Preparation method of compound

Abstract

The invention discloses a preparation method of a compound. The preparation method comprises the following steps: step 1, Friedel-Crafts acylation reaction; step 2, etherification reaction; step 3, carrying out nucleophilic addition reaction; step 4, hydrogenation reduction reaction; the alpha-functionalized nitroso derivative is adopted as a nitrogen source to introduce hydroxylamine, so that explosive azide is prevented from being used in the production process, potential risks are avoided, and compared with the prior art, the method has higher safety; the production period is greatly shortened by reducing the carbonyl alpha-site functionalization step, so that the production efficiency is effectively improved; according to the method, the reaction conditions are mild, so that high-end complex equipment does not need to be used, strict environment control is also not needed, and the operation threshold is greatly reduced; the raw materials are low in cost and easy to obtain, supply stability is guaranteed from the source, large-scale commercialized production can be achieved easily, and wide application prospects are achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical engineering, and particularly to a preparation method of a compound. Background Art

[0002] 2-Amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one, with the CAS number 1942014-79-0, is a colorless oily liquid, which is an intermediate of the pesticide isopropylthiofungamide and also an important intermediate in medicine and chemical engineering, having broad application prospects in the fields of medicine, chemical engineering, scientific research, etc.

[0003] The existing synthesis methods of 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one mainly include the following: The patent with the publication number CN101001528 discloses a bactericidal composition containing an amide derivative, in which the 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one fragment uses m-cresol as the raw material, and is obtained through Friedel-Crafts acylation, etherification, bromination, azidation, and reduction to obtain 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one. This route involves the explosive reagent potassium azide, and there is a certain danger in industrialization; The patent with the publication number JP2006511485 reports a method starting from 4-isopropoxy-2-methylbenzonitrile, and obtaining 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one through Grignard reaction, bromination, azidation, and hydrogenation reduction. This route also involves the use of explosive azide reagents, and the industrialization risk coefficient is high; The patent WO2023 / 82149, 2023, A1 reports a method starting from m-cresol, and obtaining 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one through Friedel-Crafts acylation, etherification, bromination, nitration, and reduction. This route avoids the use of azide reagents, but the reaction route is long, and the α-position of the ketone carbonyl still needs to be functionalized first, and the process route is relatively cumbersome, and the intermediate nitro compound also has a certain safety risk; Some existing technologies use m-cresol as the starting material, and obtain 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one through Friedel-Crafts acylation, etherification, bromination, and Gabriel reaction. The reproducibility of this route in the laboratory is poor, and the Gabriel reaction mainly obtains the 1,4-addition product after halogen elimination, which is not suitable for industrialization. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of a compound to solve the problems raised in the above background art.

[0005] To achieve the above object, the present invention provides the following technical solutions: A method for preparing a compound, comprising the following steps: Step 1, Friedel-Crafts acylation reaction; Step 2, etherification reaction; Step 3, nucleophilic addition reaction; Step 4, hydrogenation reduction reaction;

[0006] Wherein in the above Step 1, m-cresol is dispersed in a solvent, an acid is added as a catalyst, and isobutyryl chloride is added, and after sufficient reaction, 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one is obtained;

[0007] Wherein in the above Step 2, 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one obtained in Step 1 is dispersed in a solvent, 2-bromopropane and a base are added, and after sufficient reaction, 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one is obtained;

[0008] Wherein in the above Step 3, under an inert atmosphere, 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one obtained in Step 2 is dispersed in a solvent, a base is added, after stirring treatment, an α-functionalized nitroso derivative is added, the reaction temperature is controlled and the reaction is fully stirred, and after post-treatment, 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one is obtained;

[0009] Wherein in the above Step 4, the raw material 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one obtained in Step 3 is dispersed in a solvent, a reducing agent and a catalyst are added, and after reduction, 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one is obtained.

[0010] Preferably, in the above Step 1, the solvent is one of halogenated alkanes and nitro compounds, preferably dichloromethane.

[0011] Preferably, in the above Step 1, the acid is one of inorganic acids and organic acids. The inorganic acids specifically include aluminum trichloride, ferric trichloride, and titanium tetrachloride. The organic acids specifically include methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid; the inorganic acid is preferably aluminum trichloride, and the organic acid is preferably trifluoromethanesulfonic acid.

[0012] Preferably, in the above Step 1, the reaction temperature is controlled at -10 - 100 °C, preferably -10 - 20 °C.

[0013] Preferably, in the above Step 2, the solvent is one of ethers, alkanes, halogenated alkanes, alcohols, and water, preferably methyl tert-butyl ether.

[0014] Preferably, in the second step, the base is one of an organic base and an inorganic base. The organic base specifically includes sodium ethoxide, sodium methoxide, sodium tert-butoxide, and 1,8-diazabicyclo[5.4.0]undec-7-ene. The inorganic base specifically includes sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, and preferably sodium hydroxide.

[0015] Preferably, in the third step, the general formula of the α-functionalized nitroso derivative is as follows:

[0016]

[0017] Among them, R is an aromatic group or an alkyl group of C 1 -C 15 wherein the alkyl group includes a cycloalkyl group, a linear alkyl group, and an alkyl group containing a heteroatom; X is one of a halogen, a cyano group, a trifluoromethanesulfonic acid group, and a p-toluenesulfonic acid group.

[0018] Preferably, in the third step, the base is one of a metal hydride, an alcoholate of a metal, an amide of a metal, an alkyl metal, an inorganic base, and an organic base. The metal hydride specifically includes sodium hydride, potassium hydride, and lithium hydride. The alcoholate of a metal specifically includes sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. The amide of a metal specifically includes sodium amide, lithium amide, potassium amide, lithium diisopropylamide, sodium diisopropylamide, magnesium diisopropylamide, lithium bis(trimethylsilyl)amide, and sodium bis(trimethylsilyl)amide. The general formula of the alkyl metal is R-M, where R is an alkyl group of C 1 -C 15 and M is lithium, sodium, potassium, or magnesium. The alkyl metal specifically includes n-butyllithium, tert-butyllithium, and n-butylsodium. The inorganic base specifically includes sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide. The organic base specifically includes pyrrolidine, piperidine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, and 4-dimethylaminopyridine.

[0019] Preferably, in the third step, the reaction temperature is controlled at -78 to 50 °C, preferably -30 to 10 °C, and the reaction time is controlled at 10 to 120 min.

[0020] Preferably, in the fourth step, the reducing agent is one of hydrogen, iron powder, and zinc powder, and preferably hydrogen; the catalyst is one of homogeneous palladium, homogeneous platinum, homogeneous nickel, supported palladium, supported platinum, and supported nickel.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention uses α-functionalized nitroso derivatives as the nitrogen source to introduce hydroxylamine, thus avoiding the use of explosive azides in the production process, thereby avoiding potential risks and having higher safety compared with the prior art; The present invention greatly shortens the production cycle by reducing the carbonyl α-position functionalization step, and thus effectively improves the production efficiency; The reaction conditions of the present invention are mild, so there is no need to use high-end and complex equipment, nor is it necessary to carry out strict environmental control, thereby greatly reducing the operation threshold; The raw material cost of the present invention is low and easy to obtain, which ensures the stability of supply at the source, is conducive to realizing large-scale commercial production, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the process flow chart of the present invention;

[0023] Figure 2 is the synthetic route diagram of 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0025] Please refer to the attached Figure 1 -attached Figure 2 , a technical solution provided by the present invention:

[0026] Example 1:

[0027] A method for preparing a compound, comprising the following steps: Step 1, Friedel-Crafts acylation reaction; Step 2, etherification reaction; Step 3, nucleophilic addition reaction; Step 4, hydrogenation reduction reaction;

[0028] Among them, in the above Step 1, in a 1L three-necked flask, 133.33 g (1.0 mol) of aluminum trichloride and 300 mL of dichloromethane were added. After cooling to 0 °C, 54.07 g (0.5 mol) of raw material m-cresol was added, and 63.93 g (0.6 mol) of isobutyryl chloride was slowly added dropwise, controlling the temperature below 5 °C. The reaction was carried out at this temperature for 8 h. After the reaction was completed, dichloromethane and water were separated, and the organic phase was collected. After drying and concentration, 45.62 g of Friedel-Crafts acylation product 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one was obtained (yield: 51.2%);

[0029] In the above step two, 45.62 g (0.26 mol) of 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one was added to a 500 mL three-necked flask, and the solvent acetonitrile (200 mL) was added. The temperature was lowered to 0 °C, 12.29 g (0.31 mol) of sodium hydroxide was added, and the mixture was stirred for 30 min. Finally, 33.06 g (0.27 mol) of 2-bromopropane was added dropwise. After stirring at 0 °C for 30 min, the ice bath was removed, and the reaction was continued for 2 h. After the reaction was completed, the solvent was removed under reduced pressure, and the organic phase was separated from the ethyl acetate and water. After drying, the solvent was removed again under reduced pressure to obtain 54.97 g of 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one (yield: 97.5%);

[0030] In the above step three, 54.97 g (0.25 mol) of 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one was added to a dry 2.5 L three-necked flask, and dry tetrahydrofuran (400 mL) was added. The temperature was lowered to -78 °C, and 270 mL (0.27 mol; 1.0 M in THF) of lithium bis(trimethylsilyl)amide was slowly added dropwise. After stirring for 30 min, the temperature was raised to -25 °C, and 650 mL (0.26 mol; 0.4 M in MTBE) of 2-methyl-2-nitropropanenitrile was added dropwise. The stirring was continued for 1 h, and the reaction was quenched with 20% hydrochloric acid. The mixture was stirred at room temperature for 2 h, the aqueous phase was collected, the pH was adjusted to neutral, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, filtered, and the solvent was removed under reduced pressure to obtain 56.24 g of 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one (yield: 89.7%);

[0031] In the above step four, 56.24 g (0.22 mol) of 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one was added to an autoclave, 300 mL of methanol and 500 mg of platinum-carbon catalyst were added, hydrogen gas at 3.0 MPa was introduced, and the temperature was raised to 50 °C and stirred for 16 h. After the reaction was completed, the catalyst was directly filtered off, and the mother liquor was concentrated to obtain 50.18 g of 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one (yield: 95.3%).

[0032] Example 2:

[0033] Using the same method as in Example 1, only modify Step 1 as follows: In a 1 L three-necked flask, add 106.66 g (0.8 mol) of aluminum trichloride and 300 mL of chlorobenzene. After cooling to 0 °C, add 54.07 g (0.5 mol) of m-cresol as the raw material, slowly dropwise add 58.60 g (0.55 mol) of isobutyryl chloride, control the temperature below 5 °C, react at this temperature for 8 h. After the reaction is completed, dichloromethane and water are separated, the organic phase is collected, and after drying and concentration, 55.36 g of the Friedel-Crafts acylation product 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one is obtained (yield: 62.12%).

[0034] Example 3:

[0035] Using the same method as in Example 1, only modify Step 3 as follows: Add 66.06 g (0.30 mol) of 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one to a dry 2.5 L three-necked flask, add 500 mL of dry tetrahydrofuran, cool to -78 °C, slowly dropwise add 330 mL (0.33 mol; 1.0 M in THF) of triphenyl lithium. After stirring for 30 min, warm up to -25 °C, dropwise add 775 mL (0.31 mol; 0.4 M in MTBE) of α-bromonitropropane, continue stirring for 1 h, quench the reaction with 20% hydrochloric acid, stir at room temperature for 2 h, collect the aqueous phase, adjust the pH to neutral, extract with ethyl acetate, combine the organic phases, dry and filter, and then remove the solvent under reduced pressure to obtain 62.40 g of 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one (yield: 82.8%).

[0036] Example 4:

[0037] Using the same method as in Example 1, only modify Step 3 as follows: Add 57.26 g (0.26 mol) of 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one to a dry 2.5 L three-necked flask, add 500 mL of dry tetrahydrofuran, cool to -78 °C, slowly dropwise add 145 mL (0.29 mol; 2.0 M in THF) of diisopropylamine lithium. After stirring for 30 min, warm up to -25 °C, dropwise add 675 mL (0.27 mol; 0.4 M in MTBE) of α-chloronitrocyclopentane, continue stirring for 1 h, quench the reaction with 20% hydrochloric acid, stir at room temperature for 2 h, collect the aqueous phase, adjust the pH to neutral, extract with ethyl acetate, combine the organic phases, dry and filter, and then remove the solvent under reduced pressure to obtain 57.90 g of 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one (yield: 88.6%).

[0038] Example 5:

[0039] Using the same method as in Example 1, only modify Step 4 as follows: Add 62.40 g (0.25 mol) of 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one to an autoclave, add 300 mL of methanol and 500 mg of 10% palladium on carbon catalyst, introduce 3.0 MPa of hydrogen, heat up to 50 °C and stir for 16 h. After the reaction is completed, directly filter off the catalyst. After concentrating the mother liquor, 57.60 g of 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one is obtained (yield: 98.6%).

[0040] Based on the above, the advantages of the present invention are as follows. When the present invention is used, by using α-functionalized nitroso derivatives as the nitrogen source, the safety of the production process is greatly improved, potential risks are effectively avoided. At the same time, the reaction route of the present method is streamlined, greatly reducing the synthesis steps, and the reaction conditions are mild, without the need for strict environmental control. The raw materials are simple and easy to obtain, ensuring the stability of supply at the source, strongly promoting the feasibility of large-scale commercial production, and having broad application prospects.

[0041] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the present invention. Any reference signs in the claims should not be regarded as limiting the claimed rights.

Claims

1. A method for preparing a compound, comprising the following steps: Step 1, Friedel-Crafts acylation reaction; Step 2, etherification reaction; Step 3, nucleophilic addition reaction; Step 4, hydrogenation reduction reaction; characterized in that: In the above step 1, m-cresol is dispersed in a solvent, an acid is added as a catalyst, and isobutyryl chloride is added and reacted sufficiently to obtain 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one; In the above step 2, the 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one obtained in step 1 is dispersed in a solvent, 2-bromopropane and a base are added, and the mixture is fully reacted to obtain 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one; Wherein in the above step 3, under an inert atmosphere, the 2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one obtained in step 2 is dispersed in a solvent, a base is added, and after stirring, an α-functionalized nitroso derivative is added, the reaction temperature is controlled and the reaction is stirred sufficiently, and 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one is obtained by post-treatment; In the above step 4, the raw material 2-(hydroxyamino)-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one obtained in step 3 is dispersed in a solvent, a reducing agent and a catalyst are added, and reduction is performed to obtain 2-amino-2-methyl-1-[2-methyl-4-(propan-2-yloxy)phenyl]propan-1-one.

2. The method for preparing a compound according to claim 1, characterized in that: In the step 1, the solvent is one of a halogenated alkane and a nitro compound, preferably dichloromethane.

3. The method for preparing a compound according to claim 1, characterized in that: In the step 1, the acid is one of an inorganic acid and an organic acid. The inorganic acid specifically includes aluminum trichloride, ferric trichloride, and titanium tetrachloride. The organic acid specifically includes methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid. The inorganic acid is preferably aluminum trichloride, and the organic acid is preferably trifluoromethanesulfonic acid.

4. The method for preparing a compound according to claim 1, characterized in that: In the step 1, the reaction temperature is controlled at -10-100°C, preferably -10-20°C.

5. The method for preparing a compound according to claim 1, characterized in that: In the step 2, the solvent is one of ethers, alkanes, alkyl halides, alcohols, and water, preferably methyl tert-butyl ether.

6. The method for preparing a compound according to claim 1, characterized in that: In the step 2, the base is one of an organic base and an inorganic base. The organic base specifically includes sodium ethoxide, sodium methoxide, sodium tert-butoxide, and 1,8-diazobispiro[5.4.0]undec-7-ene. The inorganic base specifically includes sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide.

7. The method for preparing a compound according to claim 1, characterized in that: In the step 3, the general formula of the α-functionalized nitroso derivative is as follows: Where R is C1-C 15 The alkyl group includes a cycloalkyl group, a chain alkyl group and an alkyl group containing a heteroatom; X is one of a halogen group, a cyano group, a trifluoromethanesulfonate group and a p-toluenesulfonate group.

8. The method for preparing a compound according to claim 1, characterized in that: In the step 3, the base is one of a metal hydride, a metal alcoholate, a metal amide, a metal alkylate, an inorganic base, and an organic base. The metal hydride specifically includes sodium hydride, potassium hydride, and lithium hydride. The metal alcoholate specifically includes sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. The metal amide specifically includes sodium amide, lithium amide, potassium amide, lithium diisopropylamide, sodium diisopropylamide, magnesium diisopropylamide, lithium bistrimethylsilylamide, and sodium bistrimethylsilylamide. The general formula of the metal alkylate is RM, and R is C1-C 15 alkyl, M is lithium, sodium, potassium, or magnesium, the metal alkyl specifically includes n-butyllithium, tert-butyllithium, or n-butylsodium, the inorganic base specifically includes sodium hydroxide, potassium hydroxide, lithium hydroxide, or cesium hydroxide, and the organic base specifically includes tetrahydropyrrole, piperidine, triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, triethylenediamine, or 4-dimethylaminopyridine.

9. The method for preparing a compound according to claim 1, characterized in that: In the step 3, the reaction temperature is controlled at -78-50°C, preferably -30-10°C, and the reaction time is controlled at 10-120 min.

10. The method for preparing a compound according to claim 1, characterized in that: In the step 4, the reducing agent is one of hydrogen, iron powder, and zinc powder, preferably hydrogen; the catalyst is one of homogeneous palladium, homogeneous platinum, homogeneous nickel, supported palladium, supported platinum, and supported nickel.

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