Preparation method of 4-cyanophenyl isothiocyanate

Abstract

The invention provides a preparation method of 4-cyanophenyl isothiocyanate, which comprises the following steps: step S1, enabling 4-cyanophenyl aniline to react with phenyl thiochloroformate to generate (4-cyanophenyl) aminophenoxy-1-thioketone; and S2, removing one molecule of phenol from the (4-cyanophenyl) aminophenoxy-1-thioketone, so as to generate the 4-cyanophenyl isothiocyanate. According to the preparation method disclosed by the embodiment of the invention, the reaction operation is simple and safe; the method has the advantages of low risk of the required raw materials, avoiding of the use of reagents with high toxicity and strong smell, improvement of the experimental safety, high experimental repeatability, effective reduction of the generation of three wastes, reduction of the environmental protection pressure, and suitableness for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and more specifically, relates to a method for preparing 4-cyanophenyl isothiocyanate. Background Art

[0002] 4-Cyanophenyl isothiocyanate is an important pharmaceutical intermediate that can react with amines to form various thiourea derivatives.

[0003] At present, the preparation methods of 4-cyanophenyl isothiocyanate reported in the literature are mainly divided into the following two types.

[0004] The first method is to prepare 4-cyanophenyl isothiocyanate by reacting 4-cyanoaniline with thiophosgene. However, in this method, thiophosgene has a low boiling point and high toxicity; the reaction temperature is high and the conversion rate is low; therefore, this method is not suitable for industrial production.

[0005] The second method is to use 4-cyanoaniline and carbon disulfide to react in the presence of sodium hydroxide to prepare 4-cyanophenyl isothiocyanate. However, this method requires 10 equivalents of carbon disulfide, which not only has a strong smell and high reaction cost, but also produces a lot of wastewater and waste smoke in the post-treatment, which is environmentally unfriendly and not suitable for large-scale industrial production. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a method for preparing 4-cyanophenyl isothiocyanate which is highly safe, simple to operate and suitable for industrial production.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] The preparation method of 4-cyanophenyl isothiocyanate according to an embodiment of the present invention comprises the following steps:

[0009] Step S1, reacting 4-cyanoaniline with phenyl chlorothioformate to generate (4-cyanophenyl)aminophenoxy-1-thione;

[0010] Step S2, removing one molecule of phenol from (4-cyanophenyl)aminophenoxy-1-thione to generate 4-cyanophenyl isothiocyanate.

[0011] In some embodiments of the present invention, in step S1, the molar ratio of 4-cyanoaniline to phenylchlorothioformate is 1:(1.0-1.5).

[0012] In some embodiments of the present invention, the reaction in step S1 is carried out in a first solvent, and the first solvent is any one or more of dichloromethane, tetrahydrofuran, acetonitrile, acetone, and 1,4-dioxane.

[0013] In some embodiments of the present invention, in step S1, the reaction temperature is 10-30° C., and the reaction time is 4-20 hours.

[0014] In some embodiments of the present invention, the step S1 further includes:

[0015] After the reaction is completed, the reaction solution is poured into water, and the organic phase is separated, dried, and concentrated to obtain the (4-cyanophenyl)aminophenoxy-1-thione.

[0016] In some embodiments of the present invention, step S2 includes:

[0017] The (4-cyanophenyl)aminophenoxy-1-thione is added to a second solvent, and a base is added to remove one molecule of phenol from the (4-cyanophenyl)aminophenoxy-1-thione to generate the 4-cyanophenyl isothiocyanate.

[0018] In some embodiments of the present invention, the second solvent is any one or more of tetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, and water, and the base is any one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium carbonate, and potassium acetate.

[0019] In some embodiments of the present invention, the base is solid potassium hydroxide, and the molar ratio of the (4-cyanophenyl)aminophenoxy-1-thione to the base is 1:(1.0-1.5).

[0020] In some embodiments of the present invention, in step S2, the reaction temperature is 10-30° C., and the reaction time is 1-4 hours.

[0021] In some embodiments of the present invention, step S2 further includes:

[0022] After the reaction is completed, the reaction solution is washed with an aqueous solution, and the organic phase is separated, dried, concentrated, and recrystallized with a mixed solvent of ethyl acetate:n-heptane=1:1 to obtain the 4-cyanophenyl isothiocyanate.

[0023] The above technical solution of the present invention has at least one of the following beneficial effects:

[0024] According to the preparation method of the embodiment of the present invention, the reaction operation is simple and safe;

[0025] The raw materials required are relatively less dangerous and avoid the use of highly toxic and odorous reagents. Not only does it improve experimental safety and increase experimental repeatability, it can also effectively reduce the generation of three wastes, reduce environmental pressure, and is suitable for industrial production. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0027] The following first describes in detail the preparation method of 4-cyanophenyl isothiocyanate according to an embodiment of the present invention.

[0028] The preparation method of 4-cyanophenyl isothiocyanate according to an embodiment of the present invention comprises the following steps:

[0029] Step S1, reacting 4-cyanoaniline with phenyl chlorothioformate to generate (4-cyanophenyl)aminophenoxy-1-thione;

[0030] Step S2, removing one molecule of phenol from (4-cyanophenyl)aminophenoxy-1-thione to generate 4-cyanophenyl isothiocyanate.

[0031] That is to say, the preparation method of the present invention uses 4-cyanoaniline and phenyl chlorothioformate as starting raw materials, and after obtaining the intermediate (4-cyanophenyl)aminophenoxy-1-thione, only one molecule of phenol needs to be removed to obtain the target product 4-cyanophenyl isothiocyanate. The preparation method of the present invention avoids the use of highly toxic and odorous reagents, not only improves experimental safety, and has high experimental repeatability, but also can effectively reduce the generation of three wastes, reduce environmental pressure, and is suitable for industrial production.

[0032] Below, each step is described in detail.

[0033] Step S1, reacting 4-cyanoaniline with phenyl chlorothioformate to generate (4-cyanophenyl)aminophenoxy-1-thione.

[0034] The reaction formula is shown in the following formula (1):

[0035]

[0036] In some embodiments of the present invention, in step S1, the molar ratio of 4-cyanoaniline to phenyl chlorothioformate is 1:(1.0-1.5), preferably, the molar ratio of 4-cyanoaniline to phenyl chlorothioformate is 1:1.2. By using a slightly excess amount of phenyl chlorothioformate, it is possible to take into account both the raw material economy and the simplicity of post-treatment, and also to promote the improvement of reaction efficiency and yield.

[0037] In some embodiments of the present invention, the reaction in step S1 is carried out in a first solvent, and the first solvent is any one or more of dichloromethane, tetrahydrofuran, acetonitrile, acetone, and 1,4-dioxane. The above solvents can dissolve the starting materials of the reaction well, which is conducive to promoting the reaction, and dichloromethane is particularly preferred.

[0038] In some embodiments of the present invention, in step S1, the reaction temperature is 10-30°C and the reaction time is 4-20 hours. The reaction conditions are mild, the equipment requirements are low, and the preparation cost is low. Preferably, the reaction temperature is room temperature and the reaction time is 12 hours.

[0039] In some embodiments of the present invention, the step S1 further includes:

[0040] After the reaction is completed, the reaction solution is poured into water, and the organic phase is separated, dried, and concentrated to obtain the (4-cyanophenyl)aminophenoxy-1-thione.

[0041] Pouring the reaction solution into water can dissolve the hydrochloric acid generated by the reaction in water and remove it during the process of separating the organic phase, thereby avoiding hindering the removal of phenol.

[0042] Step S2, removing one molecule of phenol from (4-cyanophenyl)aminophenoxy-1-thione to generate 4-cyanophenyl isothiocyanate.

[0043] That is to say, after obtaining the intermediate (4-cyanophenyl)aminophenoxy-1-thione, only one molecule of phenol therein needs to be removed to obtain the target product 4-cyanophenyl isothiocyanate.

[0044] In some embodiments of the present invention, step S2 includes:

[0045] The (4-cyanophenyl)aminophenoxy-1-thione is added to a second solvent, and a base is added to remove one molecule of phenol from the (4-cyanophenyl)aminophenoxy-1-thione to generate the 4-cyanophenyl isothiocyanate.

[0046] That is, under the action of the base, the hydrogen on the amino group is removed together with the phenylmethyl group, that is, a molecule of phenol is removed from the (4-cyanophenyl)aminophenoxy-1-thione molecule to obtain the target product 4-cyanophenyl isothiocyanate.

[0047] In some embodiments of the present invention, the second solvent is any one or more of tetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, and water, and the base is any one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium carbonate, and potassium acetate.

[0048] Specifically, taking potassium hydroxide as an example, the chemical reaction formula is as shown in the following formula (2):

[0049]

[0050] In some embodiments of the present invention, the base is solid potassium hydroxide, and the molar ratio of the (4-cyanophenyl)aminophenoxy-1-thione to the base is 1:(1.0-1.5), preferably 1:1.3.

[0051] In some embodiments of the present invention, in step S2, the reaction temperature is 10-30° C., and the reaction time is 1-4 hours. Preferably, the reaction is carried out at room temperature for 2 hours. The reaction conditions are mild.

[0052] In some embodiments of the present invention, step S2 further includes:

[0053] After the reaction is completed, the reaction solution is washed with an aqueous solution, and the organic phase is separated, dried, concentrated, and recrystallized from a mixed solvent of ethyl acetate:n-heptane=1:1 to obtain the 4-cyanophenyl isothiocyanate.

[0054] Washing with an aqueous solution can effectively remove the alkali and the phenol removed.

[0055] Below, the preparation method of 4-cyanophenyl isothiocyanate of the present invention is further described in detail through specific examples.

[0056] Example 1

[0057] (1) Preparation of (4-cyanophenyl)aminophenoxy-1-thione

[0058] In a 2L three-necked flask, add 1L of dichloromethane and 118.1g of 4-cyanoaniline at room temperature, and uniformly add phenyl chlorothioformate dropwise, controlling the dropping temperature between 10-20° C. After the addition is completed, keep the reaction at room temperature for 12 hours.

[0059] After the reaction of 4-cyanoaniline was complete as detected by TLC spot plate, the reaction solution was poured into water and the organic phase was separated; anhydrous sodium sulfate was added to dry, filtered and concentrated to obtain (4-cyanophenyl)aminophenoxy-1-thione as a yellow oil, 228.6 g, with a yield of 90.0%.

[0060] The structure of the product was confirmed by NMR experiment, and the data are as follows:

[0061] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz): δ7.71-7.32 (m, 7H), 7.16 (d, 2H). The detection results were consistent with the structure of (4-cyanophenyl)aminophenoxy-1-thione.

[0062] (2) Preparation of compound 4-cyanophenyl isothiocyanate

[0063] In a 2L three-necked flask, add 1.5L of dichloromethane, 228.6g of (4-cyanophenyl)aminophenoxy-1-thione, and 65.6g of potassium hydroxide; maintain the reaction at 20°C for 2h.

[0064] After TLC spot plate detection of (4-cyanophenyl)aminophenoxy-1-thione was completely consumed, the reaction solution was washed with aqueous solution, and the organic phase was separated, dried, concentrated, and recrystallized from a mixed solvent of ethyl acetate:n-heptane = 1:1 to obtain 4-cyanophenyl isothiocyanate as a light yellow solid of 116.7 g, with a yield of 80.9%.

[0065] The structure of the product was confirmed by NMR experiment, and the data are as follows:

[0066] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz): δ7.67 (d, 2H), 7.31 (d, 2H), the detection results are consistent with the structure of 4-cyanophenyl isothiocyanate.

[0067] In summary, the preparation method of 4-cyanophenyl isothiocyanate of the present invention has the advantages of simple reaction operation, safety, low odor, and can effectively reduce the generation of three wastes and reduce environmental pressure; the raw materials required are relatively less dangerous, and the use of highly toxic and odorous reagents is avoided, the experimental safety is improved, and the experimental repeatability is high, which is suitable for industrial production.

[0068] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 4-cyanophenyl isothiocyanate, characterized in that: The steps include: Step S1, reacting 4-cyanoaniline with phenyl chlorothioformate to generate (4-cyanophenyl)aminophenoxy-1-thione; Step S2, removing one molecule of phenol from (4-cyanophenyl)aminophenoxy-1-thione to generate 4-cyanophenyl isothiocyanate.

2. The preparation method according to claim 1, characterized in that: In the step S1, the molar ratio of 4-cyanoaniline to phenylchlorothioformate is 1:(1.0-1.5).

3. The preparation method according to claim 1, characterized in that: The reaction in step S1 is carried out in a first solvent, and the first solvent is any one or more of dichloromethane, tetrahydrofuran, acetonitrile, acetone, and 1,4-dioxane.

4. The preparation method according to claim 1, characterized in that: In the step S1, the reaction temperature is 10-30° C. and the reaction time is 4-20 hours.

5. The preparation method according to claim 1, characterized in that: The step S1 further includes: After the reaction is completed, the reaction solution is poured into water, and the organic phase is separated, dried, and concentrated to obtain the (4-cyanophenyl)aminophenoxy-1-thione.

6. The preparation method according to claim 1, characterized in that: The step S2 comprises: The (4-cyanophenyl)aminophenoxy-1-thione is added to a second solvent, and a base is added to remove one molecule of phenol from the (4-cyanophenyl)aminophenoxy-1-thione to generate the 4-cyanophenyl isothiocyanate.

7. The preparation method according to claim 6, characterized in that: The second solvent is any one or more of tetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, and water, and the base is any one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium carbonate, and potassium acetate.

8. The preparation method according to claim 7, characterized in that: The base is solid potassium hydroxide, and the molar ratio of the (4-cyanophenyl)aminophenoxy-1-thione to the base is 1:(1.0-1.5).

9. The preparation method according to claim 6, characterized in that: In the step S2, the reaction temperature is 10-30° C. and the reaction time is 1-4 hours.

10. The preparation method according to claim 6, characterized in that: The step S2 also includes: After the reaction is completed, the reaction solution is washed with an aqueous solution, and the organic phase is separated, dried, concentrated, and recrystallized with a mixed solvent of ethyl acetate:n-heptane=1:1 to obtain the 4-cyanophenyl isothiocyanate.

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