A method for synthesizing gamma-amino alcohols

Abstract

The application discloses a synthesis method of gamma-amino alcohol compounds, which comprises the following steps: dissolving allyl primary alcohol or allyl secondary alcohol and different types of primary amine or secondary amine in an organic solvent, and carrying out a reverse Markovnikov hydrogenation reaction under the catalysis of a catalyst to obtain a target product gamma-amino alcohol; wherein, a reaction formula of the hydrogenation reaction is shown in Figure 1, R', R'', R''', R'''' can represent a hydrogen atom, an electron-withdrawing substituent, an electron-donating substituent, an aryl group and a hydrocarbon group, and the R''' and R'''' can be connected in a ring shape; and the catalyst is YC3, YC3 is Y(CH2SiMe3)3(THF)2. The application provides a new method for preparing gamma-amino alcohol compounds by using a rare earth catalyst, improves the synthesis yield of the gamma-amino alcohol compounds, and has the characteristics of easy availability of raw materials of the rare earth catalyst, few synthesis steps, simple preparation, high yield and no need of additional addition of alkali and activators, so that the synthesis method of the gamma-amino alcohol compounds is more inexpensive and clean.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of preparation of gamma-amino alcohols, and particularly relates to a synthesis method of gamma-amino alcohols. BACKGROUND

[0002] Gamma-amino alcohols are a class of compounds with great potential, which have wide application in the fields of agricultural chemicals and pharmaceuticals, and are intermediates for synthesizing many drugs and biologically active molecules. They can be used for synthesizing antipsychotic drugs, antihypertensive drugs, antidepressants, etc., and can also be used for anti-HIV virus research. Therefore, gamma-amino alcohols have attracted more and more attention, and their synthesis methods have also been paid great attention by pharmaceutical researchers. Therefore, how to develop a simple and rapid method for synthesizing gamma-amino alcohols with novel structure and biological activity will become a hot topic in the field of organic synthesis.

[0003] The traditional synthesis process is to use gamma-amino ketones as raw materials and to obtain them by hydrogenation reduction. Therefore, a large amount of reducing agent is needed, and the excessive reducing agent needs a large amount of organic solvent, which has high production cost and causes serious environmental pollution. Therefore, a catalyst is introduced to synthesize gamma-amino alcohols to reduce the use of reducing agent in the reaction system, but most of the catalysts contain noble metal ruthenium, which has high price, resulting in high production cost of gamma-amino alcohols.

[0004] In order to further reduce the production cost and reduce the impact on the environment, transition metals can be used to catalyze the reaction, such as: (1) through the oxidation / 1,4-conjugate addition / 1,2-reduction cascade, gamma-amino alcohols can be effectively generated. For example, the Nakamura group developed a noble metal complex as a catalyst, when the loading amount of RuClH(CO)(PPh3) is 2 mol%, pyridine diamine 2.2 mol% is a ligand, KO t Bu 3 mol% forms a catalyst system, which can realize the anti-Markovnikov hydrogenation reaction of allyl alcohol (referring to Chem. Commun, 2015, 51, 7459-7462). (2) Through the hydrogen borrowing strategy of dehydrogenation, conjugate addition, and asymmetric reaction, high-selectivity gamma- secondary amino alcohols are synthesized. For example, the Wang Chao group found that allyl alcohol can undergo dehydrogenation, Michael addition and reduction to obtain anti-Markovnikov product gamma-amino alcohol under the catalytic system composed of Fe-PNP complex, NaHBEt3 and K3PO4 (referring to J. Am. Chem. Soc, 2019, 141, 13506-13515).

[0005] The two synthetic methods described above primarily employ transition metal catalysis to generate γ-amino alcohols. The transition metal catalyst requires the addition of an external base to promote the oxidation of allyl alcohol to α,β-unsaturated ketones, followed by amine addition, and finally, the carbonyl group is reduced. The drawbacks of transition metal catalysis are: 1. It requires multiple steps to synthesize the ligand and then the transition metal complex, resulting in a complex and inefficient synthesis process; 2. The need for an external base to form the catalyst system increases the equipment requirements and reaction costs. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing γ-amino alcohol compounds, so as to solve the technical problems of high synthesis cost and complicated steps in the prior art.

[0007] To solve the above-mentioned technical problems, the present invention specifically provides the following technical solution:

[0008] This invention provides a method for synthesizing γ-amino alcohol compounds, comprising:

[0009] Allyl primary alcohol or allyl secondary alcohol is dissolved with different types of primary or secondary amines in an organic solvent, and undergoes anti-Markovnikov hydroamination reaction under the catalysis of a catalyst to obtain the target product;

[0010] The reaction formula for the hydrogenation reaction is as follows: Figure 1 As shown, R', R'', R''', R'''' can represent hydrogen atom, electron-withdrawing substituent, electron-donating substituent, aryl, and hydrocarbon groups;

[0011] The R''' and the R'''' can be connected end to end to form a ring;

[0012] YC3 represents the catalyst, and YC3 is Y(CH2SiMe3)3(THF)2.

[0013] As a preferred embodiment of the present invention, R', R'', R''' and R'''' are each independent.

[0014] In a preferred embodiment of the present invention, when R''' is a benzene ring, the order of preference of the substituents on the benzene ring is para, meta, or ortho.

[0015] As a preferred embodiment of the present invention, the synthesis of the target product includes the following steps:

[0016] Take catalyst Y(CH2SiMe3)3(THF)2, such as Figure 2 Compound A, as shown in formula (II), Figure 2 Compound B with the structure shown in formula (Ⅲ) and an organic solvent;

[0017] The compound A, the compound B and the organic solvent are sequentially added into the catalyst, the compound A and the compound B can be completely dissolved in the solvent, and a nucleophilic addition reaction is carried out to obtain the target product of the structure shown in formula (I). Figure 2

[0018] In the formula (I), the formula (II) and the formula (III), R 1 at least -H, -CH3, -OCH3, -F, -Cl, -Br;

[0019] R 2 at least -H, -Me;

[0020] R 3 at least -H, -Ph, -Et;

[0021] R 4 at least -H, -CH3, -Br;

[0022] R 5 at least -H, -Me;

[0023] R 6 at least -Me, -Et, -Ph and substituted aryl;

[0024] R 7 at least -H, -Ph.

[0025] As a preferred scheme of the present application, the organic solvent is any one of n-hexane, toluene, tetrahydrofuran and ethyl acetate.

[0026] As a preferred scheme of the present application, the organic solvent is toluene.

[0027] As a preferred scheme of the present application, the molar ratio of the compound A to the compound B is 1:2-1:3.

[0028] As a preferred scheme of the present application, the reaction conditions of the nucleophilic addition reaction are as follows:

[0029] The temperature is 70-90℃, the reaction time is 12-72h, and the catalyst loading is 10 mol%.

[0030] As a preferred scheme of the present application, the reaction conditions of the nucleophilic addition reaction are as follows:

[0031] The temperature is 80℃, and the reaction time is 48h.

[0032] As a preferred scheme of the present application, the following step is further included:​

[0033] Before the reaction, the compound A, the compound B and the organic solvent are dried so that the water content of the compound A, the compound B and the organic solvent is less than 0.1%.

[0034] As a preferred scheme of the present application, the following steps are further included:

[0035] The target product is purified by silica gel column chromatography to obtain a high-purity product.

[0036] In the purification process, the ratio of ethyl acetate to petroleum ether is 1:2-1:8.

[0037] Compared with the prior art, the present application has the following beneficial effects:

[0038] 1. The present application effectively generates gamma-aminol compounds by hydrogenation of allyl primary alcohol or allyl secondary alcohol and different types of primary amine or secondary amine nucleophilic addition, mainly using rare earth metal catalysts. Rare earth metals mainly exist in the form of positive trivalence due to the shielding of 4f electrons, and do not have the double-electron redox reaction of transition metals. Therefore, the rare earth metal catalysts can simplify the reaction steps when participating in the reaction, and the production efficiency of gamma-aminol compounds is improved.

[0039] 2. In the production, the rare earth metal catalysts are used to eliminate alkyl from allyl alcohol, then β-H elimination occurs, and the target product is synthesized through an insertion reaction. The rare earth metal catalysts can catalyze the reaction alone without the need for additional alkali, thereby reducing environmental pollution.

[0040] 3. The catalyst of the present application uses rare earth metal catalyst Y(CH2SiMe3)3(THF)2, which is a relatively inexpensive compound that is easy to obtain and has stable properties, thereby effectively reducing the cost of gamma-aminol compounds in the preparation process. BRIEF DESCRIPTION OF DRAWINGS

[0041] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings needed in the following embodiment or prior art description will be briefly introduced. Obviously, the drawings in the following description are only exemplary, and other drawings can be obtained from the provided drawings without creative labor for those skilled in the art.

[0042] Figure 1 The bond-line structure reaction formula of general formula 1 of the synthesis method of gamma-aminol compounds provided by the present application is as follows:

[0043] Figure 2 A reaction scheme of a bond line structure of Formula 2 for providing a synthesis method of a gamma-amino alcohol compound according to the present application;

[0044] Figure 3 A reaction scheme of Example 1 for providing the present application;

[0045] Figure 4 A nuclear magnetic hydrogen spectrum of a product in Example 1 for providing the present application;

[0046] Figure 5 A nuclear magnetic carbon spectrum of a product in Example 1 for providing the present application;

[0047] Figure 6 A reaction scheme of Example 2 for providing the present application;

[0048] Figure 7 A nuclear magnetic hydrogen spectrum of a product in Example 2 for providing the present application;

[0049] Figure 8 A nuclear magnetic carbon spectrum of a product in Example 2 for providing the present application;

[0050] Figure 9 A reaction scheme of Example 3 for providing the present application;

[0051] Figure 10 A nuclear magnetic hydrogen spectrum of a product in Example 3 for providing the present application;

[0052] Figure 11 A nuclear magnetic carbon spectrum of a product in Example 3 for providing the present application;

[0053] Figure 12 A reaction scheme of Example 4 for providing the present application;

[0054] Figure 13 A nuclear magnetic hydrogen spectrum of a product in Example 4 for providing the present application;

[0055] Figure 14 A nuclear magnetic carbon spectrum of a product in Example 4 for providing the present application;

[0056] Figure 15 A reaction scheme of Example 5 for providing the present application;

[0057] Figure 16 A reaction scheme of Example 6 for providing the present application;

[0058] Figure 17 A reaction scheme of Example 7 for providing the present application;

[0059] Figure 18 A reaction scheme of Example 8 for providing the present application;

[0060] Figure 19The reaction formula of Example 9 is provided for the present application.

[0061] Figure 20 The reaction formula of Example 10 is provided for the present application.

[0062] Figure 21 The reaction formula of Example 11 is provided for the present application. DETAILED DESCRIPTION

[0063] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the protection scope of the present application.

[0064] The present application provides a synthesis method of a gamma-amino alcohol compound, comprising the following steps:

[0065] The allyl alcohol compound, the organic amine compound and the organic solvent are dried, so that the water content of the allyl alcohol compound, the organic amine compound and the organic solvent is less than 0.1%.

[0066] The catalyst Y(CH2SiMe3)3(THF)2, the dried allyl alcohol compound, the dried organic amine compound and the dried organic solvent are taken, and the allyl alcohol compound, the organic amine compound and the organic solvent are added to the catalyst Y(CH2SiMe3)3(THF)2.

[0067] The temperature of the reaction system is adjusted to 70-90 DEG C, and stirring is performed at 70-90 DEG C for 12-72 h. The allyl primary alcohol or the allyl secondary alcohol and the primary amine or the secondary amine undergo an anti-Markovnikov hydroamination reaction under the catalysis of the catalyst. The reaction is tracked by thin layer chromatography, and the target product is obtained.

[0068] The hydroamination reaction, that is, the addition of an olefinic bond to an amine compound, is a kind of reaction with very high atomic economy. The reaction has two regioselectivities, Markovnikov (Markovnikov) and anti-Markovnikov (anti-Markovnikov). Therefore, the hydroamination reaction of an allyl alcohol and an amine also has two selectivities, and the products are gamma-amino alcohol or beta-amino alcohol.

[0069] This invention presents a novel method for preparing γ-amino alcohols using a rare earth catalyst obtained through anti-Markovnikov hydroamylation. Rare earth metals, due to the shielding of their 4f electrons, primarily exist in a trivalent oxidation state, lacking the two-electron redox reactions of transition metals. The reaction steps are simple, and the rare earth metal catalyst undergoes alkyl elimination followed by β-H elimination with allyl alcohol, undergoing an insertion reaction to synthesize the target product. The rare earth metal catalyst can catalyze this reaction independently. Compared to the post-transition metal catalysts (ruthenium, manganese, and iron complexes) used in the hydroamylation of allyl alcohols to prepare γ-amino alcohols, this rare earth catalyst offers advantages such as readily available raw materials, fewer synthesis steps, simple preparation, high yield, and no need for additional alkali or activators.

[0070] This rare earth catalyst is synthesized in one step using commercially available YCl3 and LiCH2SiMe3, and the operation is simple and yields high results.

[0071] The target product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2-1:8) to obtain a target product with higher purity.

[0072] Wherein, the catalyst loading is 10 mol%, and the molar ratio of compound A to compound B is 1:2-1:3;

[0073] Allyl alcohols are allyl primary alcohols or allyl secondary alcohols;

[0074] Organic amine compounds are either primary or secondary amines.

[0075] Figure 1 Formula 1 is the general formula for the synthesis of γ-amino alcohols, and Formula 1 is the bond-line structure reaction formula for this reaction.

[0076] exist Figure 1 In the general formula shown, R', R'', R''', and R'''' are each set independently. R', R'', R''', and R'''' can represent hydrogen atoms, electron-withdrawing substituents, electron-donating substituents, aryl groups, and hydrocarbon groups. R''' and R'''' can be connected end-to-end to form a ring. YC3 represents the catalyst, and YC3 is Y(CH2SiMe3)3(THF)2.

[0077] In the above-mentioned hydroamination reaction, when R''' is a benzene ring, the substituents on the benzene ring can be para, meta, or ortho. From an electronic perspective, the ortho position has greater steric hindrance, making the reaction more difficult. The meta position is the next best, while the para position is the most favorable. Therefore, the para position is preferred, followed by the meta position.

[0078] Organic solvents such as n-hexane, toluene, tetrahydrofuran, and ethyl acetate can be selected. Toluene is a non-polar solvent with a high boiling point (110℃). Other solvents have boiling points around 80℃. Since the reaction temperature is 80℃, high-boiling-point organic solvents are advantageous. Therefore, toluene is the preferred organic solvent.

[0079] Preferably, the optimal reaction conditions are obtained after screening the reaction conditions: 80 ℃, catalyst loading 10 mol%, toluene as solvent, reaction time 48 h.

[0080] When the reaction temperature is lower than 70 ℃, the reaction is difficult to proceed, and when the temperature is higher than 90 ℃, the energy consumption of the reaction is increased. In order to improve the yield, the reaction temperature is appropriately increased, and therefore the preferred temperature of the reaction is 80 ℃.

[0081] The hydrogenation reaction time is 12-72 h. However, in order to improve the yield, the reaction time is appropriately prolonged, and the preferred reaction time of the γ-aminol is 48 h. Since the conversion rate is not complete after 24 h, the reaction temperature can be appropriately increased by heating.

[0082] After the reaction is completed, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2-1:8), and high-purity product can be obtained.

[0083] The preferred molar ratio of the organic amine compound to the allyl alcohol compound is 1:2, and the amount of the substituted allyl alcohol can be appropriately increased, and the molar ratio is preferably not more than 1:3. Excessive reaction raw materials increase the difficulty of separation.

[0084] The amount of the organic solvent is that the organic amine compound and the allyl alcohol compound are completely dissolved.

[0085] In order to further explain the types of the organic amine compound and the allyl alcohol compound, the application also provides Figure 2 the general formula shown in formula (I), wherein, Figure 2 the compound A shown in formula (II) and Figure 2 the compound B shown in formula (III) are dissolved in the above-mentioned organic solvent, and can react under the catalysis of the catalyst Y (CH2SiMe3) 3 (THF) 2 to generate Figure 2 the target product shown in formula (I), that is, the γ-aminol compound.

[0086] In this process, a nucleophilic addition reaction, that is, an anti-Markovnikov hydrogenation reaction, occurs.

[0087] Figure 2 in the general formula, R 1 is a substituent group such as -H, -CH3, -OCH3, -F, -Cl, -Br, etc.; R 2 is a substituent group such as -H, -Me, etc.; R 3 is a substituent group such as -H, -Ph, -Et, etc.; R 4 is a substituent group such as -H, -CH3, -Br, etc.; R 5Substituents such as -H and -Me; R 6 Substituents include -Me, -Et, -Ph, and substituted aryl groups; R 7 Substituents include -H, -Ph, etc.

[0088] Figure 2 Formula 2 is the general formula for the synthesis of γ-amino alcohols, and Formula 2 is the bond-line structure reaction formula for this reaction.

[0089] Several examples are provided below.

[0090] Example 1

[0091] 1. Take raw materials

[0092] 3-Buten-2-ol 2.0 mmol, N-methylaniline 1.0 mmol, toluene 500 µL and catalyst Y(CH2SiMe3)3(THF)2 0.1 mmol;

[0093] 2. Synthesis:

[0094] The raw materials are dried so that the water content of 3-buten-2-ol, N-methylaniline and toluene is all below 0.1%;

[0095] Take a clean 15 mL reaction flask and add Y(CH2SiMe3)3(THF)2, 3-buten-2-ol, N-methylaniline and toluene to the reaction flask in sequence;

[0096] The reaction was stirred at 80 °C for 48 h, and the reaction was monitored by thin-layer chromatography to obtain the crude product.

[0097] After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2), which yielded a pure yellow oily liquid in 94% yield.

[0098] γ-amino alcohols are good solvents and readily soluble in polar solvents such as chloroform, ethyl acetate, and diethyl ether. Therefore, CDCl3 is used to dissolve these compounds for NMR characterization.

[0099] The characterization results are as follows:

[0100] 4-(methyl(phenyl)amino)butan-2-ol, 1H NMR (400 MHz, CDCl3, ppm): δ7.23 (t, J = 7.2 Hz, 2H, ArH), 6.78 (d, J = 8.0 Hz, 2H, ArH), 6.73 (t, J =7.2 Hz, 1H, ArH), 3.94–3.86 (m, 1H, CH), 3.49–3.35 (m, 2H, CH2N), 2.89 (s,3H, NCH3), 2.27 (br, 1H, OH), 1.72–1.65 (m, 2H, CH2), 1.21 (d, J = 6.4 Hz, 3H,CH3). 13 C NMR (100 MHz, CDCl3, ppm): δ 149.8, 129.3, 117.1, 113.4 (ArC), 66.9(OCH), 50.8 (NCH2), 38.6 (NCH3), 35.6, 24.1.

[0101] The reaction formula of Example 1 is shown as Figure 3 .

[0102] The nuclear magnetic hydrogen spectrum of the product in Example 1 is shown as Figure 4 .

[0103] The nuclear magnetic carbon spectrum of the product in Example 1 is shown as Figure 5 .

[0104] According to Figure 4 and Figure 5 analysis, the structure formula of the actual product obtained is consistent with the structure formula of the target product in the reaction formula shown as Figure 3 , Example 1 successfully obtained a high yield and high purity γ-aminol compound.

[0105] Example 2

[0106] On the basis of Example 1, the organic amine compound is changed to 4-methoxy-N-methyl aniline, and the other steps, components and component ratios are consistent;

[0107] After the reaction is completed, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain a pure yellow oily liquid with a yield of 95%.

[0108] The characterization results are as follows:

[0109] 4-((4-methoxyphenyl)(methyl)amino)butan-2-ol, 1H NMR (400 MHz, CDCl3, ppm): δ 6.89–6.82 (m, 4H, ArH), 4.02–3.94 (m, 1H, CH), 3.77 (s, 3H, OCH3),3.37–3.23 (m, 2H, NCH2), 2.81 (s, 3H, NCH3), 1.70–1.63 (m, 2H, CH2), 1.21 (d,J = 6.0 Hz, 3H, CH3). 13 C NMR (100 MHz, CDCl3, ppm): δ 153.1, 145.1, 117.5,114.6 (ArC), 67.9 (OCH), 55.7 (OCH3), 53.7 (NCH2), 40.1 (NCH3), 35.1 (CH2),23.9 (CH3). HRMS (APCI): calcd for C 12 H 19 O2N [M + H] + : 210.1489, found: 210.1490.

[0110] The reaction formula of Example 2 is shown in Figure 6 .

[0111] The nuclear magnetic hydrogen spectrum of the product in Example 2 is shown in Figure 7 .

[0112] The nuclear magnetic carbon spectrum of the product in Example 2 is shown in Figure 8 .

[0113] According to the analysis, the structure of the actual product obtained is consistent with the structure of the target product in the reaction formula shown in Figure 7 , and Example 2 successfully obtained a high yield and high purity γ-aminol compound. Figure 8 Figure 6 Example 3

[0114] On the basis of Example 1, the organic amine compound is changed to thiomorpholine, and other steps, components and component ratios are consistent;

[0115] After the reaction is completed, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:8) to obtain a pure yellow oily liquid with a yield of 97%.

[0116] The characterization results are as follows:

[0117] The characterization results are as follows:

[0118] ​4-thiomorpholinobutan-2-ol, 1 H NMR (400 MHz, CDCl3, ppm): δ 5.84 (br,1H, OH), 3.97–3.89 (m, 1H, CH), 2.90–2.86 (m, 2H, NCH2), 2.71–2.53 (m, 8H,CH2), 1.67–1.57 (m, 1H, CH2), 1.48–1.42 (m, 1H, CH2), 1.14 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3, ppm): δ 69.8 (OCH), 58.7 (NCH2), 55.2 (NCH2), 33.0 (CH2), 28.1 (SCH2), 23.4 (CH3). HRMS (APCI): calcd for C8H 17 ONS [M + H] + :176.1104, found: 176.1097.

[0119] The reaction formula for Example 3 is as follows: Figure 9 As shown.

[0120] The 1H NMR spectrum of the product in Example 3 is shown below. Figure 10 As shown.

[0121] The carbon NMR spectrum of the product in Example 3 is shown below. Figure 11 As shown.

[0122] according to Figure 10 and Figure 11 Analysis shows that the structural formula of the actual product obtained is similar to... Figure 9 The target product in the reaction formula shown has the same structure. Example 3 successfully obtained γ-amino alcohol compounds with high yield and high purity.

[0123] Example 4

[0124] Based on Example 1, the organic amine compound was replaced with 4-phenylpiperidine, while all other steps, components, and component ratios remained the same.

[0125] After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:8) to give a pure pale yellow solid with a yield of 94%.

[0126] The characterization results are as follows:

[0127] 4-(4-phenylpiperidin-1-yl)butan-2-ol, 1 H NMR (400 MHz, CDCl3, ppm): δ7.29 (t, J = 7.4 Hz, 2H, ArH), 7.21–7.18 (m, 3H, ArH), 6.48 (br, 1H, OH),4.02–3.94 (m, 1H, CH), 3.30 (d, J = 11.2 Hz, 1H, NCH2), 3.03 (d, J = 11.2 Hz,1H, NCH2), 2.72–2.65 (dt, J = 3.2, 12.0 Hz, 1H, NCH2), 2.62–2.57 (m, 1H,NCH2), 2.51–2.47 (m, 1H, CH), 2.21 (dt, J = 2.8, 12.0 Hz, 1H, NCH2), 1.95–1.61(m, 6H, NCH2 and CH2), 1.55–1.45 (m, 1H, CH2), 1.18 (d, J = 6.4 Hz, 3H, CH3). 13 C NMR (100 MHz, CDCl3, ppm): δ 145.9, 128.5, 126.8, 126.3 (ArC), 69.9 (OCH),58.2, 56.0, 52.8, 42.5, 33.9, 33.4, 33.1, 23.5 (CH3). HRMS (APCI): calcd forC 15 H 23 ON [M + H] + : 234.1852, found: 234.1857.

[0128] The reaction scheme of Example 4 is shown in Figure 12 .

[0129] The nuclear magnetic hydrogen spectrum of the product in Example 4 is shown in Figure 13 .

[0130] The nuclear magnetic carbon spectrum of the product in Example 4 is shown in Figure 14 .

[0131] According to Figure 13 and Figure 14 analysis, the structure of the actual product obtained is consistent with Figure 12The structure of the target product in the reaction formula is consistent, and the successful example 4 obtains high yield and high purity of γ-aminol alcohol compound.

[0132] Example 5

[0133] On the basis of example 1, the organic amine compound is changed to N-methyl-p-fluoroaniline, and the other steps, components and component ratios are consistent;

[0134] After the reaction, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain a pure yellow oily liquid with a yield of 91%.

[0135] The characterization results are as follows:

[0136] 4-((4-methoxyphenyl)(methyl)amino)butan-2-ol, 1 H NMR (400 MHz, CDCl3, ppm): δ 6.94 (t, J = 8.4 Hz, 2H, ArH), 6.75 (d, J = 8.4 Hz, 1H, ArH), 6.73(d, J = 8.4 Hz, 1H, ArH), 3.95–3.87 (m, 1H, CH), 3.42–3.28 (m, 2H, NCH2),2.84 (s, 3H, NCH3), 2.76 (s, 1H, OH), 1.69–1.63 (m, 2H, CH2), 1.21 (d, J = 6.4Hz, 3H, CH3). 13 C NMR (100 MHz, CDCl3, ppm): δ 156.0 (d, 1 J C-F = 235.0 Hz),146.8, 115.5 (d, 2 J C-F = 22.0 Hz), 115.3 (d, 3 J C-F = 9.0 Hz), 67.1 (OCH), 52.0(NCH2), 39.3 (NCH3), 35.3 (CH2), 23.9 (CH3). 19 F NMR (376 MHz, CDCl3, ppm): δ127.6. HRMS (APCI): calcd for C 11 H 16 ONF [M + H] +: 198.1289, found: 198.1282.

[0137] The reaction formula of Example 5 is shown as Figure 15 .

[0138] According to the analysis of the characterization results, it is known that the structure of the actual product is consistent with the structure of the target product in the reaction formula shown as Figure 15 Example 5 successfully obtained a high yield and high purity γ-aminol compound.

[0139] Example 6

[0140] On the basis of Example 1, the organic amine compound is changed to 1,2,3,4-tetrahydroisoquinoline, and the other steps, components and component ratios are consistent;

[0141] After the reaction is completed, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 16) to obtain a pure yellow oily liquid with a yield of 93%.

[0142] The characterization results are as follows:

[0143] 4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-2-ol, 1 H NMR (400 MHz, CDCl3, ppm): δ 7.15-7.11 (m, 2H, ArH), 7.10-7.08 (m, 1H, ArH), 7.03-7.01 (m, 1H, ArH), 4.04-3.96 (m, 1H, CH), 3.76 (d, J = 14.8 Hz, 1H, NCH2Ar), 3.64 (d, J = 14.8 Hz, 1H, NCH2Ar), 3.01-2.95 (m, 1H, NCH2), 2.90 (t, J = 6.0 Hz, 2H, NCH2), 2.85-2.79 (m, 1H, NCH2), 2.75-2.59 (m, 1H, CH2Ar), 1.80-1.70 (m, 1H, CH2), 1.61-1.55 (m, 1H, CH2), 1.19 (d, J = 6.4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, ppm): δ 134.1, 134.0, 128.6, 126.6, 126.3, 125.8(ArC), 69.7 (OCH), 57.5, 56.4, 50.6 (NCH2), 33.7, 28.9, 23.5.

[0144] The reaction formula of Example 6 is shown as Figure 16

[0145] According to the analysis of the characterization results, it is known that the structure of the actual product is consistent with the structure of the target product in the reaction formula shown in Figure 16 Example 6 successfully obtained a high yield and high purity of γ-aminol alcohol compound.

[0146] Example 7

[0147] On the basis of Example 1, the allyl alcohol compound is changed to 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-propen-1-ol, the organic amine compound is changed to 3-phenylpyrrolidine, and other steps, ingredients and ingredient ratios are consistent.

[0148] After the reaction is completed, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:8) to obtain a pure yellow oily liquid with a yield of 85%.

[0149] The characterization results are as follows:

[0150] 1-(2,3-dihydrobenzo[1,4]dioxin-6-piperidinyl)-3-(3-phenylpyrrolidin-1-piperidinyl)-1-propanol, 1 H NMR (400 MHz, CDCl3, ppm): δ 7.30–7.19 (m, 5H,ArH), 6.91 (s, 1H, ArH), 6.83–6.81 (m, 2H, ArH), 4.85–4.82 (m, 1H, CH), 4.21(s, 4H, OCH2), 3.39–3.36 (m, 1H, NCH2), 3.21–3.10 (m, 1H, NCH2), 3.04–2.81 (m,3H, NCH2), 2.76–2.56 (m, 2H, NCH2 and CH2), 2.37–2.28 (m, 1H, CH2), 1.96–1.70(m, 3H, CH2). 13 ​C NMR (100 MHz, CDCl3, ppm): δ 144.6, 144.3, 143.4, 142.5, 138.6, 138.5, 128.6, 128.6, 127.3, 127.2, 126.4, 126.4, 118.6, 116.9, 114.7, 114.6 (ArC), 74.9, 74.9 (OCH), 64.4, 64.4 (OCH2), 62.1, 61.9, 54.9, 54.8, 54.6, 54.5 (NCH2), 43.3, 43.2, 35.7 (CH2), 33.2, 33.1 (CH3).

[0151] The reaction formula of Example 7 is shown as Figure 17

[0152] According to the analysis of the characterization results, it is known that the structure formula of the actual product obtained is consistent with the structure formula of the target product in the reaction formula shown in Figure 17 Example 7 successfully obtained a high yield and high purity γ-aminol alcohol compound.

[0153] Example 8

[0154] On the basis of Example 1, the organic amine compound is changed to 2,3-dihydroindole, and the other steps, components and component ratios are consistent;

[0155] After the reaction is completed, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:8) to obtain a pure yellow oily liquid with a yield of 95%.

[0156] The characterization results are as follows:

[0157] 1 ​H NMR (400 MHz, CDCl3, ppm): δ 7.10 (t, J = 7.6 Hz, 2H, ArH), 6.72(t, J = 7.2 Hz, 1H, ArH), 6.61 (d, J = 7.6 Hz, 1H, ArH), 4.05–4.01 (m, 1H,CH), 3.48 (dd, J = 15.6, 8.4 Hz, 1H, NCH2), 3.35–3.29 (m, 1H, NCH2), 3.22 (d,J = 8.4 Hz, 1H, NCH2), 3.19–3.12 (m, 1H, NCH2), 3.04 (br, 1H, OH), 2.96 (t, J= 8.0 Hz, 2H, CH2), 1.79–1.73 (m, 2H, CH2CH), 1.25 (d, J = 6.0 Hz, 3H, CH3). 13 C NMR (100 MHz, CDCl3, ppm): δ 152.5, 130.5, 127.4, 124.6, 118.7, 108.2(ArC), 67.9 (OCH), 54.0 (NCH2), 48.5 (NCH2), 35.8, 28.6, 23.7 (CH3).

[0158] The reaction formula of Example 8 is shown as Figure 18 .

[0159] According to the analysis of the characterization results, the structure of the actual product is consistent with the structure of the target product in the reaction formula shown as Figure 18 , and Example 8 successfully obtained a high yield and high purity of γ-aminol alcohol compound.

[0160] Example 9

[0161] On the basis of Example 1, the organic amine compound is changed to 4-fluoroaniline, and the other steps, ingredients and ingredient ratios are consistent;

[0162] After the reaction, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:8) to obtain a pure light yellow solid with a yield of 70%.

[0163] The characterization results are as follows:

[0164] 1H NMR (400 MHz, CDCl3, ppm): δ 6.89 (t, J = 8.8 Hz, 2H, ArH), 6.58(d, J = 8.8 Hz, 1H, ArH), 6.57 (d, J = 8.8 Hz, 1H, ArH), 4.05–3.97 (m, 1H,CH), 3.29–3.18 (m, 2H, NCH2), 1.83–1.67 (m, 2H, CH2), 1.25 (d, J = 6.4 Hz, 3H,CH3). 13 C NMR (100 MHz, CDCl3, ppm): δ 156.1 (d, 1 J C-F = 234.0 Hz), 144.7, 115.6(d, 2 J C-F = 22.0 Hz), 114.2 (d, 3 J C-F = 7.0 Hz), 67.6 (OCH), 42.7 (NCH2), 37.9(CH2), 23.9 (CH3). 19 F NMR (376 MHz, CDCl3, ppm): δ 127.6. HRMS (APCI): calcdfor C 10 H 14 ONF [M + H] + : 184.1132, found: 184.1135.

[0165] The reaction formula of Example 9 is shown as follows. Figure 19

[0166] According to the analysis of the characterization results, it is known that the structure formula of the actual product is consistent with the structure formula of the target product in the reaction formula shown, and Example 9 successfully obtains a high yield and high purity γ-aminol compound. Figure 19 Example 10

[0167] On the basis of Example 1, the allyl alcohol compound is changed to 2-methyl-2-propen-1-ol, the organic amine compound is changed to 2,3-dihydroindole, and the other steps, components and component ratios are consistent;

[0168] After the reaction is completed, the crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain a pure yellow oily liquid with a yield of 61%.

[0169] ​​

[0170] The characterization results are as follows:

[0171] 1 H NMR (400 MHz, CDCl3, ppm): δ 7.10 (t, J = 7.6 Hz, 2H, ArH), 6.72(t, J = 7.6 Hz, 1H, ArH), 6.61 (d, J = 8.0 Hz, 1H, ArH), 3.66 (d, J = 6.4 Hz,2H, OCH2), 3.59–3.53 (m, 1H, NCH2), 3.25–3.14 (m, 2H, NCH2), 3.02 (br, 1H,OH), 3.01–2.95 (m, 2H, CH2), 2.89 (dd, J = 4.8, 13.2 Hz, 1H, CH2), 2.24–2.10(m, 1H, CH), 0.96 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3, ppm): δ 152.8,130.2, 127.4, 124.6, 118.6, 108.0 (ArC), 68.6 (OCH2), 56.6, 55.0 (NCH2), 34.1(CH), 28.7, 15.2. HRMS (APCI): calcd for C 12 H 17 ON [M + H] + : 192.1383, found:192.1387.

[0172] The reaction formula of Example 10 is shown in Figure 20 .

[0173] According to the analysis of the characterization results, it is known that the structure formula of the actual product obtained is consistent with the structure formula of the target product in the reaction formula shown in Figure 20 , and Example 10 successfully obtains a high yield and high purity γ-aminol compound.

[0174] Example 11

[0175] On the basis of Example 1, the allyl alcohol compound is changed to 1-phenyl-2-propen-1-ol, the organic amine compound is changed to N-methylaniline, and other steps, ingredients and ingredient ratios are consistent;

[0176] After the reaction, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 16) to obtain a pure yellow oily liquid with a yield of 86%.

[0177] The characterization results are as follows:

[0178] 1 H NMR (400 MHz, CDCl3, ppm): δ 7.36 (d, J = 4.0 Hz, 4H, ArH), 7.32–7.22 (m, 3H, ArH), 6.78 (d, J = 8.8 Hz, 2H, ArH), 6.75–6.73 (m, 1H, ArH),4.80 (dd, J = 5.2, 7.2, Hz, 1H, CH), 3.52–3.41 (m, 2H, NCH2), 2.92 (s, 3H,NCH3), 2.60 (br, 1H, OH), 2.04–1.95 (m, 2H, CH2). 13 C NMR (100 MHz, CDCl3, ppm): δ 149.8, 144.6, 129.3, 128.6, 127.7, 125.8, 117.1, 113.4 (ArC), 73.0(OCH), 50.5 (NCH2), 38.6, 35.7. HRMS (APCI): calcd for C 16 H 19 ON [M + H] + :242.1539, found: 242.1538.

[0179] The reaction formula of Example 11 is shown in Figure 21 .

[0180] According to the analysis of the characterization results, the structure of the actual product obtained is consistent with the structure of the target product in the reaction formula shown in Figure 21 , and Example 11 successfully obtained a high yield and high purity γ-aminol compound.

[0181] The synthesis method of the γ-aminol compound in this embodiment can realize efficient preparation of the γ-aminol compound, provide a new method for preparing the γ-aminol compound using a rare earth catalyst, improve the synthesis yield of the γ-aminol compound, and the method has the characteristics of easy availability of raw materials of the rare earth catalyst, fewer synthesis steps, simple preparation, high yield and no need for additional addition of alkali and activator, so that the synthesis method of the γ-aminol compound is more inexpensive and clean.

[0182] The above examples are only exemplary embodiments of the present application, and are not intended to limit the present application, and the protection scope of the present application is defined by the claims. Those skilled in the art can make various modifications or equivalent replacements to the present application within the spirit and protection scope of the present application, and such modifications or equivalent replacements are also considered to fall within the protection scope of the present application.

Claims

1. A method for synthesizing a γ-amino alcohol compound, characterized by, The method comprises the following steps: Dissolving allyl primary alcohol or allyl secondary alcohol and different types of primary amine or secondary amine in an organic solvent, and reacting under the catalysis of a catalyst to obtain a target product; The catalyst is Y(CH2SiMe3)3(THF)2; The structural formula of the allyl primary alcohol or the allyl secondary alcohol is: The structural formula of the primary amine or the secondary amine is: ； The structural formula of the target product is: The structural formula of the allyl primary alcohol or the allyl secondary alcohol is selected from compound A with the structure shown in formula (II); The primary amine or the secondary amine is selected from compound B with the structure shown in formula (III); In the formula (II) and the formula (III), R 1 selected from -H, -CH3, -OCH3, -F, -Cl, -Br; R 2 selected from -H, -Me; R 3 selected from -H, -Ph, -Et; R 4 selected from -H, -CH3, -Br; R 5 selected from -H, -Me; R 6 selected from -Me, -Ph; R 7 selected from -H, -Ph; The compound A and the compound B can be completely dissolved in the solvent to perform a nucleophilic addition reaction; The reaction conditions of the nucleophilic addition reaction are as follows: The temperature is 70-90℃, and the reaction time is 12-72h.

2. The synthesis method of the gamma-amino alcohol compound according to claim 1, wherein, The organic solvent is any one of n-hexane, toluene, tetrahydrofuran and ethyl acetate.

3. The method for synthesizing a γ-amino alcohol compound according to claim 1, characterized in that, The molar ratio of the compound B to the compound A is 1:2-1:

3.

4. The synthesis method of the gamma-amino alcohol compound according to claim 1, wherein, The reaction conditions of the nucleophilic addition reaction are as follows: The temperature is 80℃, and the reaction time is 48h.

5. The synthesis method of the gamma-amino alcohol compound according to claim 1, wherein, The method further comprises the following steps: Before the reaction, the compound A, the compound B and the organic solvent are dried, so that the water content of the compound A, the compound B and the organic solvent is less than 0.1%.

6. The synthesis method of the gamma-amino alcohol compound according to claim 1, wherein, The method further comprises the following steps: The target product is purified by silica gel column chromatography to obtain a high-purity product; In the purification process, the ratio of ethyl acetate to petroleum ether is 1:2-1:8.

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