A tetracyclic lactam compound and a preparation method thereof
The preparation of tetracyclic lactam compounds using 2-iodo-6-methoxyphenol through a two-step chemical reaction has solved the problem of cumbersome reaction steps in the prior art, achieved a high yield and simple preparation process, and is suitable for large-scale production.
Patent Information
- Application Number
- CN202310532300.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-05-12
- Publication Date
- 2025-05-30
- Estimated Expiration
- 2043-05-12
AI Technical Summary
In the prior art, the preparation of compounds with tetracyclic lactam structure requires multiple reactions, and the reaction steps are complicated and are not suitable for large-scale production.
Tetracyclic lactam compounds can be prepared by using 2-iodo-6-methoxyphenol as the reaction substrate through two-step chemical reactions. The reaction conditions are mild and the substrate is simple and easy to obtain.
The high yield and simple preparation process of tetracyclic lactam compounds are achieved, suitable for large-scale production, and reduce raw material costs.
Smart Images
Figure CN116731028B_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a tetracyclic lactam compound and a preparation method thereof. Background Art
[0002] The tetracyclic lactam structure widely exists in galanthamine alkaloids and is a high-level intermediate in the process of synthesizing galanthamine alkaloids, with broad application prospects; however, the current methods for constructing such structures are very limited.
[0003] In the prior art, compounds with a tetracyclic lactam structure need to be prepared through multiple reactions. For example, as recorded in The Journal of Organic Chemistry, 2015, 80(3): 1952-1956, European Journal of Organic Chemistry, 2016, 2016(35): 5862-5867, Organic & Biomolecular Chemistry, 2019, 17(8): 2192-2198, etc.; Organic Letters, 2012, 14(11): 2714-2717 synthesized a tetracyclic lactam structure through 6-step chemical reactions, but its reaction steps are also relatively numerous and not suitable for the large-scale production of tetracyclic lactam compounds.
[0004] Aiming at the defects existing in the preparation process of the above-mentioned tetracyclic lactam compounds, finding a preparation method with simple reaction steps and capable of simply and efficiently preparing tetracyclic lactam compounds is the current research focus. Summary of the Invention
[0005] The purpose of the present invention is to overcome the deficiencies of the above prior art and provide a tetracyclic lactam compound and a preparation method thereof. The reaction conditions of the preparation process are mild, the reaction substrates are simple and easy to obtain, and a tetracyclic lactam compound with a relatively high yield can be prepared only through two-step chemical reactions.
[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:
[0007] In the first aspect, the present invention provides a preparation method of a tetracyclic lactam compound. The structural formula of the tetracyclic lactam compound is shown as the following formula (Ⅰ), and the method includes the following steps:
[0008] S1. Mix the compound of structural formula (Ⅱ), the compound of structural formula (Ⅲ) and a phosphine ligand in an organic solvent, then add diisopropyl azodicarboxylate, fully stir and react. After the reaction is completed, carry out purification to obtain a yellow oily substance;
[0009] S2. Mix the palladium-based catalyst, phosphine ligand and organometallic catalyst, then add the nitro compound, base, water and the organic solution of the yellow oily substance obtained in step S1, mix and stir, and heat to obtain a mixed solution. Add an organic acid and paraformaldehyde to the mixed solution for reaction. After the reaction is completed, perform purification to obtain the tetracyclic lactam compound.
[0010]
[0011] In the prior art, the synthesis of tetracyclic lactam compounds usually requires relatively cumbersome reaction steps and is not suitable for the large-scale production and application of such compounds. In the present invention, 2-iodo-6-methoxyphenol represented by formula (III) is used as a reaction substrate, and the tetracyclic lactam compound can be prepared only through two-step reactions. The preparation process is simple, and the yield of the obtained tetracyclic lactam compound is relatively high.
[0012] As a preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, the phosphine ligand includes triphenylphosphine (PPh 3 ), diphenyl-1-pyrenephosphine (dppp), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP), n-butyldi(1-adamantyl)phosphine (BuPAd 2 ), and bis(2-diphenylphosphinophenyl)ether (DPEPhos).
[0013] As a more preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, the phosphine ligand is PPh 3 . The inventor has found through a large number of experiments that by using the above phosphine ligand, the yield of the finally obtained tetracyclic lactam compound can be higher.
[0014] As a preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, in step S2, the palladium-based catalyst includes palladium dichloride (PdCl 2 ), palladium acetate (Pd(OAc) 2 ), palladium trifluoroacetate (Pd(TFA) 2 ), bis(acetonitrile)palladium dichloride (Pd(CH 3 CN) 2 Cl 2 ), and tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ).
[0015] As a more preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, the palladium-based catalyst is PdCl 2 . The inventor has found through a large number of experiments that by using the above palladium-based catalyst, the yield of the finally obtained tetracyclic lactam compound can be higher.
[0016] As a preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, in the step S1, the compound of the structural formula (Ⅲ) is 2-iodo-6-methoxyphenol.
[0017] As a more preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, the preparation method of the 2-iodo-6-methoxyphenol is a conventional preparation method, which specifically includes the following steps:
[0018] S1. Dissolve 2-methoxyphenol in anhydrous dichloromethane under anaerobic conditions, then add chloromethyl methyl ether and N,N-diisopropylethylamine, stir at room temperature for 8-10 h, and separate after the reaction is completed to obtain the compound of the structural formula (Ⅳ);
[0019] S2. Drop n-butyllithium into the organic solution of the compound of the structural formula (Ⅳ) described in step S1 under anaerobic conditions, then add the organic solution of iodine, and separate after the reaction is completed to obtain the compound of the structural formula (Ⅴ);
[0020] S3. Dissolve the compound of the structural formula (Ⅴ) described in step S2 in an organic solvent, then add hydrochloric acid, mix and stir, and separate after the reaction is completed to obtain the compound of the structural formula (Ⅲ);
[0021]
[0022] As a preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, in the step S2, the nitro compound is nitromethane.
[0023] As a more preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, at least one of the following (Ⅰ)-(Ⅲ) is adopted:
[0024] (Ⅰ) In the step S2, the organometallic catalyst is molybdenum hexacarbonyl;
[0025] (Ⅱ) In the step S2, the base is diisopropylethylamine;
[0026] (Ⅲ) In the step S2, the organic acid is trifluoroacetic acid.
[0027] As a preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, the step S1 is specifically: mix the compound of the structural formula (Ⅱ), the compound of the structural formula (Ⅲ) and the phosphine ligand in an organic solvent under anaerobic conditions, drop diisopropyl azodicarboxylate at -20 to -22 °C, and then stir at room temperature overnight, and purify after the reaction is completed to obtain a yellow oily substance;
[0028] As a preferred embodiment of the preparation method of the tetracyclic lactam compound of the present invention, the step S2 is specifically as follows: Mix a palladium-based catalyst, a phosphine ligand, and an organometallic catalyst in a container. Under the vacuum condition of the container, add a nitro compound, a base, water, and an organic solution of the yellow oily substance obtained in step S1. After sealing the container, mix and stir and heat to obtain a mixed solution. After cooling to room temperature, release carbon monoxide in the container, filter, and then add an organic acid and paraformaldehyde to the filtrate. After the reaction is completed, perform purification to obtain the tetracyclic lactam compound.
[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0030] By using 2-iodo-6-methoxyphenol as a reaction substrate, the present invention can successfully prepare a tetracyclic lactam compound only through two-step reactions. The preparation process of the present invention is simple, and the yield of the obtained tetracyclic lactam compound is relatively high. At the same time, the preparation raw materials adopted by the present invention are low in price, simple to obtain, and suitable for large-scale production of tetracyclic lactam compounds. Description of the Drawings
[0031] Figure 1 It is the synthesis reaction formula of the tetracyclic lactam compound described in the present invention;
[0032] Figure 2 It is the nuclear magnetic hydrogen spectrum of the tetracyclic lactam compound described by formula (I) of the present invention;
[0033] Figure 3 It is the nuclear magnetic carbon spectrum of the tetracyclic lactam compound described by formula (I) of the present invention. Detailed Embodiments
[0034] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.
[0035] The reagents, methods, and equipment adopted in the present invention are all conventional reagents, methods, and equipment in the technical field, unless otherwise specified.
[0036] Example 1
[0037] An embodiment of the preparation method of the tetracyclic lactam compound described in the present invention. The preparation method of the tetracyclic lactam compound in this embodiment includes the following steps:
[0038] S1. Dissolve 14.53 mmol of the compound of structural formula (II), 13.21 mmol of the compound of structural formula (III), and 13.87 mmol of triphenylphosphine in 27 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere. Cool the reaction system to -20 °C, slowly add 13.87 mmol of diisopropyl azodicarboxylate dropwise. After the addition is complete, transfer the reaction system to room temperature, stir overnight, then carry out concentration under reduced pressure, and purify by silica gel column chromatography (the packing phase is petroleum ether:ethyl acetate = 20:1) to obtain a yellow oil.
[0039] S2. Add 0.01 mmol of palladium dichloride, 0.02 mmol of triphenylphosphine, and 0.6 mmol of hexacarbonylmolybdenum to a 15 mL pressure-resistant tube. After evacuating for 10 min, repeat filling with N 2 3 times. Subsequently, add 0.6 mmol of nitromethane, 0.3 mmol of diisopropylethylamine, 0.3 mmol of water, and 2 mL of a THF solution of an organic solution of the yellow oily substance obtained in step S1 (0.2 mmol). Then seal the pressure-resistant tube, place it on a heating module preheated to 120 °C, stir for 20 h to obtain a mixed solution. Cool the obtained mixed solution to room temperature, filter after releasing carbon monoxide, concentrate under reduced pressure, and add 0.6 mL of anhydrous dichloromethane, 0.2 mmol of paraformaldehyde, and 0.18 mL of trifluoroacetic acid to the mixed solution under a nitrogen atmosphere. Add an organic acid and paraformaldehyde to the mixed solution, stir and react at room temperature for 3.5 h, add 2 mL of saturated sodium bicarbonate solution to quench the reaction. The aqueous phase obtained is extracted with ethyl acetate, the organic phase is washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (the packing phase is petroleum ether:ethyl acetate = 1:3) to obtain the tetracyclic lactam compound of structural formula (I);
[0040]
[0041] In this example, the preparation method of the compound of structural formula (III) includes the following steps:
[0042] S1. Dissolve 50.0 mmol of 2-methoxyphenol in 125 mL of anhydrous dichloromethane under nitrogen protection. Cool the reaction system to 0 °C, then add 250.0 mmol of chloromethyl methyl ether and 250.0 mmol of N,N-diisopropylethylamine. After stirring at room temperature for 8 - 10 h, cool the reaction system to 0 °C again, add 120 mL of saturated sodium bicarbonate solution to quench the reaction. The aqueous phase obtained is extracted with ethyl acetate, the organic phase is washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (the packing phase is petroleum ether:ethyl acetate = 25:1) to obtain the compound of structural formula (IV);
[0043] S2. Under nitrogen protection, dissolve 48.81 mmol of the compound of structural formula (IV) in 49 mL of anhydrous tetrahydrofuran. Cool the reaction system to -45 °C, and dropwise add 53.69 mmol of n-butyllithium with a molar concentration of 2.5 M. Stir at the same temperature for 1.5 h. Then add 27.0 mL of a tetrahydrofuran solution of 53.69 mmol of iodine. Warm the reaction system to room temperature and stir for 16 h. Add 50.0 mL of saturated sodium thiosulfate solution to quench the reaction. Extract the aqueous phase with ethyl acetate. Wash the organic phase with saturated brine, then dry it over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by silica gel column chromatography (the packing phase is petroleum ether:ethyl acetate = 20:1) to obtain the compound of structural formula (V);
[0044] S3. Under an air atmosphere, dissolve 29.95 mmol of the compound of structural formula (V) described in step S2 in 150 mL of methanol solution. Then add 50 mL of hydrochloric acid, mix and stir. After the reaction is completed, concentrate under reduced pressure, and separate by silica gel column chromatography (the packing phase is petroleum ether:ethyl acetate = 10:1) to obtain the compound of structural formula (V);
[0045]
[0046] The yield of the tetracyclic lactam compound (I) in this example is: 87%, and the structural characterization is as Figure 2 、 3 shown. The structural characterization data are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 6.74 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.84 (t, J = 3.1 Hz, 1H), 4.47–4.38 (m, 2H), 3.86 (s, 3H), 3.08–2.98 (m, 5H), 2.86 (d, J = 13.8 Hz, 1H), 2.73 (dd, J = 17.6, 3.0 Hz, 1H), 2.43–2.35 (m, 1H), 2.33–2.25 (m, 1H), 2.05–2.00 (m, 2H).
[0047] 13 C NMR (126 MHz, CDCl 3 ) δ 207.4, 171.4, 146.8, 144.5, 132.4, 124.9, 120.0, 112.2, 88.4, 56.2, 52.1, 43.6, 42.2, 39.4, 36.2, 35.8, 32.7.
[0048] Example 2
[0049] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: in step S2, the palladium-based catalyst is Pd(OAc) 2 , and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 56%.
[0050] Example 3
[0051] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: in step S2, the palladium-based catalyst is Pd(TFA) 2 , and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 73%.
[0052] Example 4
[0053] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: in step S2, the palladium-based catalyst is Pd(CH 3 CN) 2 Cl 2 , and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 62%.
[0054] Example 5
[0055] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: in step S2, the palladium-based catalyst is Pd(PPh 3 ) 4 , and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 69%.
[0056] Example 6
[0057] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: the phosphine ligand is dppp, and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 55%.
[0058] Example 7
[0059] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: the phosphine ligand is BINAP, and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 77%.
[0060] Example 8
[0061] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: the phosphine ligand is BuPAd 2 , and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 75%.
[0062] Example 9
[0063] The difference between the preparation method of the tetracyclic lactam compound in this example and that in Example 1 is only that: the phosphine ligand is DPEPho, and the remaining steps are the same as those in Example 1; the yield of the tetracyclic lactam compound (I) in this example is: 70%.
[0064] The present invention can successfully prepare tetracyclic lactam compounds by only two-step reactions using 2-iodo-6-methoxyphenol as the reaction substrate. The preparation process of the present invention is simple, and the yield of the obtained tetracyclic lactam compounds is relatively high; at the same time, the raw materials used in the present invention are inexpensive, simple to obtain, and suitable for large-scale production of tetracyclic lactam compounds.
[0065] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.
Claims
1. A preparation method of a tetracyclic lactam compound, characterized in that, the structural formula of the tetracyclic lactam compound is shown as formula (Ⅰ) below, and the method comprises the following steps: S1. Mix the compound of structural formula (Ⅱ), the compound of structural formula (Ⅲ) and a phosphine ligand in an organic solvent, then add diisopropyl azodicarboxylate, stir the reaction fully, and after the reaction is completed, carry out purification to obtain a yellow oily substance; S2. Mix a palladium-based catalyst, a phosphine ligand and an organometallic catalyst, then add a nitro compound, a base, water and an organic solution of the yellow oily substance obtained in step S1, mix and stir and heat to obtain a mixed solution, add an organic acid and paraformaldehyde to the mixed solution for reaction, and after the reaction is completed, carry out purification to obtain the tetracyclic lactam compound; the phosphine ligand is selected from triphenylphosphine, diphenyl-1-pyrenephosphine, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), n-butyldi(1-adamantyl)phosphine and bis(2-diphenylphosphinophenyl)ether; the nitro compound is nitromethane; the organometallic catalyst is molybdenum hexacarbonyl.
2. The preparation method of the tetracyclic lactam compound according to claim 1, characterized in that, the phosphine ligand is triphenylphosphine.
3. The preparation method of the tetracyclic lactam compound according to claim 1, characterized in that, in step S2, the palladium-based catalyst is selected from palladium dichloride, palladium acetate, palladium trifluoroacetate, bis(acetonitrile)palladium dichloride and tetrakis(triphenylphosphine)palladium.
4. The preparation method of the tetracyclic lactam compound according to claim 1, characterized in that, in step S2, the palladium-based catalyst is palladium dichloride.
5. The preparation method of the tetracyclic lactam compound according to claim 1, characterized in that, at least one of the following (ⅠI) and (Ⅲ) is adopted: (Ⅱ) In step S2, the base is diisopropylethylamine; (Ⅲ) In step S2, the organic acid is trifluoroacetic acid.