Chiral alpha-amino alcohol compound, preparation method and application thereof

Abstract

The present application relates to a kind of chiral alpha-amino alcohol compounds and its preparation method and application, utilize Boc-L-serine methyl ester as chiral source, utilize 2,2-dimethoxypropane ring closure protection amino and hydroxyl, by simple and easy primary grignard reagent and Boc-L-serine methyl ester occur nucleophilic reaction generation hydroxyl, then alcohol hydroxyl can be eliminated into double bond under the participation of burgess reagent, finally palladium-carbon hydrogen gas reduction double bond obtains alpha-amino alcohol precursor, amino alcohol precursor is deprotected under acidic condition and can obtain N-alpha-C by secondary alkyl chain modification alpha-amino alcohol.The method compared with traditional method, with shorter time consumption, higher total yield and so on.The method is expected to be widely used in the synthesis of nitrogen-containing chiral ligand in the field of asymmetric synthesis.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, and in particular to a chiral α-amino alcohol compound, its preparation method, and its application. Background Technology

[0002] Amino alcohols are ubiquitous in many natural products, serving as important components and forming the basic structural framework of many drug and biomolecules. Surveys show that over 300,000 compounds and more than 2,000 natural products approved by food and drug regulatory authorities contain α-amino alcohol fragments. Chiral amino alcohols can also be used as organic catalysts, frequently acting as highly efficient chiral inducing catalysts in the asymmetric addition reactions of alkyl zinc reagents and aldehydes. They are also ideal chiral catalytic building blocks in asymmetric catalytic reactions involving transition metals. Furthermore, asymmetric metal catalysts coordinated with transition metal ions can be prepared using chiral amino alcohols.

[0003] Currently reported methods for synthesizing chiral 1,2-amino alcohols with N-α-C derived alkyl chains are mainly based on the synthetic routes developed by Reisman, such as... Figure 1 As shown (see reference J. Am. Chem. Soc. 2017, 139, 5684-5687).

[0004] This method uses N-tert-butylchiral sulfonylimide as a chiral framework, which then undergoes a nucleophilic reaction with a secondary alkyl Grignard reagent. Chiral induction yields a single-configuration product, followed by removal of the protecting group to obtain a chiral amino alcohol. Simultaneously, they derivatized this chiral amino alcohol to obtain a bixazoline ligand with an optical purity (ee value) as high as 99%. While this method is easy to prepare in large quantities and superior to the most advanced methods for preparing amino acids or amino alcohols from alkylene hydrogenation, it requires the preparation of different types of secondary alkyl Grignard reagents. Furthermore, the synthesis of secondary alkyl Grignard reagents is more difficult than that of primary alkyl Grignard reagents, and the types of ketones that can be used to prepare secondary alkyl halides are limited, thus restricting the substrates. Additionally, this synthetic route suffers from a long synthesis cycle and low overall yield. Summary of the Invention

[0005] The purpose of this invention is to overcome the deficiencies of the prior art by providing a chiral α-amino alcohol compound, its preparation method, and its applications. This invention utilizes Boc-L-serine methyl ester as a chiral source, and uses 2,2-dimethoxypropane for ring closure protection of the amino and hydroxyl groups. A readily available primary Grignard reagent reacts with Boc-L-serine methyl ester via a nucleophilic reaction to generate a hydroxyl group. The hydroxyl group can then be eliminated to form a double bond with the participation of a Burgess reagent. Finally, palladium carbon-hydrogen reduces the double bond to obtain the α-amino alcohol precursor. After deprotection under acidic conditions, the α-amino alcohol modified with an N-α-C secondary alkyl chain is obtained. This α-amino alcohol compound is optically active and can be used for the synthesis of nitrogen-containing chiral ligands, showing promise for widespread application in the synthesis of nitrogen-containing chiral ligands in the field of asymmetric synthesis.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] A chiral α-amino alcohol compound, the general structural formula of which is:

[0008]

[0009] Among them, R 1 Selected from -H or -CH3,

[0010] R 2 Selected from -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -(CH2)(C6H5), -(CH2)2O(CH3) or -C6H5(-Ph).

[0011] Furthermore, when R 1 When = -H, R 2 =-H; when R 1 When =-CH3, R 2 =-H; when R 1 When = -H, R 2 =-CH3; when R 1 When = -H, R 2 =-CH2-CH3; when R 1 When = -H, R 2 =-CH2-CH2-CH3; when R 1 When = -H,

[0012] R 2 =-(CH2)(C6H5); when R 1 When = -H, R 2 =-(CH2)2O(CH3); when R 1 When = -H, R 2 =-C6H5.

[0013] This invention also provides a method for preparing chiral α-amino alcohol compounds, the specific steps of which are as follows:

[0014] S1. Synthesize the product with the structure shown in Formula II using 2,2-dimethoxypropane and amino acid methyl ester as raw materials;

[0015] S2. Using the product of the structure shown in Formula II obtained in step S1 and Grignard reagent as raw materials, synthesize the product of the structure shown in Formula III.

[0016] S3. Using the product of the structure shown in Formula III obtained in step S2 and Burgess reagent as raw materials, synthesize the product of the structure shown in Formula IV.

[0017] S4. Use the product of the structure shown in Formula IV obtained in step S3 and palladium on carbon as raw materials to synthesize the product of the structure shown in Formula I.

[0018] The structural formulas I to IV are shown below:

[0019]

[0020] Among them, R 1 Selected from -H or -CH3,

[0021] R 2 Selected from -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -(CH2)(C6H5), -(CH2)2O(CH3) or -C6H5.

[0022] Furthermore, in the structure shown in Equation II, R 1 =-H;

[0023] In the structures shown in Equations I, III, and IV, R 2 Selected from -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -(CH2)(C6H5), -(CH2)2O(CH3) or -C6H5;

[0024] In the structure shown in Equation II, R 1 =-CH3;

[0025] In the structures shown in Equations I, III, and IV, R 2 Selected from -H.

[0026] Further, in step S1, the amino acid methyl ester includes Boc-L-serine methyl ester and Boc-L-threonine methyl ester.

[0027] Further, in step S1, amino acid methyl ester, 2,2-dimethoxypropane, and boron trifluoride diethyl ether solution are added to dichloromethane solution, stirred, and vacuum concentrated to remove excess solvent to obtain crude product. The crude product is then purified by silica gel column chromatography to obtain the product with the structure shown in Formula II.

[0028] Furthermore, the above describes the ratio of amino acid methyl ester: 1,2-dimethoxypropane: boron trifluoride ether solution as a molar mass ratio of (1.0–1.1): (3.0–3.5): (0.1–0.15).

[0029] Furthermore, the ratio of amino acid methyl ester to dichloromethane solution is 1 mmol to 0.7–1 mL.

[0030] Furthermore, the stirring temperature is 0°C and the stirring time is 0.3–1 h.

[0031] Further, in step S2, the Grignard reagent is selected from at least one of methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, butyl magnesium bromide, pentyl magnesium bromide, hexyl magnesium bromide, benzyl magnesium bromide, phenethyl magnesium bromide, or (3-methoxypropyl) magnesium bromide.

[0032] Further, in step S2, the product with the structure shown in Formula II obtained in step S1, cerium trichloride, and Grignard reagent are added to a tetrahydrofuran solution, stirred, and then vacuum concentrated to remove excess solvent to obtain a crude product. The crude product is then purified by silica gel column chromatography to obtain a product with the structure shown in Formula III.

[0033] Furthermore, the product of the structure shown in Formula II is expressed in a molar mass ratio as follows: cerium trichloride: Grignard reagent = (1.0–1.1):(1.0–1.2):(5.0–5.5).

[0034] Furthermore, the product of the structure shown in Formula II: tetrahydrofuran solution = 1 mmol: 8-11 mL.

[0035] Furthermore, the stirring temperature is -78°C and the stirring time is 0.3 to 1 hour.

[0036] Further, in step S3, the product with the structure shown in formula III obtained in step S2, Burgess reagent, Molecular sieves were added to an ultra-dry toluene solution, and under a nitrogen atmosphere, the solution was stirred and then vacuum concentrated to remove excess solvent to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a product with the structure shown in Formula IV.

[0037] Furthermore, according to the above, the product of the structure shown in Formula III, in molar mass ratio: Burgess reagent: Molecular sieve = (1.0~1.1):(2.5~3.0):(1g / mmol~1.1g / mmol).

[0038] Furthermore, the product of the structure shown in Formula III: ultra-dry toluene solution = 1 mmol: 60-150 mL.

[0039] Furthermore, the stirring temperature is 80°C and the stirring time is 0.3–1 h.

[0040] Further, in step S4, palladium on carbon (Pd / C) and the product with the structure shown in formula IV obtained in step S3 are added to a methanol solution, stirred under a hydrogen atmosphere, and vacuum concentrated to remove excess solvent to obtain a crude product. The crude product is then purified by silica gel column chromatography to obtain the product with the structure shown in formula I.

[0041] Furthermore, the molar mass ratio is palladium on carbon (Pd / C): product of the structure shown in Formula IV = (0.1-0.15):(1.0-1.3).

[0042] Furthermore, the product of the structure shown in Formula IV: methanol solution = 1 mmol: 3-8 mL.

[0043] Furthermore, the stirring temperature is 25°C and the stirring time is 0.5–1.5 h.

[0044] Furthermore, the present invention also provides an application of chiral α-amino alcohol compounds, wherein the above-mentioned compounds having general structural formula I are used in the synthesis of nitrogen-containing chiral ligands.

[0045] Furthermore, the specific steps of the method for synthesizing the nitrogen-containing chiral ligand compound are as follows:

[0046] A compound with general structural formula I and a hydrochloric acid-dioxane solution (HCl-dioxane solution) were added to a methanol solution (MeOH solution). After stirring, the pH was adjusted to 8, and the mixture was concentrated under vacuum to remove excess solvent, yielding a crude product. The crude product was then purified by silica gel column chromatography to obtain a chiral amino alcohol compound, the structure of which is shown in formula V.

[0047]

[0048] Among them, R 1 Selected from -H or -CH3,

[0049] R 2 Selected from -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -(CH2)(C6H5), -(CH2)2O(CH3) or -C6H5.

[0050] Furthermore, when R 1 When = -H, R 2 =-H; when R 1 When =-CH3, R 2 =-H; when R 1 When = -H, R 2 =-CH3; when R 1 When = -H, R 2 =-CH2-CH3; when R 1 When = -H, R 2 =-CH2-CH2-CH3; when R 1 When = -H, R 2 =-(CH2)(C6H5); when R 1 When = -H, R 2 =-(CH2)2O(CH3); when R 1 When = -H, R 2 =-C6H5.

[0051] Furthermore, the above is further described in the following molar mass ratio: compound having general structural formula I: hydrochloric acid-dioxane solution = (1.0~1.1):(10.0~11.0).

[0052] Furthermore, the compound having general structural formula I: methanol solution = 1 mmol: 1-3 mL.

[0053] Furthermore, the stirring temperature is 50°C and the stirring time is 0.5–1.5 h.

[0054] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0055] 1. Using readily available and inexpensive Boc-L-serine methyl ester and Boc-L-threonine methyl ester as starting substrates, the synthesis of tertiary alcohols is facilitated due to the relatively simple preparation process of primary alkyl Grignard reagents. Subsequently, the tertiary alcohol is eliminated to generate an alkene, followed by a hydrogenation reduction reaction to obtain a protecting amino alcohol precursor. By removing the protecting group through hydrolysis, a chiral amino alcohol with high correspondence selectivity is obtained. Finally, the successful synthesis of chiral Biox ligands and Pybox ligands with good chirality retention demonstrates the practicality of this synthetic strategy.

[0056] 2. The chiral α-amino alcohol synthesis route of the present invention has the advantages of short time consumption, higher yield and wider substrate range, and has great application prospects in the synthesis of a series of nitrogen-containing chiral ligands.

[0057] 3. To address the shortcomings of traditional methods for synthesizing α-amino alcohols, such as long routes and poor substrate adaptability, this invention provides a new synthetic route that can rapidly prepare a series of chiral amino alcohols with excellent enantioselectivity. Attached Figure Description

[0058] Figure 1 A schematic diagram of the synthetic route developed for Reisman;

[0059] Figure 2 This is a schematic diagram of the synthetic route for chiral α-amino alcohols in this invention. Detailed Implementation

[0060] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0061] The reaction mechanism of this invention is as follows: Figure 2 As shown, a method for preparing a chiral α-amino alcohol compound includes the following specific steps:

[0062] (1) The synthesis methods of 1a to 1b, whose general structural formula II is:

[0063]

[0064] Among them, 1a: R 1 =H; 1b:R 1 =Me;

[0065] Boc-L-serine methyl ester, 1,2-dimethoxypropane, and boron trifluoride diethyl ether solution were added to 50-60 mL of dichloromethane solution at a molar ratio of (1.0-1.1):(3.0-3.5):(0.1-0.15). The mixture was stirred at 0°C for half an hour and then slowly heated to room temperature. After the starting material was completely eliminated by TLC, the mixture was concentrated under vacuum to remove excess solvent and obtain the crude product. The crude product was purified by silica gel column chromatography to obtain products 1a-1b.

[0066] (2) The synthesis methods for 2a to 2h, with the general structural formula III as follows:

[0067]

[0068] in,

[0069] 2a: R 1 =H,R 2 =H;

[0070] 2b: R 1 =-CH3(Me), R 2 =H;

[0071] 2c: R 1 =H,R2 =Me;

[0072] 2d:R 1 =H,R 2 =-CH2-CH3(Et);

[0073] 2e:R 1 =H,R 2 =-CH2-CH2-CH3(n-Pr);

[0074] 2f:R 1 =H,R 2 =-(CH2)(C6H5);

[0075] 2g:R 1 =H,R 2 =-(CH2)2O(CH3);

[0076] 2h: R 1 =H,R 2 =-C6H5(Ph);

[0077] Cerium trichloride, products 1a-1b, and Grignard reagent were added to 50-60 mL of tetrahydrofuran solution (ultra-dry THF) at a molar ratio of (1.0-1.2):(1.0-1.1):(5.0-5.5). The mixture was stirred at -78°C for half an hour and then slowly heated to room temperature. After the reaction proceeded for 2.5-3.0 hours, the reaction was monitored by TLC until the starting material was completely eliminated. The mixture was then concentrated under vacuum to remove excess solvent and obtain the crude product. The crude product was purified by silica gel column chromatography to obtain products 2a-2h.

[0078] (3) The synthesis methods for 3a to 3h, with the general structural formula III as follows:

[0079]

[0080] in,

[0081] 3a: R 1 =H,R 2 =H;

[0082] 3b: R 1 =Me,R 2 =H;

[0083] 3c:R 1 =H,R 2 =Me;

[0084] 3d:R 1 =H,R 2 =Et;

[0085] 3e:R 1=H,R 2 =n-Pr;

[0086] 3f:R 1 =H,R 2 =-(CH2)(C6H5);

[0087] 3g:R 1 =H,R 2 =-(CH2)2O(CH3);

[0088] 3h:R 1 =H,R 2 =Ph;

[0089] The products 2a-2h, Burgess reagent, Molecular sieves (active powder, activated and dried overnight at 140°C in a vacuum drying oven) were added to 20-40 mL of ultra-dry toluene solution at a molar ratio of (1.0-1.1):(2.5-3.0):(1 g / mmol-1.1 g / mmol). The mixture was stirred at 80°C for half an hour under a nitrogen atmosphere. After the raw material was completely eliminated by TLC, the mixture was cooled to room temperature, the solid residue was filtered off, and the filter cake was washed with 10-20 mL of ethyl acetate. The mixture was then concentrated under vacuum to remove excess solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain product 3a-3h.

[0090] (4) The synthesis methods for 4a to 4h, with the general structural formula I as follows:

[0091]

[0092] in,

[0093] 4a: R 1 =H,R 2 =H;

[0094] 4b: R 1 =Me,R 2 =H;

[0095] 4c: R 1 =H,R 2 =Me;

[0096] 4d:R 1 =H,R 2 =Et;

[0097] 4e:R 1 =H,R 2 =n-Pr;

[0098] 4f:R 1 =H,R 2 =-(CH2)(C6H5);

[0099] 4g:R 1 =H,R 2 =-(CH2)2O(CH3);

[0100] 4h:R 1 =H,R 2 =Ph;

[0101] Pd / C and 3a were added to 10 mL of methanol solution at a molar ratio of (0.1–0.15):(1.0–1.3), and stirred at 25 °C for 1 hour under a hydrogen atmosphere. After the raw materials were completely eliminated by TLC monitoring, the mixture was filtered through a funnel lined with diatomaceous earth, and the excess solvent was removed by vacuum concentration to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain product 4a–4h.

[0102] In a specific embodiment, in step (2), the Grignard reagent is selected from at least one of methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, butyl magnesium bromide, pentyl magnesium bromide, hexyl magnesium bromide, benzyl magnesium bromide, phenethyl magnesium bromide, and (3-methoxypropyl) magnesium bromide. Different Grignard reagents participate in the reaction to modify different alkyl chains, thereby obtaining a series of 1,2-amino alcohol precursors with different substituents, which can be applied to the synthesis of 1,2-amino alcohols.

[0103] In a specific embodiment, in step (3), the following steps are used: The amount of molecular sieve is 0.3g.

[0104] In a specific embodiment, in step (4), 10% palladium on carbon (Pd / C) is used.

[0105] Furthermore, the present invention also provides an application of chiral α-amino alcohol compounds, wherein the above-mentioned compounds having general structural formula I are used in the synthesis of nitrogen-containing chiral ligands.

[0106] Furthermore, the specific steps of the synthesis method for compounds 5a-5h containing nitrogen-containing chiral ligands are as follows:

[0107] A compound with general structural formula I and a hydrochloric acid-dioxane solution were added to 10 mL of methanol solution at a molar ratio of (1.0–1.1):(10.0–11.0). The mixture was stirred at 50 °C for 1 hour. After the starting material was completely eliminated by TLC, the pH was adjusted to 8, and the mixture was concentrated under vacuum to remove excess solvent to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compounds 5a–5h with general structural formula V.

[0108]

[0109] in,

[0110] 5a:R 1 =H,R 2 =H;

[0111] 5b:R 1 =Me,R 2 =H;

[0112] 5c:R 1 =H,R 2 =Me;

[0113] 5d:R 1 =H,R 2 =Et;

[0114] 5e:R 1 =H,R 2 =n-Pr;

[0115] 5f:R 1 =H,R 2 =-(CH2)(C6H5);

[0116] 5g:R 1 =H,R 2 =-(CH2)2O(CH3);

[0117] 5h:R 1 =H,R 2 =Ph.

[0118] In a specific embodiment, in step (5), the equivalent ratio of the compound having general formula I to dioxane hydrochloride (4.0M) is 1 mmol: 4 mL.

[0119] The above-described embodiments will be described in more detail below with reference to specific examples.

[0120] Example 1

[0121] In this embodiment, product 1a was synthesized using 2,2-dimethoxypropane and Boc-L-serine methyl ester as raw materials, and its preparation process is as follows:

[0122]

[0123] The specific steps are as follows:

[0124] At 0°C, 20.0 mL of Boc-L-serine methyl ester (64 mmol, 1.0 equiv) diluted in anhydrous dichloromethane was slowly added dropwise to a round-bottom flask containing 50.0 mL of anhydrous dichloromethane, a stir bar, and a mixed solution of 2,2-dimethoxypropane (192 mmol, 3.0 equiv) and BF3·Et2O (6.4 mmol, 0.1 equiv). The solution initially changed from colorless to pale yellow. After the addition was complete, the mixture was transferred to room temperature and stirred for 3 hours. The solution gradually changed from pale yellow to black. TLC and GCMS monitoring showed that no starting material remained and only a single product was formed. The reaction was quenched with saturated NaOH aqueous solution. The mixture was extracted with ethyl acetate (50 mL × 3), washed with 10% NaCl aqueous solution, and the combined organic layers were dried over anhydrous Na2SO4. The combined organic layers were filtered and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (silica gel: 10% ethyl acetate: petroleum ether) to obtain the target compound. (Orange-yellow oily liquid, 99% yield, 16.4g)

[0125] The data characterizing compound 1a synthesized in Example 1 are as follows:

[0126] 1 H NMR(600MHz,Chloroform-d) δ4.42 (dd, J=6.9, 2.8Hz, 1H), 4.22-3.98 (m, 2H), 3.74 (d, J=1.5Hz, 3H), 1.81-1.33 (m, 15H).

[0127] Example 2

[0128] In this example, 2a is prepared using magnesium methyl bromide and 1a obtained in Example 1 above as raw materials. The preparation process is as follows:

[0129]

[0130] The specific steps are as follows:

[0131] Cerium chloride (5.8 mmol, 1.0 equiv.) and ultradry THF (55 mL) were added to a dried 100 mL three-necked flask equipped with a stir bar and stirred vigorously at room temperature for 10 min to form a suspension. One a (5.8 mmol, 1.0 equiv.) solution was diluted with ultradry THF (10 mL) and added to the cerium chloride suspension. The mixture was cooled to -78 °C, and 1.0 M methyl Grignard reagent (29 mmol, 5.0 equiv.) was slowly added dropwise under a nitrogen atmosphere. The reaction was stirred at -78 °C for 30 min, then slowly heated to room temperature. GC-MS analysis showed no residual starting material and no single product formation. The reaction was quenched with saturated NH4Cl, further diluted with water, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (5% ethyl acetate: petroleum ether) to obtain the target compound. (Pale yellow oily liquid, yield 96%, 1.44g).

[0132] The data for characterizing compound 2a prepared in Example 2 are as follows:

[0133] 1 H NMR(400MHz,Chloroform-d) δ5.17(s,1H),4.08(d,J=7.3Hz,1H),3.99(t,J=8.5Hz,1H),3.86(d,J=8.5Hz,1H),1.86-1.42(m,15H),0.92(t,J=7.5Hz,6H).

[0134] HRMS (ESI)m / z calcd for C 13 H 26 NO4 + [(M+H) + ]260.1856, found 260.1862.

[0135] Example 3

[0136] This embodiment describes the synthesis method of the Grignard reagent in Example 2 above. Unless otherwise specified, all raw materials and reagents used are commercially available. The preparation process is as follows:

[0137]

[0138] X = Cl or Br

[0139] The specific steps are as follows:

[0140] Magnesium flakes (90 mmol, 1.1 equiv) were activated by washing with 1.0 M hydrochloric acid, followed by washing with water, ethanol, and acetone, respectively. The solution was then transferred to a 250 mL three-necked flask dried under a hot air gun and stirred for 60 min under vacuum. The flask containing the magnesium flakes was then connected to a reflux condenser and stirred. Under a nitrogen atmosphere, the halide (RBr or RCl) was diluted in anhydrous THF (40 mL). One grain of I₂ was added to the flask containing the magnesium flakes, followed by 1 mL of the halide. The mixture was stirred and refluxed intermittently with a hot air gun for more than 2 minutes until the brownish-red solution became colorless. The remaining halide (82 mmol, 1.0 equiv) was then slowly reacted in dry tetrahydrofuran in an addition funnel for more than 40 minutes while maintaining gentle reflux. After the addition of the halide, the reaction was stirred at 75 °C until the magnesium strip completely disappeared. The mixture was cooled to room temperature and the yield was calculated by titration with a tetrahydrofuran solution of iodine.

[0141] Example 4

[0142] In this embodiment, 3a is prepared using 2a obtained in Example 2 above as raw material, and the preparation process is as follows:

[0143]

[0144] The specific steps are as follows:

[0145] In a 100 mL three-necked flask, add 2a (0.3 mmol, 1.0 equiv), Burgess reagent (0.75 mmol, 2.5 equiv), and 0.3 g (g / mmol) of molecular sieve (active powder, activated and dried overnight at 140 °C in a vacuum drying oven) was used. The mixture was evacuated and purged with nitrogen three times, then anhydrous toluene (10 mL) was added. The resulting mixture was heated to 80 °C and stirred at this temperature for 30 min. After the reaction was complete (detected by TLC or GCMS), the reaction solution was directly concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (silica gel: 3% ethyl acetate: petroleum ether) to give target compound 3a (yellow oily liquid, yield 87%, 62.9 mg).

[0146] The data for characterizing compound 3a prepared in Example 4 are as follows:

[0147] 1 H NMR(400MHz,Chloroform-d) δ4.73-4.26(m,2H),3.98-3.67(m,3H),1.73-1.41(m,15H),1.25(d,J=5.5Hz,3H).

[0148] HRMS (ESI)m / z calcd for C13 H 24 NO3 + [(M+H) + ]242.1751, found 242.1759.

[0149] Example 5

[0150] In this embodiment, 4a is prepared using 3a obtained in Example 4 as the raw material, and the preparation process is as follows:

[0151]

[0152] The specific steps are as follows:

[0153] Add 15 mL of MeOH, 0.2 mmol / C (0.1 equiv), and 3a (2.0 mmol / V, 1.0 equiv) to a 50 mL Schlenk flask. Connect a vacuum pump to the side wall of the Schlenk flask and attach it to a balloon filled with hydrogen. Introduce the flask with the balloon for 30 seconds, then close the stopcock, open the valve, and evacuate for 30 seconds. Close the stopcock, refill the flask with hydrogen, and repeat this cycle three times. Stir the flask at room temperature for 1 hour. After the reaction is complete, transfer the mixture to a funnel filled with diatomaceous earth for filtration to remove solid impurities, and wash the filter cake three times with ethyl acetate. Remove the solvent by vacuum concentration without further purification to give (S)-4-(heptane-4-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester, i.e., 4a (colorless oily liquid, yield >99%, 0.48 g).

[0154] The data for characterizing compound 4a prepared in Example 5 are as follows:

[0155] 1 H NMR(400MHz,Chloroform-d) δ3.91-3.58(m,3H),2.22-1.95(m,1H),1.65-1.35(m,15H),0.97-0.83(m,6H).

[0156] HRMS (ESI)m / z calcd for C 13 H 26 NO3 + [(M+H) + ]244.1907, found 244.1877.

[0157] Example 6

[0158] In this embodiment, product 1b is synthesized using 2,2-dimethoxypropane and Boc-L-threonine methyl ester as raw materials, and its preparation process is as follows:

[0159]

[0160] Example 6 is basically the same as Example 1 in terms of specific steps, except that Boc-L-threonine methyl ester is used instead of Boc-L-serine methyl ester as a raw material to synthesize 1b (orange-yellow oily liquid, yield 96%, 2.3g).

[0161] The data for characterizing compound 1b prepared in Example 6 are as follows:

[0162] 1 H NMR(400MHz,Chloroform-d) δ4.12-3.78(m, 2H), 3.68(s, 3H), 1.60-1.26(m, 18H).

[0163] HRMS (ESI)m / z calcd for C 13 H 24 NO5H + [(M+H) + ]274.1649, found 274.1653.

[0164] Example 7

[0165] In this example, 2c is prepared using ethyl magnesium bromide and 1a obtained in Example 1 above as raw materials. The preparation process is as follows:

[0166]

[0167] The specific steps of Example 7 are basically the same as those of Example 2, except that ethyl magnesium bromide is used instead of methyl magnesium bromide as a raw material to synthesize 2c (pale yellow oily liquid, yield 95%, 1.58 g).

[0168] The data for characterizing compound 2c prepared in Example 7 are as follows:

[0169] 1 H NMR(400MHz,Chloroform-d) δ5.07 (s, 1H), 4.16 (d, J=7.3Hz, 1H), 4.00 (t, J=8.5Hz, 1H), 3.82 (d, J=8.5Hz, 1H), 1.76-1.32 (m, 19H), 0.91 (t, J=7.5Hz, 6H).

[0170] HRMS (ESI)m / z calcd for C 15 H 30 NO4 + [(M+H) + ]288.2169, found 288.2187.

[0171] Example 8

[0172] In this embodiment, 3b is prepared using 2b as the raw material, and the preparation process is as follows:

[0173]

[0174] The specific steps of Example 8 are basically the same as those of Example 4, except that 2b is used instead of 2a as a raw material to synthesize 3b (yellow oily liquid, yield 83%, 63.4 mg).

[0175] The characterization data of compound 3b prepared in Example 8 are as follows:

[0176] 1 H NMR(400MHz,Chloroform-d) δ4.85-4.16 (m, 2H), 3.93-3.55 (m, 2H), 1.76-1.31 (m, 18H), 1.21 (d, J=5.5Hz, 3H).

[0177] HRMS (ESI)m / z calcd for C 14 H 25 NO3Na + [(M+Na) + ]278.1727, found 278.1742.

[0178] Example 9

[0179] In this embodiment, 3d is prepared using 2d as raw material, and the preparation process is as follows:

[0180]

[0181] The specific steps of Example 9 are basically the same as those of Example 4, except that 2d is used instead of 2a as a raw material to synthesize 3d (yellow oily liquid, yield 61%, 1.0g).

[0182] The data for characterizing compound 3d prepared in Example 9 are as follows:

[0183] 1 H NMR(400MHz,Chloroform-d) δ5.24 (q, J=7.2Hz, 1H), 4.36-3.96 (m, 2H), 3.81-3.56 (m, 1H), 2.24-1.24 (m, 21H), 1.05-0.75 (m, 6H).

[0184] HRMS (ESI)m / z calcd for C 17 H 32 NO3 + [(M+H) +]298.2377, found 298.2368.

[0185] Example 10

[0186] In this embodiment, 4b is prepared using 3b obtained in Example 8 as the raw material. The preparation process is basically the same as in Example 5, and its structure is as follows:

[0187]

[0188] Example 10 is basically the same as Example 5 in terms of specific steps, except that 3b is used instead of 3a as a reaction raw material to synthesize 4b (colorless oily liquid, yield 99%, 0.51g).

[0189] The data for characterizing compound 4b prepared in Example 10 are as follows:

[0190] 1 H NMR(600MHz,Chloroform-d) δ4.07-3.82 (m, 1H), 3.34-3.13 (m, 1H), 2.16-2.08 (d, 1H), 1.63-1.10 (m, 18H), 0.89-0.64 (m, 6H).

[0191] HRMS (ESI)m / z calcd for C 14 H 28 NO3 + [(M+H) + ]258.2064, found 258.2059.

[0192] Example 11

[0193] In this embodiment, 4c is prepared using 3c as the raw material. The preparation process is basically the same as in Example 5, and its structure is as follows:

[0194]

[0195] The specific steps of Example 11 are basically the same as those of Example 5, except that 3c is used instead of 3a as a reaction raw material to synthesize 4c (colorless oily liquid, yield 99%, 0.54g).

[0196] The data for characterizing compound 4c prepared in Example 11 are as follows:

[0197] 1 H NMR(400MHz,Chloroform-d) δ4.09-3.70(m, 3H), 1.85-1.35(m, 20H), 0.88-0.79(m, 6H).

[0198] HRMS(ESI)m / z calcd for C 15 H 30 NO3 + [(M+H) + ]272.2220, found 272.2215.

[0199] Example 12

[0200] In this embodiment, the 3d prepared in Example 9 above is used as the raw material to prepare 4d, and the preparation process is as follows:

[0201]

[0202] Example 12 is basically the same as Example 5 in terms of specific steps, except that 3d is used instead of 3a as a reaction raw material to synthesize 4d (colorless oily liquid, yield >99%, 0.60g).

[0203] The data for characterizing the compound prepared in Example 12 for 4d are as follows:

[0204] 1 H NMR(400MHz,Chloroform-d) δ4.03-3.72 (m, 3H), 1.96-1.77 (m, 1H), 1.63-1.22 (m, 23H), 0.86 (d, J=6.5Hz, 6H).

[0205] HRMS (ESI)m / z calcd for C 17 H 34 NO3 + [(M+H) + ]300.2533, found 300.2512.

[0206] Example 13

[0207] In this embodiment, 4e is prepared using 3e as a raw material. The preparation process is basically the same as in Example 5, and its structure is as follows:

[0208]

[0209] The specific steps are basically the same as in Example 5, except that 3e is used instead of 3a as a reaction raw material to synthesize 4e (colorless oily liquid, yield 94%, 0.67g).

[0210] The data for characterizing compound 4e prepared in Example 13 are as follows:

[0211] 1 H NMR(400MHz,Chloroform-d)δ4.03-3.74(m, 3H), 1.95-1.74(m, 1H), 1.65-1.12(m, 27H), 0.85(t, J=6.7Hz, 6H).

[0212] HRMS (ESI)m / z calcd for C 19 H 38 NO3 + [(M+H) + ]328.2846, found 328.2848.

[0213] Example 14

[0214] In this embodiment, 4f is prepared using 3f as the raw material. The preparation process is basically the same as in Example 5, and its structure is as follows:

[0215]

[0216] The specific steps are basically the same as in Example 7, except that 3f is used instead of 3a as a reaction raw material to synthesize 4f (colorless oily liquid, yield 99%, 0.84g).

[0217] The data for characterizing compound 4f prepared in Example 14 are as follows:

[0218] 1 H NMR(400MHz,Chloroform-d) δ7.36-7.18(m, 10H), 5.33-3.74(m, 3H), 3.09-2.43(m, 4H), 2.34-1.19(m, 20H).

[0219] HRMS (ESI)m / z calcd for C 27 H 38 NO3 + [(M+H) + ]424.2846, found 424.2848.

[0220] Example 15

[0221] In this embodiment, 4g is prepared using 3g as raw material. The preparation process is basically the same as in Example 5, and its structure is as follows:

[0222]

[0223] The specific steps are basically the same as in Example 5, except that 3g is used instead of 3a as the reaction raw material to synthesize 4g (colorless oily liquid, yield 99%, 0.71g).

[0224] The data for characterizing 4g of the compound prepared in Example 15 are as follows:

[0225] 1 H NMR(400MHz,Chloroform-d) δ3.96-3.72(m, 3H), 3.38-3.17(m, 10H), 1.92-1.73(m, 1H), 1.70-1.03(m, 23H).

[0226] HRMS (ESI)m / z calcd for C 19 H 38 NO5 + [(M+H) + 360.2744, found 360.2726.

[0227] Example 16

[0228] In this embodiment, 4h is prepared using 3h as the raw material. The preparation process is basically the same as in Example 5, and its structure is as follows:

[0229]

[0230] The specific steps are basically the same as in Example 5, except that 3h is used instead of 3a as the reaction raw material to synthesize 4h (colorless oily liquid, yield 99%, 0.71g).

[0231] The data for characterizing the compound prepared in Example 16 over 4 hours are as follows:

[0232] 1 H NMR(600MHz,Chloroform-d) δ7.41-6.95 (m, 10H), 4.10-3.76 (m, 3H), 3.17-2.56 (m, 2H), 2.48-2.13 (m, 2H), 1.66-1.33 (m, 16H).

[0233] HRMS (ESI)m / z calcd for C 25 H 34 NO3 + [(M+H) + ]396.2533,found396.2523.Mp50.4-51.3℃

[0234] Performance verification:

[0235] (1) Using 4a obtained in Example 5 above as raw material, 5a is prepared, and the preparation process is as follows:

[0236]

[0237] The specific steps are as follows:

[0238] In a 50 mL Schlenk flask, 10 mL of MeOH and 4a (2 mmol, 1.0 equiv) were added, followed by the addition of 10 equiv of HCl-dioxane solution at room temperature. The mixture was stirred at 50 °C for 1 hour, until it turned pale amber. After the reaction was complete, the mixture was cooled to room temperature, and a saturated aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH to 8. The aqueous layer was extracted with a 3:1 CHCl3:i-PrOH mixture (50 mL × 3). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude amino alcohol was purified by silica gel column chromatography using 1% Et3N in ethyl acetate as eluent, followed by elution with 10% MeOH in DCM to give (S)-2-amino-3-propylhexane-1-ol as 5a (colorless oily liquid, 98%, 0.2 g).

[0239] The data characterizing compound 5a are as follows:

[0240] 1 H NMR(400MHz,Chloroform-d) δ4.46-4.34 (m, 2H), 4.18-3.95 (m, 4H), 1.89-1.74 (m, J=6.8Hz, 2H), 0.98 (d, J=6.8Hz, 6H), 0.88 (d, J=6.8Hz, 6H).

[0241] 13 C NMR(101MHz,Chloroform-d) δ64.6, 58.5, 31.2, 19.4, 18.4.

[0242] (2) 7a was prepared using compound 5a as a raw material. The preparation process was as follows:

[0243]

[0244] The specific steps are as follows:

[0245] 5a (1.9 mmol, 2 equiv) and dimethyl oxalate (0.95 mmol, 1 equiv) were dissolved in ultra-dry PhMe (20 mL) and heated to 80 °C. The reaction was stirred overnight, and a white solid precipitated. The reaction was cooled to room temperature and concentrated under vacuum to give a crude diol as a viscous white solid. The crude diol was dissolved in PhMe (20 mL) and heated to 70 °C, then sulfoxide (2.1 mmol, 2.2 equiv) was added. The mixture was stirred at 70 °C for 0.5 h, then heated to 90 °C and reacted for 1.5 h. The reaction was cooled to room temperature and poured into a 20% KOH solution cooled to 0 °C. The aqueous layer was separated and extracted using DCM (50 mL × 3), and the organic layer was washed with 20% KOH solution, NaHCO3, and brine. The combined organic layers were dried over Na2SO4, filtered through a funnel lined with diatomaceous earth, and concentrated under reduced pressure to give a viscous brown solid. The crude product was dissolved in MeOH (20 mL) and KOH (2.4 mmol, 2.5 equiv) was added. The reaction was heated under reflux for 14 hours. The reaction was cooled to room temperature and concentrated to remove MeOH. The crude mixture was purified by silica gel column chromatography with 0.1% triethylamine:petroleum ether as the alkalizing agent, using 30% ethyl acetate:petroleum ether as the eluent, to give a white solid 7a.

[0246] The data characterizing compound 7a are as follows:

[0247] 1 H NMR(400MHz,Chloroform-d) δ4.46-4.34 (m, 2H), 4.18-3.95 (m, 4H), 1.89-1.74 (m, J=6.8Hz, 2H), 0.98 (d, J=6.8Hz, 6H), 0.88 (d, J=6.8Hz, 6H).

[0248] 13 C NMR(101MHz,Chloroform-d) δ154.6, 73.2, 71.1, 32.5 19.0, 18.3.HPLCanalysis CHIRALCEL IC-H column, 10% i-PrOH in hexanes, 1.0mL / min, 254nm UVdetector, t R (minor) = 18.5 min, t R (major) = 24.1 min.

[0249] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for preparing a chiral α-amino alcohol compound, characterized in that, The specific steps are as follows: S1. Synthesize the product with the structure shown in Formula II using 2,2-dimethoxypropane and amino acid methyl ester as raw materials, wherein the amino acid methyl ester is Boc-L-serine methyl ester and Boc-L-threonine methyl ester. S2. Using the product of the structure shown in Formula II obtained in step S1 and Grignard reagent as raw materials, synthesize the product of the structure shown in Formula III. S3. Using the product of the structure shown in Formula III obtained in step S2 and Burgess reagent as raw materials, synthesize the product of the structure shown in Formula IV. S4. Use the product of the structure shown in Formula IV obtained in step S3 and palladium on carbon as raw materials to synthesize the product of the structure shown in Formula I. The structural formulas I to IV are shown below: Among them, R 1 Selected from -H or -CH3, R 2 Selected from -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -(CH2)(C6H5), -(CH2)2O(CH3) or -C6H5.

2. The method for preparing a chiral α-amino alcohol compound according to claim 1, characterized in that, In step S1, amino acid methyl ester, 2,2-dimethoxypropane, and boron trifluoride diethyl ether solution are added to dichloromethane solution, stirred, and vacuum concentrated to remove excess solvent to obtain crude product. The crude product is purified by silica gel column chromatography to obtain the product with the structure shown in Formula II. The molar mass ratio of amino acid methyl ester: 1,2-dimethoxypropane: boron trifluoride diethyl ether solution is (1.0–1.1):(3.0–3.5):(0.1–0.15). Amino acid methyl ester: dichloromethane solution = 1 mmol: 0.7-1 mL.

3. The method for preparing a chiral α-amino alcohol compound according to claim 1, characterized in that, In step S2, the Grignard reagent is selected from at least one of methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, butyl magnesium bromide, pentyl magnesium bromide, hexyl magnesium bromide, benzyl magnesium bromide, phenethyl magnesium bromide, or (3-methoxypropyl) magnesium bromide; In step S2, the product with the structure shown in formula II obtained in step S1, cerium trichloride, and Grignard reagent are added to a tetrahydrofuran solution. After stirring, the solution is concentrated under vacuum to remove excess solvent and obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a product with the structure shown in formula III. The product of the structure shown in Formula II is expressed in a molar mass ratio as follows: cerium trichloride : Grignard reagent = (1.0–1.1):(1.0–1.2):(5.0–5.5). The product of the structure shown in Formula II: tetrahydrofuran solution = 1 mmol: 8-11 mL.

4. The method for preparing a chiral α-amino alcohol compound according to claim 1, characterized in that, In step S3, the product with the structure shown in formula III obtained in step S2, Burgess reagent, Molecular sieves were added to an ultra-dry toluene solution, and under a nitrogen atmosphere, the solution was stirred and then vacuum concentrated to remove excess solvent to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a product with the structure shown in Formula IV. Molecular mass ratio, product of the structure shown in Formula III: Burgess reagent: Molecular sieve = (1.0–1.1):(2.5–3.0):(1 g / mmol–1.1 g / mmol), The product with the structure shown in Formula III: ultra-dry toluene solution = 1 mmol: 60-150 mL.

5. The method for preparing a chiral α-amino alcohol compound according to claim 1, characterized in that, Palladium on carbon and the product with the structure shown in Formula IV obtained in step S3 were added to a methanol solution, stirred under a hydrogen atmosphere, and vacuum concentrated to remove excess solvent to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the product with the structure shown in Formula I. At a molar mass ratio, palladium on carbon: product with the structure shown in formula IV = (0.1–0.15):(1.0–1.3). The product of the structure shown in Formula IV: methanol solution = 1 mmol: 3-8 mL.

6. An application of a chiral α-amino alcohol compound, characterized in that, The compound having general structural formula I obtained by any of the preparation methods described in claims 1-5 is used for the synthesis of nitrogen-containing chiral ligands. The specific steps of the synthesis method for the nitrogen-containing chiral ligand compound are as follows: A compound with general structural formula I and a hydrochloric acid-dioxane solution were added to a methanol solution. After stirring, the pH was adjusted to 8, and the solution was concentrated under vacuum to remove excess solvent, yielding a crude product. The crude product was then purified by silica gel column chromatography to obtain a chiral amino alcohol compound, the structure of which is shown in formula V. Among them, R 1 Selected from -H or -CH3, R 2 Selected from -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -(CH2)(C6H5), -(CH2)2O(CH3) or -C6H5; The molar mass ratio of compounds with general structural formula I is: hydrochloric acid-dioxane solution = (1.0–1.1):(10.0–11.0). Compounds with general structural formula I: methanol solution = 1 mmol: 1-3 mL.

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