Method for preparing L-navidine through kinetic resolution

Abstract

The invention discloses a method for preparing levo-nalvidine by kinetic resolution, which comprises the following steps: adding racemic nalvidine and a proper amount of chiral resolution catalyst into a reaction container, then adding a mixed solvent formed by alcohol and organic amine, and stirring the whole reaction system at 60-80 DEG C until a clear solution is formed; immediately cooling to 30-50 DEG C, and then preserving heat for 24-72 hours; cooling to room temperature, continuously stirring for 1-3 hours at room temperature, filtering, leaching the obtained solid with a mixed solvent, and drying at room temperature; the chiral resolution catalyst is a chiral phenylethylamine derivative and is selected from any one compound in the following structural formula: # imgabs0 #. According to the method, the high-optical-purity levo-nalvidine can be obtained at high yield by adopting a simple operation process under a mild condition, and the chiral resolution catalyst is low in cost, easy to obtain, suitable for large-scale application and suitable for industrial production. The method has an important value for realizing large-scale production of L-galanthamine.

Description

Technical Field

[0001] The present invention relates to a method for preparing levo-narwedine by kinetic resolution, belonging to the technical field of chemical synthesis. Background Art

[0002] Galanthamine is a selective, competitive and reversible acetylcholinesterase inhibitor, which is mainly used clinically for the treatment of myasthenia gravis and mild to moderate Alzheimer's disease (AD). As an anti-Alzheimer's disease (AD) drug, galanthamine was first marketed in the UK and Ireland in July 2000 after being approved by the European Union. Galanthamine hydrobromide tablets were approved for marketing by the FDA on February 28, 2001, under the trade name RAZADYNE, and are mainly used in the United States for the treatment of mild to moderate Alzheimer's disease. At the same time, the benzoate derivative of galanthamine (Zunveyl) has also been approved for the treatment of mild to moderate Alzheimer's disease. In China, the oral immediate-release dosage form and injection of galanthamine have been included in the Class B of the national medical insurance catalog. This product has currently been recommended as the first-choice drug for the treatment of AD in many countries and has broad market application prospects.

[0003] Since natural galanthamine can only be extracted from daffodils in specific regions, there are problems such as limited resources, complex extraction processes, and low yields, resulting in the long-term high price of galanthamine and inability to meet market needs. Therefore, since the discovery of galanthamine, the research on its synthetic route has been ongoing. So far, researchers have proposed various synthetic strategies, such as intramolecular phenolic oxidative condensation method, intramolecular Heck reaction method, etc. Although certain progress has been made in the synthesis of galanthamine, it still cannot well meet the requirements of industrial production because there are 3 chiral carbon atoms in the structure of galanthamine, and the existing technology cannot obtain highly optically pure levo-galanthamine with high yield, and there are problems such as complex processes and high costs.

[0004] Narwedine (its CAS number is 510-77-0, molecular formula is C 17 H 19 NO3, molecular weight is 285) is a precursor compound of galanthamine. Existing research has found that: by resolving racemic Narwedine to obtain levo-Narwedine, its chemical structural formula is shown as follows:

[0005] Then, by selectively reducing it with a large steric hindrance reducing reagent, levo-galanthamine: (-)-Galanthamine can be easily obtained. However, the current methods for resolving racemic Narwedine are limited to the following 3 types:

[0006] ① Using (-)-Narwedine as a seed crystal

[0007] A small amount of (-)-Narwedine seeds was added to a supersaturated solution of racemic Narwedine with V(ethanol):(triethylamine) = 9:1, and then filtered to obtain (-)-Narwedine crystals;

[0008] ② Using (+)-Galanthamine as an inducer

[0009] In a supersaturated solution of racemic Narwedine with V(ethanol):(triethylamine) = 9:1, a catalytic amount of (+)-galanthamine was added as seeds at 80 °C, and then cooled to 40 °C and allowed to stand for 19 hours to obtain optically pure (-)-narwedine;

[0010] ③ Using D-(+)-di-p-toluoyl tartaric acid as an inducer

[0011] A small amount of D-(+)-di-p-toluoyl tartaric acid was added to a saturated ethanol solution of racemic Narwedine. Under thermodynamic control, a salt formed by narwedine and D-(+)-di-p-toluoyl tartaric acid was obtained. Then, this salt was reduced with L-Selectride, and the free base was obtained by neutralization with an excess of base. Finally, column chromatography separation was performed to obtain (-)-galanthamine crystals;

[0012] Since the first method above requires obtaining optically pure (-)-narwedine seeds in advance, and the second method requires obtaining optically pure (+)-galanthamine seeds in advance, both have problems such as difficulty in obtaining a large amount of seeds and high cost of obtaining seeds. Therefore, these two resolution methods cannot be applied to industrial production; and the third method is not only complex in process, but also has high cost of chiral reagents and low resolution yield. Therefore, it also cannot meet the industrial production requirements such as cheap and easily available raw materials, simple operation, and low cost. Summary of the Invention

[0013] In view of the above problems and requirements existing in the prior art, the object of the present invention is to provide a method for kinetic resolution preparation of (-)-narwedine with cheap and easily available resolution catalysts, mild resolution conditions, simple resolution operation, high resolution efficiency, low cost, and easy industrialization, providing strong support for the industrial preparation of optically pure (+)-galanthamine.

[0014] To achieve the above object, the present invention adopts the following technical solutions:

[0015] A method for kinetic resolution preparation of (-)-narwedine, comprising the following steps:

[0016] a) First, racemic narwedine and an appropriate amount of chiral resolution catalyst are added to a reaction vessel, then a mixed solvent formed by an alcohol and an organic amine is added, and then the entire reaction system is stirred at 60-80 °C until it becomes a clear solution;

[0017] b) Then cool down the temperature to 30 - 50 °C immediately, and then keep the temperature for 24 - 72 hours;

[0018] c) Then cool down the temperature to room temperature, and continue to stir for 1 - 3 hours at room temperature, filter, wash the obtained solid with the mixed solvent in step a), and then dry it at room temperature. The obtained solid is levo-narwedine;

[0019] Among them, the chiral resolution catalyst is a chiral phenethylamine derivative, and is selected from any one of the following structural formulas:

[0020]

[0021] In the formula, the R group is H, 4-methoxy or 4-F, and the R 1 group is H, n-propyl, n-butyl or n-pentyl, and the R 2 group is selected from any one of H, n-propyl, n-butyl, n-pentyl, tert-butoxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-bromobenzenesulfonyl, p-tert-butylbenzenesulfonyl, 3,4-dimethoxybenzenesulfonyl.

[0022] As a preferred scheme, the chiral resolution catalyst is selected from any one of R-(+)-phenethylamine, N,N-dipropyl-R-(+)-phenethylamine, N,N-dibutyl-R-(+)-phenethylamine, N,N-dipentyl-R-(+)-phenethylamine, N,N-cyclobutyl-R-(+)-phenethylamine, N-Boc-R-(+)-phenethylamine, N-p-toluenesulfonyl-R-(+)-phenethylamine, 4-methoxy-R-(+)-phenethylamine, L-phenylalanine.

[0023] As a preferred scheme, the molar ratio of the chiral resolution catalyst to racemic narwedine is (0.1% - 5%):1.

[0024] As a preferred scheme, in step a), the alcohol used is 95% ethanol or isopropanol, and the organic amine is selected from any one of triethylamine, N,N-diisopropylethylamine (DIPEA), tert-butylamine, diisopropylamine.

[0025] As a preferred scheme, the mixed solvent in step a) is formed by mixing alcohol and organic amine at a volume ratio of (9 - 30):1.

[0026] As a preferred scheme, in step a), 12 - 20 mL of the mixed solvent is used for 1 g of racemic narwedine.

[0027] Compared with the prior art, the present invention has the following significant beneficial effects:

[0028] Experimental results show that by selecting the chiral resolution catalyst of the present invention, not only can highly optically pure (-)-navenidine be obtained in high yield under mild conditions with a simple operation process, but also the chiral resolution catalyst has the advantages of low cost and easy availability, making it very suitable for large-scale applications. Therefore, the present invention is of great significance and application value for realizing the large-scale production of (-)-galanthamine. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Optical purity diagram of (-)-navenidine prepared in Example 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0030] The present application will be further described below in conjunction with the embodiments, examples and drawings.

[0031] It should be understood that the following embodiments are only used to illustrate the present application and not to limit the scope of the present application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0032] In the present application, when referring to a numerical interval (i.e., a numerical range), unless otherwise specified, the optional numerical values are considered continuous within the above numerical interval, and include the two numerical endpoints (i.e., the minimum value and the maximum value) of this numerical range, as well as each numerical value between these numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of this numerical range, as well as each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0033] The temperature parameters in the present application, unless otherwise specified, are allowed to be constant temperature or to vary within a certain temperature range. It should be understood that the so-called constant temperature is allowed to fluctuate within a range such as ±0.5 °C, ±0.4 °C, ±0.3 °C, ±0.2 °C, ±0.1 °C.

[0034] The ee value described in the following examples represents the percentage of excess of the (-)-enantiomer, which is determined by chiral high performance liquid chromatography under the following conditions: IC-3 chromatographic column, 10% i-PrOH, t R = 90 min, and the calculation formula is:

[0035] ee = (Rs - Rd) / (Rs + Rd) × 100%, where Rs and Rd represent the peak areas or peak heights of the (-)-enantiomer and the (+)-enantiomer in the sample, respectively.

[0036] The present inventor first conducted optimization experiments on the kinetic resolution conditions. The chiral resolution catalysts used in the optimization experiments were all R-(+)-phenylethylamine (CAS No. 3886-69-9, molecular formula C8H 11 N, molecular weight 121, chemical structural formula: (commercially available). The specific optimization experiment operations are as follows:

[0037] a) First, add (300 mg, 1.05 mmol) of (±)-Narwedine and an appropriate amount of R-(+)-phenylethylamine (the specific feeding amount is shown in Table 1) to the reaction vessel, then add 4.8 mL of a mixed solvent formed by alcohol and organic amine in a certain volume ratio (the specific composition of the mixed solvent is shown in Table 1) (equivalent to 16 mL of the mixed solvent for 1 g of racemic narwedine), and then stir the entire reaction system at 80 °C until it becomes a clear solution;

[0038] b) Immediately cool down (the specific cooling temperature is shown in Table 1), and then keep warm (the specific holding time is shown in Table 1);

[0039] c) Cool down to room temperature again, and continue to stir at room temperature for 2 hours, filter, wash the obtained solid with the mixed solvent in step a), and then dry it at room temperature. The obtained white solid is (-)-narwedine. The specific yield and the ee value detected by Chiral HPLC are both shown in Table 1.

[0040] Table 1 Optimization experiment results of kinetic resolution conditions

[0041]

[0042] As can be seen from the experimental results numbered 1 to 4 in Table 1: The feeding amount of the chiral resolution catalyst described in the present invention can be 0.1 mol% to 5 mol% of the molar feeding amount of racemic narwedine (Narwedine), but under the same conditions, 1 mol% is the best; further, as can be seen from the experimental results numbered 2 and 5 to 9 in Table 1: The alcohol in the mixed solvent described in the present invention can be 95% ethanol or isopropanol, and the organic amine in the mixed solvent described in the present invention can be any one of triethylamine, N,N-diisopropylethylamine (DIPEA), tert-butylamine, and diisopropylamine, but under the same conditions, the mixed solvent described in the present invention is best in the combination of 95% ethanol and triethylamine; however, the inventor found that even if other conditions are the same, if the mixed solvent is a combination of pure ethanol and triethylamine, the obtained ee value is -80%; in addition, as can be seen from the experimental results numbered 2 and 10 to 13 in Table 1: The mixed solvent described in the present invention can be formed by 95% ethanol and triethylamine in a volume ratio of (9 to 30):1, but under the same conditions, the mixed solvent formed by 95% ethanol and triethylamine in a volume ratio of 20:1 is the best; furthermore, as can be seen from the experimental results numbered 2 and 14 to 16 in Table 1: The heat preservation temperature in step b) of the present invention can be 30 to 50 °C, but under the same conditions, 40 °C is the best, and the inventor found that even if other conditions are the same, if the heat preservation temperature is 60 °C, the obtained ee value is only 11%; in addition, as can be seen from the experimental results numbered 2 and 17 to 19 in Table 1: The heat preservation time in step b) of the present invention can be 24 to 72 hours, but the inventor found that even if other conditions are the same, if the heat preservation time is 12 hours, the obtained ee value is -18%.

[0043] Example 1

[0044] a) First, add (300 mg, 1.05 mmol) of (±)-Narwedine and 0.0105 mmol (equivalent to 1 mol% of the feeding amount of the substrate (±)-Narwedine) of R-(+)-phenylethylamine to the reaction vessel, then add 4.8 mL of a mixed solvent formed by 95% ethanol and triethylamine in a volume ratio of 20:1 (equivalent to using 16 mL of the mixed solvent for 1 gram of racemic narwedine), and then stir the entire reaction system at 80 °C until it becomes a clear solution;

[0045] b) Immediately cool down to 40 °C, and then keep warm for 24 hours;

[0046] c) Cool down to room temperature again, and continue to stir at room temperature for 2 hours, filter, wash the obtained solid with a mixed solvent formed by 95% ethanol and triethylamine in a volume ratio of 20:1, and then place it in a room temperature condition for drying to obtain 249 mg of white solid, which is levorotatory narwedine, with a yield of 83%. After detection by Chiral HPLC, its ee value is 98.89% (see detailsFigure 1 (as shown in the optical purity diagram).

[0047] Example 2

[0048] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced by N,N-dipropyl-R-(+)-phenylethylamine (CAS No. 180259-76-1, and the chemical structural formula is: This chiral resolution catalyst can be prepared by the method described in the reference: Chemistry-A European Journal (2009), 15, (35), 8703-8708. The relevant structure confirmation data are as follows:

[0049] 1 H NMR(400MHz,CDCl3)ppm:7.37-7.35(m,2H),7.29(t,J=8.0Hz,2H),7.24-7.18(m,1H),3.83(q,J=6.4Hz,1H),2.45-2.38(m,2H),2.34-2.27(m,2H),1.47-1.38(m,4H),1.32(d,J=6.8Hz,3H),0.82(t,J=7.2Hz,6H).

[0050] Under the condition that the remaining content is the same as that described in Example 1, the yield of the kinetic resolution preparation of levonavitidine in this example is 85%, and the ee value is 87%.

[0051] Example 3

[0052] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced by N,N-dibutyl-R-(+)-phenylethylamine (CAS No. 1193363-21-1, and the chemical structural formula is: This chiral resolution catalyst can be prepared by the method described in the reference: Chemistry-A European Journal (2009), 15, (35), 8703-8708. The relevant structure confirmation data are as follows:

[0053] 1 H NMR(400MHz,CDCl3)ppm:7.69(d,J=6.4Hz,2H),7.47-7.39(m,3H),4.27(q,J=6.8Hz,1H),3.04(s,4H),1.87(d,J=6.8Hz,3H),1.78(s,4H),1.44-1.24(m,4H),0.91(s,6H).

[0054] Under the same conditions as those described in Example 1 for the rest of the content, the yield of preparing levonavitidine by kinetic resolution in this example is 72%, and the ee value is 81%.

[0055] Example 4

[0056] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced from R-(+)-phenylethylamine with N,N-dipentyl-R-(+)-phenylethylamine (CAS No. 2659361-18-7, and the chemical structural formula is: This chiral resolution catalyst can be prepared by the method described in the reference: Chemistry - A European Journal (2009), 15, (35), 8703 - 8708. The relevant structure confirmation data are as follows:

[0057] 1 H NMR(400MHz,CDCl3)ppm:7.36 - 7.34(m,2H),7.29(t,J = 8.0Hz,2H),7.20(t,J = 6.8Hz,1H),3.83(q,J = 6.8Hz,1H),2.47 - 2.40(m,2H),2.37 - 2.30(m,2H),1.44 - 1.37(m,4H),1.32(d,J = 6.8Hz,3H),1.29 - 1.18(m,8H),0.86(t,J = 7.2Hz,6H).

[0058] Under the same conditions as those described in Example 1 for the rest of the content, the yield of preparing levonavitidine by kinetic resolution in this example is 78%, and the ee value is 84%.

[0059] Example 5

[0060] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced from R-(+)-phenylethylamine with N,N-cyclobutyl-R-(+)-phenylethylamine (CAS No. 61451-86-3, and the chemical structural formula is: This chiral resolution catalyst can be prepared by the method described in the reference: Tetrahedron (2015), 71, (38), 6796 - 6802. The relevant structure confirmation data are as follows:

[0061] 1 H NMR(400MHz,CDCl3)ppm:7.70 - 7.67(m,2H),7.45 - 7.37(m,3H),4.05(q,J = 6.8Hz,1H),3.09(br,4H),2.10(s,4H),1.85(d,J = 5.6Hz,3H).

[0062] Under the condition that the rest of the content is the same as that described in Example 1, the yield of preparing levonavitidine by kinetic resolution in this example is 77%, and the ee value is 72%.

[0063] Example 6

[0064] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced from R-(+)-phenylethylamine to N-Boc-R-(+)-phenylethylamine (CAS No. 184888-43-5, and the chemical structural formula is: This chiral resolution catalyst can be prepared by the method described in the reference: Journal of Medicinal Chemistry (2008), 51, (12), 3414-3421. The relevant structure confirmation data are as follows:

[0065] 1 H NMR (400 MHz, CDCl3) ppm: 7.34 - 7.28 (m, 4H), 7.26 - 7.21 (m, 1H), 4.88 (br, 2H), 1.52 (s, 1H), 1.45 - 1.42 (m, 11H).

[0066] Under the condition that the rest of the content is the same as that described in Example 1, the yield of preparing levonavitidine by kinetic resolution in this example is 77%, and the ee value is 80%.

[0067] Example 7

[0068] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced from R-(+)-phenylethylamine to N-p-toluenesulfonyl-R-(+)-phenylethylamine (CAS No. 72984-27-1, and the chemical structural formula is: This chiral resolution catalyst can be prepared by the method described in the reference: Advanced Synthesis & Catalysis (2016), 358, (2), 226-239. The relevant structure confirmation data are as follows:

[0069] 1 H NMR (400 MHz, CDCl3) ppm: 7.62 (d, J = 8.0 Hz, 2H), 7.17 - 7.14 (m, 5H), 7.11 - 7.09 (m, 2H), 5.36 (d, J = 7.2 Hz, 1H), 4.45 (q, J = 7.2 Hz, 1H), 2.37 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H).

[0070] Under the condition that the rest of the content is the same as that described in Example 1, the yield of preparing levonavitidine by kinetic resolution in this example is 65%, and the ee value is 75%.

[0071] Example 8

[0072] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced by 4-methoxy-R-(+)-phenylethylamine (CAS No. 22038-86-4, and the chemical structural formula is: This chiral resolution catalyst is commercially available.

[0073] Under the condition that the rest of the content is the same as that described in Example 1, the yield of preparing levonavitidine by kinetic resolution in this example is 73%, and the ee value is 55%.

[0074] Example 9

[0075] The difference between this example and Example 1 is only that the chiral resolution catalyst therein is replaced by L-phenylalanine (CAS No. 63-91-2, and the chemical structural formula is: This chiral resolution catalyst is commercially available.

[0076] Under the condition that the rest of the content is the same as that described in Example 1, the yield of preparing levonavitidine by kinetic resolution in this example is 80%, and the ee value is 73%.

[0077] Finally, it should be pointed out here that the above are only some preferred embodiments of the present invention, and should not be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention all fall within the protection scope of the present invention.

Claims

1. A method for preparing levonavitidine by kinetic resolution, comprising the following steps: a) Add racemic navitidine and an appropriate amount of chiral resolution catalyst to a reaction vessel first, then add a mixed solvent formed by an alcohol and an organic amine, and then stir the entire reaction system at 60-80 °C until it becomes a clear solution; b) Immediately cool down to 30-50 °C, and then keep the temperature for 24-72 hours; c) Cool down to room temperature again, and continue to stir at room temperature for 1-3 hours, filter, wash the obtained solid with the mixed solvent in step a), and then dry it at room temperature. The obtained solid is levonavitidine; It is characterized in that: Wherein, The chiral resolution catalyst is a chiral phenethylamine derivative, and is selected from any one of the following structural formulas: The R group in the formula is H, 4-methoxy or 4-F, and the R 1 group is H, n-propyl, n-butyl or n-pentyl, and the R 2 group is selected from any one of H, n-propyl, n-butyl, n-pentyl, tert-butoxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-bromobenzenesulfonyl, p-tert-butylbenzenesulfonyl, 3,4-dimethoxybenzenesulfonyl.

2. The method for preparing levonavitidine by kinetic resolution according to claim 1, characterized in that: The chiral resolution catalyst is selected from any one of R-(+)-phenethylamine, N,N-dipropyl-R-(+)-phenethylamine, N,N-dibutyl-R-(+)-phenethylamine, N,N-dipentyl-R-(+)-phenethylamine, N,N-cyclobutyl-R-(+)-phenethylamine, N-Boc-R-(+)-phenethylamine, N-p-toluenesulfonyl-R-(+)-phenethylamine, 4-methoxy-R-(+)-phenethylamine, and L-phenylalanine.

3. The method for preparing levonavitidine by kinetic resolution according to claim 1, wherein: The molar ratio of the chiral resolution catalyst to racemic navitidine in the feeding is (0.1% - 5%):

1.

4. The method for preparing (-)-navenidine by kinetic resolution according to claim 1, characterized in that: In step a), the alcohol used is 95% ethanol or isopropanol, and the organic amine used is selected from any one of triethylamine, N,N-diisopropylethylamine, tert-butylamine, and diisopropylamine.

5. The method for preparing levonavitidine by kinetic resolution according to claim 1, characterized in that: The mixed solvent in step a) is formed by the alcohol and the organic amine in a volume ratio of (9-30):

1.

6. The method for preparing levonavitidine by kinetic resolution according to claim 1, characterized in that: In step a), 12-20 mL of the mixed solvent is used per 1 g of racemic navitidine.

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