and heat to 65°C, dissolve and become transparent, then drop ethyl acetate solution of trans-2,6-dimethyl-1-indenamine (16.1g indenamine and 80g ethyl acetate), add dropwise after the dropwise addition is completed in 30 minutes, slowly cool the system to room temperature after 3 hours, keep it for 1 hour, filter, wash the filter cake with ethyl acetate and drain, add it to 50g of 15% sodium hydroxide aqueous solution, extract it with 50g of methyl tert-butyl ether, dry it with anhydrous sodium sulfate, and concentrate to obtain 7.92g of (1R,2S)-2,6-dimethyl-1-indenamine, with a resolution yield of 98.4%. After derivatization, liquid chromatography analysis shows 98.7% ee.

[0045] Example 5

[0046]

[0047] Add 20.5g of N-benzyl-L-proline and 160g of anhydrous ethanol to a 500ml four-necked bottle, stir and heat to 80°C, and after dissolving and becoming transparent, add dropwise a solution of trans-2,6-dimethyl-1-indenylamine in ethyl acetate (16.1g indenylamine and 80g ethyl acetate). After 30 minutes of dropwise addition, the system is slowly cooled down, and after 3 hours, it is cooled down to room temperature, maintained for 1 hour, filtered, the filter cake is washed with ethyl acetate and then dried, added to 90g of 20% sodium hydroxide aqueous solution, extracted with 50g of methyl tert-butyl ether, dried with anhydrous sodium sulfate, and concentrated to obtain 7.85g of (1R,2S)-2,6-dimethyl-1-indenylamine, with a resolution yield of 97.5%. After derivatization, liquid chromatography analysis yields 98.1% ee.

[0048] Example 6

[0049]

[0050] Add 15.7g of N-propyl-L-proline and 75g of anhydrous ethanol to a 500ml four-necked bottle, stir and heat to 60°C, dissolve and become transparent, then drop ethyl acetate solution of trans-2,6-dimethyl-1-indenamine (16.1g indenamine and 85g ethyl acetate), add dropwise after the dropwise addition is completed in 30 minutes, slowly cool the system to room temperature after 3 hours, keep it for 1 hour, filter, wash the filter cake with ethyl acetate and drain, add it to 60g of 10% sodium hydroxide aqueous solution, extract it with 50g of methyl tert-butyl ether, dry it with anhydrous sodium sulfate, and concentrate to obtain 7.7g of (1R,2S)-2,6-dimethyl-1-indenamine, with a resolution yield of 95.6%. After derivatization, liquid chromatography analysis shows 97.1% ee.

Claims

1. A method for preparing trans-isomer chiral indaneamine using a chiral amino acid resolving agent, characterized in that: The chiral amino acid resolving agent has the following general structural formula (Formula 1): Wherein, the R group is one or more of methyl, ethyl, n-propyl, isopropyl, phenyl or benzyl; The chiral amino acid resolving agent is used to resolve racemic trans-2,6-dimethyl-1-indenamine to prepare (1R, 2S)-2,6-dimethyl-1-indenamine.

2. The method according to claim 1, characterized in that: The chiral amino acid resolving agent is added to the solvent, stirred and heated at 40-120°C until dissolved and clarified, and then the ethyl acetate solution of trans-2,6-dimethyl-1-indenylamine is added dropwise. After the addition is completed, the heating is stopped and the temperature is cooled to room temperature to precipitate 2,6-dimethyl-1-indenylamine salt. The ammonium salt obtained by filtration is added to a sodium hydroxide solution, extracted with methyl tert-butyl ether, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain the trans-isomer chiral indenylamine, i.e. (1R, 2S)-2,6-dimethyl-1-indenylamine, whose structural formula is shown in (Formula 2):

3. The method according to claim 2, characterized in that: The solvent is one or more of methanol, ethanol, toluene, petroleum ether, ethyl acetate or water.

4. The method according to claim 2 or 3, characterized in that: The mass ratio of the chiral amino acid derivative to the solvent is 1:1-20, preferably 1:2-8.

5. The method according to claim 2, characterized in that: The mass ratio of trans-2,6-dimethyl-1-indenylamine to ethyl acetate is 1:1-20, preferably 1:2-8.

6. The method according to claim 2, characterized in that: The molar ratio of trans-2,6-dimethyl-1-indenylamine to the chiral amino acid resolving agent is 1:0.1-2, preferably 1:0.5-1.

7. The method according to claim 2, characterized in that: The temperature of the reaction system is 40-120°C, preferably 50-100°C.

8. The method according to claim 2, characterized in that: The mass concentration of the sodium hydroxide solution is 5-50%, preferably 10-30%; The mass ratio of the ammonium salt to the sodium hydroxide solution is 1:1-20, preferably 1:5-10.

9. The method according to claim 1 or 2, characterized in that: The splitting agent can be recycled.

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