Organic amine small-molecule catalyst with chiral ure structure, preparation method and application

Abstract

The application discloses an organic amine small-molecule catalyst with a chiral ure structure, a preparation method and application, and belongs to the technical field of organic amine compound preparation. The preparation method uses an o-phenylenediamine compound as a starting material, and sequentially performs steps of selective amino protection, ure bond construction, removal of an amino protecting group and reductive amination, so that the target catalyst can be efficiently constructed with good yield. The catalyst is applied to a kinetic ester exchange resolution reaction of a carboxylic acid phthalimide ester, can effectively resolve chiral substrates, and provides an efficient candidate approach for new drug creation.

Description

Technical Field

[0001] This invention belongs to the field of organic amine compound preparation technology, specifically relating to an organic amine small molecule catalyst with a chiral urea structure, its preparation method, and its application. Background Technology

[0002] Chiral molecules are widely present in bioactive molecules. Different chiral molecules may exhibit different physiological activities in organisms, and the preparation of their two enantiomers is one of the most fundamental tasks in organic synthesis, medicinal chemistry, and materials science. For a long time, chiral chemical synthesis has mainly relied on two major categories of catalysts: metal catalysts and enzyme catalysts. Organic catalysts, as a third type of chiral catalyst, are a class of catalysts based on small organic molecules. Around 2000, List and MacMillan independently reported the use of organic catalysts to catalyze asymmetric reactions. Due to their advantages such as simple structure, ease of design and modification, good stability, and environmental friendliness, organic catalysts have long attracted widespread attention and become an important area of ​​research in organic chemistry and medicinal chemistry.

[0003] In recent years, chiral thiourea / urea catalysts, as a typical class of bifunctional small-molecule organic catalysts, have been widely used in various asymmetric reactions due to their ability to activate electrophiles through hydrogen bonding and to precisely control enantioselectivity through their chiral framework. Meanwhile, with the deepening of enantioselective catalysis research, kinetic resolution, as an important chiral preparation strategy, remains irreplaceable in practical applications when racemic substrates are inexpensive, suitable enantioselective methods are unavailable, or classical resolution is ineffective. However, most existing kinetic transesterification reactions face problems such as insufficient catalytic activity of traditional organic catalysts and low enantioselectivity of products, especially in the efficient and mild preparation of chiral carboxylic acid intermediates, where an ideal catalytic system is still lacking. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and to provide an organic amine small molecule catalyst with a chiral urea structure, its preparation method, and its application.

[0005] The specific technical solution adopted in this invention is as follows:

[0006] In a first aspect, the present invention provides an organic amine small molecule catalyst with a chiral urea structure, the specific chemical structural formula of which is as follows:

[0007] ;

[0008] Where: R 1 and R 2 The substituents are methyl, ethyl, tert-butyl, methoxy, or hydroxyl groups located on the benzene ring.

[0009] Preferably, the chemical structural formula is one or more of the following:

[0010] , , , , , , , , or .

[0011] Secondly, the present invention provides a method for preparing organic amine small molecule catalysts with chiral urea structures, the specific steps of which are as follows:

[0012] S1: Using o-phenylenediamine compounds as substrates, reacting with phthalic anhydride under the action of an acid catalyst to protect one amino group in the o-phenylenediamine compound, yielding a first intermediate with an amino protecting group;

[0013] S2: The first intermediate undergoes an addition reaction with 3,5-ditrifluoromethyl isocyanate to obtain a second intermediate having a urea bond;

[0014] S3: In the presence of hydrazine compounds, the second intermediate undergoes a hydrazolysis reaction to remove the ammonia protecting group, yielding the third intermediate;

[0015] S4: Dissolve the third intermediate in an organic solvent, then add a salicylaldehyde compound for amination; subsequently add sodium borohydride for reduction, and finally obtain an organic amine small molecule catalyst with a chiral urea structure;

[0016] The structural formula of the salicylaldehyde compound is as follows: ;

[0017] Where R 1 and R 2 The substituents are methyl, ethyl, tert-butyl, methoxy, or hydroxyl groups located on the benzene ring.

[0018] Preferably, the o-phenylenediamine compound in step S1 is o-phenylenediamine; the molar ratio of o-phenylenediamine to phthalic anhydride is 1:1; the reaction temperature in step S1 is 140°C and the reaction time is 3h; in step S2, the first intermediate is mixed with 3,5-ditrifluoromethyl isocyanate in a molar ratio of 1:1, and the addition reaction is carried out at 20~25°C for 10h.

[0019] Preferably, the hydrazine compound in step S3 is hydrated hydrazine; the molar ratio of the second intermediate to hydrated hydrazine is 2:5; and the hydrazolysis reaction is carried out at 100°C for 6 h.

[0020] Preferably, in step S4, the third intermediate and the salicylaldehyde compound are mixed in a molar ratio of 1:1 and then subjected to an amination reaction at 20-25°C; the molar ratio of sodium borohydride to the third intermediate is 2:1, and the reduction reaction is carried out at 0°C.

[0021] Furthermore, the salicylaldehyde compound is one of salicylaldehyde, 2-hydroxy-6-methylbenzaldehyde, 2,5-dihydroxybenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, 2-hydroxy-3-methylbenzaldehyde, 2,6-dihydroxybenzaldehyde, 3-methoxy-2-hydroxybenzaldehyde, 5-tert-butyl-2-hydroxybenzaldehyde, 3-tert-butyl-2-hydroxybenzaldehyde, or 3,5-di-tert-butylsalicylaldehyde.

[0022] As a preferred method, after the reduction reaction is completed, the organic phase is extracted with dichloromethane, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product is then purified by column chromatography. The volume ratio of dichloromethane to methanol in the eluent used in the purification process is 20:1. The fraction with an Rf value of 0.4 is collected, which is the small molecule organic amine catalyst with a chiral urea structure.

[0023] Thirdly, the present invention provides an organic amine small molecule catalyst with a chiral urea structure obtained by the preparation method described in the second aspect.

[0024] Fourthly, the present invention provides an application of the small molecule organic amine catalyst with a chiral urea structure described in the third aspect in a kinetic resolution reaction. In an organic solvent, using racemic carboxylic acid phthalimide ester as a substrate, a kinetically controlled transesterification reaction is carried out with a nucleophilic reagent under the combined action of the small molecule organic amine catalyst with a chiral urea structure, a Lewis acid, and a base, thereby achieving chiral resolution of the substrate.

[0025] Preferably, the racemic phthalimide carboxylic acid ester is the phthalimide active ester of ibuprofen; the nucleophile is acetaldehyde-protected diphenylphosphine oxide;

[0026] The organic solvent used is one of ethyl acetate, methanol, acetonitrile, tetrahydrofuran, dichloromethane, isopropanol, and tert-butanol;

[0027] Lewis acids are selected from aluminum trichloride, ferric chloride, magnesium chloride, zinc chloride, copper chloride, and nickel chloride.

[0028] The alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium acetate, sodium acetate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate.

[0029] Compared with the prior art, the present invention has the following advantages:

[0030] (1) The method for preparing organic amine compounds with chiral urea structures provided by the present invention has a simple reaction route and mild conditions. Using inexpensive and readily available o-phenylenediamine compounds as starting materials, the target catalyst can be efficiently constructed with good yield through steps such as selective amino protection, urea bond construction, protecting group removal and reductive amination.

[0031] (2) Using the organic amine compounds with chiral urea structures prepared in this invention as catalysts, and applying them to the kinetic transesterification resolution reaction of carboxylic acid phthalimide esters, can achieve effective chiral resolution of racemic substrates, providing an efficient candidate route for the creation of new drugs.

[0032] The above kinetic resolution method, on the one hand, eliminates the use of expensive metal catalysts (such as Pd, Rh, Ir, Ru, etc.) commonly used in existing synthetic methods, avoiding their potential toxicity problems; on the other hand, the reaction process is simple and mild, overcoming the operational risks and uncertainties caused by the cumbersome steps and harsh conditions of existing synthetic methods. This method uses small organic molecule catalysts, which have the characteristics of high catalytic efficiency, environmental friendliness, and energy conservation. Attached Figure Description

[0033] Figure 1 A chemical reaction flow chart for preparing small organic amine catalysts with chiral urea structures provided by the present invention;

[0034] Figure 2 A chemical reaction flow diagram of the kinetic resolution process of esters provided by the present invention;

[0035] Figure 3 The kinetic resolution product C in Example 11 1 H NMR spectrum;

[0036] Figure 4 The kinetic resolution product C in Example 11 31 P NMR spectrum;

[0037] Figure 5 The kinetic resolution product C in Example 11 13 C NMR spectrum;

[0038] Figure 6 This is the liquid chromatogram of the racemic mixture of raw material A in Example 11;

[0039] Figure 7 The chiral liquid chromatogram of raw material A in Example 11;

[0040] Figure 8 The liquid chromatogram of the racemic product C in Example 11;

[0041] Figure 9The image shows the chiral liquid chromatogram of product C from Example 11. Detailed Implementation

[0042] The present invention will be further described and illustrated below with reference to the accompanying drawings and specific embodiments. The technical features of each embodiment of the present invention can be combined accordingly, provided that there is no mutual conflict.

[0043] Example 1

[0044] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the process of which is as follows: Figure 1 As shown, the specific steps are as follows:

[0045] (1) o-Phenylenediamine and phthalic anhydride were mixed, and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) was added as a catalyst. The mixture was reacted at 140 °C for 3 h to protect one of the amino groups in o-Phenylenediamine, yielding a crude product. The crude product was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was evaporated. After vacuum drying, the first intermediate was obtained. In this reaction, the molar ratio of chiral o-Phenylenediamine to p-toluenesulfonic acid monohydrate was 1:1.

[0046] (2) The first intermediate was mixed with 3,5-ditrifluoromethyl isocyanate and subjected to an addition reaction at room temperature (20~25℃) for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was then purified by column chromatography (eluent: dichloromethane / methanol = 100:1, v / v). The fraction with Rf = 0.5 was collected to obtain the second intermediate with urea bonds.

[0047] (3) Add hydrazine hydrate to the second intermediate, and the molar ratio of the second intermediate to hydrazine hydrate is 2:5. Under the condition of hydrazine, the second intermediate undergoes hydrazolysis to remove the ammonia protecting group, and a third intermediate is obtained. The third intermediate is a pale yellow solid.

[0048] (4) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 244 mg of salicylaldehyde (2 mmol) to carry out the amination reaction. The reaction time is 1 hour. The reaction solution gradually turns into a deep yellow color and a solid precipitates out to obtain the crude product.

[0049] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-1, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((2-hydroxybenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 85%. The structural formula is shown below:

[0050] .

[0051] Example 2

[0052] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0053] (1) The preparation of the third intermediate is the same as in Example 1.

[0054] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 272 mg of 2-hydroxy-6-methylbenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and solid precipitates out to obtain the crude product.

[0055] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-2, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((2-hydroxy-5-methylbenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 85%. The structural formula is shown below:

[0056] .

[0057] Example 3

[0058] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0059] (1) The preparation of the third intermediate is the same as in Example 1.

[0060] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 276 mg of 2,5-dihydroxybenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and a solid precipitates out to obtain the crude product.

[0061] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-3, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((2,5-dihydroxybenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 85%. The structural formula is shown below:

[0062] .

[0063] Example 4

[0064] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0065] (1) The preparation of the third intermediate is the same as in Example 1.

[0066] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 272 mg of 2-hydroxy-4-methylbenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and solid precipitates out to obtain the crude product.

[0067] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-4, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((2-hydroxy-4-methylbenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 85%. The structural formula is shown below:

[0068] .

[0069] Example 5

[0070] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0071] (1) The preparation of the third intermediate is the same as in Example 1.

[0072] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 272 mg of 2-hydroxy-3-methylbenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and solid precipitates out to obtain the crude product.

[0073] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-5, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((2-hydroxy-3-methylbenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 85%. The structural formula is shown below:

[0074] .

[0075] Example 6

[0076] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0077] (1) The preparation of the third intermediate is the same as in Example 1.

[0078] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 276 mg of 2,6-dihydroxybenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and solid precipitates out to obtain the crude product.

[0079] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-6, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((2,6-dihydroxybenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 88%. The structural formula is shown below:

[0080] .

[0081] Example 7

[0082] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0083] (1) The preparation of the third intermediate is the same as in Example 1.

[0084] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 304 mg of 3-methoxy-2-hydroxybenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and a solid precipitates out to obtain the crude product.

[0085] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-7, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((2-hydroxy-3-methoxybenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 85%. The structural formula is shown below:

[0086] .

[0087] Example 8

[0088] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0089] (1) The preparation of the third intermediate is the same as in Example 1.

[0090] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 356 mg of 5-tert-butyl-2-hydroxybenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and a solid precipitates out to obtain the crude product.

[0091] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-8, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((5-tert-butyl-2-hydroxybenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 52%. The structural formula is shown below:

[0092] .

[0093] Example 9

[0094] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0095] (1) The preparation of the third intermediate is the same as in Example 1.

[0096] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 356 mg of 3-tert-butyl-2-hydroxybenzaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and a solid precipitates out to obtain the crude product.

[0097] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-9, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((3-tert-butyl-2-hydroxybenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 74%. The structural formula is shown below:

[0098] .

[0099] Example 10

[0100] This embodiment provides a method for preparing small organic amine compounds with chiral urea structures, the specific steps of which are as follows:

[0101] (1) The preparation of the third intermediate is the same as in Example 1.

[0102] (2) Take 934 mg of the prepared third intermediate (2 mmol) and place it in a 25 mL round-bottom flask. Add 10 mL of methanol and stir until the solid is completely dissolved. Then add 468 mg of 3,5-di-tert-butylsalicylaldehyde (2 mmol) for amination reaction. The reaction time is 1 hour. The reaction solution gradually turns dark yellow and a solid precipitates out to obtain the crude product.

[0103] (5) The above reaction system was cooled to 0°C in an ice-water bath, and then 151.2 mg of sodium borohydride (4 mmol) was added in portions. A large number of bubbles were generated in the system. After the reduction reaction was completed, saturated sodium carbonate aqueous solution was added dropwise to quench the bubbles until no more bubbles were generated. The organic phase was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20:1, v / v), and the fraction with Rf = 0.4 was collected to obtain product VIII-10, namely 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((3,5-di-tert-butyl-2-hydroxybenzyl)amino)-1,2-diphenylethyl)urea, with a calculated yield of 62%.

[0104] The structural formula of the product prepared in the example is shown below:

[0105] .

[0106] In this embodiment, nuclear magnetic resonance spectroscopy was also used to confirm the structure of product VIII-10, and its properties were measured separately. 1 H NMR, 19 F NMR and 13 The C10 NMR spectra are shown in Table 1. The results confirm the above chemical structural formula.

[0107] Table 1 Physicochemical parameters of product VIII-10

[0108]

[0109] Example 11

[0110] In this embodiment, product VIII-10 prepared in Example 10 was used as a catalyst in the kinetic resolution process of esters. The chemical reaction flow is as follows: Figure 2 As shown. Specifically:

[0111] Using racemic ibuprofen phthalimide active ester (rac-A) as the substrate and acetaldehyde-protected diphenylphosphine oxide (B) as the nucleophile, a kinetic transesterification reaction was carried out at room temperature under the combined action of a Lewis acid (10 mol%), product VIII-10 prepared in Example 10 (10 mol%), and a base (1 eq.) to give chiral products C and A. The molar ratio of rac-A to B was controlled at 2:3, the molar ratio of rac-A to Lewis acid at 10:1, and the molar ratio of rac-A to product VIII-10 at 10:1.

[0112] In this reaction, the organic solvent used is one of ethyl acetate, methanol, acetonitrile, tetrahydrofuran, dichloromethane, isopropanol, or tert-butanol. The Lewis acid used is one of aluminum trichloride, ferric chloride, magnesium chloride, zinc chloride, copper chloride, or nickel chloride. The base used is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium acetate, sodium acetate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate; those skilled in the art can select the appropriate base based on actual needs.

[0113] In this embodiment, nuclear magnetic resonance spectroscopy was also used to confirm the structure of product C, and its properties were measured separately. 1 H NMR, 31 P NMR and 13 The C NMR spectrum, the results are as follows Figures 3-5 As shown in the figure, under optimal reaction conditions, the yield of recovered raw material A is 48%, with a measured ee value of 93%; the yield of product C is 50%, with a dr ratio of 20:1 and a measured ee value of 84%. Both the recovered raw material A and product C exhibit good enantioselectivity control. Figures 6-7 These are the liquid chromatograms of the racemic mixture of raw material A and the chiral liquid chromatogram. Figures 8-9 The figures show the liquid chromatograms of the racemic form of product C and the chiral liquid chromatogram of product C. This demonstrates that the organic amine compounds with chiral urea structures prepared in this invention can achieve effective chiral separation of racemic starting materials, providing an efficient candidate pathway for new drug development.

[0114] The above kinetic resolution method, on the one hand, eliminates the use of expensive metal catalysts (such as Pd, Rh, Ir, Ru, etc.) commonly used in existing synthetic methods, avoiding their potential toxicity problems; on the other hand, the reaction process is simple and mild, overcoming the operational risks and uncertainties caused by the cumbersome steps and harsh conditions of existing synthetic methods. This method uses small organic molecule catalysts, which have the characteristics of high catalytic efficiency, environmental friendliness, and energy conservation.

[0115] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the invention. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all technical solutions obtained through equivalent substitution or transformation fall within the protection scope of the present invention.

Claims

1. A small molecule organic amine catalyst with a chiral urea structure, characterized in that, The specific chemical structural formula is as follows: ； Where: R 1 and R 2 The substituents are methyl, ethyl, tert-butyl, methoxy, or hydroxyl groups located on the benzene ring.

2. The small molecule organic amine catalyst with a chiral urea structure according to claim 1, characterized in that, The chemical structural formula is one or more of the following: , , , , , , , , or .

3. A method for preparing an organic amine small molecule catalyst with a chiral urea structure, characterized in that, The specific steps are as follows: S1: Using o-phenylenediamine compounds as substrates, reacting with phthalic anhydride under the action of an acid catalyst to protect one amino group in the o-phenylenediamine compound, yielding a first intermediate with an amino protecting group; S2: The first intermediate undergoes an addition reaction with 3,5-ditrifluoromethyl isocyanate to obtain a second intermediate having a urea bond; S3: In the presence of hydrazine compounds, the second intermediate undergoes a hydrazolysis reaction to remove the ammonia protecting group, yielding the third intermediate; S4: Dissolve the third intermediate in an organic solvent, then add a salicylaldehyde compound for amination; subsequently add sodium borohydride for reduction, and finally obtain an organic amine small molecule catalyst with a chiral urea structure; The structural formula of the salicylaldehyde compound is as follows: ; Where R 1 and R 2 The substituents are methyl, ethyl, tert-butyl, methoxy, or hydroxyl groups located on the benzene ring.

4. The preparation method according to claim 3, characterized in that, In step S1, the o-phenylenediamine compound is o-phenylenediamine; the molar ratio of o-phenylenediamine to phthalic anhydride is 1:1; the reaction temperature in step S1 is 140℃ and the reaction time is 3h; in step S2, the first intermediate is mixed with 3,5-ditrifluoromethyl isocyanate in a molar ratio of 1:1, and the addition reaction is carried out at 20~25℃ for 10h.

5. The preparation method according to claim 3, characterized in that, The hydrazine compound used in step S3 is hydrated hydrazine; the molar ratio of the second intermediate to hydrated hydrazine is 2:5; the hydrazolysis reaction is carried out at 100°C for 6 h.

6. The preparation method according to claim 3, characterized in that, In step S4, the third intermediate and the salicylaldehyde compound are mixed in a molar ratio of 1:1 and then subjected to an amination reaction at 20-25°C. The molar ratio of sodium borohydride to the third intermediate is 2:1, and the reduction reaction is carried out at 0°C.

7. The preparation method according to claim 6, characterized in that, The salicylaldehyde compound is selected from salicylaldehyde, 2-hydroxy-6-methylbenzaldehyde, 2,5-dihydroxybenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, 2-hydroxy-3-methylbenzaldehyde, 2,6-dihydroxybenzaldehyde, 3-methoxy-2-hydroxybenzaldehyde, 5-tert-butyl-2-hydroxybenzaldehyde, 3-tert-butyl-2-hydroxybenzaldehyde, or 3,5-di-tert-butylsalicylaldehyde.

8. The preparation method according to claim 3, characterized in that, After the reduction reaction was completed, the organic phase was extracted with dichloromethane, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography. The volume ratio of dichloromethane to methanol in the eluent used in the purification process was 20:

1. The fraction with an Rf value of 0.4 was collected, which is the small molecule organic amine catalyst with a chiral urea structure.

9. An organic amine small molecule catalyst with a chiral urea structure obtained by the preparation method according to any one of claims 3 to 8.

10. The application of the small molecule organic amine catalyst with a chiral urea structure as described in claim 9 in a kinetic resolution reaction, characterized in that, In an organic solvent, racemic phthalimide carboxylic acid esters are used as substrates. Under the combined action of small molecule organic amine catalysts with chiral urea structures, Lewis acids, and bases, a kinetically controlled transesterification reaction is carried out with nucleophiles to achieve chiral resolution of the substrates. Preferably, the racemic phthalimide carboxylic acid ester is the phthalimide active ester of ibuprofen; the nucleophile is acetaldehyde-protected diphenylphosphine oxide; The organic solvent used is one of ethyl acetate, methanol, acetonitrile, tetrahydrofuran, dichloromethane, isopropanol, and tert-butanol; Lewis acids are selected from aluminum trichloride, ferric chloride, magnesium chloride, zinc chloride, copper chloride, and nickel chloride. The alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium acetate, sodium acetate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate.

Images