KR20040049158A - Method of selective bromination of asymmetric ketones - Google Patents

Abstract

PURPOSE: Provided is an economical method for brominating asymmetric ketone selectively, which produces an asymmetric ketone derivative substituting bromine at a non-activated alpha-position in the high purity. CONSTITUTION: The method is performed by brominating the asymmetric ketone derivative non-selectively by reacting the asymmetric ketone derivative and a brominating agent and then debrominating selectively by using a bromine remover to produce a compound represented by the formula 1, wherein the brominating agent is selected from the group consisting of a bromine molecule, hypobromous acid, bromous acid and hydrogen bromide, bromic acid and hydrogen bromide, and an oxidant and Br- and the bromine remover is selected from acetone, dihydrobenzoquinone, sodium sulfite, and etc. In the formula, R1 and R2 are independently aryl having at least one identical or different substituents selected from the group consisting of hydrogen, cyano, nitro, C1-C24 alkyl, or halogen, C1-C6 alkyl, C1-C8 alkoxy; alkyl- or aryl-substituted carbonyl; carboxyl; alkyl- or aryl-substituted carboxylic acid ester, R3 is halogen, hydrogen, or C1-C24 alkyl.

Description

Selective Bromination Method of Asymmetric Ketones {METHOD OF SELECTIVE BROMINATION OF ASYMMETRIC KETONES}

The present invention relates to a novel method for selectively brominating at an inactivated alpha position of an asymmetric ketone derivative.

Specifically, the present invention is a method for preparing a compound represented by the following Chemical Formula 1 by non-selective bromination of an asymmetric ketone derivative from a reaction with an asymmetric ketone derivative and a bromination reagent, followed by selective debromination using a brominating agent.

[Formula 1]

(Wherein R ¹ and R ² are each independently a hydrogen atom, a cyano group, a nitro group, C ₁ ~ C ₂₄ alkyl group, not substituted, or a halogen atom, C ₁ ~ C ₆ alkyl, C alkoxy of ₁ ~ C ₈ An aryl group wherein one or more substituents selected from the group consisting of groups are the same or differently substituted; a carbonyl group substituted with an alkyl group or an aryl group; a carboxyl group; a carboxylic ester group substituted with an alkyl group or an aryl group, and R ³ is Selected from the group consisting of halogen atoms, hydrogen atoms, alkyl groups of C ₁ to C ₂₄ )

Alpha bromoketones are materials used as important intermediates for the preparation of various linear or ring compounds, especially heterocyclic compounds. Since the position of the substituent in the product varies according to the brominated substituted position of the asymmetric ketone, the brominated substituted compounds at the inactivated alpha position are used as intermediates which are very important in the preparation of various compounds, and have been studied for a long time. Has been. These methods can be broadly classified into two methods: firstly, a regioselective bromination reaction from a reactant having a functional group which specifies a position to be substituted for bromine, or secondly, a regioselective bromination reaction using a thermodynamic equilibrium reaction. have.

First, examples of the regioselective bromination reaction from a reactant having a functional group which designates the position of bromine substitution are Acta Chemica Scandinavica, 1986 , B (40) , 700 to (trimethylsilyl) methyl ketone from bromine molecules. A bromination method using a bromine substitution reaction is disclosed, and Arch. Pharmaz., 1975 , 38 , 755 and Liebigs Ann Chem., 1986 , 177 disclose a process for bromination from diazommethyl ketones using a bromine substitution reaction with bromic acid, and Chem. Lett. 1983 , 1841 and J. Org. Chem. 1973, 38, 185 has each of NaBrO method is disclosed using an oxidation reaction of olefins by _{2, CrO 2 Cl 2, Synthesis} . 1990 , 595 discloses methods for preparing brominated substituted compounds at inactivated alpha positions by protecting with ester groups with positional substituents and by ester removal after bromination.

However, the above prior arts are a method of obtaining purely brominated ketones in an inactivated alpha position, but the reactants are very expensive and thus difficult to use for industrial scale synthesis.

Second, an example of using thermodynamic equilibrium to introduce bromine to a less reactive kinetics, but thermodynamically more stable, is Helvetica Chimica Acta, 1983 , 66 , 1475 which uses asymmetric ketones as reactants. A method of dissolving in dichloromethane, adding 1 equivalent of bromine at −10 ° C. for 90 minutes, and leaving the product at room temperature for 3 hours, followed by distillation under reduced pressure, discloses a method of J. Org. Chem., 1947 , 12 , 342, asymmetric ketones were dissolved in ether as a reactant, 1 equivalent of bromine was added at 0 ° C. for 90 minutes, left at room temperature for 24 hours, washed with alkaline solution, and distilled under reduced pressure. Japanese Unexamined Patent Publication No. 2000-336064 discloses a method of dissolving asymmetric ketones in n-chlorobutane as a reactant, adding 1 equivalent of bromine at -10 DEG C for 2 hours, and incubating for 16 hours. Methods for obtaining the product by distillation under reduced pressure are presented. However, the conventional techniques using the thermodynamic equilibrium described above are very economically obtainable brominated substituted ketones to the inactivated alpha position, but occur due to the decrease in yield and the limitation of thermodynamic equilibrium due to long reaction time. There is a problem that the purity of the product is low.

As described above, the selective substitution reactions of the asymmetric ketone derivatives known to date have problems that the reactants are expensive, the yield of the product is low, or the purity is low.

Therefore, there is a need in the art for new industrial methods for the production of economically and highly purified brominated substituted asymmetric ketone derivatives at inactivated alpha positions.

Accordingly, an object of the present invention is a method for producing a brominated substituted asymmetric ketone derivative in the deactivated alpha position by a selective debromination reaction after the dibromination, to produce an economical, high purity brominated substituted asymmetric ketone derivative To provide a method.

The present invention relates to a process for the economic and high purity production of asymmetric ketone derivatives brominated at inactivated alpha positions which are very widely used as intermediates for the preparation of various compounds.

Non-selective bromination of the asymmetric ketone derivative from the reaction with the asymmetric ketone derivative and the bromination reagent, followed by selective debromination using a bromination agent to prepare a compound represented by the following formula (1), A method of selective bromination of asymmetric ketones, characterized in that the molar ratio is 1 to 2.5, and the molar ratio of the bromate to the asymmetric ketone is 0.5 to 10.

[Formula 1]

(Wherein R ¹ and R ² are each independently a hydrogen atom, a cyano group, a nitro group, C ₁ ~ C ₂₄ alkyl group, not substituted, or a halogen atom, C ₁ ~ C ₆ alkyl, C alkoxy of ₁ ~ C ₈ An aryl group wherein one or more substituents selected from the group consisting of groups are the same or differently substituted; a carbonyl group substituted with an alkyl group or an aryl group; a carboxyl group; a carboxylic ester group substituted with an alkyl group or an aryl group, and R ³ is Selected from the group consisting of halogen atoms, hydrogen atoms, alkyl groups of C ₁ to C ₂₄ )

The present inventors use the starting material as an asymmetric ketone derivative in a method of preparing a brominated substituted asymmetric ketone derivative at an inactivated alpha position, and as a bromination reagent, bromine molecule, hypobromic acid, abromic acid and hydrogen bromide, bromic acid and hydrogen bromide, And an oxidizing agent and a reactant capable of acting as Br ⁻ , a bromine remover as an inorganic reducing agent, sulfur, hydrogen sulfide, sodium sulfite or sodium hydrogen sulfite as sulfurous acid or a sulfur compound; Metals that include hydrogen and can react with acids to generate hydrogen include iron, zinc, magnesium, aluminum or tin; Aluminum hydride, boron hydride or sodium hydride as the metal hydride; Organic bromine removers include secondary alcohols such as isopropanol or isobutanol; Carbonyls with alpha hydrogen include acetone, formaldehyde or acetaldehyde; Nitromethane with nitro alkanes activated by nitro groups; Activated olefins include ethylene, propylene or butylene; When the removal reaction is selected from phenol, aniline, anisol, furan, pyrrole, thiophene or dihydrobenzoquinone as an activated aromatic compound,

i) By optimizing the amount of bromine to be loaded, the amount of hydrogen bromide produced and the amount of bromate remover to be loaded can be minimized,

ii) In consideration of the solubility according to the asymmetric ketone, by selecting a specific solvent to minimize the amount of solvent required for the reaction, by selecting a specific bromine remover dropping, it was possible to simplify the purification process of the resulting bromoketone.

According to the present invention, the reaction scheme for preparing an asymmetric ketone derivative brominated at an inactivated alpha position is shown in Scheme 1 below.

That is, after the dibromination reaction in which the asymmetric ketone is brominated with both the activated and deactivated alpha positions by the reversible equilibrium reaction between the bromination and debromination reactions, the reaction system is changed to irreversible conditions by the introduction of the bromine remover. By selectively removing only bromine introduced at the activated alpha position by the generated hydrogen bromide, an asymmetric ketone derivative in which bromine is substituted only at the inactivated alpha position is prepared.

A preferred embodiment of the present invention is characterized by dropping a bromination reagent in a specific solvent and dropping the asymmetric ketone dissolved in a specific solvent under atmospheric pressure, and then adding a bromine remover after a certain time.

Hereinafter, a method for preparing a brominated substituted asymmetric ketone derivative at an inactivated alpha position will be described in detail.

In the bromination reaction of the asymmetric ketone represented by the formula (1), bromine is substituted first in the activated place, and then bromine is substituted in the inactive place, and the reaction mechanism is shown in Scheme 2 below.

The bromination reaction proceeds further where it is activated, i.e. where it is stabilized, such as enol. And as shown in Scheme 2, the reverse bromination reaction proceeds through the same reaction intermediate as the bromination reaction, so that the enol is further stabilized, that is, further activated.

In conclusion, using the fact that first brominated sites are first debrominated, the activated and inactivated sites of the asymmetric ketones are replaced with bromine, and then the bromines of the activated sites are selectively removed to deactivate the asymmetric ketones. It is a feature of the present invention that a compound is optionally substituted with bromine at the alpha position.

The inventors of the present invention tested various solvents that were not reactive with bromine for the selection of preferred solvents, and also tested various bromate removers to select preferred bromates, and for universal applications of this invention. Various asymmetric ketone derivatives were tested as reactants and the results are shown in Table 1 below.

TABLE 1

menstruum Reactant / Brominated Reagent (Equivalent) Time1 / time2 Bromine Remover (Equivalent) Yield (%) Reactant product By-product Acetic acid 1 / Bromine (2.2) 6/30 Acetone (10) 5 85 6 Acetic acid 2 / bromine (1.3) 2/30 Dihydrobenzoquinone (0.6) 11 85 One Acetic acid 3 / Bromine (2.0) 3 / 0.5 Acetone (10) 0 95 0 Acetic acid 4 / Bromine (1.5) 0.5 / 1 Dihydrobenzoquinone (1.3) 3 90 3 Acetic acid 5 / Bromine (2.2) 6/30 Sodium sulfite (2.0) 3 85 3 Dichloromethane 1 / Bromine (2.2) 24/30 Acetone (10) 4 80 4 Acetic acid 1 / bromic acid (0.8) + hydrobromic acid 4/30 Sodium sulfite (2.0) 3 82 5

Note) Reactants:

In Table 1 above, in the reaction for introducing bromine to the deactivated alpha position of the asymmetric ketone as described above, the inventors conducted various studies on the solvent, bromination reagent, bromine remover and reactants.

First, as a solvent, an organic solvent which is not reactive with a bromination reagent is preferably a C _1-4 aliphatic compound substituted with a halogen group or a C _1-4 fatty acid, particularly preferably acetic acid, dichloromethane, chloroform, or tetrachloromethane. Can be mentioned. As shown in Table 1 above, it can be seen that acetic acid shows higher yields in a shorter time. However, industrially, low boiling solvents such as dichloromethane are expected to be more advantageous for simple and economical purification of the product.

Secondly, as bromine remover, all compounds reactive with bromine are possible, but sodium sulfite is used as inorganic reducing agent, acetone is used as ketone with alpha hydrogen, and dihydroquinone is used as activated aromatic compound. It has advantages and disadvantages and should be selected and used in some cases.

Third, as the bromination reagent, various reagents for the bromination reaction are possible, but in the present invention, bromine and bromic acid and hydrobromic acid were used.

Fourth, as a reactant, compounds 1 to 5 were tested among all reactants represented by asymmetric ketones. For each reactant, the reaction time, the amount of bromine dropped and the amount of bromine remover were determined differently. Of the reactants represented, 1 and 5, in which R ¹ is a phenyl group, must drop 2.2 equivalents of bromine due to the small activation capacity of R ¹ .

As described above, the method of the present invention is to be carried out in consideration of various conditions such as the dropping amount of bromine, the pH according to the type and amount of the solvent, the type and amount of the bromine remover, the reaction time and temperature according to the kind of reactant In each case, it is necessary to confirm the progress of the reaction through HPLC (high pressure liquid chromatography).

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

EXAMPLE

All solvents and reagents used in the examples below were commercially available and used without special purification.

Example 1

Into a 100 mL round bottom flask was placed 1-phenyl-2-propanone (4.0 g, 29.85 mmol), acetic acid (10 mL) and 48% hydrobromic acid (5 mL) and dissolved in acetic acid (15 mL), bromine (10.5). g, 65.6 mmol, 2.2 equiv) was added dropwise for 1 minute. Thereafter, after standing at room temperature for 6 hours, acetone (22 ml, 17.34 g, 10 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, and then remaining acetone and bromo for 10 hours under reduced pressure. Acetone was removed, and the reaction mixture was transferred to a 500 ml beaker containing 200 ml of water, extracted with dichloromethane (100 ml), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics. -Phenyl-2-propanone (1.52 mmol, 5%), 1-bromo-1-phenyl-2-propanone (1.01 mmol, 3%), 1-bromo-3-phenyl-2-propanone ( 25.25 mmol, 85%), 1,3-dibromo-1-phenyl-2-propanone (1.01 mmol, 3%) was obtained (6.09 g).

1-phenyl-2-propanone (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.15-7.40 (m, 5H), 3.68 (s, 2H), 2.14 (s, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 206.1, 134.0, 129.1, 128.4, 126.7, 50.6, 28.9.

1-bromo-1-phenyl-2-propanone (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.34-7.44 (m, 5H), 5.44 (s, 1H), 2.29 (s, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 199.0, 135.1, 129.1, 129.0, 128.7, 56.2, 26.1.

MS (CI) 215 (M ⁺ +1), 213 (M ⁺ +1), 175, 173, 163, 161, 135, 133 (100), 117, 105,

91, 57, 43.

1-bromo-3-phenyl-2-propanone (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.20-7.35 (m, 5H), 3.94 (s, 2H), 3.91 (s, 2H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 199.2, 133.2, 129.4, 128.9, 127.5, 46.8, 33.3.

MS (CI) 215 (M ⁺ +1), 213 (M ⁺ +1), 175, 173, 163, 161, 145, 143, 135 (100), 133,

119, 105, 91.

1, 3-dibromo-1-phenyl-2-propanone (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30-7.50 (m, 5H), 5.84 (s, 1H), 4.23 (d, J = 12.8

Hz, 1H), 4.04 (d, J = 12.8 Hz, 1H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 192.8, 134.2, 129.5, 129.1, 128.9, 51.3, 30.8.

MS (CI) 295 (M ⁺ +1), 293 (M ⁺ +1), 291 (M ⁺ +1), 213, 211, 133 (100), 131, 104, 91.

Example 2

1-phenyl-1,3-butanedione (2.30 g, 14.13 mmol) and acetic acid (10 mL) were placed in a 100 mL round bottom flask, and bromine (2.94 g, 65.6 mmol, 1.3 equivalents) was dissolved in acetic acid (7 mL). ) Was added dropwise for 1 minute. Then, after standing at room temperature for 2 hours, dihydrobenzoquinone (1.0 g, 9.1 mmol, 0.64 equiv) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, followed by 500 containing 200 ml of water. Transfer to a beaker, extracted with dichloromethane (100 mL), dehydrated with anhydrous sodium sulfate, and then pass through a short silica column to remove inorganics. 1-phenyl-1,3-butanedione (2.04 mmol, 11.1%) , 1-bromo-4-phenyl-1,3-butanedione (15.7 mmol, 85.2%), 1-dibromo-4-phenyl-1,3-butanedione (0.16 mmol, 1%) A mixture (3.78 g) was obtained.

1-phenyl-1, 3-butanedione (keto form: enol form = 0.09: 1.0) (enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 16.19 (bs, 1H), 7.80-7.90 (m, 2H), 7.30-7.60 (m,

3H), 6.17 (s, 1 H), 2.19 (s, 3 H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 193.7, 183.3, 134.8, 132.2, 128.5, 126.9, 96.6,

25.7.

(keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 4.09 (s, 2H), 2.29 (s, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 128.7.

2-bromo-1-phenyl-1, 3-butanedione (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.90-8.00 (m, 2H), 7.60-7.70 (m, 1H), 7.40-7.60 (m,

2H), 5.65 (s, 1H), 2.46 (s, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 198.2, 189.9, 134.5, 133.6, 129.2, 129.0, 52.9,

27.1.

4-bromo-1-phenyl-1, 3-butanedione (enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 15.63 (bs, 1H), 7.87-7.92 (m, 2H), 7.40-7.60 (m,

3H), 6.45 (s, 1 H), 3.97 (s, 2 H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 188.4, 184.0, 133.9, 132.9, 128.7, 127.1, 95.4,

31.2.

2, 4-dibromo-1-phenyl-1, 3-butanedione (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.00 (dd, J = 7.0, 1.4 Hz, 2H), 7.67 (t, J = 7.3

Hz, 1H), 7.47-7.57 (m, 2H), 6.12 (s, 1H), 4.43 (d,

J = 13.8 Hz, 1H), 4.30 (d, J = 13.8 Hz, 1H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 192.0, 189.7, 134.7, 133.2, 129.2, 129.0, 49.4,

32.0.

4, 4-dibumomo-1-phenyl-1, 3-butanedione. (enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 14.89 (bs, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.46-7.64

(m, 3 H), 6.66 (s, 1 H), 5.95 (s, 1 H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 188.8, 181.9, 133.1, 132.9, 128.8, 127.1, 92.0,

39.6.

Example 3

2-acetylalphatetralone (79 mg, 0.422 mmol) and acetic acid (2 mL) were added to a 25 mL round bottom flask, and bromine (135 mg, 0.84 mmol, 2.0 equiv) dissolved in acetic acid (2 mL) was added 1 It was dripped for minutes. Then, after standing at room temperature for 3 hours, acetone (0.3 mL, 4.22 mmole, 10 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 minutes, followed by a 250 mL beaker containing 100 mL of water. After transferring, the mixture was extracted with dichloromethane (50 mL), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics, thereby obtaining 2-bromoacetylalphatetralone (107 mg, 0.401 mmol, 95.0%). Got it.

2-acetylalphatetralone (enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 16.36 (bs, 1H), 7.94 (dd, J = 7.2, 1.6 Hz, 1H),

7.27-7.45 (m, 2H), 7.20 (dd, J = 6.8, 1.0 Hz, 1H),

2.88 (t, J = 8.0 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H),

2.24 (s, 3 H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 193.8, 176.8, 140.7, 131.8, 131.0, 127.5, 126.7,

125.7, 105.9, 28.1, 23.8, 22.6.

2-bromoacetylalphatetralone (enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 15.82 (bs, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.20-7.45

(m, 2H), 7.18 (d, J = 7.2 Hz, 1H), 4.03 (s, 3H),

2.87 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 184.0, 181.2, 141.3, 132.6, 130.8, 127.7, 126.8,

126.1, 105.6, 28.5, 27.8, 22.5.

Example 4

Acetoacetic acid ethyl ester (894 mg, 14.13 mmol) and acetic acid (4 mL) were added to a 50 mL round bottom flask, and bromine (1.65 g, 10.3 mmol, 1.5 equiv) dissolved in acetic acid (2 mL) was added dropwise for 1 minute. It was. Thereafter, after standing at room temperature for 30 minutes, dihydrobenzoquinone (1.0 g, 9.1 mmol, 1,3 equiv) was added dropwise to the reaction mixture, and further left at room temperature for 1 hour, followed by 100 ml of water. Transfer to a 250 mL beaker, extract with dichloromethane (50 mL), dehydrate with anhydrous sodium sulfate, and pass through a short silica column to remove inorganics. A mixture (1.390 g) containing acetoacetic acid ethyl ester (6.204 mmol, 90.2%) and 4,4-dibromoacetoacetic acid ethyl ester (0.223 mmol, 3.2%) were obtained.

Acetoacetic acid ethyl ester (keto form: enol form = 1.0: 0.1)

¹ H NMR (200 MHz, CDCl ₃ ) δ 4.21 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 2.28 (s,

3H), 1.29 (t, J = 7.3 Hz, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 200.4, 166.9, 61.0, 49.8, 29.8, 13.8.

(enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 12.12 (bs, 1H), 4.98 (s, 1H), 1.96 (s, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 175.2, 89.5, 59.6, 20.8, 14.0.

2-bromoacetoacetic acid ethyl ester (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 4.77 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.45 (s,

3H), 1.32 (t, J = 7.1 Hz, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 196.3, 165.1, 63.1, 49.1, 26.4, 13.8.

MS (CI) 211 (M ⁺ +1), 209 (M ⁺ +1), 183, 181, 131 (100), 103, 85.

4-bromoacetoacetic acid ethyl ester (keto form: enol form = 1.0: 0.21) (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 4.21 (q, J = 7.2 Hz, 2H), 4.08 (s, 2H), 3.71 (s,

2H), 1.29 (t, J = 7.1 Hz, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 194.3, 166.4, 61.6, 46.0, 33.8, 13.9.

(enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 11.99 (s, 1H), 5.29 (s, 1H), 4.23 (q, J = 7.0 Hz,

2H), 3.87 (s, 2H), 1.30 (t, J = 7.0 Hz, 3H).

MS (CI) 211 (M ⁺ +1), 209 (M ⁺ +1, 100), 165, 163, 131, 129, 101, 85, 47.

2,2-dibromoacetoacetic acid ethyl ester (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 4.36 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.33 (t, J

= 7.2 Hz, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 190.9, 163.6, 64.7, 59.8, 23.5, 13.7.

MS (CI) 291 (M ⁺ +1), 289 (M ⁺ +1), 287 (M ⁺ +1), 263, 261, 256, 245, 243, 241, 211,

209, 207, 131 (100), 105, 85, 47.

4,4-dibromoacetoacetic acid ethyl ester (keto form: enol form = 1.0: 0.25) (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 6.02 (s, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.96 (s,

2H), 1.30 (t, J = 6.8 Hz, 3H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 188.7, 166.1, 61.9, 42.0, 41.8, 14.0.

(enol form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 12.10 (bs, 1H), 5.92 (s, 1H), 5.42 (s, 1H), 4.26

(q, J = 6.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H).

Example 5

Into a 100 mL round bottom flask was placed 1-phenyl-2-butanone (2.0 g, 13.5 mmol), acetic acid (10 mL) and 48% hydrobromic acid (2 mL), and bromine (4.32) dissolved in acetic acid (5 mL). g, 27.0 mmol, 2.0 equiv) was added dropwise for 1 minute. Thereafter, after standing at room temperature for 6 hours, sodium sulfite (3.4 g, 2 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, the reaction mixture was 500 ml containing 200 ml of water. Transferred to a beaker, extracted with dichloromethane (100 mL), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics. 1-phenyl-2-butanone (0.41 mmol, 3%), 1- Mixture comprising bromo-3-phenyl-2-butanone (11.5 mmol, 85%), 1,3-dibromo-1-phenyl-2-butanone (0.41 mmol, 3%) (2.80 g) Got.

1-phenyl-2-butanone (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.15-7.40 (m, 5H), 3.68 (s, 2H), 2.40 (q, J = 7.2

Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H).

1-bromo-1-phenyl-2-butanone (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.34-7.44 (m, 5H), 5.44 (s, 1H), 2.42 (q, J = 7.2

Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H).

1-bromo-3-phenyl-2-butanone (keto form)

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.20-7.35 (m, 5H), 4.11 (q, J = 7.2 Hz, 1H), 3.91

(s, 2H), 1.65 (d, J = 7.2 Hz, 3H).

Example 6

1-phenyl-2-propanone (4.0 g, 29.85 mmol), dichloromethane (20 mL) and 48% hydrobromic acid (2 mL) were added to a 100 mL round bottom flask, and bromine dissolved in dichloromethane (15 mL). (9.55 g, 59.7 mmol, 2.0 equiv) was added dropwise for 1 minute. Then, after standing at room temperature for 24 hours, acetone (22 mL, 17.34 g, 10 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, after which the reaction mixture contained water (200 mL). The resulting mixture was transferred to a 500 ml beaker, followed by extraction with additional dichloromethane (100 ml), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics. 1-phenyl-2-propanone (1.22 mmol , 4%), 1-bromo-1-phenyl-2-propanone (1.22 mmol, 4%), 1-bromo-3-phenyl-2-propanone (23.76 mmol, 80%) (5.37 g) was obtained.

Example 7

1-phenyl-2-propanone (4.0 g, 29.85 mmol), acetic acid (20 mL) and bromic acid (3.60 g, 23.9 mmol, 0.8 equiv) were added to a 100 mL round bottom flask, and 48% hydrobromic acid (5 mL) was added. ) Was added dropwise. Thereafter, after standing at room temperature for 4 hours, sodium sulfite (7.52 g, 59.7 mmol, 2 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, the reaction mixture contained 200 ml of water. After transferring to a 500 mL beaker, extracted with dichloromethane (100 mL), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics, 1-phenyl-2-propanone (0.90 mmol, 3%) , 1-bromo-1-phenyl-2-propanone (0.60 mmol, 2%), 1-bromo-3-phenyl-2-propanone (24.48 mmol, 82%), 1,3-dibromo A mixture (5.73 g) containing -1-phenyl-2-propanone (0.90 mmol, 3%) was obtained.

The present invention can be used in a novel industrial process that can be produced economically and with high purity of asymmetric ketones selectively brominated at an inactivated alpha position of an asymmetric ketone, which is widely used as an intermediate for the preparation of various compounds.

Claims (4)

Non-selective bromination of the asymmetric ketone derivative from the reaction with the asymmetric ketone derivative and the bromination reagent, followed by selective debromination using a bromination agent to prepare a compound represented by the following formula (1), A method of selective bromination of asymmetric ketones, characterized in that the molar ratio is 1 to 2.5, and the molar ratio of the bromate to the asymmetric ketone is 0.5 to 10. [Formula 1] (Wherein R ¹ and R ² are each independently a hydrogen atom, a cyano group, a nitro group, C ₁ ~ C ₂₄ alkyl group, not substituted, or a halogen atom, C ₁ ~ C ₆ alkyl, C alkoxy of ₁ ~ C ₈ An aryl group wherein one or more substituents selected from the group consisting of groups are the same or differently substituted; a carbonyl group substituted with an alkyl group or an aryl group; a carboxyl group; a carboxylic ester group substituted with an alkyl group or an aryl group, and R ³ is Selected from the group consisting of halogen atoms, hydrogen atoms, alkyl groups of C ₁ to C ₂₄ ) The method of claim 1, wherein the bromination reagent is selected from the group consisting of bromine molecules, hypobromic acid, abromic acid and hydrogen bromide, bromic acid and hydrogen bromide, and an oxidizing agent and Br ⁻ . The method of claim 1, wherein the bromine remover is an inorganic reducing agent sulfurous acid or a sulfur compound sulfur, hydrogen sulfide, sodium sulfite or sodium hydrogen sulfite; Metals that include hydrogen and can react with acids to generate hydrogen include iron, zinc, magnesium, aluminum or tin; Aluminum hydride, boron hydride or sodium hydride as the metal hydride; Organic bromine removers include secondary alcohols such as isopropanol or isobutanol; Carbonyls with alpha hydrogen include acetone, formaldehyde or acetaldehyde; Nitromethane with nitro alkanes activated by nitro groups; Activated olefins include ethylene, propylene or butylene; A process for selective bromination of asymmetric ketones, characterized in that the activated aromatic compound is selected from phenol, aniline, anisol, furan, pyrrole, thiophene or dihydrobenzoquinone. The method of claim 1, wherein the organic solvent is a C ₁ to C ₄ aliphatic compound or C ₁ to C ₄ fatty acid substituted with a halogen group.