Synthesis method of benzocycloalkyl alcohol derivative

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthesis method of a benzocycloalkyl alcohol derivative, which comprises the following steps: taking a benzocycloalkyl ketone derivative # imgabs0 # as an initial raw material; in the presence of hypochlorous acid metal salt and an organic solvent, a reaction is carried out to generate a benzocycloalkyl carboxylic acid derivative # imgabs1 #, and then a reduction reaction is carried out to obtain a benzocycloalkyl alcohol derivative # imgabs2 #, wherein R1 is COCH3, R2 is COOH, and R3 is CH2OH. The synthesis method has the advantages of high yield, low synthesis cost and the like, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for synthesizing benzocycloalkyl alcohol derivatives. Background Art

[0002] Benzocycloalkyl alcohol derivatives are important intermediates in the field of organic synthesis and can be used to construct various organic compounds with specific structures and functions. By means of various chemical reactions such as esterification and etherification, different functional groups can be introduced, and then various organic products such as drugs, fragrances, and pesticides can be synthesized.

[0003] Currently, the main synthetic methods for such compounds are as follows:

[0004] Route 1:

[0005]

[0006] This route uses 2,3-dihydro-1H-indene-2-carbaldehyde as the starting material and reacts in the presence of ethanol and sodium borohydride to obtain (2,3-dihydro-1H-inden-2-yl)methanol. This route uses 2,3-dihydro-1H-indene-2-carbaldehyde as the starting material, which has a high raw material cost and is not easily available.

[0007] (2) Route 2:

[0008]

[0009] This route uses 2,3-dihydro-1H-indene-2-carboxylic acid as the starting material and reacts in the presence of lithium aluminum hydride and tetrahydrofuran to obtain (2,3-dihydro-1H-inden-2-yl)methanol. This route uses lithium aluminum hydride, which is highly dangerous and difficult to post-treat. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a method for synthesizing benzocycloalkyl alcohol derivatives with high yield, which is more suitable for industrial production.

[0011] To achieve the above object, the technical solution adopted by the present invention is:

[0012] A method for synthesizing benzocycloalkyl alcohol derivatives, comprising the following steps:

[0013] S1. Reacting a benzocycloalkyl ketone derivative represented by Formula I in the presence of a metal hypochlorite and an organic solvent to generate a benzocycloalkyl carboxylic acid derivative represented by Formula II;

[0014] S2. Performing a reduction reaction on the benzocycloalkyl carboxylic acid derivative represented by Formula II to generate a benzocycloalkyl alcohol derivative represented by Formula III;

[0015] The structural formula of the benzocycloalkyl ketone derivative shown in Formula I is as follows: Wherein, R1 is COCH3;

[0016] The structural formula of the benzocycloalkyl carboxylic acid derivative shown in Formula II is as follows: Wherein, R2 is COOH;

[0017] The structural formula of the benzocycloalkyl alcohol derivative shown in Formula III is as follows: Wherein, R3 is CH2OH;

[0018] Wherein, in Formula I, Formula II, and Formula III, a is 1, 2, 3, or 4.

[0019] Optionally, a is 2 or 3.

[0020] Optionally, the benzocycloalkyl ketone derivative shown in Formula I is selected from the following compounds:

[0021]

[0022] Optionally, the benzocycloalkyl alcohol derivative shown in Formula III is selected from the following compounds:

[0023]

[0024] Optionally, in step S1, the metal hypochlorite is selected from one or a combination of several of sodium hypochlorite, potassium hypochlorite, and calcium hypochlorite.

[0025] Optionally, the molar ratio of the metal hypochlorite to the compound shown in Formula I is greater than or equal to 1, further 1 - 10:1, and even further 4 - 10:1.

[0026] Optionally, the metal hypochlorite is added in the form of an aqueous solution.

[0027] Optionally, the metal hypochlorite is added in multiple portions.

[0028] Optionally, the concentration of the solution of the metal hypochlorite is 1 - 3 M.

[0029] Optionally, in step S1, the reaction is carried out at 50 - 90 °C, and the reaction time is 8 - 18 h; further, the reaction is carried out at 60 - 80 °C, and the reaction time is 10 - 16 h.

[0030] Further optionally, in the step S1, the benzocycloalkyl ketone derivative shown in the formula I, an organic solvent, and a part of the metal hypochlorite are mixed and reacted at 60-80 °C for 4-6 h, and then the remaining metal hypochlorite is added and reacted for another 6-10 h, wherein the amount of the part of the metal hypochlorite accounts for 40-60% by weight of the total amount of the metal hypochlorite.

[0031] Optionally, in the step S1, the organic solvent is one or a combination of several of 1,4-dioxane and N,N-dimethylformamide.

[0032] Optionally, in the step S1, after the reaction is completed, impurities are removed from the reaction solution, the pH is adjusted to less than 6, extraction is performed, and recrystallization is carried out to obtain the benzocycloalkyl carboxylic acid derivative shown in the formula II.

[0033] Further, in the step S1, the pH is adjusted to 2-3.

[0034] Optionally, in the step S2, the reduction reaction is carried out in the presence of an organic solvent, a metal borohydride, and boron trifluoride ether complex.

[0035] Optionally, in the step S2, the metal borohydride is one or a combination of several of sodium borohydride, potassium borohydride, and lithium borohydride.

[0036] Optionally, in the step S2, the boron trifluoride ether complex is one or a combination of several of boron trifluoride-dimethyl ether complex and boron trifluoride diethyl ether complex.

[0037] Optionally, in the step S2, under an ice bath condition, the metal borohydride and the boron trifluoride ether complex are dissolved in an organic solvent, and then the benzocycloalkyl carboxylic acid derivative shown in the formula II is added. After the addition is completed, the temperature is raised to 15-35 °C and reacted for 10-14 h.

[0038] Optionally, in the step S2, it is controlled that the benzocycloalkyl carboxylic acid derivative shown in the formula II is added completely within 20-40 min, and the benzocycloalkyl carboxylic acid derivative shown in the formula II is fed under an ice bath condition to prevent the temperature from rising too fast during the reaction, resulting in incomplete reaction and difficult temperature control.

[0039] Optionally, in the step S2, the organic solvent is one or a combination of several of tetrahydrofuran and N,N-dimethylformamide.

[0040] Optionally, in the step S2, the feeding mass ratio of the metal borohydride to the boron trifluoride ether complex is 1:3-5.

[0041] Optionally, in the step S2, after the reduction reaction is completed, the organic solvent is rotary evaporated, impurities are extracted, the pH is adjusted to be greater than 7.5, extraction is carried out, drying is performed, and rotary evaporation is carried out to obtain the benzo-cycloalkyl alcohol derivative shown in the formula III.

[0042] Further, in the step S2, the pH is adjusted to 8-10.

[0043] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0044] The synthesis method of the present invention uses a benzo-cycloalkyl ketone derivative as a starting material, reacts in the presence of a metal hypochlorite and an organic solvent to generate a benzo-cycloalkyl carboxylic acid derivative, and then obtains a benzo-cycloalkyl alcohol derivative through a reduction reaction, and has the advantages of high yield, low synthesis cost, etc., and is suitable for industrial production. Description of the Drawings

[0045] Figure 1 It is the nuclear magnetic spectrum of 2,3-dihydro-1H-indene-5-carboxylic acid in Example 1.

[0046] Figure 2 It is the nuclear magnetic spectrum of the product (2,3-dihydro-1H-indene-5-yl) methanol in Example 1. Detailed Description of the Invention

[0047] The technical solution of the present invention will be further described in detail below with specific examples and comparative examples.

[0048] The raw materials and ingredients used in the following examples and comparative examples are all obtained commercially.

[0049] Example 1

[0050] The present example provides a synthesis method of (2,3-dihydro-1H-indene-5-yl) methanol, and the method route and method are as follows:

[0051]

[0052] Step S1: Add 1-(2,3-dihydro-1H-indene-5-yl)ethan-1-one (1 g, 6.25 mmol), 5 mL of 1,4-dioxane, and 10 mL of sodium hypochlorite aqueous solution (concentration 2 M) into a three-necked flask, heat up to 70 °C and stir for 5 hours, then add another 10 mL of sodium hypochlorite aqueous solution and stir for 8 hours until the reaction is completed. After impurity extraction with methyl tert-butyl ether (3×15 mL), the aqueous phase is adjusted to pH = 2-3 with 4 M hydrochloric acid, and the product is extracted with ethyl acetate (3×10 mL), and recrystallization is carried out to precipitate a solid product of 2,3-dihydro-1H-indene-5-carboxylic acid (1.0 g, 98.8%).

[0053] The NMR spectrum of 2,3-dihydro-1H-indene-5-carboxylic acid is as follows Figure 1 as shown

[0054] 1 H NMR(400MHz,CDCl3)δ10.60(s,1H),7.94(m,2H),7.31(d,1H),2.97(t,4H),2.13(p,2H).

[0055] Step S2: Under ice bath conditions, add 0.2 g of sodium borohydride and 0.8 g of boron trifluoride-dimethyl ether complex to a three-necked flask, dissolve them in 15 mL of tetrahydrofuran solution, control the ice bath temperature, and add 2,3-dihydro-1H-indene-5-carboxylic acid (0.6 g, 3.7 mmol) in portions. The feeding process is completed within 30 minutes, and then the temperature is gradually raised to room temperature and stirred for reaction for 12 hours until the reaction ends. Rotavaporize the tetrahydrofuran solvent, extract impurities four times with ethyl acetate (4×30 mL), adjust the pH of the aqueous phase to 9.5 with sodium hydroxide solution, then extract the organic phase with dichloromethane, dry over anhydrous Na2SO4, and rotavaporize to obtain (2,3-dihydro-1H-inden-5-yl)methanol (0.55 g, 100%).

[0056] (2,3-Dihydro-1H-inden-5-yl)methanol NMR spectrum is as follows Figure 2 as shown

[0057] 1 H NMR(400MHz,CDCl3)δ7.18(m,3H),4.64(d,2H),2.90(td,4H),2.08(p,2H),1.63(t,1H).

[0058] Example 2

[0059] This example provides a method for synthesizing (2,3-dihydro-1H-inden-4-yl)methanol

[0060]

[0061] Step S1: Add (2,3-dihydro-1H-inden-4-yl)ethan-1-one (6.25 mmol), 5 mL of 1,4-dioxane, and 10 mL of sodium hypochlorite aqueous solution (concentration 2 M) to a three-necked flask, heat to 70 °C and stir for reaction for 5 hours, then add another 10 mL of sodium hypochlorite aqueous solution and stir for reaction for 8 hours until the reaction ends. After extracting impurities with methyl tert-butyl ether (3×15 mL), adjust the pH of the aqueous phase to 2 - 3 with 4 M hydrochloric acid, extract the product with ethyl acetate (3×10 mL), and perform recrystallization to precipitate the solid product 2,3-dihydro-1H-indene-4-carboxylic acid (99.0%).

[0062] Step S2: Under ice bath conditions, add 0.2 g of sodium borohydride and 0.8 g of boron trifluoride-dimethyl ether complex to a three-necked flask, dissolve them in 15 mL of tetrahydrofuran solution, control the ice bath temperature, and add 2,3-dihydro-1H-indene-4-carboxylic acid (3.7 mmol) in portions. The feeding process should be completed within 30 minutes. After the feeding is completed, gradually raise the temperature to room temperature and stir the reaction for 12 hours until the reaction ends. Rotavaporize the tetrahydrofuran solvent, extract impurities four times with ethyl acetate (4×30 mL), adjust the pH of the aqueous phase to 9.5 with sodium hydroxide solution, then extract the organic phase with dichloromethane, dry it over anhydrous Na2SO4, and rotavaporize to obtain (2,3-dihydro-1H-indene-4-yl)methanol (100%).

[0063] The NMR results are as follows:

[0064] 1 H NMR (400 MHz, CDCl3) δ 7.14 (m, 3H), 4.52 (m, 2H), 2.86 (td, 4H), 2.15 (p, 2H) 1.59 (t, 1H).

[0065] Example 3

[0066] This example provides a method for synthesizing 1-(5,6,7,8-tetrahydro-2-naphthalenyl)methanol

[0067]

[0068] Step S1: Add 1-(5,6,7,8-tetrahydro-2-naphthalenyl)ethanone (6.25 mmol), 5 mL of 1,4-dioxane, and 10 mL of sodium hypochlorite aqueous solution (concentration 2 M) to a three-necked flask. Heat to 70 °C and stir the reaction for 5 hours, then add another 10 mL of sodium hypochlorite aqueous solution and stir the reaction for 8 hours until the reaction ends. After extracting impurities with methyl tert-butyl ether (3×15 mL), adjust the pH of the aqueous phase to 2 - 3 with 4 M hydrochloric acid, extract the product with ethyl acetate (3×10 mL), and perform recrystallization to precipitate the solid product 5,6,7,8-tetrahydroxy-2-naphthoic acid (97.9%).

[0069] Step S2: Under ice bath conditions, add 0.2 g of sodium borohydride and 0.8 g of boron trifluoride - dimethyl ether complex to a three - necked flask, dissolve them in 15 mL of tetrahydrofuran solution. Control the ice bath temperature and add 5,6,7,8 - tetrahydroxy - 2 - naphthoic acid (3.7 mmol) in portions. The feeding process should be completed within 30 minutes. After the feeding is completed, gradually raise the temperature to room temperature and stir the reaction for 12 hours until the reaction ends. Rotavaporize the tetrahydrofuran solvent, extract impurities four times with ethyl acetate (4×30 mL), adjust the pH of the aqueous phase to 9.5 with sodium hydroxide solution, then extract the organic phase with dichloromethane, dry it with anhydrous Na2SO4, and rotavaporize to obtain 1 - (5,6,7,8 - tetrahydro - 2 - naphthyl) methanol (99.8%).

[0070] The NMR results are as follows:

[0071] 1 H NMR(400MHz,CDCl3)δ7.10(m,2H),6.98(h,1H),4.78(dt,2H),4.23(s,1H),2.77(dtd,4H),1.74(m,4H).

[0072] Example 4

[0073] This example provides a method for synthesizing 1 - (5,6,7,8 - tetrahydronaphthalen - 1 - yl) methanol

[0074]

[0075] Step S1: Add 1 - (5,6,7,8 - tetrahydronaphthalen - 1 - yl) ethanone (6.25 mmol), 5 mL of 1,4 - dioxane, and 10 mL of sodium hypochlorite aqueous solution (concentration 2 M) to a three - necked flask. Heat to 70 °C and stir the reaction for 5 hours, then add an additional 10 mL of sodium hypochlorite aqueous solution and stir the reaction for 8 hours until the reaction ends. After extracting impurities with methyl tert - butyl ether (3×15 mL), adjust the pH of the aqueous phase to 2 - 3 with 4 M hydrochloric acid, and extract the product with ethyl acetate (3×10 mL). Recrystallize to precipitate the solid product 5,6,7,8 - tetrahydroxynaphthalene - 1 - carboxylic acid (98.6%).

[0076] Step S2: Under ice bath conditions, add 0.2 g of sodium borohydride and 0.8 g of boron trifluoride-dimethyl ether complex to a three-necked flask, dissolve them in 15 mL of tetrahydrofuran solution, control the ice bath temperature, and add 5,6,7,8-tetrahydroxynaphthalene-1-carboxylic acid (3.7 mmol) in portions. The feeding process should be completed within 30 minutes. After the feeding is completed, gradually raise the temperature to room temperature and stir the reaction for 12 hours until the reaction ends. Rotavaporize the tetrahydrofuran solvent, extract impurities four times with ethyl acetate (4 × 30 mL), adjust the pH of the aqueous phase to 9.5 with sodium hydroxide solution, then extract the organic phase with dichloromethane, dry over anhydrous Na2SO4, and rotavaporize to obtain 1-(5,6,7,8-tetrahydronaphthalen-1-yl)methanol (99.9%).

[0077] The NMR results are as follows:

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.15 (m, 3H), 4.65 (t, 1H), 4.47 (dd, 2H), 2.81 (m, 4H), 1.73 (m, 4H).

[0079] Example 5

[0080] This example provides a method for synthesizing (2,3-dihydro-1H-inden-5-yl)methanol, which is basically the same as the steps in Example 1, except that: in step S1, N,N-dimethylformamide (DMF) is used to replace 1,4-dioxane. The total yield of (2,3-dihydro-1H-inden-5-yl)methanol finally obtained is 11.3%.

[0081] Example 6

[0082] This example provides a method for synthesizing (2,3-dihydro-1H-inden-5-yl)methanol, which is basically the same as the steps in Example 1, except that: in step S1, potassium hypochlorite is used to replace sodium hypochlorite. The total yield of (2,3-dihydro-1H-inden-5-yl)methanol finally obtained is 34%.

[0083] Comparative Example 1

[0084] This comparative example provides a method for synthesizing (2,3-dihydro-1H-inden-5-yl)methanol, which is basically the same as the steps in Example 1, except that: in step S1, tetrahydrofuran is used to replace 1,4-dioxane. No product spot was detected as a result.

[0085] Comparative Example 2

[0086] This comparative example provides a method for synthesizing (2,3-dihydro-1H-inden-5-yl)methanol, which is basically the same as the steps of Example 1, except that: in step S2, boron trifluoride methanol complex is used to replace boron trifluoride-dimethyl ether complex. No product spot was detected as a result.

[0087] Comparative Example 3

[0088] This comparative example provides a method for synthesizing (2,3-dihydro-1H-inden-5-yl)methanol, which is basically the same as the steps of Example 1, except that: the Lewis acid aluminum trichloride is used instead of sodium hypochlorite. No product spot was detected as a result.

[0089] The above embodiments are only used to illustrate the embodiments of the present invention, rather than to limit the embodiments of the present invention. Those of ordinary skill in the relevant technical fields can also 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 belong to the scope of the embodiments of the present invention. The patent protection scope of the embodiments of the present invention shall be defined by the claims.

Claims

1. A method for synthesizing a benzocycloalkyl alcohol derivative, characterized in that, The synthesis method includes the following steps: S1. React the benzocycloalkyl ketone derivative represented by Formula I in the presence of a metal hypochlorite and an organic solvent to generate the benzocycloalkyl carboxylic acid derivative represented by Formula II; S2. Perform a reduction reaction on the benzocycloalkyl carboxylic acid derivative represented by Formula II to generate the benzocycloalkyl alcohol derivative represented by Formula III; The structural formula of the benzocycloalkyl ketone derivative represented by Formula I is as follows: wherein, R1 is COCH3; The structural formula of the benzocycloalkyl carboxylic acid derivative shown in Formula II is as follows: wherein R2 is COOH; The structural formula of the benzocycloalkyl alcohol derivative represented by Formula III is as follows: wherein, R3 is CH2OH; Wherein, in Formula I, Formula II, and Formula III, a is 1, 2, 3, or 4.

2. The synthesis method of the benzocycloalkyl alcohol derivative according to claim 1, wherein The a is 2 or 3.

3. The synthesis method of the benzocycloalkyl alcohol derivative according to claim 1, wherein In the step S1, the metal hypochlorite is selected from one or a combination of several of sodium hypochlorite, potassium hypochlorite, and calcium hypochlorite.

4. The synthesis method of the benzo-cycloalkyl alcohol derivative according to claim 1 or 3, characterized in that, The metal hypochlorite is added in the form of an aqueous solution; and / or, In the step S1, the organic solvent is one or a combination of several of 1,4-dioxane and N,N-dimethylformamide; and / or, In the step S1, the reaction is carried out at 50-90 °C, and the reaction time is 8-18 h.

5. The method for synthesizing the benzocycloalkyl alcohol derivative according to claim 4, wherein The concentration of the metal hypochlorite solution is 1-3 M; and / or, In the step S1, mix the benzocycloalkyl ketone derivative represented by Formula I, the organic solvent, and a part of the metal hypochlorite, react at 60-80 °C for 4-6 h, then add the remaining metal hypochlorite, and react for another 6-10 h, wherein the amount of the part of the metal hypochlorite accounts for 40-60% by weight of the total amount of the metal hypochlorite.

6. The synthetic method of the benzo-cycloalkyl alcohol derivative according to claim 1, wherein, In the step S1, after the reaction is completed, perform impurity extraction on the reaction solution, adjust the pH to less than 6, extract, and recrystallize to obtain the benzocycloalkyl carboxylic acid derivative represented by Formula II.

7. The synthesis method of the benzocycloalkyl alcohol derivative according to claim 1, wherein In the step S2, the reduction reaction is carried out in the presence of an organic solvent, a metal borohydride, and a boron trifluoride ether complex.

8. The method for synthesizing a benzocycloalkyl alcohol derivative according to claim 7, characterized in that, In the step S2, the metal borohydride is one or a combination of several of sodium borohydride, potassium borohydride, and lithium borohydride; and / or, In the step S2, the boron trifluoride ether complex is one or a combination of several of boron trifluoride-dimethyl ether complex and boron trifluoride ethyl ether complex; and / or, In the step S2, the organic solvent is one or a combination of several of tetrahydrofuran and N,N-dimethylformamide.

9. The synthesis method of the benzocycloalkyl alcohol derivative according to claim 7, characterized in that, In the step S2, under an ice bath condition, dissolve the metal borohydride and the boron trifluoride ether complex in the organic solvent, then add the benzocycloalkyl carboxylic acid derivative represented by Formula II, and after the feeding is completed, raise the temperature to 15-35 °C and react for 10-14 h.

10. The method for synthesizing the benzocycloalkyl alcohol derivative according to claim 9, wherein In the step S2, control the feeding of the benzocycloalkyl carboxylic acid derivative represented by Formula II to be completed within 20-40 min; and / or, In the step S2, the feeding mass ratio of the metal borohydride to the boron trifluoride ether complex is 1:3-5; and / or, In the step S2, after the reduction reaction is completed, spin-dry the organic solvent, perform impurity extraction, adjust the pH to greater than 7.5, extract, dry, and spin-dry to obtain the benzocycloalkyl alcohol derivative represented by Formula III.

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