Synthesis method of (r)-tert-butyl (1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

Abstract

The invention relates to the technical field of organic synthesis, and provides a synthesis method of (r)-tert-butyl (1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate, which comprises the following steps: S1, reacting (R)-3-([1, 1'-biphenyl]-4-yl)-2-aminopropane-1-alcohol with a chiral resolution reagent to obtain an intermediate product A; s2, synthesizing a (r)-tert-butyl (1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate crude product from the intermediate product A and Boc anhydride under an alkaline condition, extracting, and concentrating, so as to obtain (r)-tert-butyl (1-([1, 1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate; during extraction, an adopted extraction agent comprises an ether extraction agent and an aromatic hydrocarbon extraction agent, and the volume ratio of the ether extraction agent to the aromatic hydrocarbon extraction agent is 1: (1-5). Through the technical scheme, the problems of low yield and low purity in the synthesis of (r)-tert-butyl (1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate in related technologies are solved.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate. Background Art

[0002] (r)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate is an organic compound with a specific structure. Its molecular structure contains biphenyl structure, hydroxyl group and carbamate functional group, which endows it with unique chemical properties and has important application prospects in the field of medicine. However, in the synthesis process of (r)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, some catalysts are not selective enough for the reaction, which leads to the occurrence of some side reactions and the generation of impurities with similar structures to the target product, affecting the purity and yield. Therefore, it is necessary to propose a method for synthesizing (r)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate to improve its yield and purity. Summary of the invention

[0003] The invention provides a method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate, which solves the problems of low yield and low purity in the synthesis of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate in the related art.

[0004] The technical solution of the present invention is as follows: The present invention provides a method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate, comprising the following steps: S1, (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol react with a chiral resolution agent to obtain an intermediate product A; S2, the intermediate product A and Boc anhydride are used to synthesize a crude product of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate under alkaline conditions, and then the crude product is extracted and concentrated to obtain (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate; The extractants used in the extraction include ether extractants and aromatic hydrocarbon extractants, and the volume ratio of the ether extractants to the aromatic hydrocarbon extractants is 1:1-5.

[0005] As a further technical solution, the volume ratio of the ether extractant to the aromatic hydrocarbon extractant is 1:2-3.

[0006] As a further technical solution, the volume mass ratio of the added amount of the extractant to the (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol is 8L:227~230g.

[0007] As a further technical solution, the ether extractant includes one or more of aromatic ether, aliphatic ether and cyclic ether.

[0008] In the present invention, the ether extractant is preferably an aromatic ether, the aromatic part in the structure of which can generate a π-π stacking force with the biphenyl structure in the target product, thereby enhancing the solubility of the target product in the aromatic ether, and further improving the yield and purity of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate.

[0009] As a further technical solution, the aromatic ether includes one or more of anisole, phenethyl ether, and diphenyl ether, the fatty ether includes one or more of ethyl ether, propyl ether, and methyl tert-butyl ether, and the cyclic ether includes one or two of tetrahydrofuran and 1,4-dioxane.

[0010] As a further technical solution, the aromatic hydrocarbon extractant includes one or more of benzene, toluene, and xylene.

[0011] As a further technical solution, the preparation of the intermediate product A in S1 includes the following steps: dissolving (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol in solvent I, stirring evenly, adding a chiral resolution reagent to react, and obtaining the intermediate product A after cooling, crystallization, and filtering.

[0012] As a further technical solution, the dissolving temperature is 70-90°C.

[0013] As a further technical solution, the solvent I is ethanol, and the volume mass ratio of the solvent I to the (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol is 6L:227~230g.

[0014] As a further technical solution, the reaction time in S1 is 2-4 hours, and the reaction temperature is 70-90°C.

[0015] As a further technical solution, the crystallization temperature is 0-5°C, and the crystallization time is 5-7h.

[0016] As a further technical solution, the chiral resolution reagent includes one or both of L-tartaric acid and D-aspartic acid.

[0017] As a further technical solution, the synthesis in S2 includes the following steps: dissolving the intermediate product A in solvent II, adjusting the pH to 9-11, adding BOC anhydride for synthesis, and obtaining (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate after extraction and concentration.

[0018] As a further technical solution, the solvent II in S2 is composed of water and ethanol in a volume ratio of 5:8, the substance used to adjust the pH is triethylamine, and the temperature at which the intermediate product A is dissolved in the solvent II is 70-90°C.

[0019] As a further technical solution, when BOC anhydride is added to S2 for synthesis reaction, the reaction temperature is room temperature and the reaction time is 1 to 5 hours.

[0020] As a further technical solution, after the concentration in S2, pulping, filtering and drying are performed in sequence.

[0021] As a further technical solution, the extractant further comprises cyclohexane, and the volume ratio of the cyclohexane to the ether extractant and the aromatic hydrocarbon extractant is 1-2:1:3.

[0022] In the present invention, cyclohexane is added as an extractant and used in combination with an ether extractant and an aromatic hydrocarbon extractant to adjust the polarity of the extraction system and improve the solubility of the target product in the extraction system, thereby better separating impurities from the target product and improving the yield and purity of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate.

[0023] As a further technical solution, the molar ratio of the chiral resolution agent to the (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol is 1-1.5:1.

[0024] The working principle and beneficial effects of the present invention are: In the invention, (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol is used as a raw material, reacted with a chiral resolution agent and Boc anhydride in sequence, extracted and concentrated to obtain (r)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate. During the extraction, an ether extractant and an aromatic hydrocarbon extractant are used as extractants at the same time to exert the synergistic effect of the two, effectively remove different types of impurities in the mixture, promote the solubility of the target product in the extractant, improve the extraction efficiency of the target product, reduce the product loss, and thus improve the yield and purity of (r)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate. DETAILED DESCRIPTION

[0025] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] Example 1 A method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate comprises the following steps: S1. Weigh 227.3 g (1 mol) of (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol, add it to 6 L of ethanol, heat it to 70°C, stir it evenly, add 150.1 g (1 mol) of L-tartaric acid, react for 2 h, cool it to 0°C with ice water for crystallization for 5 h, and filter it to obtain intermediate product A; S2. Add 2.8 L of water and 4.48 L of ethanol to the intermediate product A, heat it to 70°C, stir evenly, add triethylamine dropwise, adjust the pH to 9, cool to room temperature, add 218.28 g (1 mol) of Boc anhydride, stir at room temperature for 5 h to obtain a reaction solution, concentrate the reaction solution to 2.8 L, add 5 L of water and 8 L of extractant, extract, dry and concentrate, add 500 mL of n-heptane for slurrying, stir for 15 min, filter and dry to obtain 282.93 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate; wherein the extractant is composed of ether and benzene in a volume ratio of 1:1, the yield is 86.4%, and the purity is 98.11%.

[0027] Example 2 A method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate comprises the following steps: S1. Weigh 227.3 g (1 mol) of (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol, add it to 6 L of ethanol, heat it to 70°C, stir it evenly, add 180.12 g (1.2 mol) of L-tartaric acid, react for 3 h, cool it to 2°C with ice water for crystallization for 6 h, and filter it to obtain intermediate product A; S2. Add 2.8 L of water and 4.48 L of ethanol to the intermediate product A, heat it to 70°C, stir evenly, add triethylamine dropwise, adjust the pH to 10, cool to room temperature, add 218.28 g (1 mol) of Boc anhydride, stir at room temperature for 5 h to obtain a reaction solution, concentrate the reaction solution to 2.8 L, add 5 L of water and 8 L of extractant, extract, dry and concentrate, add 500 mL of n-heptane for slurrying, stir for 20 min, filter and dry to obtain 289.15 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate; wherein the extractant is composed of ether and toluene in a volume ratio of 1:2, the yield is 88.3%, and the purity is 98.54%.

[0028] Example 3 A method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate comprises the following steps: S1. Weigh 227.3 g (1 mol) of (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol, add it to 6 L of ethanol, heat it to 70°C, stir it evenly, add 225.15 g (1.5 mol) of L-tartaric acid, react for 4 h, cool it to 5°C with ice water for crystallization for 7 h, and filter it to obtain intermediate product A; S2. Add 2.8 L of water and 4.48 L of ethanol to the intermediate product A, heat it to 70°C, stir evenly, add triethylamine dropwise, adjust the pH to 11, cool to room temperature, add 218.28 g (1 mol) of Boc anhydride, stir at room temperature for 5 h to obtain a reaction solution, concentrate the reaction solution to 2.8 L, add 5 L of water and 8 L of extractant, extract, dry and concentrate, add 500 mL of n-heptane for slurrying, stir for 25 min, filter and dry to obtain 287.18 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate; wherein the extractant is composed of ether and xylene in a volume ratio of 1:5, with a yield of 87.7% and a purity of 98.32%.

[0029] Example 4 Compared with Example 2, the difference of Example 4 is that the extractant consists of ether and xylene in a volume ratio of 1:3; 291.44 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 89.0% and a purity of 98.76%.

[0030] Example 5 Compared with Example 4, the difference of Example 5 is that the extractant consists of anisole and xylene in a volume ratio of 1:3; 296.35 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 90.5% and a purity of 98.92%.

[0031] Example 6 Compared with Example 4, the difference of Example 6 is that the extractant consists of tetrahydrofuran and xylene in a volume ratio of 1:3; 294.39 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 89.9% and a purity of 98.81%.

[0032] Example 7 Compared with Example 5, the difference of Example 6 is that the extractant is cyclohexane; 226.60 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 69.2% and a purity of 97.24%.

[0033] Example 8 Compared with Example 7, the difference of Example 8 is that the extractant consists of cyclohexane, anisole and xylene in a volume ratio of 1:1:3; 302.57 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 92.4% and a purity of 99.15%.

[0034] Example 9 Compared with Example 7, the difference of Example 9 is that the extractant consists of cyclohexane, anisole and xylene in a volume ratio of 2:1:3; 307.16 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 93.8% and a purity of 99.27%.

[0035] Comparative Example 1 Compared with Example 2, the difference in Comparative Example 1 is that the extractant is ether; 239.37 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 73.1% and a purity of 97.68%.

[0036] Comparative Example 2 Compared with Example 2, the difference of Comparative Example 2 is that the extractant is xylene; 231.51 g of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate was obtained with a yield of 70.7% and a purity of 97.45%.

[0037] Compared with Comparative Examples 1 and 2, Example 2 simultaneously adds an ether extractant and an aromatic hydrocarbon extractant. As a result, the yield and purity of Example 2 are better than those of Comparative Examples 1 and 2, indicating that the ether extractant and the aromatic hydrocarbon extractant have a synergistic effect, which can improve the yield and purity of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate.

[0038] Compared with Example 4, Examples 5 and 6 added different types of ether extractants. As a result, the yield and purity of Example 5 were better than those of Examples 4 and 6, indicating that when the added ether extractant was aromatic ether, the yield and purity of the obtained (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate were higher.

[0039] Compared with Examples 5 and 7, Examples 8 and 9 simultaneously added cyclohexane, anisole and xylene as extractants. As a result, the yield and purity of Examples 8 and 9 were better than those of Examples 5 and 7, indicating that when cyclohexane, anisole and xylene were added as extractants at the same time, the yield and purity of the obtained (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate were higher.

[0040] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate, characterized in that: The following steps are involved: S1, (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol react with a chiral resolution agent to obtain an intermediate product A; S2, the intermediate product A and Boc anhydride are used to synthesize a crude product of (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate under alkaline conditions, and then the crude product is extracted and concentrated to obtain (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate; The extractants used in the extraction include ether extractants and aromatic hydrocarbon extractants, and the volume ratio of the ether extractants to the aromatic hydrocarbon extractants is 1:1-5.

2. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The volume ratio of the ether extractant to the aromatic hydrocarbon extractant is 1:2-3.

3. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The ether extractant includes one or more of aromatic ether, aliphatic ether and cyclic ether.

4. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 3, characterized in that: The aromatic ether includes one or more of anisole, phenethyl ether, and diphenyl ether; the aliphatic ether includes one or more of ethyl ether, propyl ether, and methyl tert-butyl ether; and the cyclic ether includes one or two of tetrahydrofuran and 1,4-dioxane.

5. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The aromatic hydrocarbon extractant includes one or more of benzene, toluene and xylene.

6. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The reaction time in S1 is 2-4 hours, and the reaction temperature is 70-90°C.

7. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The chiral resolution reagent includes one or both of L-tartaric acid and D-aspartic acid.

8. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: After the concentration in S2, beating, filtering and drying are performed in sequence.

9. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The extractant further comprises cyclohexane, and the volume ratio of the cyclohexane to the ether extractant and the aromatic hydrocarbon extractant is 1-2:1:

3.

10. The method for synthesizing (r)-tert-butyl (1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The molar ratio of the chiral resolution agent to the (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropane-1-ol is 1-1.5:1.