JP2627829B2 - Method for producing alpha-hydroxy ketone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION α-Hydroxy ketone exists widely in nature, and adriamycin and baunomycin are used as anticancer agents [J. Am. Chem. Soc. , 85 , 53
34 (1964)], and betamethasone and cortisone are steroid hormones [J. Am. Chem. S
oc. , 80 , 6687 (1958)], and cyproterone is an anti-androgen [Ger Offen 1
18991 (1965)], whose physiological activities are known and very important. The present invention relates to a method for producing them.

[0002]

2. Description of the Related Art These methods for synthesizing α-hydroxyketones include, for example, the oxidation of diols [J. Org
nanomet. Chem. 5, 263 (196
6)], oxidative cleavage of the epoxide [(J. Org. Ch.
em. , 26 , 1681 (1961)], acyloin condensation [J. 0rg. Chem. , 40 , 393 (197
5)] and the like are known. In addition, only a method using a stoichiometric amount of potassium permanganate is known as a synthesis method from an olefin.

[0003] The inventors have found that α-
While continuing research on the subject of selectively producing hydroxyketones with high yield, the problem could be solved by using a ruthenium compound as a catalyst. Ruthenium compounds are known to exhibit a catalytic action in the oxidation reaction of certain organic compounds (Chemistry, Inc., Vol. 45, No. 6, pp. 426-427, 1990). From the viewpoint of the specificity of the catalytic action, α-
No catalytic activity was expected in the process for producing hydroxyketones.

[0004]

According to the present invention, there is provided a compound represented by the general formula (A):

Embedded image (However, R ¹ in the formula is an alkyl group, an aryl group or an alkoxycarbonyl group which may have a substituent, and R ² and R ³ are a hydrogen atom, an alkyl group which may have a substituent or An aryl group, R ² and R ³ are not hydrogen atoms at the same time, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may form a ring, and R ¹ and R ² and R ² and R ³ may form a ring at the same time) with an oxidizing agent in the presence of a ruthenium compound and water.

Embedded image (However, R ¹ , R ² and R ³ in the formula have the same meanings as described above.)

In the above formula, (1) Examples of the alkyl group which may have a substituent include an acetoxyalkyl group, a 2-methyl-4-acetoxypentyl group, a benzyloxymethyl group and a benzoyloxymethyl group. (2) Examples of the aryl group which may have a substituent include an acetoxybenzyl group, and (3) examples of the alkoxycarbonyl group include a methoxycarbonyl group and an ethoxycarbonyl group. Hereinafter, the present invention will be described in detail by dividing the sections.

(Olefin) Examples of the olefin (A) as a raw material of the present invention include cyclopentene, cyclohexene, cyclooctene, trans-2-butene, cis-2-butene, 4-octene, β-methylstyrene,
Cyclohexadiene, cyclooctadiene, indene,
1-methyl-cyclopentene, 1-methylcyclohexene, ethylidenecyclohexane, 2-methyl-4,4-
Examples include dimethylpentene, methyl crotonate, ethyl crotonate, methyl cinnamate, ethyl 3-methylcrotonate, pentylidenecyclohexane, ethylidenecyclopentane and the like.

(Ruthenium compound) The ruthenium compound used as a catalyst in the present invention is Compreh.
sensitive Organometallic Che
mistry Vol.4, pages 651 to 930 Perga
mon Press (1982). (1) RuX ₃ (C) wherein X represents a halogen atom, an acyloxy group represented by R ⁴ COO (where R ⁴ represents a lower alkyl group) or acetylacetonate. Specific examples of the ruthenium compound include, for example, ruthenium trichloride, ruthenium tribromide, ruthenium triiodide and hydrates thereof, ruthenium acetylacetonate, ruthenium acetate and the like.

(2) Ruthenium complex Ruthenium phosphine complex HRuCl (PPh ₃ ) ₃ , RuCl ₂ (PPh ₃ ) ₃
, H ₂ Ru (PPh ₃ ) ₄ , Ru ₂ Cl ₄ (BINA
P) ₂ (NEt ₃ ), Ru (OAc) ₂ (BINA)
P), Ru ₂ Cl ₄ (1,4-diphos) ₂ , HR
uCl (BINAP) ₂ , [Ru (bpy) ₂ (O)
(PPh ₃ )] (ClO ₄ ) ₂ , [Ru (bpy)
₂ (O) (PEt ₃ )] (ClO ₄ ) ₂ , [Ru (H ₂
O) (bpy) ₂ (PPh ₃ )] (ClO ₄ ) ₂ etc. (where Et is an ethyl group, Ph is a phenyl group,
Ac is an acetyl group, BINAP is 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, bp
y means bipyridyl, and so on. ) Ruthenium-nitrosyl complex Ru (NO) Cl ₃ .H ₂ O

Ruthenium-carbonyl complex Ru ₃ (CO) ₁₂ , [RuCl ₂ (CO) ₃ ] ₂ , R
uCl ₂ (CO) ₂ (PPh ₃ ) ₂ ruthenium-oxo complex RuO ₂ ruthenium-olefin complex RuCl ₂ (COD) (COD represents 1,5-cyclooctadiene) and the like. (3) Ruthenium metal powder Ruthenium-carbon, ruthenium-graphite, ruthenium-alumina, ruthenium-silica, ruthenium-zeolite, ruthenium-zirconium oxide and the like. It is preferable that the ruthenium compound of the catalyst is used in an amount of 0.01 to 0.2 times, particularly 0.03 to 0.1 times, the mole of the compound (A).

(Oxidizing agent) The oxidizing agent used in the present invention is not particularly limited. For example, peroxides of various carboxylic acids, specifically, peracetic acid, perpropionic acid,
Metachloroperbenzoic acid and the like can be mentioned. These may be used as ordinary commercial products, or may be separately prepared from carboxylic acid and hydrogen peroxide by a conventional method before the reaction and used. The oxidizing agent is preferably used in an amount of 1 to 8 times, particularly 2 to 3 times the mole of the compound (A).

(Operation method) In order to carry out the present invention, water and a ruthenium compound are dissolved or suspended in compound (A) in the following appropriate solvent, and the mixture is stirred at a temperature of -10 to 30 ° C. The reaction is carried out by adding an ethyl acetate solution or an acetic acid solution of the acid and reacting. The order and method of adding the raw material compounds, the catalyst, and the like are not particularly limited, but it is desirable that the oxidizing agent be gradually added last. As the solvent, acetonitrile, methylene chloride, dichloroethane, chlorobenzene and the like and a mixture thereof are used. In order to isolate the target substance from the reaction mixture, means known per se, for example, distillation,
Column chromatography and the like can be employed.

[0012]

EXAMPLES Next, examples will be described below, but the present invention is not limited to these examples. Example 1 A thermometer and a dropping funnel were attached to a 50 ml kolben, a stirrer was put therein, and 10 ml of methylene chloride, 10 ml of acetonitrile, 10 ml of water, and 0.82 g (10 mmol) of cyclohexene were added.
And 78 ml of RuCl ₃ .3H ₂ O (0.3
Mmol). The mixture was cooled to 18 ° C. while stirring with a magnetic stirrer, and 7.6 g (30 mmol) of peracetic acid was added.
(30% ethyl acetate solution) was added dropwise over 2 hours. After the dropwise addition, the mixture was further stirred at room temperature for 2 hours, and the reaction solution was extracted three times with 50 ml of methylene chloride. The extracts were combined, washed with 50 ml of saturated saline, and finally dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 0.843 g of 2-hydroxycyclohexanone (α-hydroxycyclohexanone). The yield was 74%. ¹ H NMR (CDCl ₃ , 270 MHz) δ: 1.45
-1.93 (m, 4H), 2.10 (m, 1H), 2.
32 (m, 3H), 3.65 (b, 1H), 4.12
(Ddd, J = 11.9.6.8, 1.5, 1H), ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 2
3.4, 27.6, 36.8, 39.5, 75.4, 2
11.3.

Example 2 A thermometer and a dropping funnel were attached to a 50 ml kolben, and methylene chloride (10 ml), acetonitrile (10 ml), water (10 ml),
1.12 g (10 mmol) of octene and 78 mg (0.3 mmol) of ruthenium trichloride are added. A stirrer was put therein, and 7.6 g (30 mmol) of peracetic acid (30% ethyl acetate solution) was added dropwise at 15 ° C. for 1.5 hours while stirring with a magnetic stirrer. After the addition, the mixture was further stirred at room temperature for 2 hours. The reaction solution was extracted three times with 30 ml of methylene chloride, and the extract was washed with 30 ml of a saturated saline solution, and finally dried over anhydrous magnesium sulfate. -Octanone was obtained. The obtained crude 4-hydroxy-3-octanone was subjected to silica gel column chromatography (eluent: n-
It is a 10: 1 mixture of hexane and ethyl acetate. ) To give 0.87 g of the desired product, namely 4-hydroxy-
3-Octanone was obtained. The yield was 59%. ¹ H NMR (CDCl ₃ , 270 MHz) δ: 0.9
4 (t, J = 7.5, 3H), 0.97 (t, J = 7.5.
3,3H), 1.40 (b, 1H), 1.48 (m, 2
H), 1.66 (tq, J = 5.1, 7.3, 2H
), 1.72 (m, 2H), 2.45 (dt, J =
7.2 (gem.), 5.1, 2H), 4.18 (t,
J = 3.5, 1H). ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 1
3.6, 13.8, 17.2, 18.2, 35.9, 3
9.8, 76.3.

Example 3 A thermometer and a dropping funnel were attached to a 50 ml colben, and under a nitrogen atmosphere, 10 ml of methylene chloride, 10 ml of acetonitrile, 5 ml of water, 0.82 g (10 mmol) of cyclohexene and HRuCl
It was added _{(PPh 3)} 3 277mg (0.3 mmol). At 20 ° C. with stirring, 7.6 g (30 mmol) of peracetic acid
(30% ethyl acetate solution) was added dropwise over 2 hours. After the dropwise addition, the mixture was further stirred at room temperature for 1 hour and treated in the same manner as in Example 1 to obtain 0.68 g of 2-hydroxycyclohexanone (α-hydroxycyclohexanone). The yield was 60%. ¹ H-NMR was the same as in Example-1.

Examples 4 to 12 The same operation as in Example 1 was performed, and the results shown in Table 1 were obtained.

[0016]

[Table 1]

The properties of the products of Examples 4 to 12 were as follows: Example 4 2-Hydroxycyclooctanone Melting Point 140-14
5 ° C. amorphous powder ¹ H NMR (CDCl ₃ , 270 MHz) δ: 0.9
5 (m, 1H), 1.30-2.10 (m, 7H),
2.36 (m, 3H), 2.75 (ddd, J = 3.
9, 12.0, 12.0, 1H), 3.80 (b, 1
H, OH), 4.18 (dd, J = 2.9, 6.6, 1
H). ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 2
2.1, 24.6, 25.6, 28.9, 29.1, 3
7.3, 76.2, 217.4.

Example 5 1-Phenyl-1-oxo-2-propanol ¹ H NMR (CDCl ₃ , 270 MHz) δ: 1.4
5 (d, J = 7.1, 3H), 3.77 (d, J = 5.
4,1H), 5.15 (dq, J = 5.4, 7.1,1
H), 7.30-7.95 (m, 5H). ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 2
2.3, 69.4, 127.4, 128.4, 128.
8, 129.0, 134.0, 138.1, 202.
4. 1-phenyl-2-oxo- ¹ -propanol ¹ H NMR (CDCl ₃ , 270 MHz) δ: 2.0
8 (s, 3H), 4.28 (d, J = 3.9, 1H),
5.09 (d, J = 3.9, 1H), 7.30-7.9
5 (m, 5H). ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 2
5.2, 80.2, 128.7, 128.9, 129.
0, 133.5, 207.1.

Example 6 2-Hydroxy- ¹ -indanone ¹ H NMR (CDCl ₃ , 270 MHz) δ: 3.0
1 (dd, J = 16.6, 5.1, 1H), 3.27
(B, 1H), 3.56 (dd, J = 16.6,5.
1,1H), 4.54 (dd, J = 7.8, 5.1,1
H), 7.39-7.77 (m, 4H).

Example 7 6-Hydroxy-2-cyclohexen- ¹ -one ¹ H NMR (CDCl ₃ , 270 MHz) δ: 1.8
8 (m, 1H), 2.41 (m, 1H), 2.54
(M, 2H), 3.70 (b, 1H), 4.20 (d
d, J = 13.7, 5.6, 1H), 6.12 (dd
d, J = 9.8, 3.7, 1.8, 1H), 7.02
(M, 1H), ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 2
5.7, 31.3, 72.9, 127.0, 152.
0, 200.4.

Example 8 2-Hydroxy-2-methylcyclopentan-1-one ¹ H NMR (CDCl ₃ , 270 MHz) δ: 1.2
6 (S, 3H), 1.82 (m, 1H), 2.01
(M, 3H), 2.33 (m, 2H), 2.56 (b,
1H). ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 1
7.3, 23, 0, 34.3, 36.9, 76.6, 2
19.9.

Example 9 2-Hydroxy-2-methylcyclohexane- ¹ -one ¹ H NMR (CDCl ₃ , 270 MHz) δ: 1.4
0 (S, 3H), 1.60-1.80 (m, 4H),
2.12 (m, 2H), 2.50 (m, 2H), 3.9
3 (b, 1H), ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 2
3.0, 25.1, 27.9, 37.8, 42.1, 7
6.4, 214.3.

Example 10 1-acetylcyclohexane- ¹ -ol ¹ H NMR (CDCl ₃ , 270 MHz) δ: 1.4
0-1.80 (m, 10H), 2.24 (S, 3H),
3.50 (b, 1H). ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 2
0.5, 23.7, 25.3, 33.9, 78.1, 2
12.7.

Example 11 Ethyl 2-hydroxy-3-oxobutyrate ¹ H NMR (CDCl ₃ , 270 MHz) δ: 1.3
2 (t, J = 7.0, 3H), 2.35 (s, 3H),
4.30 (q, 2H, J = 7.0), 4.30 (b, 1
H), 4.77 (s, 1H). ¹³ C NMR (CDCl ₃ , 67.5 MHz) δ: 1
4.1, 26.0, 62.6, 78.3, 168.3,
202.0.

Example 12 Methyl 3-hydroxy-2-oxo-3-phenylpropionate ¹ H NMR (CDCl ₃ 270 MHz) δ: 3.72
(S, 3H), 4.30 (b, 1H), 5.61 (s,
1H), 7.43-8.12 (m, 5H).

Examples 13-22 A thermometer and a dropping funnel were attached to a 50 ml colben, and methylene chloride (7 ml), water (7 ml), 1-methyl-1-cyclohexene (2 mmol) and a ruthenium catalyst (0 ml) were used. .1 mmol). A stirrer was put in, and 1.52 g (6 mmol) of peracetic acid (30% ethyl acetate solution) was added dropwise at room temperature for 2 hours while stirring with a magnetic stirrer. After the addition, the mixture was further stirred at room temperature for 2 hours. The reaction solution was extracted three times with 20 ml of methylene chloride, and the extract was washed with 30 ml of saturated saline and finally dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain crude 2-methyl-2-hydroxy-1
-Cyclohexanone was obtained. The obtained crude 2-methyl-2-hydroxy-1-cyclohexanone was purified by silica gel column chromatography (eluent was a 5: 1 mixture of n-hexane and ethyl acetate) to obtain a purified product. . The results are as shown in Table 2.

[0027]

[Table 2]

Examples 23 to 34 The same treatment as in Example 1 was carried out, and the following results were obtained.

[0029]

[Table 3]

[0030]

[Table 4]

[0031]

Industrial Applicability The process of the present invention is an industrially advantageous process capable of selectively producing a physiologically active substance and an .alpha.-hydroxy ketone which is important as an intermediate thereof in a simple operation with a high yield. is there.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location C07C 49/337 9049-4H C07C 49/337 49/487 9049-4H 49/487 49/747 9049− 4H 49/747 49/80 9049-4H 49/80 67/313 67/313 69/16 69/16 69/716 69/716 69/738 69/738 // C07B 61/00 300 C07B 61/00 300

Claims (4)

(57) [Claims] 1. A compound of the general formula (A) (Wherein R ¹ is an alkyl group, an aryl group or an alkoxycarbonyl group which may have a substituent, and R ² and R ³ are a hydrogen atom, an alkyl group or an aryl which may have a substituent. R ² and R ³ are not hydrogen atoms at the same time, but R ¹ and R ² , R ¹ and R ³ or R
² and R ³ may form a ring, and R ¹ and R ² and R ²
And R ³ may simultaneously form a ring. An oxidizing agent is allowed to act on the compound represented by the formula (B) in the presence of a ruthenium compound and water. (However, R ¹ , R ² and R ³ in the formula have the same meanings as described above.) 2. A ruthenium compound represented by the following general formula (C): RuX ₃ (C) wherein X is a halogen atom or R ⁴ COO.
(However, R ⁴ represents a lower alkyl group.) Represents an acyloxy group or an acetylacetonate group. ]
The method for producing an α-hydroxy ketone according to claim 1, which is a compound represented by the formula: 3. The ruthenium compound is a ruthenium-phosphine complex, a ruthenium-nitrosyl complex, a ruthenium-
The method for producing an α-hydroxy ketone according to claim 1, which is a ruthenium complex selected from a carbonyl complex, a ruthenium oxo complex and a ruthenium olefin complex. 4. The process according to claim 1, wherein the ruthenium compound is a ruthenium metal or ruthenium carrier.