Preparation method of 2-naphthyl methanol

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of 2-naphthyl methanol. The invention provides a preparation method of 2-naphthyl methanol. The preparation method comprises the following steps: (1) converting 2-naphthoic acid into 2-naphthoyl halide under the action of a halogenating reagent; (2) the 2-naphthoyl halide reacts with ROH to be converted into 2-naphthoic acid ester, and R is alkyl; and (3) in the presence of an organic solvent, reacting the 2-naphthoic acid ester with sodium borohydride to prepare the 2-naphthyl methanol. According to the preparation method, the yield reaches 100%, the reaction conditions are safer and milder, and industrial application is more facilitated. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing 2-naphthalenemethanol. Background Art

[0002] 2-Naphthylmethanol is a chemical intermediate with a wide range of uses and is used in the synthesis and production of a large number of drugs and materials.

[0003] In the prior art, the most common method for preparing 2-naphthyl alcohol is to directly reduce 2-naphthoic acid. For example, Preparation of enzymes of substituted fluoromethylnaphthalenes (Dixon, Elisabeth A. et al., Canadian Journal of Chemistry, 1981, 59, 2629-2641) discloses a method of using LiAlH4 reduction with a yield of 65%. However, this method not only has a low yield, but also has a high activity of LiAlH4, which is very dangerous when used in large quantities in industry.

[0004] At the same time, there is a common knowledge document (Wen Ren, ed., Drug Synthesis Reactions (3rd Edition), Beijing: Chemical Industry Press, 2011) that the effect of using sodium borohydride alone on ester reduction is poor and usually cannot reduce carboxylic acids. If sodium borohydride is needed to reduce esters or carboxylic acids, Lewis acid needs to be added to improve the reaction efficiency.

[0005] Another method for preparing 2-naphthyl alcohol is disclosed in Reduction of Symmetric and Mixed Anhydrides of Carboxylic Acids by Sodium Borohydride with Dropwise Addition of Methanol (Synthesis, 1987, 7, 647-648), which uses 2-naphthyl carboxylic acid and anhydride compound 4i as intermediates, and then uses NaBH4 for reduction to obtain 2-naphthyl alcohol with a yield of 93%. However, the ethyl chloroformate used in the first step is a highly toxic reagent, and the experimental operation is too dangerous, especially for large-scale use in industry.

[0006]

[0007] Therefore, how to prepare 2-naphthalenemethanol efficiently, safely and conveniently remains a technical problem that researchers in this field need to solve urgently.

[0008] Instruction Manual

[0009] In order to overcome the technical problems of low yield and dangerous reagents in the prior art, a preparation method of 2-naphthalenemethanol is proposed. The preparation method can prepare 2-naphthalenemethanol with a yield of 100% under safe reaction conditions, which is conducive to industrial utilization.

[0010] The present invention provides a method for preparing 2-naphthalenemethanol, which comprises the following steps:

[0011] (1) 2-naphthoic acid is converted into 2-naphthoyl halide under the action of a halogenating agent;

[0012] (2) the 2-naphthoyl halide is reacted with ROH to be converted into 2-naphthoic acid ester, wherein R is an alkyl group;

[0013] (3) reacting the 2-naphthoic acid ester with sodium borohydride in the presence of an organic solvent to obtain 2-naphthyl alcohol;

[0014]

[0015] In one embodiment, the halogenating agent may be one or more of sulfoxide halide, phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, oxalyl chloride, and triphenylphosphine halide; preferably, the halogenating agent is thionyl chloride.

[0016] In one embodiment, R is C 1-6 Alkyl; preferably, R is C 1-3 Alkyl; for example, methyl or ethyl.

[0017] In one embodiment, the organic solvent may be a mixed solvent of solvent A and solvent B, wherein solvent A may be one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, acetonitrile, and ethyl acetate; preferably tetrahydrofuran; solvent B may be an alkyl alcohol solvent, preferably methanol and / or ethanol.

[0018] In one embodiment, the organic solvent may be a mixed solvent of tetrahydrofuran and methanol.

[0019] In one embodiment, the volume ratio of the solvent A to the solvent B may be (3-10):1, preferably (4-6):1, for example 5:1.

[0020] In one embodiment, the volume mass ratio of the halogenating agent to the 2-naphthoic acid may be (5-20) mL:1 g; preferably (5-10) mL:1 g.

[0021] In one embodiment, the volume mass ratio of the ROH to the 2-naphthoic acid may be (5-20) mL:1 g, preferably (5-10) mL:1 g.

[0022] In one embodiment, the molar ratio of the sodium borohydride to the 2-naphthoic acid may be (2-10):1, preferably (2-5):1, for example 2.5:1.

[0023] In one embodiment, the volume mass ratio of the organic solvent to the 2-naphthoic acid may be (5-20) mL:1 g; preferably (5-10) mL:1 g, for example 6 mL:1 g.

[0024] In one embodiment, the reaction temperature of step (1) can be 65-80°C, preferably 70-75°C.

[0025] In one embodiment, the reaction time of step (1) can be 10-60 min, preferably 30 min.

[0026] In one embodiment, the reaction temperature of step (2) can be 50-60°C, preferably 55°C.

[0027] In one embodiment, the reaction time of step (2) can be 10-60 min, preferably 30 min.

[0028] In one embodiment, the reaction temperature of step (3) can be 55-70°C, preferably 60-65°C.

[0029] In one embodiment, the reaction time of step (3) can be 10-60 min, preferably 30 min.

[0030] In one embodiment, the reaction process of the 2-naphthalenemethanol is:

[0031] (1) heating 2-naphthoic acid and thionyl chloride to 65-80° C., stirring for 10-60 min, removing the halogenating agent, and obtaining 2-naphthoyl chloride;

[0032] (2) adding methanol to the 2-naphthoyl chloride, heating to 50-60° C., reacting for 10-60 min, removing methanol, and converting into 2-naphthoic acid ester;

[0033] (3) Add the 2-naphthoic acid ester and sodium borohydride to tetrahydrofuran, raise the temperature to 55-70° C., add methanol, and stir to react for 10-60 minutes; concentrate the reaction solution, add water to quench, extract with dichloromethane, and concentrate the organic phase to obtain 2-naphthyl methanol.

[0034] Beneficial effects of the present invention

[0035] The invention provides a new method for preparing 2-naphthylmethanol, wherein 2-naphthoic acid is sequentially converted into 2-naphthoyl chloride and 2-naphthoic acid methyl ester, and 2-naphthoic acid methyl ester is then reduced by sodium borohydride to be converted into 2-naphthylmethanol. The whole process only requires simple post-treatment to achieve a product purity of more than 97% and a total yield of nearly 100%.

[0036] Furthermore, on the one hand, the preparation method can avoid the use of highly active lithium aluminum tetrahydride, thereby making the reaction conditions milder, the production safer, and conducive to industrial application; on the other hand, it also breaks through the common knowledge and achieves the reduction of aromatic acids / esters with sodium borohydride in high yield without the addition of Lewis acid. DETAILED DESCRIPTION

[0037] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0038] The reagents and raw materials used in the present invention are commercially available.

[0039] Example 1

[0040]

[0041] Under nitrogen protection, 10g 2-naphthoic acid (58mmol, 1.0eq) and 50mL thionyl chloride were placed in a 250mL three-necked flask, heated to 70-75°C, reacted for 30min, concentrated to remove thionyl chloride, added 50mL methanol, heated to 50-60°C, reacted for 30min, concentrated to remove methanol, and obtained a white solid.

[0042] Add 50 mL of tetrahydrofuran (THF) and 5.48 g of sodium borohydride (145 mmol, 2.5 eq) to the white solid obtained above, raise the temperature to 60-65°C, dropwise add 10 mL of methanol, react for 30 min, concentrate the reaction solution, add water and stir, extract with dichloromethane, and concentrate the organic phase to obtain 9.13 g of white solid. Based on 2-naphthoic acid, the yield is 99.3% and the purity is 98.6%.

[0043] Example 2

[0044]

[0045] Under nitrogen protection, 1kg 2-naphthoic acid (5.8mol, 1.0eq) and 5L thionyl chloride were placed in a 25L reaction bottle, reacted at 70-75°C for 60min, concentrated to remove thionyl chloride, added 5L methanol, heated to 50-60°C, reacted for 60min, concentrated to remove methanol, and obtained a white solid.

[0046] To the white solid obtained above, add 5L tetrahydrofuran (THF) and 548.5g sodium borohydride (14.5mol, 2.5eq), raise the temperature to 60-65°C, add 1L methanol dropwise, react for 60min, concentrate the reaction solution, add water and stir, extract with dichloromethane, and concentrate the organic phase to obtain 916g white solid, with a yield of 99.6% and a purity of 97.4% based on 2-naphthoic acid.

[0047] Comparative Example 1

[0048]

[0049] Under nitrogen protection, 10g 2-naphthoic acid (58mmol, 1.0eq) and 50mL thionyl chloride were placed in a 250mL three-necked flask, heated to 70-75°C, reacted for 30min, concentrated to remove thionyl chloride, added 50mL methanol, heated to 50-60°C, reacted for 30min, concentrated to remove methanol, and obtained a white solid.

[0050] To the white solid obtained above, 60 mL of tetrahydrofuran (THF) and 5.48 g of sodium borohydride (145 mmol, 2.5 eq) were added and stirred. If the mixture was not completely dissolved, the temperature was raised to 60-65°C and the mixture was reacted at 60-65°C for 30 min. The reaction liquid was filtered and concentrated, water was added and stirred, and the mixture was extracted with dichloromethane. The organic phase was concentrated to obtain 6.51 g of a white solid. The yield was 71% and the purity was 97.0%.

[0051] Comparative Example 2

[0052]

[0053] 1.86 g of methyl 2-naphthoate (commercially available, 10 mmol, 1.0 eq), 0.76 g of sodium borohydride (20 mmol, 2.0 eq), 1.21 g of N,N-dimethylaniline (10 mmol, 1.0 eq), 1.36 g of zinc chloride (10 mmol, 1.0 eq) and 10 mL of tetrahydrofuran (THF) were added to a 50 mL reaction bottle, heated to reflux and reacted for 2 h.

[0054] The reaction solution was filtered, concentrated, added with water and stirred, extracted with dichloromethane, and the organic phase was concentrated to obtain 1.2 g of white solid with a yield of 77.6% and a purity of 95.2%.

[0055] Comparative Example 3

[0056]

[0057] 1.86 g of methyl 2-naphthoate (commercially available, 10 mmol, 1.0 eq), 0.76 g of sodium borohydride (20 mmol, 2.0 eq), 1.36 g of zinc chloride (10 mmol, 1.0 eq) and 10 mL of tetrahydrofuran (THF) were added to a 50 mL reaction bottle, heated to reflux, and reacted for 2 h.

[0058] The reaction solution was filtered, concentrated, stirred with water, extracted with dichloromethane, and the organic phase was taken and sent to HPLC for detection, which showed only trace amounts of product.

[0059] The above embodiment provides a new method for preparing 2-naphthylmethanol, wherein 2-naphthoic acid is successively converted into 2-naphthoyl chloride and 2-naphthoic acid methyl ester, and 2-naphthoic acid methyl ester is then reduced with sodium borohydride to be converted into 2-naphthylmethanol. The whole process does not require purification of the intermediate, only simple post-treatment is required, the purity of the final product reaches more than 97%, and the total yield is nearly 100%. Furthermore, the preparation method can avoid the use of highly active lithium aluminum tetrahydride on the one hand, thereby making the reaction conditions milder, the production safer, and more conducive to industrial application; on the other hand, it also breaks through the cognition of common knowledge, and realizes the reduction of aromatic acid / ester with sodium borohydride in high yield without the additional addition of Lewis acid.

[0060] Furthermore, when methyl 2-naphthoate is reduced using sodium borohydride, the applicant unexpectedly discovered that adding a small amount of methanol to the reaction solution can further improve the reaction yield of this step. The applicant speculates that this may be because a small amount of methanol is conducive to improving the solubility of sodium borohydride in the solvent and thus promoting the reaction.

Claims

1. A method for preparing 2-naphthalenemethanol, characterized in that: Here are the steps: (1) 2-naphthoic acid is converted into 2-naphthoyl halide under the action of a halogenating agent; (2) the 2-naphthoyl halide is reacted with ROH to be converted into 2-naphthoic acid ester, wherein R is an alkyl group; (3) reacting the 2-naphthoic acid ester with sodium borohydride in the presence of an organic solvent to obtain 2-naphthyl alcohol; 2. The preparation method according to claim 1, characterized in that The halogenating agent is one or more of sulfoxide halides, phosphorus trihalides, phosphorus pentahalides, phosphorus oxyhalides, oxalyl chloride, and triphenylphosphine halides.

3. The preparation method according to claim 1, characterized in that: R is C 1-6 alkyl.

4. The preparation method according to claim 1, characterized in that: The organic solvent is a mixed solvent of solvent A and solvent B, wherein solvent A is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, acetonitrile, and ethyl acetate; and solvent B is an alkyl alcohol solvent.

5. The preparation method according to claim 4, characterized in that: The volume ratio of the solvent A to the solvent B is (3-10):

1.

6. The preparation method according to claim 1, characterized in that: The volume mass ratio of the halogenating agent to the 2-naphthoic acid is (5-20) mL:1 g.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the sodium borohydride to the 2-naphthoic acid is (2-10):

1.

8. The preparation method according to claim 1, characterized in that: The volume mass ratio of the ROH to the 2-naphthoic acid is (5-20) mL:1 g.

9. The preparation method according to claim 1, characterized in that: The volume mass ratio of the organic solvent to the 2-naphthoic acid is (5-20) mL:1 g.

10. The preparation method according to claim 1, characterized in that: The reaction temperature of step (1) is 65-80°C; the reaction time of step (1) is 10-60min; The reaction temperature of step (2) is 50-60°C; the reaction time of step (2) is 10-60min; The reaction temperature of step (3) is 55-70°C; the reaction time of step (3) is 10-60min.

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