Preparation process of 3-amino-2-cyclohexene-1-one

Abstract

The present invention relates to a method for synthesizing 3-amino-2-cyclohexene-1-one and its salts. Specifically, a diol is used as the solvent of the reaction system, and 5-oxohexanenitrile is used as the raw material. A cyclization reaction occurs under the action of a base. The diol is preferably a pinacol-type di-tert-alcohol (such as 3,4-dimethylhexane-3,4-diol, 2,3-dimethyl-2,3-butanediol, 3,4-diethyl-3,4-hexanediol, etc.), more preferably R1 = R2 = R3 = R4 (such as 2,3-dimethyl-2,3-butanediol, 3,4-diethyl-3,4-hexanediol, 1,1,2,2-tetraphenylethane-1,2-diol, etc.), and even more preferably 2,3-dimethyl-2,3-butanediol (R1 = R2 = R3 = R4 = CH3).

Description

Technical Field

[0001] The present invention relates to a preparation process of 3-amino-2-cyclohexene-1-one. Background Art

[0002] The molecular structure of 3-amino-2-cyclohexene-1-one (Formula A) is as follows:

[0003]

[0004] 3-Amino-2-cyclohexene-1-one is an important basic intermediate in organic chemical industry and can be used to prepare many types of compounds such as benzocarbazole derivatives and tetrahydroquinoline derivatives, and has wide applications in the fields of biopharmaceuticals, pesticides, etc.

[0005] In 1979, Mitsui Petrochemical Industries, Ltd. of Japan disclosed a preparation method of 3-amino-2-cyclohexene-1-one in its patent application JP54092942A. Using 5-oxohexanenitrile as a raw material, in a reaction solvent, heating in the presence of a base, a cyclization reaction occurs to generate 3-amino-2-cyclohexene-1-one, and the main by-product is 3,4-dihydro-6-methylpyridin-2-one. The reaction equation is shown as follows:

[0006]

[0007] The reaction selectivity problem of this prior art solution is mainly affected by two key factors, namely the reaction temperature and the reaction solvent.

[0008] (1) In the preferred reaction temperature range (i.e., 170 - 200 °C) for this cyclization reaction, the reaction selectivity is relatively good. Outside this range, the reaction selectivity drops sharply. However, it should be noted that this temperature range has exceeded the boiling points of all the solvents disclosed by it.

[0009] (2) The solvents disclosed by this prior art are low-boiling monohydric alcohol solvents such as methanol, ethanol, tert-butanol, or mixtures of these alcohol solvents and other non-polar solvents. It should be emphasized that all the disclosed alcohol solvents are monohydric alcohols.

[0010] Through a large number of experimental investigations on the above prior art, the inventors found the following series of problems with the above method:

[0011] (1) The preferred reaction temperature of this prior art method exceeds the boiling points of all the disclosed reaction solvents. This means that in order to obtain relatively ideal results, pressure-resistant equipment must be used to implement this prior art solution. Therefore, this requirement for the reaction to be carried out under pressurized conditions directly leads to operational inconvenience and extremely high requirements for the reaction equipment. Since the preferred reaction temperature of this prior art method is 170 - 200 °C, the temperature control must also be relatively precise. If the temperature is too low, the proportion of the by-product 3,4-dihydro-6-methylpyridin-2-one will increase; if the temperature is too high, the product 3-amino-2-cyclohexen-1-one will undergo further side reactions, resulting in a low yield.

[0012] (2) The reaction rate of this prior art method is relatively slow and the required reaction time is long. In multiple preferred embodiments of the prior art, the reaction time is as long as 1 hour to 3 hours.

[0013] (3) This prior art method needs to be implemented at extremely dilute concentrations and requires a large amount of solvent. If the concentration of the reaction solution is increased, the product will react further with the unconsumed raw materials, resulting in a sharp decrease in the yield. Example 7 is a preferred embodiment of the prior art (JP54092942A). In this embodiment, the initial concentration of the raw materials in the reaction solution is the highest, but it only reaches 0.11 mol / L. In Example 7, the main product 3-amino-2-cyclohexen-1-one accounts for 82.7%, the by-product 3,4-dihydro-6-methylpyridin-2-one accounts for 13.0%, and the ratio of the main product to the by-product is 6.4:1. The inventor repeated Example 7 and took a sample for analysis after 3 hours of reaction. The proportion of 3-amino-2-cyclohexen-1-one was 58.7%, the proportion of the by-product 3,4-dihydro-6-methylpyridin-2-one was 19.0%, and the ratio of the main product to the by-product was 3.1:1.

[0014] (4) Since the proportion of by-products of the prior art method is too high, the task of separating the products is extremely onerous.

[0015] The present invention solves the above problems existing in the prior art and provides an improved technical solution, a preparation method of 3-amino-2-cyclohexen-1-one that is more suitable for commercial production. Summary of the Invention

[0016] The present invention well solves the above-existing problems by selecting a pinacol-type di-tert-alcohol as the solvent for the reaction system.

[0017] The "pinacol-type di-tert-alcohol" or "pinacol" referred to in the present invention refers to a class of compounds containing the basic structure "R1R2C(OH)C(OH)R3R4". Among them, R1, R2, R3, and R4 can be selected from alkyl groups such as methyl and ethyl, and aryl groups such as phenyl, respectively.

[0018] The present invention provides a preparation process of 3-amino-2-cyclohexen-1-one. Specifically, a diol is used as the solvent of the reaction system, and 5-oxohexanenitrile is used as the raw material. Under the action of a base, a cyclization reaction occurs to generate the target product 3-amino-2-cyclohexen-1-one.

[0019] In one or more specific embodiments, the diol is preferably a pinacol-type ditertiary alcohol (such as 3,4-dimethylhexane-3,4-diol, 2,3-dimethyl-2,3-butanediol, 3,4-diethyl-3,4-hexanediol, etc.), more preferably a pinacol-type ditertiary alcohol with R1 = R2 = R3 = R4 (such as 2,3-dimethyl-2,3-butanediol, 3,4-diethyl-3,4-hexanediol, 1,1,2,2-tetraphenylethane-1,2-diol, etc.), and even more preferably 2,3-dimethyl-2,3-butanediol (R1 = R2 = R3 = R4 = CH3).

[0020] In one or more specific embodiments, the pinacol-type ditertiary alcohol is preferably 3,4-dimethylhexane-3,4-diol (CAS: 1185-02-0; normal boiling point 200.8 °C), 2,3-dimethyl-2,3-butanediol (CAS: 76-09-5; normal boiling point 174.4 °C), 3,4-diethyl-3,4-hexanediol (CAS: 6931-71-1; normal boiling point 229.7 °C).

[0021] In one or more specific embodiments, the normal boiling point or normal reflux temperature of the diol is 150 - 230 °C. The normal boiling point or normal reflux temperature of the diol is preferably 170 - 230 °C, more preferably a pinacol-type ditertiary alcohol, even more preferably a pinacol-type ditertiary alcohol with R1 = R2 = R3 = R4, and still more preferably 2,3-dimethyl-2,3-butanediol (R1 = R2 = R3 = R4 = CH3).

[0022] In one or more specific embodiments, the normal boiling point or normal reflux temperature of the pinacol-type ditertiary alcohol is 150 - 230 °C. The normal boiling point or normal reflux temperature of the pinacol-type ditertiary alcohol is preferably 170 - 230 °C, more preferably a pinacol-type ditertiary alcohol with R1 = R2 = R3 = R4, and still more preferably a pinacol-type ditertiary alcohol with R1 = R2 = R3 = R4, and still more preferably 2,3-dimethyl-2,3-butanediol (R1 = R2 = R3 = R4 = CH3).

[0023] In one or more specific embodiments, the amount of 2,3-dimethyl-2,3-butanediol used is 5 to 20 times the weight of 5-oxohexanenitrile, preferably 10 times.

[0024] In one or more specific embodiments, the base can be selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides (such as potassium alcoholate or sodium alcoholate), preferably an alkali metal hydroxide, and more preferably potassium hydroxide.

[0025] In one or more specific embodiments, the amount of the base used is 0.05 to 1.5 times the amount of substance of 5-oxohexanenitrile, preferably about 0.2 to 0.5 times. Those skilled in the art should understand that the product 3-amino-2-cyclohexen-1-one itself is acidic and will inevitably undergo a neutralization reaction with the base added in the initial stage of the reaction to form a salt. Therefore, part or all of the products generated by using the method of the present invention actually exist in the form of salts, and the specific ratio depends on the amount of the base used. We also found that the reaction system of the present invention can complete most of the conversions without a base with an equivalent stoichiometry to the reactants, and the base plays a catalytic role in the reaction. Therefore, in one or more specific embodiments, if the amount of the base is reduced to 0.1 times, the cyclization reaction can also reach a yield level of about 60%.

[0026] In one or more specific embodiments, the reaction temperature of the cyclization reaction is about 150 °C to the reflux temperature of the diol.

[0027] In one or more specific embodiments, the reaction temperature of the cyclization reaction is about 150 °C to the reflux temperature of the pinacol-type ditertiary alcohol. In one or more specific embodiments, the pinacol-type ditertiary alcohol is preferably 3,4-dimethylhexane-3,4-diol (CAS: 1185-02-0; normal boiling point 200.8 °C), 2,3-dimethyl-2,3-butanediol (CAS: 76-09-5; normal boiling point 174.4 °C), 3,4-diethyl-3,4-hexanediol (CAS: 6931-71-1; normal boiling point 229.7 °C).

[0028] In one or more specific embodiments, the reaction temperature of the cyclization reaction is about 150 °C to the reflux temperature of 2,3-dimethyl-2,3-butanediol (the normal boiling point of 2,3-dimethyl-2,3-butanediol is 174.4 °C, and the reflux temperature is usually near the normal boiling point value and is generally slightly higher than the normal boiling point). The preferred reaction conditions are that the cyclization reaction is carried out at the reflux temperature of 2,3-dimethyl-2,3-butanediol, and the solvent 2,3-dimethyl-2,3-butanediol refluxes in the reaction system.

[0029] In one or more specific embodiments, the reaction pressure of the cyclization reaction is normal pressure.

[0030] In one or more specific embodiments, the reaction time of the cyclization reaction is about 5 minutes to 30 minutes, preferably about 8 minutes to 12 minutes.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below.

[0032] One of ordinary skill in the art will understand "about", and it will vary to some extent in the context in which it is used. If the use of the term is unclear to one of ordinary skill in the art, considering the context in which it is used, "about" will mean up to plus or minus 20% of the particular term.

[0033] The term "and / or" when used to connect two or more alternatives shall be understood to mean any one of the alternatives or any two or more of the alternatives.

[0034] As used herein, the term "comprising" or "including" means including the recited elements, integers or steps, but does not exclude any other elements, integers or steps. In this document, when the term "comprising" or "including" is used, unless otherwise specified, the case consisting of the recited elements, integers or steps is also covered. For example, when referring to "comprising" or "including" a specific component, it is also intended to cover a mixture consisting of that specific component.

[0035] "Consisting essentially of" as described herein refers to the main components constituting the mixture. Unless otherwise specified, generally a weight percentage content higher than 50% can be called the main component. The main component can be a pure substance or can be composed of a mixture of a class of structures or chemical properties that are similar and that one of ordinary skill in the art can know that they can generally be classified into one category.

[0036] Any temperature range, pH range, weight (mass) range, molecular weight range, percentage range, etc. herein, whether expressed using the term "range" or "each range", includes the specified endpoints and all points between the two endpoints.

[0037] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0038] First, the reaction can be carried out under normal pressure. The normal boiling point of 2,3-dimethyl-2,3-butanediol is about 174 °C. Operating at its boiling point temperature can obtain satisfactory results, so there is no need to use pressure-resistant equipment.

[0039] Second, the reaction rate is extremely fast, and the reaction time can be shortened to 5 minutes. The use of 2,3-dimethyl-2,3-butanediol greatly improves the reaction rate, and almost complete conversion can be achieved in 5 minutes.

[0040] Finally, the material concentration in the reaction system can be significantly increased, and the solvent usage can be greatly reduced. When the reaction solution concentration is actually increased to 0.87 mol / L, the result is still satisfactory.

[0041] Using the technical solution of the present invention, the reaction yield reaches 77.3%. The typical analysis data of the reaction solution are as follows: 3-amino-2-cyclohexene-1-one accounts for 82.7%, the by-product 3,4-dihydro-6-methylpyridin-2-one accounts for 4.9%, and the ratio of the main product to the by-product is as high as 16.9:1. 2,3-Dimethyl-2,3-butanediol can be conveniently recovered by distillation, extraction and other methods.

[0042] In summary, the improved technical solution of the present invention is more suitable for industrial production than the prior art (JP54092942A). Specific Embodiments

[0043] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following embodiments are usually determined according to national standards. If there is no corresponding national standard, it is carried out according to general international standards, conventional conditions, or conditions recommended by the manufacturer. Unless otherwise specified, all parts are parts by weight and all percentages are percentages by weight.

[0044] Example 1

[0045] 20.0 g of 2,3-dimethyl-2,3-butanediol was added with 0.1 g of potassium hydroxide. After the system was purged with nitrogen, the system was heated to 170 °C. 2.0 g of 5-oxohexanenitrile was added dropwise to the system within 5 minutes. After the addition was completed, the reaction was carried out at 170 °C for 25 minutes.

[0046] The sample was quenched with acetic acid and analyzed by GC (area%). The remaining raw material 5-oxohexanenitrile was 2.6%, the product 3-amino-2-cyclohexene-1-one was 78.0%, and the by-product 3,4-dihydro-6-methylpyridin-2-one was 6.9%.

[0047] Example 2 (Comparative Example)

[0048] A 50 ml autoclave was charged with 30 ml of tert-butanol, 16.8 mg of potassium hydroxide, and 354.6 mg of 5-oxohexanenitrile. After the system was purged with argon, the system was heated to 180 °C and reacted for 3 h.

[0049] The sample was quenched with acetic acid and analyzed by GC (area%). The remaining raw material 5-oxohexanenitrile was 7.5%, the product 3-amino-2-cyclohexene-1-one was 58.7%, and the by-product 3,4-dihydro-6-methylpyridin-2-one was 19.0%.

[0050] Example 3

[0051] 100.0 g of 2,3-dimethyl-2,3-butanediol was added with 5.0 g of potassium hydroxide. After the system was purged with nitrogen, the temperature of the system was raised to 170 °C. 10.0 g of 5-oxohexanenitrile was added dropwise to the system within 5 minutes. After the addition was completed, the reaction was carried out at 170 °C for 5 minutes.

[0052] After sampling and quenching with acetic acid, GC analysis (area%) was carried out. 1.6% of the raw material 5-oxohexanenitrile remained, 79.5% of the product 3-amino-2-cyclohexen-1-one, and 9.0% of the by-product 3,4-dihydro-6-methylpyridin-2-one.

[0053] The reaction was cooled, acetic acid was added to quench potassium hydroxide, and 2,3-dimethyl-2,3-butanediol was recovered by vacuum concentration. 30 ml of butyl acetate was added to the concentrated solution for slurry purification to obtain 7.0 g of 3-amino-2-cyclohexen-1-one, and the GC purity of the product was 99.5%.

[0054] Example 4

[0055] 10.0 g of 2,3-dimethyl-2,3-butanediol was added with 0.3 g of potassium tert-butoxide. After the system was purged with argon, the temperature of the system was raised to 170 °C. 1.0 g of 5-oxohexanenitrile was added dropwise to the system within 5 minutes. After the addition was completed, the reaction was carried out at 170 °C for 5 minutes.

[0056] Sampling was carried out for GC analysis (area%). 1.4% of the raw material 5-oxohexanenitrile remained, 82.7% of the product 3-amino-2-cyclohexen-1-one, and 5.2% of the by-product 3,4-dihydro-6-methylpyridin-2-one.

[0057] Example 5

[0058] 40.0 g of 2,3-dimethyl-2,3-butanediol was added with 0.2 g of potassium hydroxide. After the system was purged with argon, the temperature of the system was raised to 172 °C. 2.0 g of 5-oxohexanenitrile was added dropwise to the system within 5 minutes. After the addition was completed, the reaction was carried out at 172 °C for 10 minutes.

[0059] After sampling and quenching with acetic acid, GC analysis (area%) was carried out. 3.6% of the raw material 5-oxohexanenitrile remained, 81.1% of the product 3-amino-2-cyclohexen-1-one, and 10.0% of the by-product 3,4-dihydro-6-methylpyridin-2-one. The content of 3-amino-2-cyclohexen-1-one was calculated by the external standard method of GC, and the reaction yield was 76.7%.

[0060] Example 6

[0061] 16.6 g of 2,3-dimethyl-2,3-butanediol was added with 0.1 g of potassium hydroxide. After the system was purged with argon, the temperature of the system was raised to 172 °C. 1.1 g of 5-oxohexanenitrile was added dropwise to the system within 5 minutes. After the addition was completed, the reaction was carried out at 172 °C for 10 minutes.

[0062] The sample was quenched with acetic acid and then analyzed by GC (area%). 4.9% of the raw material 5-oxohexanenitrile remained, 84.6% of the product 3-amino-2-cyclohexen-1-one, and 4.9% of the by-product 3,4-dihydro-6-methylpyridin-2-one. The content of 3-amino-2-cyclohexen-1-one was calculated by the external standard method of GC, and the reaction yield was 77.3%.

[0063] Examples 7-10

[0064] According to the operation of Example 1, the bases used in the reaction, the molar ratio of the base to 5-oxohexanenitrile, the reaction temperature, the reaction time, and the selectivity data of the product 3-amino-2-cyclohexen-1-one are shown in the following table:

[0065] Number Type of base Ratio of base Reaction temperature Reaction time Reaction yield Example 7 LiOH 0.2 eq 174℃ 10 minutes 8.7％ Example 8 NaOH 0.1 eq 174℃ 20 minutes 65.2％ Example 9 KOH 0.3 eq 174℃ 20 minutes 79.1％ Example 10 t-BuOK 0.1 eq 174℃ 10 minutes 70.8％

[0066] Example 11

[0067] 100.0 g of 2,3-dimethyl-2,3-butanediol was added with 10.1 g of potassium tert-butoxide. After the system was purged with nitrogen, the temperature of the system was raised to 170 °C. 10.0 g of 5-oxohexanenitrile was added dropwise to the system within 5 minutes. After the addition was completed, the reaction was carried out at 170 °C for 5 minutes.

[0068] The sample was quenched with acetic acid and then analyzed by GC (area%). 1.5% of the raw material 5-oxohexanenitrile remained, 90.5% of the product 3-amino-2-cyclohexen-1-one, and 4.5% of the by-product 3,4-dihydro-6-methylpyridin-2-one.

[0069] The reaction was cooled, concentrated under reduced pressure to recover 2,3-dimethyl-2,3-butanediol, and the concentrated solution was purified by slurrying with methyl tert-butyl ether to obtain 13.4 g of the potassium salt of 3-amino-2-cyclohexen-1-one. The product purity was 98.5%, and the yield was 80.4%.

[0070] The above specific examples are merely illustrations for clearly explaining the present invention, rather than specific limitations on the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description, and the conventional alternative solutions applied to other similar requirements are obviously equivalent technical solutions protected by the claims of the present invention.

Claims

1. A preparation process of 3-amino-2-cyclohexene-1-one, using 5-oxohexanenitrile as a raw material, and undergoing a cyclization reaction under the action of a base to generate the target product 3-amino-2-cyclohexene-1-one, which is characterized in that: The solvent is 2,3-dimethyl-2,3-butanediol, and the weight of 2,3-dimethyl-2,3-butanediol is 5 to 20 times the weight of 5-oxohexanenitrile; the base is selected from at least one of alkali metal hydroxides, alkali metal carbonates, and alkali metal alkoxides other than Li, and the molar amount of the base is 0.05 to 1.5 times the amount of substance of 5-oxohexanenitrile; the reaction temperature is 150-230 °C, and the reaction pressure is atmospheric pressure; the reaction time of the cyclization reaction is 5-30 minutes.

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