Preparation method of diamine chiral resolving agent

Abstract

The invention relates to a preparation method of a diamine chiral resolving agent. The method comprises the following steps: by taking chiral alpha-amino acid as a raw material, reacting the chiral alpha-amino acid with (Boc) 2O and alkali in a solvent to obtain Boc-protected amino acid; in a solvent, the Boc-protected amino acid and secondary amine are subjected to catalysis of a condensing agent and alkali to obtain Boc amino-protected secondary amide; dissolving the Boc amino protected secondary amide in an organic solvent, and removing a Boc protecting group under an acidic condition to obtain chiral alpha-amino secondary amide; and reducing the chiral alpha-amino secondary amide into amine under the action of a reducing agent to obtain chiral amino secondary amine, namely the target product diamine chiral resolving agent. The chiral alpha-amino acid required by the preparation method is cheap and easy to obtain, the operation is simple, the obtained chiral diamine resolving agent is novel in structure, the variety of alkaline resolving agents is enriched, and the chiral diamine resolving agent is applied to resolution of racemic propionic acid compounds such as non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen and has practicability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology. Specifically, it relates to a method for preparing a diamine-based chiral resolving agent. Background Technology

[0002] Chiral resolution refers to the process of separating a racemic mixture (containing equal amounts of enantiomers) into a single enantiomer. It has wide applications in pharmaceuticals, life science research, asymmetric synthesis, and food and flavor science. The two enantiomers of a chiral compound may have drastically different biological activities; for example, the (R)-configuration of thalidomide has a sedative effect, while the (S)-configuration is teratogenic. Efficient resolution of racemic compounds is crucial. Various countries have imposed strict requirements on the optical activity control of chemical entities containing chiral centers in the review of Class 1.1 new chemical drugs. Furthermore, Class 2.1 new drugs, which contain "optical isomers of known active ingredients obtained by resolution or synthesis," are also a hot topic in my country's new drug development, such as the development from flurbiprofen to esflurbiprofen. Therefore, the development and invention of new chiral resolution methods with specific advantages are valuable and necessary.

[0003] The following is an overview of the reported basic chiral resolving agents:

[0004] 1. Natural alkaloids

[0005] Natural alkaloids are widely used due to their inherent chiral centers and basicity: strychnine is used for the resolution of NSAIDs such as naproxen and ibuprofen; quinine and quinidine are used for the resolution of racemic 2-arylpropionic acids and phosphoric acid compounds; cinconidine is widely used for the resolution of racemic compounds containing carboxyl groups due to its high selectivity for certain carboxylic acids, such as the preferential precipitation of (S)-salts after cooling of racemic naproxen and cinconidine in ethanol, with yields >70% and ee values ​​>95%. Although natural alkaloids are widely used as resolving agents, limitations exist, including limited resources, the high toxicity of some alkaloids (such as strychnine), and difficulties in large-scale application.

[0006] 2. Synthesis of chiral amines

[0007] Currently reported synthetic chiral amine resolving agents, such as (R) / (S)-α-phenylethylamine, are suitable for the resolution of compounds like mandelic acid and racemic 2-phenylpropionic acid; 1,2-diphenylethylenediamine is mostly used for the resolution of dicarboxylic acids such as tartaric acid; and ephedrine derivatives are suitable for the resolution of β-hydroxy acids and amino acids. Although synthetic chiral amine resolving agents have advantages such as high stability, low cost, and industrial production capability, the number of reported synthetic chiral amine resolving agents is very limited, and their effectiveness in resolving most racemic acid drugs is unsatisfactory or even disappointing.

[0008] 3. Novel chiral resolving agents

[0009] 3.1 Chiral Ionic Liquids (CILs)

[0010] Chiral ionic liquids (CILs) are a class of ionic liquids with chiral centers (such as asymmetric carbon, phosphorus, or nitrogen atoms), composed of chiral cations, chiral anions, or both. Their characteristics include: a wide liquid range (stable from room temperature to high temperatures); high designability (solubility, chiral selectivity, and catalytic activity can be controlled by adjusting the cation and anion structures); and recyclability. For example, the resolution of ibuprofen: the cation in chiral ionic liquids (CILs) is an L-proline-derived chiral imidazole onion salt, and the anion is bis(trifluoromethanesulfonyl)imide. The resolution mechanism involves the formation of a diastereomeric complex between the chiral CIL and racemic ibuprofen, followed by separation of (S)-ibuprofen (ee value > 90%) by crystallization or extraction. However, CIL resolution suffers from high synthesis costs, and some CILs have high viscosity, affecting mass transfer efficiency.

[0011] 3.2 Immobilized chiral resolving agents

[0012] Immobilized chiral resolving agents refer to traditional soluble chiral resolving agents (such as alkaloids and chiral amines) that are fixed on a solid support (such as polymers, silica gel, magnetic nanoparticles, etc.) through chemical bonding or physical adsorption, forming an insoluble material that retains its chiral recognition ability. Its core characteristics are: recyclability (it can be recovered through simple filtration or magnetic separation, reducing costs); enhanced stability (avoiding dissolution loss, possessing temperature and solvent resistance); and suitability for continuous production (it can be packed into chromatographic columns or flow reactors). For example, the immobilized (R)-α-phenylethylamine resolving mandelic acid: (R)-α-phenylethylamine (PEA) is covalently fixed on the silica gel surface (SiO2-PEA); racemic mandelic acid and SiO2-PEA form a salt in ethanol; the (R)-mandelic acid-PEA salt is preferentially adsorbed onto the silica gel, separated by filtration; acid hydrolysis of the filter cake yields (R)-mandelic acid (ee value > 90%), and SiO2-PEA can be reused more than 5 times. Immobilized chiral resolving agents have problems such as immobilization potentially reducing chiral recognition activity, carrier pores potentially limiting mass transfer efficiency, and poor universality for complex substrates.

[0013] 3.3 Supramolecular chiral resolving agents

[0014] Supramolecular chiral resolving agents are chiral materials that selectively bind to target racemates through non-covalent interactions (such as hydrogen bonding, π-π stacking, hydrophobic interactions, host-guest inclusion, etc.), thereby achieving enantiomer separation. Their characteristics include: dynamic reversibility (mild and easily tunable binding process); multiple recognition sites (enhancing chiral selectivity through synergistic effects); and structural diversity (including cyclodextrins, crown ethers, calixarenes, hydrogen-bonded frameworks, etc.). For example, β-cyclodextrin (β-CD) resolves ibuprofen: racemic ibuprofen is mixed with β-CD in an aqueous solution. β-CD preferentially includes (S)-ibuprofen (due to higher matching degree between the aromatic ring and the cavity), the (S)-isomer forms a precipitate, and the (R)-isomer remains in solution, with an ee value reaching 80%. β-CD can be recycled. However, this method also has drawbacks, such as potentially insufficient selectivity for structurally similar enantiomers, solvent polarity affecting hydrogen bonding, and low mass transfer efficiency in large-scale production.

[0015] 3.4 Enzyme-Chemical Co-resolution

[0016] Enzyme-chemical synergistic resolution refers to the combination of biological enzyme catalysis and chemical chiral resolving agents to achieve efficient separation and transformation of racemic mixtures through multi-step synergistic action. Its core characteristics are: dynamic kinetic resolution (enzyme selectively transforms one enantiomer, while the chemical resolving agent captures the other enantiomer, achieving a theoretical yield of 100%); complementary advantages (high stereoselectivity of enzymes and broad applicability of chemical resolving agents); and green and efficient (reduced byproducts and improved atom economy). For example, in the resolution of racemic 1-phenylethanol, the enzyme is *Candida antarcticis* lipase B (CAL-B, selectively acetylates (S)-alcohols). The acyl donor in the chemical reagent is vinyl acetate (the reaction generates acetaldehyde to drive equilibrium), and the chiral acid is (R)-mandelic acid (which forms a salt with unreacted (R)-alcohol). The specific process involves CAL-B catalysis to acetylate (S)-1-phenylethanol to (S)-ester (retaining (R)-alcohol), where (R)-1-phenylethanol forms an insoluble salt with (R)-mandelic acid. The salt is separated by filtration and acid hydrolysis to obtain (R)-1-phenylethanol (ee > 99%). This method suffers from high cost and poor compatibility between the enzyme and chemical reagents. Summary of the Invention

[0017] The purpose of this invention is to provide a method for preparing a chiral diamine resolving agent. This invention uses a chiral α-amino acid as a raw material, reacting it under the action of (Boc)₂O and a base to obtain a Boc-protected amino acid. In a solvent, the Boc-protected amino acid reacts with a secondary amine under the action of a condensing agent and a base catalysis to obtain a Boc-amino-protected secondary amide. The Boc-amino-protected secondary amide is dissolved in an organic solvent, and the Boc protecting agent is removed under acidic conditions to obtain a chiral α-amino secondary amide. The chiral α-amino secondary amide is reduced to an amine under the action of a reducing agent to obtain a chiral amino secondary amine, i.e., the target product, a chiral diamine resolving agent. The chiral α-amino acid required by this preparation method is inexpensive and readily available, the operation is simple, and the resulting chiral diamine resolving agent has a novel structure, enriching the types of basic resolving agents. It has been applied to the resolution of racemic propionic acid compounds such as nonsteroidal anti-inflammatory drugs ibuprofen, flurbiprofen, and naproxen, demonstrating its practicality.

[0018] To achieve the objectives of this invention, the technical solution is as follows:

[0019] (1) Using one or two solvents, namely acetonitrile, 1,4-dioxane, tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, isopropanol, and pure water, a chiral α-amino acid is reacted with (Boc)₂O and a base to obtain a Boc-protected amino acid, wherein the molar equivalent ratio of the chiral α-amino acid to (Boc)₂O and the base is 1.0:1.0-2.0:2.0-3.0, preferably 1.0:1.5:2.5, and the chiral α-amino acid has the following structure:

[0020]

[0021] R1 is one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, p-hydroxyphenyl, naphthyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, and indole; the chiral amino acid can be either levorotatory or dextrorotatory.

[0022] This chiral amino acid includes, but is not limited to, the following structures:

[0023]

[0024] (2) In a solvent selected from dichloromethane, chloroform, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, toluene, and benzene, a Boc-protected amino acid reacts with a secondary amine under the action of a condensing agent and a base catalysis to yield a Boc-amino-protected secondary amide, wherein the secondary amine has the following structure:

[0025]

[0026] This secondary amine includes, but is not limited to, the following structures:

[0027]

[0028] The condensing agents are dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 4-N,N-dimethylpyridine, 1-hydroxybenzotriazole, O-(7-azabenzotriazole-1-yl)-di(dimethylamino)carbodiium hexafluorophosphate, O-(benzotriazole-1-yl)-di(dimethylamino)carbodiium hexafluorophosphate, O-( The compound is one or two of the following: benzotriazole-1-yl)-di(dimethylamino)carbomonium tetrafluoroborate, O-(N-succinimide)-di(dimethylamino)carbomonium tetrafluoroborate, benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, and benzotriazole-1-yloxy-tris(tetrahydropyrrole)phosphonium hexafluorophosphate; the base is one of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine, and 4-dimethylpyridine.

[0029] (3) The Boc-protected secondary amide is dissolved in one of the organic solvents of dichloromethane, ethyl acetate, butyl acetate, methyl tert-butyl ether, diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, acetone, acetonitrile, acetic acid and toluene, and the Boc protecting agent is removed under one of the acidic conditions of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, formic acid, acetyl chloride and trifluoroacetic acid to obtain a chiral α-amino secondary amide.

[0030] (4) The chiral α-amino secondary amide is reduced to an amine by a reducing agent among lithium aluminum hydride, borane, sodium borohydride and triethylsilane to obtain an amino secondary amine, which is the target product diamine chiral resolving agent.

[0031] The technical approach of this invention is as follows:

[0032]

[0033] R1, R2, and R3 are each one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, p-hydroxyphenyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, and indole; the chiral amine is either levorotatory or dextrorotatory.

[0034] The diamine chiral resolving agent prepared according to the above route has the following structure:

[0035]

[0036] The diamine chiral resolving agent includes, but is not limited to, the following structures:

[0037] .

[0038] The preparation method of the diamine chiral resolving agent of the present invention, compared with the prior art, is as follows:

[0039] (1) The resolving agent is novel and inexpensive: The chiral diamine resolving agent prepared from inexpensive and readily available amino acids has a novel structure;

[0040] (2) Enriched the variety of basic resolving agents: Currently, there are very few basic resolving agents. Diamine resolving agents prepared from chiral amino acids have greatly enriched the variety of basic resolving agents.

[0041] (3) The obtained diamine resolving agent is practical: This type of resolving agent has been used to resolve nonsteroidal anti-inflammatory drugs such as ibuprofen, naproxen and flurbiprofen. The resolution results show that the optical purity is high.

[0042] (4) Simple preparation process: No high temperature and high pressure equipment is used in the process, the process is safe and controllable, the operation is simple, and the post-processing is convenient. Attached Figure Description

[0043] The accompanying drawings of this application are used to illustrate the structure or process of the technical solution. Although there may be differences in the clarity of the drawings, the technical features of the present invention have been described in detail in the text. Those skilled in the art can implement the present invention based on the content of the specification. Therefore, the clarity of the drawings does not affect the sufficiency of the disclosure of the technical content.

[0044] Appendix Figure 1 It is (S)-N,N-di-n-propyl-3,3-dimethylbutane-1,2-diamine 1 H NMR.

[0045] Appendix Figure 2 It is (S)-N,N-di-n-propyl-3,3-dimethylbutane-1,2-diamine 13 C NMR.

[0046] Appendix Figure 3 (S)-N,N-diisopropyl-3,3-dimethylbutane-1,2-diamine 1 H NMR.

[0047] Appendix Figure 4 (S)-N,N-diisopropyl-3,3-dimethylbutane-1,2-diamine 13 C NMR.

[0048] Appendix Figure 5(S)-N,N-diethyl-3,3-dimethylbutane-1,2-diamine 1 H NMR.

[0049] Appendix Figure 6 (S)-N,N-diethyl-3,3-dimethylbutane-1,2-diamine 13 C NMR.

[0050] Appendix Figure 7 (S)-N,N-diethyl-2-phenylethane-1,2-diamine 1 H NMR.

[0051] Appendix Figure 8 (S)-N,N-diethyl-2-phenylethane-1,2-diamine 13 C NMR.

[0052] Appendix Figure 9 It is (S)-N,N-di-n-propyl-2-phenylethane-1,2-diamine 1 H NMR.

[0053] Appendix Figure 10 It is (S)-N,N-di-n-propyl-2-phenylethane-1,2-diamine 13 C NMR.

[0054] Appendix Figure 11 It is (S)-N,N-diisopropyl-2-phenylethane-1,2-diamine 1 H NMR.

[0055] Appendix Figure 12 It is (S)-N,N-diisopropyl-2-phenylethane-1,2-diamine 13 C NMR. Detailed Implementation

[0056] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any way. It should be noted that those skilled in the art can make several modifications or improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

[0057] Example 1

[0058] Name: (S)-N,N-di-n-propyl-3,3-dimethylbutane-1,2-diamine

[0059] Process route:

[0060]

[0061] Specific operations:

[0062] Step (1) Preparation of (S)-2-Boc-amino-3,3-dimethylbutyric acid

[0063] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-2-amino-3,3-dimethylbutyric acid (20 g, 0.15 mol, 1.0 eq), an aqueous solution (150 ml) containing sodium hydroxide (12 g, 0.3 mol, 2.0 eq), and 1,4-dioxane (150 ml) were added. After stirring until completely dissolved, (Boc)₂O (34.4 g, 0.16 mol, 1.05 eq) was added, and the mixture was stirred at room temperature for 4–8 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spot in the reaction solution. Extracted with ethyl acetate (2 × 300 ml), the alkaline aqueous phase was collected, the pH of the alkaline aqueous phase was adjusted to 1-3 with hydrochloric acid, extracted with ethyl acetate (2 × 300 ml), the organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to give approximately 32.7 g of (S)-2-Boc-amino-3,3-dimethylbutyric acid, with a yield of approximately 92.8%.

[0064] ESI-MS m / z 232.18 [M+H] + .

[0065] 1 H NMR(500 MHz, CDCl3) δ 10.35(s, 1H), 5.12-5.08(d, J = 9.3 Hz, 1H), 4.12-4.06(d, J = 9.5 Hz, 1H), 1.43(s, 12H), 1.01(s, 12H).

[0066] 13 C NMR(126 MHz, CDCl3) δ 176.89, 155.79, 80.15, 61.78, 34.63, 28.46,26.66.

[0067] Step (2) Preparation of (S)-N,N-di-n-propyl-2-Boc-amino-3,3-dimethylbutyramide

[0068] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, condenser, and dropping funnel, add (S)-2-Boc-amino-3,3-dimethylbutyric acid (23.1 g, 0.1 mol, 1.0 eq), O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoroboric acid (44.9 g, 0.14 mol, 1.4 eq), di-n-propylamine (11.1 g, 0.11 mol, 1.1 eq), and dichloromethane (250 ml). Cool to 0 °C, and add N,N-diisopropylethylamine (27.9 g, 0.25 mol, 2.5 eq) dropwise. After the addition is complete, continue stirring for 2–3 h. Monitor with TLC, and the reaction endpoint is defined as the disappearance of the starting material spots in the reaction solution. Add water (300 ml), separate the liquid and collect the organic phase. Extract the aqueous phase with about 300 ml of dichloromethane. Combine the organic phases and wash successively with 10% citric acid aqueous solution (300 ml), saturated sodium bicarbonate solution (300 ml), and saturated saline solution (300 ml). Dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure at 50 °C to give about 26.1 g of (S)-N,N-di-n-propyl-2-Boc-amino-3,3-dimethylbutyramide, with a yield of about 82.8%.

[0069] ESI-MS m / z 315.17 [M+H] + .

[0070] 1 H NMR(500 MHz, CDCl3) δ 4.26(s, 1H), 3.23-3.13(m, 4H), 1.63-1.59(m,4H), 1.42(s, 9H), 0.94(s, 9H), 0.86-0.82(d, J = 12.4 Hz, 4H).

[0071] 13 C NMR (126 MHz, CDCl3) δ 173.07, 156.94, 79.42, 67.26, 52.52, 52.51,35.44, 28.61, 25.88, 21.09, 10.84.

[0072] Step (3) Preparation of (S)-N,N-di-n-propyl-2-amino-3,3-dimethylbutyramide

[0073] Add (S)-N,N-di-n-propyl-2-Boc-amino-3,3-dimethylbutyramide (25 g, 0.08 mol, 1.0 eq) and methanol (250 ml) obtained in step (2) to a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, dropping funnel, and condenser. Stir until completely dissolved, then add acetyl chloride (12.5 g, 0.16 mol, 2.0 eq) dropwise. After the addition is complete, reflux and stir for 1–2 h. Monitor with TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. The solution was cooled to 0°C, and a saturated sodium bicarbonate solution was added dropwise to adjust the pH to 9-10. The solvent was removed by concentration under reduced pressure at 50°C. The residue was extracted with dichloromethane (2 × 300 ml), and the organic phases were combined. The mixture was washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to give approximately 14.6 g of (S)-N,N-di-n-propyl-2-amino-3,3-dimethylbutyramide, with a yield of approximately 85.4%.

[0074] ESI-MS m / z 215.09 [M+H] + .

[0075] 1 H NMR(500 MHz, CDCl3) 3.34-3.31(m, 1H), 3.24-3.19(m, 4H), 1.66-1.61(m,4H), 0.96(s, 9H), 0.86-0.82(d, J = 12.4 Hz, 6H).

[0076] 13 C NMR (126 MHz, CDCl3) δ 171.93, 73.65, 53.46, 54.45, 40.11, 26.88,20.31, 11.07.

[0077] Step (4) Preparation of (S)-N,N-di-n-propyl-3,3-dimethylbutane-1,2-diamine

[0078] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-N,N-di-n-propyl-2-amino-3,3-dimethylbutyramide (14 g, 65.4 mmol, 1.0 eq) and tetrahydrofuran (200 ml) were added. The mixture was cooled to below 0 °C, and lithium aluminum hydride (3.8 g, 98.1 mmol, 1.5 eq) was added in portions. After the addition was complete, the mixture was stirred for 1 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spots in the reaction solution. 3.8 ml of pure water, 3.8 ml of 10% sodium hydroxide solution, 11.4 ml of pure water, and approximately 30 g of anhydrous magnesium sulfate were added sequentially. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 50°C. The residue was adjusted to pH 2-3 with 5% hydrochloric acid, extracted with ethyl acetate (2×200 ml), and the aqueous phase was collected. The aqueous phase was adjusted to pH 10-13 with 5% sodium hydroxide solution, extracted with ethyl acetate (2×200 ml), and the organic phases were combined. The mixture was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to give approximately 10.1 g of (S)-N,N-di-n-propyl-3,3-dimethylbutane-1,2-diamine, with a yield of approximately 73.6%.

[0079] ESI-MS m / z 201.18 [M+H] + .

[0080] 1 H NMR(500 MHz, CDCl3) δ 2.60(s, 2H), 2.50(dd, J = 11.0, 2.5 Hz, 1H), 2.41-2.28(m, 3H), 2.26-2.16(m, 2H), 2.10-2.08(dd, J = 12.4, 11.1 Hz, 1H),1.45-1.30(m, 4H), 0.83(s, 9H), 0.80(t, J = 7.4 Hz, 6H).

[0081] 13 C NMR (126 MHz, CDCl3) δ 57.31, 56.55, 56.53, 32.81, 26.28, 20.35,11.86.

[0082] Example 2

[0083] Name: (S)-N,N-Diisopropyl-3,3-dimethylbutane-1,2-diamine

[0084] Process route:

[0085]

[0086] Specific operations:

[0087] Step (1) Preparation of (S)-2-Boc-amino-3,3-dimethylbutyric acid

[0088] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-2-amino-3,3-dimethylbutyric acid (15 g, 0.11 mol, 1.0 eq), an aqueous solution (100 ml) containing sodium hydroxide (11 g, 0.27 mol, 2.5 eq), and 1,4-dioxane (100 ml) were added. After stirring until completely dissolved, (Boc)₂O (36 g, 0.16 mol, 1.5 eq) was added, and the mixture was stirred at room temperature for 4–8 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spots in the reaction solution. Extracted with ethyl acetate (2 × 300 ml), the alkaline aqueous phase was collected and the pH of the alkaline aqueous phase was adjusted to 1-3 with 5% hydrochloric acid. Extracted with ethyl acetate (2 × 300 ml), the organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to give approximately 24 g of (S)-2-Boc-amino-3,3-dimethylbutyric acid, with a yield of approximately 94%.

[0089] ESI-MS m / z 232.18 [M+H] + .

[0090] 1 H NMR(500 MHz, CDCl3) δ 10.35(s, 1H), 5.12-5.08(d, J = 9.3 Hz, 1H), 4.12-4.06(d, J = 9.5 Hz, 1H), 1.43(s, 12H), 1.01(s, 12H).

[0091] 13 C NMR(126 MHz, CDCl3) δ 176.89, 155.79, 80.15, 61.78, 34.63, 28.46,26.66.

[0092] Step (2) Preparation of (S)-N,N-diisopropyl-2-Boc-amino-3,3-dimethylbutyramide

[0093] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, condenser, and dropping funnel, add (S)-2-Boc-amino-3,3-dimethylbutyric acid (23.1 g, 0.1 mol, 1.0 eq), O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoroboric acid (35.3 g, 0.11 mol, 1.1 eq), diisopropylamine (10.1 g, 0.1 mol, 1.0 eq), and dichloromethane (250 ml) obtained in step (1). Cool to 0 °C, and then add N,N-diisopropylethylamine (27.9 g, 0.22 mol, 2.2 eq) dropwise. After the addition is complete, continue stirring for 2–3 h. Monitor with TLC, and the reaction endpoint is defined as the disappearance of the starting material spots in the reaction solution. Add water (300 ml), separate the liquid and collect the organic phase. Extract the aqueous phase with dichloromethane (300 ml). Combine the organic phases and wash successively with 10% citric acid aqueous solution (300 ml), saturated sodium bicarbonate solution (300 ml), and saturated saline solution (300 ml). Dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure at 50 °C to obtain approximately 25.6 g of (S)-N,N-diisopropyl-2-Boc-amino-3,3-dimethylbutyramide, with a yield of approximately 81.6%.

[0094] ESI-MS m / z 315.23 [M+H] + .

[0095] 1 H NMR(500 MHz, CDCl3) δ 3.86-3.84(m, 1H), 3.63-3.60(dd, J = 12.1, 7.0Hz, 2H), 1.53-1.39(m, 9H), 1.29-1.27(d, J = 8.5 Hz, 6H), 1.22-1.20(d, J = 6.8Hz, 6H), 0.94(s, 9H).

[0096] 13 C NMR (126 MHz, CDCl3) δ 174.39, 156.91, 79.22, 67.16, 57.92, 57.02, 35.41, 28.49, 25.86, 21.31.

[0097] Step (3) Preparation of (S)-N,N-diisopropyl-2-amino-3,3-dimethylbutyramide

[0098] Add (S)-N,N-diisopropyl-2-Boc-amino-3,3-dimethylbutyramide (25 g, 79.6 mmol, 1.0 eq) and ethanol (160 ml) obtained in step (2) to a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, dropping funnel, and condenser. Stir until completely dissolved, then add acetyl chloride (15.6 g, 0.19 mol, 2.5 eq) dropwise. After the addition is complete, reflux and stir for 1–2 h. Monitor by TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. The solution was cooled to 0°C, and a saturated sodium bicarbonate solution was added dropwise to adjust the pH to 9-10. The solvent was removed by concentration under reduced pressure at 50°C. The residue was extracted with dichloromethane (2 × 300 ml). The organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to give approximately 14.4 g of (S)-N,N-diisopropyl-2-amino-3,3-dimethylbutyramide, with a yield of approximately 84.6%.

[0099] ESI-MS m / z 215.14 [M+H] + .

[0100] 1 H NMR(500 MHz, CDCl3) δ 3.85-3.81(m, 2H), 3.35-3.31(m, 1H), 1.26-1.21(d, J = 8.6 Hz, 6H), 1.22-1.20(, J = 8.2 Hz, 6H), 0.97(s, 9H).

[0101] 13 C NMR(126 MHz, CDCl3) δ 172.13, 73.68, 57.36, 57.34, 40.12, 29.88,24.30, 24.27.

[0102] Step (4) Preparation of (S)-N,N-diisopropyl-3,3-dimethylbutane-1,2-diamine

[0103] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-N,N-diisopropyl-2-amino-3,3-dimethylbutyramide (14 g, 65.4 mmol, 1.0 eq) and tetrahydrofuran (200 ml) were added. The mixture was cooled to below 0 °C, and lithium aluminum hydride (3 g, 78.4 mmol, 1.2 eq) was added in portions. After the addition was complete, the mixture was stirred for 1 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spots in the reaction solution. Then, 3 ml of pure water, 3 ml of 10% sodium hydroxide solution, 9 ml of pure water, and approximately 20 g of anhydrous magnesium sulfate were added sequentially. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 50°C. The residue was adjusted to pH 2-3 with 5% hydrochloric acid, extracted with ethyl acetate (2×100 ml), and the aqueous phase was collected. The aqueous phase was adjusted to pH 10-13 with 5% sodium hydroxide solution, extracted with ethyl acetate (2×100 ml), and the organic phases were combined. The mixture was washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to give approximately 9.4 g of (S)-N,N-diisopropyl-3,3-dimethylbutane-1,2-diamine, with a yield of approximately 71.9%.

[0104] ESI-MS m / z 201.23 [M+H] + .

[0105] 1 H NMR(500 MHz, CDCl3) δ 3.80-3.75(dd, J = 11.3, 3.3 Hz, 1H), 3.73-3.47(m, 4H), 2.89-2.84(dd, J = 9.8, 3.4 Hz, 1H), 1.01(s, 3H), 0.96(s, 9H),0.90(s, 3H).

[0106] 13 C NMR (126 MHz, CDCl3) δ 62.26, 60.47, 56.44, 36.45, 27.17, 26.58.

[0107] Example 3

[0108] Name: (S)-N,N-Diethyl-3,3-dimethylbutane-1,2-diamine

[0109] Process route:

[0110]

[0111] Specific operations:

[0112] Step (1) Preparation of (S)-2-Boc-amino-3,3-dimethylbutyric acid

[0113] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-2-amino-3,3-dimethylbutyric acid (15 g, 0.11 mol, 1.0 eq), an aqueous solution (100 ml) containing sodium hydroxide (8.8 g, 0.22 mol, 2.0 eq), and 1,4-dioxane (100 ml) were added. After stirring until completely dissolved, (Boc)₂O (31 g, 0.11 mol, 1.0 eq) was added, and the mixture was stirred at room temperature for 4–8 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spots in the reaction solution. Extracted with ethyl acetate (2 × 300 ml), the alkaline aqueous phase was collected and the pH of the alkaline aqueous phase was adjusted to 1-3 with 5% hydrochloric acid. Extracted with ethyl acetate (2 × 300 ml), the organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to give approximately 25.3 g of (S)-2-Boc-amino-3,3-dimethylbutyric acid, with a yield of approximately 95.6%.

[0114] ESI-MS m / z 232.18 [M+H] + .

[0115] 1 H NMR(500 MHz, CDCl3) δ 10.35(s, 1H), 5.12-5.08(d, J = 9.3 Hz, 1H), 4.12-4.06(d, J = 9.5 Hz, 1H), 1.43(s, 12H), 1.01(s, 12H).

[0116] 13 C NMR(126 MHz, CDCl3) δ 176.89, 155.79, 80.15, 61.78, 34.63, 28.46,26.66.

[0117] Step (2) Preparation of (S)-N,N-diethyl-2-Boc-amino-3,3-dimethylbutyramide

[0118] In a 500 ml three-necked round-bottom flask equipped with a thermometer, condenser, and dropping funnel, add (S)-2-Boc-amino-3,3-dimethylbutyric acid (20 g, 86.5 mmol, 1.0 eq), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (41.6 g, 0.13 mol, 1.5 eq), diethylamine (6.3 g, 86.5 mmol, 1.0 eq), and dichloromethane (250 ml). Cool to 0 °C, and then add N,N-diisopropylethylamine (27.9 g, 0.22 mol, 2.5 eq) dropwise. After the addition is complete, continue stirring for 2–3 h. Monitor with TLC, and the reaction endpoint is defined as the disappearance of the starting material spots in the reaction solution. Add water (300 ml), separate the liquid and collect the organic phase. Extract the aqueous phase with dichloromethane (300 ml). Combine the organic phases and wash successively with 10% citric acid aqueous solution (300 ml), saturated sodium bicarbonate solution (300 ml), and saturated saline solution (300 ml). Dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure at 50 °C to give approximately 21 g of (S)-N,N-diethyl-2-Boc-amino-3,3-dimethylbutyramide, with a yield of approximately 84.9%.

[0119] ESI-MS m / z 287.23 [M+H] + .

[0120] 1 H NMR(500 MHz, CDCl3) δ 3.69-3.57(m, 1H), 3.53-3.50(dt, J = 14.1, 7.0Hz, 1H), 3.35-3.29(m, 1H), 3.15-3.11(td, J = 14.2, 6.9 Hz, 1H), 3.06-2.95(m,1H), 2.73-2.69(dd, J = 7.0, 2.4 Hz, 1H), 1.13-1.09(dd, J = 11.6, 4.6 Hz, 3H), 1.07-1.01(m, 3H), 0.94-0.87(dd, J = 7.1, 2.4 Hz, 9H).

[0121] 13 C NMR (126 MHz, CDCl3) δ 173.55, 156.95, 79.15, 67.06, 43.55, 43.02, 35.41, 25.09, 12.68.

[0122] Step (3) Preparation of (S)-N,N-diethyl-2-amino-3,3-dimethylbutyramide

[0123] Add (S)-N,N-diethyl-2-Boc-amino-3,3-dimethylbutyramide (20 g, 69.8 mmol, 1.0 eq) obtained in step (2) and methanol (150 ml) to a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, dropping funnel, and condenser. Stir until completely dissolved, cool to 0°C, and purge with hydrogen chloride gas until the pH reaches 1-2. Stir at room temperature for 1-3 h. Monitor by TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. The pH was adjusted to 9-10 by adding saturated sodium bicarbonate solution dropwise to the reaction solution. The solvent was removed by concentration under reduced pressure at 50°C. The residue was extracted with ethyl acetate (2 × 300 ml). The organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to give approximately 11.4 g of (S)-N,N-diethyl-2-amino-3,3-dimethylbutyramide, with a yield of approximately 87.7%.

[0124] ESI-MS m / z 187.17 [M+H] + .

[0125] 1 H NMR(500 MHz, CDCl3) δ 3.71-3.69(m, 1H), 3.53(dt, J = 14.1, 7.0 Hz,1H), 3.35-3.29(m, 4H), 3.26-3.21(m, 1H), 1.21-1.17(dd, J = 11.6, 4.6 Hz, 4H), 1.12-1.04(m, 3H), 0.96-0.91(dd, J = 7.1, 2.4 Hz, 9H).

[0126] 13 C NMR (126 MHz, CDCl3) δ 173.55, 57.36, 42.10, 40.02, 34.81, 34.80, 26.09, 14.42, 12.68.

[0127] Step (4) Preparation of (S)-N,N-diethyl-3,3-dimethylbutane-1,2-diamine

[0128] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-N,N-diethyl-2-amino-3,3-dimethylbutyramide (10 g, 53.7 mmol, 1.0 eq) and tetrahydrofuran (200 ml) were added. The mixture was cooled to below 0 °C, and lithium aluminum hydride (2.2 g, 59.1 mmol, 1.1 eq) was added in portions. After the addition was complete, the mixture was stirred for 1 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spot in the reaction solution. 2.2 ml of pure water, 2.2 ml of 10% sodium hydroxide solution, 6.6 ml of pure water, and approximately 10 g of anhydrous magnesium sulfate were added sequentially. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 50 °C to obtain approximately 7 g of (S)-N,N-diethyl-3,3-dimethylbutane-1,2-diamine, with a yield of approximately 75.6%.

[0129] ESI-MS m / z 173.17 [M+H] + .

[0130] 1 H NMR(500 MHz, CDCl3) δ 3.76-2.92(m, 1H), 2.47-2.16(m, 5H), 1.96-1.94(dd, J = 47.6, 12.1 Hz, 1H), 1.76(s, 2H), 0.83-0.74(m, 6H), 0.68(d, J = 1.4Hz, 9H).

[0131] 13 C NMR (126 MHz, CDCl3) δ 62.29, 61.56, 56.97, 55.27, 47.14, 32.76, 26.17, 26.05, 11.84.

[0132] Example 4

[0133] Name: (S)-N,N-Diethyl-2-phenylethane-1,2-diamine

[0134] Process route:

[0135]

[0136] Specific operations:

[0137] Step (1) Preparation of (S)-2-Boc-amino-phenylacetic acid

[0138] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, add (S)-2-amino-3,3-dimethylbutyric acid (20 g, 0.13 mol, 1.0 eq), an aqueous solution (150 ml) containing sodium hydroxide (15.6 g, 0.39 mol, 3.0 eq), and tetrahydrofuran (100 ml). Stir until completely dissolved, then add (Boc)₂O (37 g, 0.17 mol, 2.0 eq) and stir at room temperature for 4–8 h. Monitor by TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. Extracted with ethyl acetate (2 × 300 ml), the alkaline aqueous phase was collected and the pH of the alkaline aqueous phase was adjusted to 1-3 with 5% sulfuric acid. Extracted with ethyl acetate (2 × 300 ml), the organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to give approximately 31.9 g of (S)-2-Boc-amino-phenylacetic acid, with a yield of approximately 97.7%.

[0139] ESI-MS m / z 252.12 [M+H] + .

[0140] 1 H NMR(500 MHz, CDCl3) δ 8.14-8.09(d, J = 4.9 Hz, 1H), 7.44-7.39(d, J= 7.3 Hz, 2H), 7.36-7.29(m, 3H), 5.13-5.08(d, J = 5.2 Hz, 1H), 1.21(s, 9H).

[0141] 13 C NMR (126 MHz, CDCl3) δ 173.53, 157.14, 138.50, 129.10, 128.75, 128.55, 128.08, 127.34, 81.79, 58.99, 28.11.

[0142] Step (2) Preparation of (S)-N,N-diethyl-2-Boc-amino-phenylacetamide

[0143] In a 1 L three-necked round-bottom flask equipped with a thermometer, condenser, and dropping funnel, add (S)-2-Boc-amino-phenylacetic acid (31.8 g, 0.13 mol, 1.0 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.9 g, 0.13 mol, 1.0 eq), 1-hydroxybenzotriazole (17.6 g, 0.13 mol, 1.0 eq), diethylamine (9.5 g, 0.13 mol, 1.0 eq), and dichloromethane (350 ml). Cool to 0 °C, and add triethylamine (26.3 g, 0.26 mol, 2.0 eq) dropwise. After the addition is complete, continue stirring for 4–8 h. Monitor with TLC, and the reaction endpoint is defined as the disappearance of the starting material spots in the reaction solution. Add water (400 ml), separate the liquid and collect the organic phase. Extract the aqueous phase with dichloromethane (400 ml), combine the organic phases, and wash successively with 10% citric acid aqueous solution (400 ml), 10% sodium bicarbonate solution (400 ml), and saturated brine (400 ml). Dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure at 50 °C to obtain approximately 32.8 g of (S)-N,N-diethyl-2-Boc-amino-phenylacetamide, with a yield of approximately 82.5%.

[0144] ESI-MS m / z 307.21 [M+H] + .

[0145] 1 H NMR(500 MHz, CDCl3) δ 7.43-7.23(m, 5H), 4.67(s, 1H), 3.50-3.44(dq,J = 14.1, 7.1 Hz, 1H), 3.34-3.19(m, 2H), 3.07-3.01(dq, J = 14.4, 7.1 Hz, 1H), 1.11-1.07(t, J = 7.1 Hz, 3H), 0.96-0.91(t, J = 7.1 Hz, 3H).

[0146] 13 C NMR (126 MHz, CDCl3) δ 171.65, 168.71, 140.55, 128.76, 127.25, 126.74, 57.59, 41.04, 40.55, 13.92, 13.58.

[0147] Step (3) Preparation of (S)-N,N-diethyl-2-amino-phenylacetamide

[0148] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, dropping funnel, and condenser, add (S)-N,N-diethyl-2-Boc-amino-phenylacetamide (20 g, 65.3 mmol, 1.0 eq) obtained in step (2) and approximately 200 ml of ethyl acetate. Stir until completely dissolved. Then, add dropwise a solution of 4 mol / L ethyl hydrochloride (50 ml, 0.2 mol, 3.0 eq). After the addition is complete, continue stirring for 4–8 h. Monitor the reaction by TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. The solution was cooled to 0°C, and a saturated potassium carbonate solution was added dropwise to adjust the pH to 9-10. The mixture was separated, and the alkaline aqueous phase was extracted with ethyl acetate (300 ml). The organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to give approximately 11.5 g of (S)-N,N-diethyl-2-amino-phenylacetamide, with a yield of approximately 85.5%.

[0149] ESI-MS m / z 307.15 [M+H] + .

[0150] 1 H NMR(500 MHz, CDCl3) δ 7.46-7.22(m, 5H), 4.65(s, 1H), 3.46-3.42(m,2H), 3.33-3.17(m, 2H), 1.14-1.11(m, 4H), 0.99-0.96(t, J = 6.8 Hz, 6H).

[0151] 13 C NMR (126 MHz, CDCl3) δ 171.65, 141.69, 128.80, 127.48, 126.81, 56.56, 40.96, 40.23, 13.52, 13.47.

[0152] Step (4) Preparation of (S)-N,N-diethyl-2-phenylethane-1,2-diamine

[0153] In a 500 ml three-necked round-bottom flask equipped with a thermometer, dropping funnel, and magnetic stirrer, (S)-N,N-diethyl-2-amino-phenylacetamide (11.4 g, 55.3 mmol, 1.0 eq) and tetrahydrofuran (200 ml) were added. The mixture was cooled to below 0 °C, and lithium aluminum hydride (3.1 g, 82.9 mmol, 1.5 eq) was added in portions. After the addition was complete, stirring was continued for 1 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spot in the reaction solution. 3.1 ml of pure water, 3.1 ml of 10% sodium hydroxide solution, 9.3 ml of pure water, and approximately 11.4 g of anhydrous magnesium sulfate were added sequentially. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 50 °C to obtain approximately 7.6 g of (S)-N,N-diethyl-2-phenylethane-1,2-diamine, with a yield of approximately 71.5%.

[0154] ESI-MS m / z 307.15 [M+H] + .

[0155] 1 H NMR(500 MHz, CDCl3) δ 7.46-7.22(m, 5H), 4.45(s, 1H), 3.47-3.43(m,2H), 3.35-3.21(m, 2H), 2.42-2.39(q, J = 6.8 Hz, 3H), 0.99-0.96(t, J = 6.8 Hz, 3H).

[0156] 13 C NMR (126 MHz, CDCl3) δ 142.33, 128.46, 127.35, 126.57, 67.62, 57.37, 47.21, 11.85.

[0157] Example 5

[0158] Name: (S)-N,N-di-n-propyl-2-phenylethane-1,2-diamine

[0159] Process route:

[0160]

[0161] Specific operations:

[0162] Step (1) Preparation of (S)-2-Boc-amino-phenylacetic acid

[0163] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, add (S)-2-amino-3,3-dimethylbutyric acid (20 g, 0.13 mol, 1.0 eq), an aqueous solution (150 ml) containing sodium hydroxide (13 g, 0.33 mol, 2.5 eq), and tetrahydrofuran (150 ml). Stir until completely dissolved, then add (Boc)₂O (34 g, 0.16 mol, 1.2 eq) and stir at room temperature for 4–8 h. Monitor by TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. Extracted with ethyl acetate (2 × 300 ml), the alkaline aqueous phase was collected and the pH of the alkaline aqueous phase was adjusted to 1-3 with 5% sulfuric acid. Extracted with ethyl acetate (2 × 300 ml), the organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to give approximately 27.8 g of (S)-2-Boc-amino-phenylacetic acid, with a yield of approximately 85.1%.

[0164] ESI-MS m / z 252.13 [M+H] + .

[0165] 1 H NMR(500 MHz, CDCl3) δ 8.14-8.09(d, J = 4.9 Hz, 1H), 7.44-7.39(d, J= 7.3 Hz, 2H), 7.36-7.29(m, 3H), 5.13-5.08(d, J = 5.2 Hz, 1H), 1.21(s, 9H).

[0166] 13 C NMR (126 MHz, CDCl3) δ 173.53, 157.14, 138.50, 129.10, 128.75, 128.55, 128.08, 127.34, 81.79, 58.99, 28.11.

[0167] Step (2) Preparation of (S)-N,N-di-n-propyl-2-Boc-amino-phenylacetamide

[0168] In a 1 L three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, condenser, and dropping funnel, (S)-2-Boc-amino-phenylacetic acid (25.1 g, 0.1 mol, 1.0 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.9 g, 0.13 mol, 1.3 eq), 1-hydroxybenzotriazole (17.5 g, 0.13 mol, 1.3 eq), di-n-propylamine (13.3 g, 0.13 mol, 1.1 eq), and dichloromethane (350 ml) obtained in step (1) were added. The mixture was cooled to 0 °C, and triethylamine (39.4 g, 0.39 mol, 3.0 eq) was added dropwise. After the addition was complete, stirring was continued for 4–8 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spots in the reaction solution. Add water (400 ml), separate the liquid and collect the organic phase. Extract the aqueous phase with dichloromethane (400 ml), combine the organic phases, and wash successively with 10% citric acid aqueous solution (400 ml), 10% sodium bicarbonate solution (400 ml), and saturated brine (400 ml). Dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure at 50 °C to obtain approximately 28.5 g of (S)-N,N-di-n-propyl-2-Boc-amino-phenylacetamide, with a yield of approximately 82.9%.

[0169] ESI-MS m / z 345.44 [M+H] + .

[0170] 1 H NMR(500 MHz, CDCl3) δ 7.46-7.24(m, 5H), 5.67(s, 1H), 3.29-3.24(m,4H), 1.80-1.76(m, 4H), 1.52(s, 9H), 1.26-1.21(t, J = 8.4, 4.2 Hz, 6H).

[0171] 13 C NMR(126 MHz, CDCl3) δ 172.52, 168.85, 139.89, 129.22, 128.76,127.25, 126.74, 126.67,80.25, 61.04, 53.28, 28.88, 21.36, 12.04.

[0172] Step (3) Preparation of (S)-N,N-diisopropyl-2-amino-phenylacetamide

[0173] In a 1 L three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, dropping funnel, and condenser, add (S)-N,N-diisopropyl-2-Boc-amino-phenylacetamide (28 g, 31.3 mmol, 1.0 eq) obtained in step (2) and methanol (400 ml). Stir until completely dissolved, then add acetyl chloride (10 ml, 0.12 mol, 4.0 eq) dropwise. After the addition is complete, continue stirring for 4–8 h. Monitor with TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. The solution was cooled to 0°C, and a saturated potassium carbonate solution was added dropwise to adjust the pH to 9-10. The solvent was removed by concentration under reduced pressure at 50°C. Ethyl acetate (400 ml) and pure water (300 ml) were added to the residue. The mixture was separated, and the organic phase was collected. The organic phase was washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to give approximately 16.5 g of (S)-N,N-di-n-propyl-2-amino-phenylacetamide, with a yield of approximately 83.5%.

[0174] ESI-MS m / z 245.44 [M+H] + .

[0175] 1 H NMR(500 MHz, CDCl3) δ 7.47-7.23(m, 5H), 4.87(s, 1H), 3.26-3.22(m,4H), 1.69-1.61(m, 4H), 1.26-1.23(d, J = 8.4 Hz, 6H).

[0176] 13 C NMR (126 MHz, CDCl3) δ 170.87, 138.56, 129.85, 129.56, 128.80, 127.42, 126.57, 58.41, 52.43, 21.03, 12.01.

[0177] Step (4) Preparation of (S)-N,N-diisopropyl-2-phenylethane-1,2-diamine

[0178] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-N,N-di-n-propyl-2-amino-phenylacetamide (15 g, 61.4 mmol, 1.0 eq) and tetrahydrofuran (200 ml) were added. The mixture was cooled to below 0 °C, and lithium aluminum hydride (4.6 g, 0.12 mol, 2.0 eq) was added in portions. After the addition was complete, the mixture was stirred for 1 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spot in the reaction solution. 4.6 ml of pure water, 4.6 ml of 10% sodium hydroxide solution, 13.8 ml of pure water, and approximately 25 g of anhydrous magnesium sulfate were added sequentially. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 50 °C to obtain approximately 10.1 g of (S)-N,N-diisopropyl-2-phenylethane-1,2-diamine, with a yield of approximately 75.1%.

[0179] ESI-MS m / z 221.34 [M+H] + .

[0180] 1 H NMR (500 MHz, CDCl3) δ 7.28(m, 1H), 7.25(dd, J = 4.4, 2.0 Hz, 1H), 7.24-7.21(m, 1H), 7.19-7.13(m, 2H), 3.93-3.90(t, J = 7.0 Hz, 1H), 2.44-2.40(m, 2H), 2.40-2.38(m, 2H), 2.31-2.26(m, 2H), 1.45-1.34(m, 4H), 0.84-0.79(t, J= 7.4 Hz, 6H).

[0181] 13 C NMR (126 MHz, CDCl3) δ 144.35, 128.64, 128.40, 127.12, 126.80, 126.64, 126.62, 63.82, 56.67, 53.89, 20.49, 12.00.

[0182] Example 6

[0183] Name: (S)-N,N-Diisopropyl-2-phenylethane-1,2-diamine

[0184] Process route:

[0185]

[0186] Specific operations:

[0187] Step (1) Preparation of (S)-2-Boc-amino-phenylacetic acid

[0188] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, add (S)-2-amino-3,3-dimethylbutyric acid (20 g, 0.13 mol, 1.0 eq), an aqueous solution (150 ml) containing sodium hydroxide (15.6 g, 0.39 mol, 3.0 eq), and tetrahydrofuran (100 ml). Stir until completely dissolved, then add (Boc)₂O (42.5 g, 0.19 mol, 1.5 eq) and stir at room temperature for 4–8 h. Monitor by TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. Extracted with ethyl acetate (2 × 300 ml), the alkaline aqueous phase was collected and the pH of the alkaline aqueous phase was adjusted to 1-3 with 5% hydrochloric acid. Extracted with ethyl acetate (2 × 300 ml), the organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to give approximately 27.6 g of (S)-2-Boc-amino-phenylacetic acid, with a yield of approximately 84.8%.

[0189] ESI-MS m / z 252.14 [M+H] + .

[0190] 1 H NMR(500 MHz, CDCl3) δ 8.14-8.09(d, J = 4.9 Hz, 1H), 7.44-7.39(d, J= 7.3 Hz, 2H), 7.36-7.29(m, 3H), 5.13-5.08(d, J = 5.2 Hz, 1H), 1.21(s, 9H).

[0191] 13 C NMR (126 MHz, CDCl3) δ 173.53, 157.14, 138.50, 129.10, 128.75, 128.55, 128.08, 127.34, 81.79, 58.99, 28.11.

[0192] Step (2) Preparation of (S)-N,N-diisopropyl-2-Boc-amino-phenylacetamide

[0193] In a 1 L three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, condenser, and dropping funnel, (S)-2-Boc-amino-phenylacetic acid (25.1 g, 0.1 mol, 1.0 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.1 g, 0.11 mol, 1.1 eq), 1-hydroxybenzotriazole (14.8 g, 0.11 mol, 1.1 eq), diisopropylamine (9.5 g, 0.13 mol, 1.0 eq), and dichloromethane (350 ml) obtained in step (1) were added. The mixture was cooled to 0 °C, and triethylamine (25.3 g, 0.25 mol, 2.5 eq) was added dropwise. After the addition was complete, stirring was continued for 4–8 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spots in the reaction solution. Add water (400 ml), separate the liquid and collect the organic phase, wash successively with 10% citric acid aqueous solution (400 ml), 10% sodium bicarbonate solution (400 ml) and saturated saline solution (400 ml), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure at 50 °C to obtain approximately 28.1 g of (S)-N,N-diisopropyl-2-Boc-amino-phenylacetamide, with a yield of approximately 81.6%.

[0194] ESI-MS m / z 345.46 [M+H] + .

[0195] 1 H NMR(500 MHz, CDCl3) δ 7.46-7.24(m, 5H), 5.67(s, 1H), 3.89-3.84(m,1H), 3.80-3.76(m, 1H), 1.51(s, 9H), 1.26-1.21(d, J = 7.1 Hz, 4H).

[0196] 13 C NMR(126 MHz, CDCl3) δ 172.54, 168.83, 140.04, 129.22, 128.76,127.25, 126.74, 126.67,80.55, 61.02, 57.59, 28.84, 13.92, 22.08.

[0197] Step (3) Preparation of (S)-N,N-diisopropyl-2-amino-phenylacetamide

[0198] In a 1 L three-necked round-bottom flask equipped with a thermometer, dropping funnel, and condenser, add (S)-N,N-diisopropyl-2-Boc-amino-phenylacetamide (25 g, 72.6 mmol, 1.0 eq) obtained in step (2) and approximately 200 ml of ethyl acetate. Stir until completely dissolved. Then, add dropwise a solution of 4 mol / L ethyl hydrochloride (80 ml, 0.32 mol, 4.4 eq). After the addition is complete, continue stirring for 4–8 h. Monitor the reaction by TLC, and the reaction endpoint is defined as the disappearance of the starting material spot in the reaction solution. Cool to 0℃, add saturated potassium carbonate solution dropwise to adjust pH to 9-10, separate the liquid and collect the organic phase, extract the alkaline aqueous phase with ethyl acetate (300 ml), combine the organic phases, wash with saturated brine (300 ml), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure at 50℃ to obtain approximately 14.5 g of (S)-N,N-diisopropyl-2-amino-phenylacetamide, with a yield of approximately 82.3%.

[0199] ESI-MS m / z 245.45 [M+H] + .

[0200] 1 H NMR(500 MHz, CDCl3) δ 7.48-7.23(m, 5H), 4.88(s, 1H), 3.86-3.82(m,2H), 1.29-1.27(d, J = 14.4 Hz, 6H), 1.25-1.23(d, J = 8.4 Hz, 6H).

[0201] 13 C NMR(126 MHz, CDCl3) δ 171.67, 141.44, 129.6, 129.2, 128.80,127.48, 126.81, 58.46, 56.45, 21.23.

[0202] Step (4) Preparation of (S)-N,N-diisopropyl-2-phenylethane-1,2-diamine

[0203] In a 500 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and dropping funnel, (S)-N,N-diisopropyl-2-amino-phenylacetamide (14.3 g, 58.5 mmol, 1.0 eq) and methyltetrahydrofuran (200 ml) were added. The mixture was cooled to below 0 °C, and lithium aluminum hydride (3.1 g, 81.9 mmol, 1.4 eq) was added in portions. After the addition was complete, the mixture was stirred for 1 h. The reaction was monitored by TLC, and the endpoint was defined as the disappearance of the starting material spot in the reaction solution. 3.1 ml of pure water, 3.1 ml of 10% sodium hydroxide solution, 9.3 ml of pure water, and approximately 14 g of anhydrous magnesium sulfate were added sequentially. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 50 °C to obtain approximately 8.8 g of (S)-N,N-diisopropyl-2-phenylethane-1,2-diamine, with a yield of approximately 68.7%.

[0204] ESI-MS m / z 221.35 [M+H] + .

[0205] 1 H NMR(500 MHz, CDCl3) δ 7.29(dd, J = 8.1, 0.9 Hz, 2H), 7.22-7.19(t, J= 7.6 Hz, 2H), 7.15-7.10(m, 1H), 3.87-3.84(dd, J = 10.4, 3.6 Hz, 1H), 3.02-2.93(m, 2H), 2.53-2.47(dd, J = 13.5, 3.7 Hz, 1H), 2.29-2.24(dd, J = 13.5,10.5 Hz, 1H), 0.99-0.94(d, J = 6.8 Hz, 6H), 0.87-0.83(d, J = 6.6 Hz, 6H).

[0206] 13 C NMR (126 MHz, CDCl3) δ 144.65, 128.21, 126.90, 126.74, 54.08, 53.97, 47.96, 22.42, 19.55.

Claims

1. A method for preparing a diamine-based chiral resolving agent, characterized in that, This diamine-based chiral resolving agent is prepared by the following steps: (1) Using chiral α-amino acids as raw materials, react with (Boc)2O and base in a solvent to obtain Boc-protected amino acids; (2) In a solvent, Boc-protected amino acids and secondary amines react with a condensing agent and a base to obtain Boc-protected secondary amides. (3) Boc-protected secondary amides dissolve in organic solvents and, under acidic conditions, remove the Boc protecting group to obtain chiral α-amino secondary amides; (4) The chiral α-amino secondary amide is reduced to an amine by a reducing agent to obtain a chiral amino secondary amine, which is the target product diamine chiral resolving agent.

2. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: The solvent in step 1 is one or two of acetonitrile, 1,4-dioxane, tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, isopropanol, and pure water; the base in step 1 is one of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

3. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: In step 1, the chiral α-amino acid has the following structure: R1 is one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, p-hydroxyphenyl, naphthyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, and indole; the chiral amino acid can be either levorotatory or dextrorotatory.

4. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: In step 1, the molar equivalent ratio of chiral α-amino acid to (Boc)2O and base is 1.0:1.0-2.0:2.0-3.0, and the preferred molar equivalent ratio is 1.0:1.5:2.

5.

5. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: The solvent in step 2 is one of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, toluene, and benzene; the condensing agent in step 2 is dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 4-N,N-dimethylpyridine, 1-hydroxybenzotriazole, O-(7-azabenzotriazole-1-yl)-di(dimethylamino)carbomony hexafluorophosphate, O-(benzotriazole-1-yl)-di(dimethylamino)carbomony hexafluorophosphate, O-(5-chlorobenzotriazole) -1-yl)-di(dimethylamino)carbomonium hexafluorophosphate, O-(benzotriazol-1-yl)-di(dimethylamino)carbomonium tetrafluoroborate, O-(N-succinimide)-di(dimethylamino)carbomonium tetrafluoroborate, benzotriazol-1-yloxy-tri(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yloxy-tri(tetrahydropyrrole)phosphonium hexafluorophosphate are one or two of these; the base in step 2 is one of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine and 4-dimethylpyridine.

6. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: The secondary amine in step 2 has the following structure: R2 and R3 are one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, p-hydroxyphenyl, naphthyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl and triphenylmethyl, respectively.

7. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: The organic solvent in step 3 is one of dichloromethane, ethyl acetate, butyl acetate, methyl tert-butyl ether, diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, acetone, acetonitrile, acetic acid, and toluene. The acid in step 3 is one of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, formic acid, acetyl chloride, and trifluoroacetic acid.

8. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: The reducing agent in step 4 is one of lithium aluminum hydride, borane, sodium borohydride, and triethylsilane.

9. The method for preparing a diamine-based chiral resolving agent according to claim 1, characterized in that: The diamine chiral resolving agent in step 4 has the following structure: R1, R2, and R3 are respectively one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, p-hydroxyphenyl, naphthyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, and indole; the chiral amine is either levorotatory or dextrorotatory.

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