Synthetic method of ethynyl benzocycloalkyl alcohol derivative
By reacting benzocycloalkyl ketones with acetylene donors in the presence of organic solvents and catalysts, the problem of low yield of acetylene-based benzocycloalkyl alcohol derivatives has been solved, realizing a high-yield synthesis method suitable for industrial applications.
Patent Information
- Application Number
- CN202511288066.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-10
- Publication Date
- 2025-12-16
AI Technical Summary
Existing methods for synthesizing ethynylbenzocycloalkyl alcohol derivatives have low yields and are not suitable for industrial production.
In the presence of an organic solvent and a catalyst, the benzocycloalkyl ketone derivative shown in Formula I is reacted with an acetylenic donor. The acetylenic lithium ethylenediamine complex and diethylaluminum bromide are used as catalysts, and the reaction conditions, such as an ice bath and a nitrogen atmosphere, are controlled to prepare the acetylenic benzocycloalkyl alcohol derivative.
The synthesis yield of acetylene-based benzocycloalkyl alcohol derivatives is improved, the steps are simple, and it is suitable for industrial production.
Smart Images
Figure CN121135564A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of an ethynyl benzocycloalkyl alcohol derivative. BACKGROUND
[0002] The ethynyl benzocycloalkyl alcohol derivative is an important organic synthesis intermediate, and can be used in pharmaceutical chemistry, for example, as an anti-tumor drug skeleton, as disclosed in Access to spirocyclic vinyl sulfones via radical cyclization and functional group migration, Chemical Sicence (2025), 16 (22), 9715-9719, as follows:
[0003]
[0004] The compound 5 can be used as a precursor of an anti-tumor drug.
[0005] Currently, the synthesis method of the ethynyl benzocycloalkyl alcohol derivative mainly uses cerium acetylide chloride, ethynyl lithium or ethynyl magnesium bromide as an ethynyl donor to react with a benzocycloalkyl ketone to prepare. However, these methods have the problem of low yield, and are not suitable for industrial production. SUMMARY
[0006] In view of this, the technical problem to be solved by the application is to provide a synthesis method of an ethynyl benzocycloalkyl alcohol derivative with high yield.
[0007] To achieve the above object, the technical scheme adopted by the application is:
[0008] A synthesis method of an ethynyl benzocycloalkyl alcohol derivative, comprising reacting a benzocycloalkyl ketone derivative shown in formula I with an ethynyl donor in the presence of an organic solvent and a catalyst to obtain an ethynyl benzocycloalkyl alcohol derivative shown in formula II.
[0009] The structural formula of the benzocycloalkyl ketone derivative shown in formula I is R1 and R2 are connected together to form a ketone group, and R3 and R4 are independently selected from H; or R1 and R2 are independently selected from H, and R3 and R4 are connected together to form a ketone group.
[0010] The structural formula of the ethynyl benzocycloalkyl alcohol derivative shown in formula II is R5 is OH, R6 is an ethynyl group, and R7 and R8 are independently selected from H; or R5 and R6 are independently selected from H, R7 is OH, and R8 is an ethynyl group.
[0011] In Formula I and Formula II, n is 1 or 2, and X is H, halogen, C1-C6 alkyl, or C1-C3 alkoxy.
[0012] The catalyst is an organometal halide.
[0013] In this invention, the ethynyl benzocycloalkyl alcohol derivative shown in Formula II is prepared by reacting the benzocycloalkyl ketone derivative shown in Formula I with an ethynyl donor. When R1 and R2 are linked together to form a ketone group, and R3 and R4 are each independently selected from H, R5 is OH, R6 is ethynyl, and R7 and R8 are each independently selected from H; when R1 and R2 are each independently selected from H, and R3 and R4 are linked together to form a ketone group, R5 and R6 are each independently selected from H, R7 is OH, and R8 is ethynyl.
[0014] In the above-described method for synthesizing ethynylbenzocycloalkyl alcohol derivatives, optionally, the halogen is selected from fluorine, chlorine, bromine, and iodine; further, the halogen is selected from fluorine, chlorine, and bromine.
[0015] In the above-described method for synthesizing ethynylbenzocycloalkyl alcohol derivatives, optionally, the alkyl groups of C1-C6 are selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl; and the alkoxy groups of C1-C3 are selected from methoxy and ethoxy.
[0016] In the above-described method for synthesizing ethynylbenzocycloalkyl alcohol derivatives, X may optionally be H.
[0017] In the above-described method for synthesizing acetylenyl benzocycloalkyl alcohol derivatives, optionally, the acetylenyl donor is one or a combination of several of lithium acetylenide ethylenediamine complex, lithium acetylenide, and magnesium acetylenide bromide.
[0018] In the above-described method for synthesizing ethynylbenzocycloalkyl alcohol derivatives, the organic solvent may optionally be one or a combination of diethyl ether, tetrahydrofuran, ethanol, and dioxane.
[0019] When the acetylene donor is a lithium ethylenediamine complex, the catalyst is diethylaluminum bromide, and the organic solvent is diethyl ether, it helps to obtain a higher yield of the acetylene benzocycloalkyl alcohol derivative.
[0020] In the above-described method for synthesizing ethynylbenzocycloalkyl alcohol derivatives, the reaction may optionally be carried out under ice bath conditions.
[0021] In the above-described method for synthesizing ethynylbenzocycloalkyl alcohol derivatives, the reaction may optionally be carried out under a nitrogen or inert gas atmosphere.
[0022] In the above-described method for synthesizing acetylenyl benzocycloalkyl alcohol derivatives, optionally, the molar ratio of the benzocycloalkyl ketone derivative represented by Formula I to the lithium ethylenediamine complex is 1:1 to 1.5.
[0023] In the above-described method for synthesizing ethynylbenzylcycloalkyl alcohol derivatives, optionally, the molar ratio of the benzocycloalkyl ketone derivative shown in Formula I to the catalyst is 1:0.05 to 0.12.
[0024] Optionally, the specific implementation of the synthesis method includes adding the benzocycloalkyl ketone derivative of Formula I, an ethynyl donor, a catalyst and an organic solvent to a reactor under ice bath conditions, reacting for 6-10 hours under a nitrogen or inert gas atmosphere, and then post-treating the reaction solution to obtain the ethynylbenzocycloalkyl alcohol derivative of Formula II.
[0025] Optionally, the post-treatment includes heating the reaction solution to room temperature, adjusting the pH to acidic, and then sequentially performing extraction, washing with water, drying and evaporation, column chromatography purification, and evaporation to obtain the ethynylbenzocycloalkyl alcohol derivative represented by Formula II.
[0026] Optionally, the synthesis method further includes the step of adding an organic solvent during the reaction.
[0027] In this invention, room temperature refers to 20–25°C.
[0028] In the above-described method for synthesizing ethynylbenzocycloalkyl alcohol derivatives, optionally, the pH value is adjusted to 5-6 using hydrochloric acid; the extraction is performed using ethyl acetate; and the drying is performed using anhydrous Na2SO4.
[0029] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:
[0030] The synthesis method of this invention involves reacting an acetylene donor with a benzocycloalkyl ketone derivative in the presence of a catalyst and an organic solvent to obtain an acetylene benzocycloalkyl alcohol derivative. This method features high yield, simple steps, and mild reaction, making it suitable for industrial production. Attached Figure Description
[0031] Figure 1 The NMR spectrum of 1-ethynyl-2,3-dihydro-1H-inden-1-ol is shown in Example 1. Detailed Implementation
[0032] The technical solution of the present invention will be further described in detail below with reference to specific embodiments and comparative examples.
[0033] The raw materials and ingredients used in the following examples and comparative examples were all commercially available.
[0034] Example 1
[0035] This embodiment provides a method for synthesizing 1-ethynyl-2,3-dihydro-1H-inden-1-ol. The synthetic route and method are as follows:
[0036]
[0037] Under ice bath and nitrogen atmosphere, 1-dihydroindanone (1.32 g, 10 mmol), lithium ethynylene ethylenediamine complex (1.08 g, 12 mmol), and diethyl ether (15 mL) were added to a three-necked flask. After stirring for 10 minutes, diethylaluminum bromide (0.17 g, 1 mmol) was added, followed by 5 mL of diethyl ether. The reaction was maintained at 0 °C for 8 hours. After the reaction was completed, the temperature was raised to room temperature, and the pH of the reaction solution was adjusted to 5-6 by adding 2N HCl dropwise. The solution was then extracted with ethyl acetate (3 × 10 mL), washed several times with water, and the organic phases were combined, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was purified by column chromatography (using ethyl acetate / petroleum ether as the eluent (V / V = 1 / 10)) and evaporated to dryness to give 1-ethynyl-2,3-dihydro-1H-indan-1-ol (1.57 g, 99.5%).
[0038] 1 H NMR (400MHz, CDCl3) δ7.30(m,4H),5.21(s,1H),3.21(ddtd,2H),2.53(m,2H),2.49(s,1H).
[0039] The NMR spectrum of 1-ethynyl-2,3-dihydro-1H-inden-1-ol is shown below. Figure 1 As shown.
[0040] Example 2
[0041] This embodiment provides a method for synthesizing 2-ethynyl-2,3-dihydro-1H-inden-2-ol.
[0042]
[0043] The synthesis method in this example is the same as that in Example 1, except that 1,3-dihydro-2H-indanone is used instead of 1-dihydroindanone, and the yield of the final product 2-ethynyl-2,3-dihydro-1H-indanone is 99.7%.
[0044] 1 H NMR (400MHz, CDCl3) δ7.32(m,4H),4.48(s,1H),3.14(ddd,4H),2.47(s,1H).
[0045] Example 3
[0046] This embodiment provides a method for synthesizing 1-ethynyl-1,2,3,4-tetrahydronaphthalene-1-ol.
[0047]
[0048] The synthesis method in this example is the same as that in Example 1, except that 3,4-dihydronaphth-1(2H)-one is used instead of 1-dihydroindanone, and the yield of the final product 1-ethynyl-1,2,3,4-tetrahydronaphth-1-ol is 99.3%.
[0049] 1 H NMR (400MHz, CDCl3) δ7.36(dd,1H),7.23(m,2H),7.04(ddt,1H),4.79(s,1H),2.80(td,2H),2.49(s,1H),2.15(m,2H),1.96(m,2H).
[0050] Example 4
[0051] This embodiment provides a method for synthesizing 2-ethynyl-1,2,3,4-tetrahydronaphthalene-2-ol.
[0052]
[0053] The synthesis method in this example is the same as that in Example 1, except that 3,4-dihydronaphth-2(1H)-one is used instead of 1-dihydroindanone, and the yield of the final product 2-ethynyl-1,2,3,4-tetrahydronaphth-2-ol is 99.5%.
[0054] 1 H NMR (400MHz, CDCl3) δ7.20(m,2H),7.11(ddt,1H),6.98(ddt,1H),4.69(s,1H),3.01(m,2H),2.82(m,2H),2.43(s,1H),2.03(m,2H).
[0055] Example 5
[0056] This example provides a method for synthesizing 1-ethynyl-2,3-dihydro-1H-inden-1-ol, which is basically the same as the steps in Example 1, except that tetrahydrofuran is used instead of diethyl ether. As a result, the yield of 1-ethynyl-2,3-dihydro-1H-inden-1-ol is 33.6%.
[0057] Example 6
[0058] This example provides a method for synthesizing 1-ethynyl-2,3-dihydro-1H-inden-1-ol, which is basically the same as the steps in Example 1, except that ethynyl lithium is used instead of the ethynyl lithium ethylenediamine complex, resulting in a yield of 60.1% for 1-ethynyl-2,3-dihydro-1H-inden-1-ol.
[0059] Example 7
[0060] This example provides a method for synthesizing 1-ethynyl-2,3-dihydro-1H-inden-1-ol, which is basically the same as the steps in Example 1, except that magnesium acetylenide bromide is used instead of lithium acetylenide ethylenediamine complex. As a result, the yield of 1-ethynyl-2,3-dihydro-1H-inden-1-ol is 63.4%.
[0061] Comparative Example 1
[0062] This example provides a method for synthesizing 1-ethynyl-2,3-dihydro-1H-inden-1-ol, which is basically the same as the steps in Example 1, except that ammonium chloride is used instead of diethylaluminum bromide, and no reaction occurs.
[0063] The above embodiments are only used to illustrate the embodiments of the present invention, and are not intended to limit the embodiments of the present invention. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the embodiments of the present invention. Therefore, all equivalent technical solutions also fall within the scope of the embodiments of the present invention, and the patent protection scope of the embodiments of the present invention should be defined by the claims.
Claims
1. A method for synthesizing an ethynylbenzocycloalkyl alcohol derivative, characterized in that: The synthetic method includes reacting the benzocycloalkyl ketone derivative of Formula I with an acetylenic donor in the presence of an organic solvent and a catalyst to obtain the acetylenic benzocycloalkyl alcohol derivative of Formula II. The structural formula of the benzocycloalkyl ketone derivative shown in Formula I is as follows: R1 and R2 are linked together to form a ketone group, and R3 and R4 are each independently selected from H; or, R1 and R2 are each independently selected from H, and R3 and R4 are linked together to form a ketone group. The structural formula of the acetylene-benzocycloalkyl alcohol derivative shown in Formula II is: R5 is OH, R6 is ethynyl, and R7 and R8 are each independently selected from H; or, R5 and R6 are each independently selected from H, R7 is OH, and R8 is ethynyl. In Formula I and Formula II, n is 1 or 2, and X is H, halogen, C1-C6 alkyl, or C1-C3 alkoxy. The catalyst is an organometal halide.
2. The method for synthesizing ethynylbenzocycloalkyl alcohol derivatives according to claim 1, characterized in that: The halogen is selected from fluorine, chlorine, and bromine; the alkyl group of C1-C6 is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl; and the alkoxy group of C1-C3 is selected from methoxy and ethoxy.
3. The method for synthesizing acetylene-benzocycloalkyl alcohol derivatives according to claim 1, characterized in that: X is H.
4. The method for synthesizing ethynylbenzocycloalkyl alcohol derivatives according to claim 1, characterized in that, The acetylene-based donor is one or a combination of several of the following: lithium acetylene ethylenediamine complex, lithium acetylene, and magnesium acetylene bromide.
5. The method for synthesizing ethynylbenzocycloalkyl alcohol derivatives according to claim 4, characterized in that, The acetylene-based donor is a lithium ethylenediamine complex.
6. The method for synthesizing ethynylbenzocycloalkyl alcohol derivatives according to claim 1, characterized in that: The organic solvent is one or a combination of several of diethyl ether, tetrahydrofuran, ethanol, and dioxane.
7. The method for synthesizing ethynylbenzocycloalkyl alcohol derivatives according to claim 1, characterized in that: The reaction was carried out under ice bath conditions; And / or, the reaction is carried out under a nitrogen or inert gas atmosphere; and / or, The molar ratio of the benzocycloalkyl ketone derivative represented by Formula I to the lithium ethylenediamine complex is 1:1 to 1.5; and / or, The molar ratio of the benzocycloalkyl ketone derivative shown in Formula I to the catalyst is 1:0.05–0.12; and / or, The acetylene-based donor is lithium ethylenediamine complex, the catalyst is diethylaluminum bromide, and the organic solvent is diethyl ether.
8. The method for synthesizing the ethynylbenzocycloalkyl alcohol derivative according to any one of claims 1 to 7, characterized in that: The specific implementation of the synthesis method includes adding the benzocycloalkyl ketone derivative of Formula I, an ethynyl donor, a catalyst, and an organic solvent to a reactor under ice bath conditions, reacting for 6-10 hours under a nitrogen or inert gas atmosphere, and then post-treating the reaction solution to obtain the ethynylbenzocycloalkyl alcohol derivative of Formula II.
9. The method for synthesizing ethynylbenzocycloalkyl alcohol derivatives according to claim 8, characterized in that: The post-treatment includes heating the reaction solution to room temperature, adjusting the pH to acidic, and then sequentially performing extraction, washing with water, drying and evaporating, column chromatography purification, and evaporating again to obtain the ethynylbenzocycloalkyl alcohol derivative of Formula II; and / or, The synthesis method also includes the step of adding organic solvent during the reaction.
10. The method for synthesizing ethynylbenzocycloalkyl alcohol derivatives according to claim 9, characterized in that: The pH value is adjusted to 5-6 using hydrochloric acid; and / or the extraction is performed using ethyl acetate; and / or the drying is performed using anhydrous Na2SO4.