Preparation method of (3S, 4R)-4-aminotetrahydro-2H-thiapyran-3-ol hydrochloride
The synthesis of (3S,4R)-4-aminotetrahydro-2H-thiole-3-ol salt is achieved through a straightforward multi-step process using DMF, L-arginine, diazomethane, sulfuric acid, and 9-BBN, addressing the inefficiencies of existing methods by producing the compound with high yield and purity at room temperature, suitable for pharmaceutical applications.
Patent Information
- Application Number
- CN202411858732.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-17
- Publication Date
- 2025-03-25
AI Technical Summary
Current methods for synthesizing nuclides lack efficiency, complexity, and specificity in producing targeted nuclides, particularly for (3S,4R)-4-aminotetrahydro-2H-thiole-3-ol salt, which is a compound of interest for its potential pharmaceutical applications.
A multi-step synthetic process involving DMF, L-arginine, diazomethane, sulfuric acid, and 9-BBN, followed by deprotection under acidic conditions, to yield the target compound with high purity and yield, utilizing readily available starting materials and simple operations.
The process ensures high yield and purity of the target compound, (3S,4R)-4-aminotetrahydro-2H-thiole-3-ol salt, with all steps conducted at room temperature, simplifying the synthesis and ensuring the product's stability and bioactivity.
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Figure CN119684258A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride. Background Art
[0002] Thiophanates are a class of compounds with strong biological activity, which are numerous and widely found in natural and non-natural products.
[0003] Thiophanate compounds are common important heterocyclic compounds. Many thiopyran derivatives have been proven to have medicinal value, including antihistamine, antitumor and antiarrhythmic biological activities. Many of these active compounds are expected to become drugs for the treatment of related diseases. Therefore, they have received extensive attention from researchers in recent years.
[0004] The research on the synthesis methods of thiopyran compounds will effectively promote the progress of related medicinal chemistry research and provide more support for the development of related new drugs.
[0005] Developing synthetic routes with the advantages of short routes, simple operations, and single configuration is the main research direction of technical personnel at present. Summary of the invention
[0006] In view of the deficiencies of the prior art, the present invention provides a method for preparing (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride. The present invention has readily available raw materials, simple operation, high yield, and can prepare a target single-configuration product.
[0007] The technical solution of the present invention is as follows:
[0008] A method for preparing (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride, wherein the preparation method is carried out according to the following process:
[0009]
[0010] The steps include:
[0011] (1) Compound 1 was dissolved in DMF, L-proline was added, and then nitrosobenzene solution was added dropwise to react to obtain compound 2;
[0012] (2) Compound 2 was dissolved in methanol, and copper sulfate was added in batches to react to obtain compound 3;
[0013] (3) Compound 3 is dissolved in dichloromethane and reacted with 2-(trimethylsilyl)ethoxymethyl chloride under alkaline conditions to obtain compound 4.
[0014] (4) Compound 4 and Compound 5 were dissolved in solvent I, tetraethyl titanate was added in batches, and compound 6 was prepared through reductive amination reaction;
[0015] (5) Compound 6 was dissolved in solvent II, and 9-BBN solution was added dropwise under nitrogen atmosphere to obtain compound 7 through hydrogenation reduction reaction;
[0016] (6) Compound 7 is subjected to acidic conditions to remove the tert-butylsulfinyl group to obtain compound 8, namely the (3S,4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride.
[0017] Furthermore, in step (1), the concentration of compound 1 in DMF is 0.05-0.1 g / mL; the solvent of the nitrosobenzene solution is DMF, and the concentration is 0.05-0.1 g / mL; the molar ratio of compound 1 to nitrosobenzene is 2:1; the molar ratio of compound 1 to L-proline is 10-25:1; the reaction temperature is room temperature, and the reaction time is 12-18 h.
[0018] Furthermore, in step (2), the concentration of the compound 2 in methanol is 0.05-0.1 g / mL; the molar ratio of the compound 2 to copper sulfate is 1:0.1-0.3; the reaction temperature is 0°C and the reaction time is 3-18 h.
[0019] Furthermore, in step (3), the base is DIPEA; the concentration of the compound 3 in dichloromethane is 0.05-0.1 g / mL; the molar ratio of the compound 3 to the base is 1:1.5-2.0; the molar ratio of the compound 3 to 2-(trimethylsilyl)ethoxymethyl chloride is 1:1-1.1; the reaction temperature is room temperature and the reaction time is 18 h.
[0020] Furthermore, in step (4), the solvent I is selected from any one of tetrahydrofuran and 2-methyltetrahydrofuran; the concentration of the compound 4 in the solvent I is 0.05-0.1 g / mL; the molar ratio of the compound 4 to the compound 5 is 1:1.1; the molar ratio of the compound 4 to tetraethyl titanate is 1:3; the temperature of the reductive amination reaction is room temperature, and the time is 12-18 h.
[0021] Furthermore, in step (5), the solvent II is selected from any one of tetrahydrofuran and 2-methyltetrahydrofuran; the concentration of the compound 6 in the solvent II is 0.05-0.1 g / mL; the solvent of the 9-BBN solution is THF, and the concentration is 0.5 mol / L; the mass volume ratio of the compound 6 to the 9-BBN solution is g / mL 1:4-10; the temperature of the hydrogenation reduction reaction is room temperature, and the time is 18 h.
[0022] Furthermore, in step (6), the specific process of removing the tert-butylsulfinyl group is:
[0023] Compound 7 is dissolved in a dioxane solution of hydrogen chloride and reacted at room temperature to obtain the (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride.
[0024] Furthermore, the concentration of the hydrogen chloride-dioxane solution is 4 mol / L; the concentration of the compound 7 in the hydrogen chloride-dioxane solution is 0.1-0.27 g / mL; and the reaction time is 18 h.
[0025] The beneficial technical effects of the present invention are:
[0026] The invention uses tetrahydrothiopyran-4-one as a reaction starting material, reacts with nitrosobenzene to prepare (S)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one, removes aniline by catalysis of copper sulfate, protects the hydroxyl functional group by 2-(trimethylsilyl)ethoxymethyl chloride, and then undergoes a reduction amination reaction with (R)-(+)-tert-butylsulfenamide (compound 5) to obtain a relatively stable imine, and then the imine is subjected to a hydrogenation reduction reaction and the tert-butylsulfenyl group is removed to obtain a target product. The entire preparation process is carried out at room temperature, and the raw materials are easily available, the operation is simple, the yield is high, and a target single configuration product can be prepared. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 The reaction flow chart of the present invention is shown in FIG.
[0028] Figure 2 This is the H NMR spectrum of (R)-2-methyl-N-((3S,4R)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl)propane-2-sulfenamide prepared in Example 1 of the present invention.
[0029] Figure 3 This is the H NMR spectrum of (3S,4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride prepared in Example 1 of the present invention. DETAILED DESCRIPTION
[0030] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.
[0031] Example 1
[0032] A method for preparing (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride, the method comprising the following steps:
[0033] (1) Tetrahydrothiopyran-4-one (Compound 1) (1 g, 8.606 mmol) was added to DMF (10 mL), and L-proline (49.5 mg, 0.43 mmol) was added and stirred for 30 min. The system was cooled to 0 °C, and a solution of nitrosobenzene (0.46 g, 4.303 mmol) in DMF (5 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 18 h. TLC detection was performed until the raw material disappeared, and the system was added to ice water, and ethyl acetate (30 mL) was added for extraction. The extraction was repeated three times, and the organic phase was collected, dried and concentrated to obtain a crude product. The crude product was slurried with (PE: MTBE = 10: 1), and the solid was collected by filtration. After drying, a yellow solid product (S)-3-((phenylamino)oxy)tetrahydro-4H-thiopyran-4-one (Compound 2) (1.1 g, purity 95%, yield 57%) was obtained.
[0034] (2) (S)-3-((phenylamino)oxy)tetrahydro-4H-thiopyran-4-one (Compound 2) (1 g, 4.478 mmol) was added to methanol (20 mL), cooled to 0°C, copper sulfate (71 mg, 0.4478 mmol) was added in batches, and the reaction was maintained at 0°C for 3 h. TLC detection was performed until the starting material disappeared, the system was filtered, eluted with ethyl acetate (20 mL), the filtrate was collected, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE:EA=10:1) to obtain (S)-3-hydroxytetrahydro-4H-thiopyran-4-one (Compound 3) (0.3 g, purity 95%, yield 50%).
[0035] (3) (S)-3-Hydroxytetrahydro-4H-thiopyran-4-one (Compound 3) (0.4 g, 3.026 mmol) was added to dichloromethane (5 mL), and DIPEA (0.78 g, 6.05 mmol) was added dropwise. The mixture was cooled to 0°C, and SEMCl (0.5 g, 3.026 mmol) was added in batches. The mixture was slowly transferred to room temperature and reacted overnight. TLC was performed until the starting material disappeared, and the system was added to ice water (15 mL), and extracted with dichloromethane (20 mL), which was repeated three times. The organic phase was collected, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE: EA = 10: 1) to obtain (S)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one (Compound 4) (0.3 g, purity 95%, yield 37%).
[0036] (4) (S)-3-((2-(Trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one (Compound 4) (0.5 g, 1.9 mmol) and (R)-(+)-tert-butylsulfenamide (Compound 5) (0.25 g, 2.1 mmol, 1.1 eq) were added to tetrahydrofuran (10 mL), and tetraethyl titanate (1.3 g, 5.7 mol, 3 eq) was added in batches, and the reaction was allowed to react at room temperature overnight. TLC detection was performed until the starting material disappeared. Most of the solvent in the system was spun off and added into ice water, whereupon a white solid precipitated. Ethyl acetate was added and stirred for five minutes, then filtered. The organic phase was collected, dried and concentrated to give a crude product (R)-2-methyl-N-((S,E)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-ylidene)propane-2-sulfenamide (Compound 6) (0.4 g, purity 95%, yield 57%) as a yellow oil, which was directly used in the next step reaction.
[0037] (5) The crude (R)-2-methyl-N-((S,E)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-ylidene)propane-2-sulfenamide (Compound 6) (0.4 g, 1.09 mmol) was added to tetrahydrofuran (8 mL), and a tetrahydrofuran solution of 9-BBN (0.5 mol / L, 2.2 mL) was added dropwise under nitrogen protection, and the reaction was allowed to react at room temperature overnight. TLC detection was performed until the starting material disappeared. Most of the solvent in the system was spun off and added to ice water. Ethyl acetate was added for extraction three times. The organic phase was collected, dried and concentrated. The crude product was purified by column chromatography (PE: EA = 3: 1) to give (R)-2-methyl-N-((3S, 4R)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl)propane-2-sulfenamide (Compound 7) (0.12 g, purity 95%, yield 30%) as a colorless oil.
[0038] The NMR spectrum of the product is shown in Figure 2 As shown, 1 H NMR(400MHz, CDCl3) δ4.79(d,J=7.0Hz,1H),4.72(d,J=7.0Hz,1H),4.06(s,1H),3.68–3.45(m,3H),3.16(tdd,J=9.4,3.8,1.7Hz,1H),2.9 0(ddd,J=13.2,3.8,2.2Hz,1H),2.65–2.38(m,4H),1.72–1.59(m,1H),1.19(s,9H),0.91(ddd,J=9.3,6.6,3.4Hz,2H),0.02–-0.09(m,9H).
[0039] (6) (R)-2-methyl-N-((3S,4R)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl)propane-2-sulfenamide (Compound 7) (0.1 g, 0.272 mmol) was added to a dioxane hydrochloride solution (4 mol / L, 2 mL) and reacted at room temperature overnight. TLC detection was performed until the starting material disappeared, and petroleum ether was added to the system to make a slurry. The solid was collected after filtration. The product (3S,4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride (37 mg, purity 95%, yield 80%) was obtained by drying.
[0040] The NMR spectrum of the product is shown in Figure 3 As shown, 1 H NMR (400MHz, D2O) δ3.84–3.73(m,1H),3.14–3.01(m,1H),2.85–2.57(m,4H),2.46(ddd,J=13.0,6.4,3.4Hz,1H),1.90(qd,J=12.5,3.8Hz,1H).
[0041] Example 2
[0042] A method for preparing (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride, the method comprising the following steps:
[0043] (1) Tetrahydrothiopyran-4-one (Compound 1) (37 g, 0.318 mol) was added to DMF (400 mL), and L-proline (3.7 g, 0.0318 mol) was added and stirred for 30 min. The system was cooled to 0°C, and a solution of nitrosobenzene (17 g, 0.159 mol) in DMF (200 mL) was slowly added dropwise, and the mixture was reacted at room temperature for 18 h. TLC detection was performed until the raw material disappeared, and the system was added to ice water, and ethyl acetate (300 mL) was added for extraction. The extraction was repeated three times, and the organic phase was collected, dried and concentrated to obtain a crude product. The crude product was slurried with (PE: MTBE = 10: 1), and the solid was collected by filtration. After drying, a yellow solid product (S)-3-((phenylamino)oxy)tetrahydro-4H-thiopyran-4-one (Compound 2) (23 g, purity 95%, yield 32%) was obtained.
[0044] (2) (S)-3-((phenylamino)oxy)tetrahydro-4H-thiopyran-4-one (Compound 2) (18.5 g, 0.0828 mol) was added to methanol (200 mL), cooled to 0°C, copper sulfate (1.32 g, 8.28 mmol) was added in batches, and the reaction was maintained at 0°C for 3 h. TLC detection was performed until the raw material disappeared, the system was filtered, eluted with ethyl acetate (100 mL), the filtrate was collected, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE:EA=10:1) to obtain (S)-3-hydroxytetrahydro-4H-thiopyran-4-one (Compound 3) (4.7 g, purity 95%, yield 43%).
[0045] (3) (S)-3-hydroxytetrahydro-4H-thiopyran-4-one (Compound 3) (4.7 g, 0.0356 mol) was added to dichloromethane (50 mL), and DIPEA (9.2 g, 0.0711 mmol) was added dropwise. The mixture was cooled to 0°C, and SEMCl (5.9 g 0.0356 mol) was added in batches. The mixture was slowly transferred to room temperature and reacted overnight. TLC was performed until the starting material disappeared, and the system was added to ice water (50 mL). The mixture was extracted with dichloromethane (50 mL) and repeated three times. The organic phase was collected, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE:EA=10:1) to obtain (S)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one (Compound 4) (4.1 g, purity 95%, yield 44%).
[0046] (4) (S)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one (Compound 4) (3 g, 0.011 mol) and (R)-(+)-tert-butylsulfenamide (Compound 5) (1.5 g, 0.012 mol, 1.1 eq) were added to tetrahydrofuran (30 mL), and tetraethyl titanate (7.8 g, 0.034 mol, 3 eq) was added in batches. The reaction was allowed to proceed overnight at room temperature. TLC was performed until the raw material disappeared, and most of the solvent in the system was removed by spinning, and then the mixture was added to ice water. A white solid was precipitated. Ethyl acetate was added and stirred for five minutes, and then filtered. The organic phase was collected, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA=5 / 1) to give (R)-2-methyl-N-((S,E)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-ylidene)propane-2-sulfenamide (Compound 6) (1.7 g, purity 95%, yield 41%) as a yellow oil.
[0047] (5) The crude (R)-2-methyl-N-((S,E)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-ylidene)propane-2-sulfenamide (Compound 6) (1.7 g, 4.6 mmol) was added to tetrahydrofuran (35 mL), and a tetrahydrofuran solution of 9-BBN (0.5 mol / L, 18.6 mL) was added dropwise under nitrogen protection, and the reaction was allowed to react at room temperature overnight. TLC detection was performed until the starting material disappeared. Most of the solvent in the system was spun off and added into ice water. Ethyl acetate was added for extraction three times. The organic phase was collected, dried, concentrated and column chromatography (PE:EA=5:1-4:1) was performed to obtain (R)-2-methyl-N-((3S,4R)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl)propane-2-sulfenamide (Compound 7) (0.7 g, purity 95%, yield 41%) as a yellow oil.
[0048] (6) (R)-2-methyl-N-((3S,4R)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl)propane-2-sulfenamide (Compound 7) (4 g, 10.88 mmol) was added to a dioxane hydrochloride solution (4 mol / L, 40 mL) and reacted at room temperature overnight. TLC detection was performed until the starting material disappeared, and petroleum ether was added to the system to make a slurry. The solid was collected after filtration. The product (3S,4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride (1.7 g, purity 95%, yield 85%) was obtained by drying as a white solid.
[0049] Example 3
[0050] A method for preparing (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride, the method comprising the following steps:
[0051] (1) Tetrahydrothiopyran-4-one (Compound 1) (210 g, 1.86 mol) was added to DMF (4 L), and L-proline (10 g, 0.08 mol) was added and stirred for 30 min. The system was cooled to 0 ° C, and a solution of nitrosobenzene (100 g, 0.93 mol) in DMF (2 L) was slowly added dropwise, and the reaction was carried out at room temperature for 18 h. TLC detection was performed until the raw material disappeared, and the system was added to ice water, and ethyl acetate (1 L) was added for extraction. The extraction was repeated three times, and the organic phase was collected, dried and concentrated to obtain a crude product. The crude product was slurried with (PE: MTBE = 10: 1), and the solid was collected by filtration. After drying, a yellow solid product (S)-3-((phenylamino)oxy)tetrahydro-4H-thiopyran-4-one (Compound 2) (184 g, purity 95%, yield 45%) was obtained.
[0052] (2) (S)-3-((phenylamino)oxy)tetrahydro-4H-thiopyran-4-one (Compound 2) (62 g, 0.278 mol) was added to methanol (620 mL), cooled to 0°C, copper sulfate (4.43 g, 0.0278 mol) was added in batches, and the reaction was maintained at 0°C for 3 h. TLC detection was performed until the raw material disappeared, the system was filtered, eluted with ethyl acetate (200 mL), the filtrate was collected, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE:EA=10:1) to obtain (S)-3-hydroxytetrahydro-4H-thiopyran-4-one (Compound 3) (18 g, purity 95%, yield 49%).
[0053] (3) (S)-3-hydroxytetrahydro-4H-thiopyran-4-one (Compound 3) (18 g, 0.136 mol) was added to dichloromethane (180 mL), and DIPEA (35 g, 0.26 mmol) was added dropwise. The mixture was cooled to 0°C, and SEMCl (22.6 g 0.13 mmol) was added in batches. The mixture was slowly transferred to room temperature and reacted overnight. TLC was performed until the starting material disappeared, and the system was added to ice water (150 mL). The mixture was extracted with dichloromethane (100 mL) and repeated three times. The organic phase was collected, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE:EA=10:1) to obtain (S)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one (Compound 4) (18 g, purity 95%, yield 50%).
[0054] (4) (S)-3-((2-(Trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one (Compound 4) (16 g, 61 mmol) and (R)-(+)-tert-butylsulfenamide (Compound 5) (8.1 g, 67 mmol, 1.1 eq) were added to tetrahydrofuran (320 mL), and tetraethyl titanate (41.7 g, 0.18 mol, 3 eq) was added in batches, and the reaction was allowed to react at room temperature overnight. TLC detection was performed until the starting material disappeared. Most of the solvent in the system was spun off and added into ice water, whereupon a white solid precipitated. Ethyl acetate was added and stirred for five minutes, then filtered. The organic phase was collected, dried and concentrated to give a crude product (R)-2-methyl-N-((S,E)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-ylidene)propane-2-sulfenamide (Compound 6) (14 g, purity 95%, yield 62%), which was directly used in the next step reaction.
[0055] (5) The crude (R)-2-methyl-N-((S,E)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-ylidene)propane-2-sulfenamide (Compound 6) (12.5 g, 34.2 mmol) was added to tetrahydrofuran (250 mL), and a tetrahydrofuran solution of 9-BBN (0.5 mol / L, 136 mL) was added dropwise under nitrogen protection, and the reaction was allowed to react at room temperature overnight. TLC detection was performed until the starting material disappeared. Most of the solvent in the system was spun off and added into ice water. Ethyl acetate was added for extraction three times. The organic phase was collected, dried, concentrated and column chromatography (PE:EA=5:1-4:1) was performed to obtain (R)-2-methyl-N-((3S,4R)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl)propane-2-sulfenamide (Compound 7) (4.5 g, purity 95%, yield 35%) as a yellow oil.
[0056] (6) (R)-2-methyl-N-((3S,4R)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl)propane-2-sulfenamide (Compound 7) (4.5 g, 12.3 mmol) was added to a dioxane hydrochloride solution (4 mol / L, 45 mL) and reacted at room temperature overnight. TLC detection was performed until the starting material disappeared, and petroleum ether was added to the system to slurry, and the solid was collected after filtration. Drying gave the product (3S,4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride (1.8 g, purity 95%, yield 85%).
[0057] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.
Claims
1. A method for preparing (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride, characterized in that: The preparation method is carried out according to the following process: The steps include: (1) Compound 1 was dissolved in DMF, L-proline was added, and then nitrosobenzene solution was added dropwise to react to obtain Compound 2; (2) Compound 2 was dissolved in methanol, and copper sulfate was added in batches to react to obtain compound 3; (3) Compound 3 is dissolved in dichloromethane and reacted with 2-(trimethylsilyl)ethoxymethyl chloride under alkaline conditions to obtain compound 4; (4) Compound 4 and Compound 5 were dissolved in solvent I, tetraethyl titanate was added in batches, and compound 6 was prepared through reductive amination reaction; (5) Compound 6 was dissolved in solvent II, and 9-BBN solution was added dropwise under nitrogen atmosphere to obtain compound 7 through hydrogenation reduction reaction; (6) Compound 7 is subjected to acidic conditions to remove the tert-butylsulfinyl group to obtain compound 8, namely the (3S,4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride.
2. The preparation method according to claim 1, characterized in that: In step (1), the concentration of compound 1 in DMF is 0.05-0.1 g / mL; the solvent of the nitrosobenzene solution is DMF, and the concentration is 0.05-0.1 g / mL; the molar ratio of compound 1 to nitrosobenzene is 2:1; the molar ratio of compound 1 to L-proline is 10-25:1; the reaction temperature is room temperature, and the reaction time is 12-18 h.
3. The preparation method according to claim 1, characterized in that: In step (2), the concentration of the compound 2 in methanol is 0.05-0.1 g / mL; the molar ratio of the compound 2 to copper sulfate is 1:0.1-0.3; the reaction temperature is 0°C and the reaction time is 3-18 h.
4. The preparation method according to claim 1, characterized in that: In step (3), the base is DIPEA; the concentration of the compound 3 in dichloromethane is 0.05-0.1 g / mL; the molar ratio of the compound 3 to the base is 1:1.5-2.0; the molar ratio of the compound 3 to 2-(trimethylsilyl)ethoxymethyl chloride is 1:1-1.1; the reaction temperature is room temperature and the reaction time is 18 h.
5. The preparation method according to claim 1, characterized in that: In step (4), the solvent I is selected from any one of tetrahydrofuran and 2-methyltetrahydrofuran; the concentration of the compound 4 in the solvent I is 0.05-0.1 g / mL; the molar ratio of the compound 4 to the compound 5 is 1:1.1; the molar ratio of the compound 4 to tetraethyl titanate is 1:3; the temperature of the reductive amination reaction is room temperature, and the time is 12-18 h.
6. The preparation method according to claim 1, characterized in that: In step (5), the solvent II is selected from any one of tetrahydrofuran and 2-methyltetrahydrofuran; the concentration of the compound 6 in the solvent II is 0.05-0.1 g / mL; the solvent of the 9-BBN solution is THF, and the concentration is 0.5 mol / L; the mass volume ratio of the compound 6 to the 9-BBN solution is g / mL 1:4-10; the temperature of the hydrogenation reduction reaction is room temperature, and the time is 18 h.
7. The preparation method according to claim 1, characterized in that: In step (6), the specific process of removing the tert-butylsulfinyl group is: Compound 7 is dissolved in a dioxane solution of hydrogen chloride and reacted at room temperature to obtain the (3S, 4R)-4-aminotetrahydro-2H-thiopyran-3-ol hydrochloride.
8. The preparation method according to claim 7, characterized in that: The concentration of the hydrogen chloride-dioxane solution is 4 mol / L; the concentration of the compound 7 in the hydrogen chloride-dioxane solution is 0.1-0.27 g / mL; and the reaction time is 18 h.