JPH09110787A - Acetylation of primary alcohol and phenol by solvent-free reaction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply and profitably obtain an acetate ester useful as a synthetic raw material or intermediate for medicines and various compounds by reacting an specific OH group-containing compound with acetylimidazole in the absence of a solvent in a high selectivity and in a high yield with scarcely polluting an environment. SOLUTION: (A) A primary alcohol or a phenolic OH group-having compound is reacted with (B) acetylimidazole e.g. in an A/B molar ratio of 1/(1-2.2), especially 1/(1.2-2.2), in an opened air atmosphere at a temperature of -30 to 100 deg.C, especially 10-40 deg.C, to produce an acetic ester. When the component A is solid, the components A and B are concretely sufficiently ground with a mortar, etc., and subsequently leave them in stationary state for their reaction.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing acetates which are useful as pharmaceuticals, various synthetic raw materials or intermediates.

[0002]

2. Description of the Related Art Heretofore, there have been no proposals for a method for selectively synthesizing primary alcohols or acetate derivatives of phenolic hydroxyl groups. On the other hand, "Journal of the
American Chemical Societ
Y., 99, 3531 (1977), a method of reacting pyridinyl alcohol with acetylimidazole in the presence of a platinum catalyst to synthesize corresponding acetates is disclosed. However, this method requires a long reaction time, a reaction solvent, a reaction in an inert gas atmosphere, an expensive platinum catalyst, and a general reaction example. Was missing. Also,
Regarding the solvent-free reaction, some examples have already been known and their usefulness has been recognized. For example, "Journal o
f Chemical Society, Chemical
al Communications "p. 958 (19
(1988) discloses a method for obtaining ester and lactone compounds by solid phase Bayer-Villiger reaction, but its application range is limited.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to overcome the above-mentioned disadvantages and drawbacks of the conventional methods and provide a synthetically advantageous method for producing acetates. In particular, an object of the present invention is to provide a method for industrially producing an acetate compound of a compound having a primary alcohol and a phenolic hydroxyl group by a reaction operation which is easier and milder than conventional methods.

[0004]

The present invention is characterized in that a primary alcohol, a secondary alcohol having less steric hindrance or a compound having a phenolic hydroxyl group is reacted with acetylimidazole in the substantial absence of a solvent. And a method for producing an acetate compound of a compound having a primary alcohol or a phenolic hydroxyl group. Acetylimidazole reacts with primary alcohols or compounds with phenolic hydroxyl groups to give the corresponding acetic acid esters.
It does not react with cyclic secondary alcohols, but it reacts with limited alcohols having less steric hindrance among chain secondary alcohols. It does not react with tertiary alcohols. Therefore, the method of the present invention can be used to selectively acetylate only a specific hydroxyl group of a compound having two or more hydroxyl groups in the same molecule. Further, since the method of the present invention can carry out the reaction substantially without using a solvent, there are remarkable economical merits such as cost reduction of the solvent and omission of removal of the solvent after the reaction. In addition, not using a solvent reduces the chance of environmental pollution and is also excellent in terms of environmental protection. As a result, it is easier to expand the reaction scale than using a solvent. When two or more primary alcohol groups or phenolic hydroxyl groups are present in one molecule, it is possible to acetylate only one or both by adjusting the amount of acetylimidazole used. The reaction scheme of the method of the present invention is as follows.

[0005]

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R in R-OH in the above reaction formula is R
There is no particular limitation as long as it forms a compound having a primary alcohol, a secondary alcohol with less steric hindrance, or a phenolic hydroxyl group, which is bound to the compound, but it may have a substituent chain saturated or unsaturated. An aliphatic group or an aromatic group which may have a substituent is preferable. The chain saturated or unsaturated aliphatic group may be linear or branched, preferably an aliphatic hydrocarbon group having 1 to 20 carbon atoms, and more preferably an aliphatic hydrocarbon group having 1 to 15 carbon atoms. Examples of the group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, a citronellyl group, and a farnesyl group. These chain saturated or unsaturated aliphatic groups may be substituted with a cyclic aliphatic group which may have a substituent, a monocyclic or polycyclic aromatic group or a heterocyclic group. Often, specific examples thereof include a cyclohexyl group, a phenyl group, a pyridyl group, a naphthyl group, a hydroxymethyloctahydronaphthalene group, a phthalimido group, a dimethylbenzyl alcohol group, and a tetrahydropyranyloxy group. The aromatic group which may have a substituent is preferably a phenyl group or a naphthyl group, but may be a heteroaromatic ring. The substituent of these aromatic groups is not particularly limited as long as it does not participate in the reaction, but is preferably a lower aliphatic hydrocarbon group having 1 to 10 carbon atoms, more preferably a lower aliphatic hydrocarbon group having 1 to 5 carbon atoms. Examples thereof include an aliphatic hydrocarbon group, and specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a t-butyl group and the like.

Further, these compounds may further have a substituent which does not participate in the reaction. Examples of these substituents include ester groups, ketone groups, formyl groups, ketal groups, ether groups, cyano groups, amide groups, amino groups, nitro groups, azo groups, halogens, organic silicon groups, organic sulfur groups, and organic groups. Examples thereof include all functional groups other than protic such as selenium group and organic phosphorus group. Further, the compound represented by the formula R-OH may further have one or more hydroxyl groups in addition to the hydroxyl group represented by the formula. These second or more hydroxyl groups may form a primary alcohol or a phenol derivative, but may be other ones. As described above, R in the above reaction formula may be any of the above unless it has a group that inhibits this reaction, and further has a group such as sugar, steroid, peptide and protein. You may. In the case where these groups further include active hydrogen having reactivity with this reaction, the active hydrogen can be protected with a protecting group, if necessary. As this protecting group, those commonly used in peptide synthesis and the like can also be used.

The amount of the acetylimidazole used in the present invention is less than 2.5 mol, preferably 1 to 2.2 mol, based on 1 mol of the compound having a primary alcohol or a phenolic hydroxyl group as the other raw material. More preferably 1.
It is 2 to 2.2 mol. This reaction can be carried out under pressure, atmospheric pressure or reduced pressure, but atmospheric pressure is preferred. Although this reaction can use a solvent, it is preferably carried out in the substantial absence of a solvent. When a solvent is used, a small amount of a hydrocarbon solvent such as pentane, hexane and heptane, an ether solvent such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, chloroform, methylene dichloride, carbon tetrachloride. It is also possible to use halogen-based solvents such as 1,2-dichloroethane, aromatic solvents such as benzenetoluene and xylene, and aprotic highly polar solvents such as dimethylformamide. The method of carrying out this reaction substantially without solvent is another feature of the present invention. When both raw material compounds are solids, the reaction can be terminated by thoroughly grinding both raw materials in a mortar or the like and allowing the mixture to stand. This reaction can be carried out under an inert gas atmosphere, but is preferably in open air.
Reaction temperature is -30 to 100 ° C, preferably 10 to 40 ° C
Range, more preferably room temperature. The reaction time is generally 30 minutes to 24 hours, preferably 45 minutes to 12 hours, although it depends on the reaction temperature, the amount of the charged raw materials and the like. The reaction product can be isolated and purified by a unit operation known per se such as chromatography, distillation, recrystallization, sublimation method or the like after extraction with a solvent, if necessary. The method of direct column chromatography is preferred.

[0009]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples. Example 1 134 ml (1 mmol) of β-citronellol and 166 mg (1.5 mmol) of acetylimidazole were well ground in a mortar and allowed to stand overnight at room temperature. Hexane /
101 mg (51% yield) purified with silica gel column using ethyl acetate {4/1 (volume ratio)} as developing solvent.
Oil was obtained. The analysis results of this crystal were as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 1732,145
7, 1369, 1256, 1054 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 0.91 (3H, d, J6.4), 1.6 (3H,
s), 1.68 (3H, s), 1.1 to 1.9 (5H,
m), 1.9 to 2.3 (2H, m), 2.03 (3H,
s), 4.09 (2H, m), 5.08 (1H, m) (3) MS [EI, m / e (relative int
energy)] 138 (M ⁺ -AcOH, 46), 123 (100),
109 (44), 95 (61), 83 (25), 82
(62), 81 (79), 69 (73), 68 (3
8), 67 (98), 55 (49), 43 (76), 4
1 (63) From the above analytical values, it was confirmed that the product was citronellyl acetate. This reaction is shown by the reaction formula as follows.

[0010]

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Example 2 (1S ^* , 2S ^* , 4aR ^* , 8S ^* , 8aS ^* )-8
-Hydroxy-2-methyl-1,2,4a, 5,6,
197 mg (1 mmol) of 7,8a, 8b-octahydronaphthalene-1-methanol and 167 mg (1.5 mmol) of acetylimidazole were well ground in a mortar and allowed to stand at room temperature for 2 hours. Acetylimidazole 5
5 mg (0.5 mmol) was added and mashed. After 1 hour, add this to hexane / ethyl acetate {1/4 (volume ratio)}
Is used as a developing solvent and purified using a silica gel column.
3 mg (yield 89%) of crystals (melting point: 76 ° C) were obtained.
The analysis results of this crystal were as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 1725, 137
3,1259,1034 (2) ¹ H-NMR (CDCl ₃ , δ (ppm)] 0.95 (1H, m), 1.05 (3H, d, J7),
1.55 to 1.65 (3H, m), 1.65 to 1.9
(3H, m), 2.06 (3H, s), 2.15-2.
2 (2H, m), 3.93 (1H, dd, J11, 8.
6), 4.03 (1Hs), 4.72 (1H, dd, J
11, 4.5), 5.44 (2H, s) (3) MS [EI, m / e (relative in
tensity)] 173 (32), 155 (30), 144 (56), 1
42 (100), 130 (70), 103 (72), 8
9 (40), 78 (27), 54 (28) From the above analytical values, the product was (1S ^* , 2S ^* , 4a
It was confirmed to be R ^* , 8S ^* , 8aS ^* )-8-hydroxy-2-methyl-1,2,4a, 5,6,7,8a, 8b-octahydronaphthalene-1-methyl acetate. This reaction is shown by the reaction formula as follows.

[0012]

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Example 3 N-hydroxyethyl phthalimide 192 mg (1 mm
ol), 167 mg of acetylimidazole (1.5 mm
ol) was ground well in a mortar and allowed to stand overnight at room temperature. 225 mg of this was purified using a silica gel column with hexane / ethyl acetate {1/2 (volume ratio)} as a developing solvent.
(Yield 96%) crystals (melting point 88 ° C) were obtained. The analysis results of this crystal were as follows. (1) IR (CHCl3, cm-1) 1775, 174
0, 1717, 1429, 1373, 1235 (2) 1H-NMR [CDCl3, d (ppm)] 2.03 (3H, s), 3.97 (2H, t, J5.
2), 4.32 (2H, t, J5.2), 7.75 (2
H, m), 7.86 (2H, m) (3) MS [EI, m / e (relative int
(energy)] 190 (M + -Ac, 6), 173 (99), 161
(60), 160 (100), 133 (19), 130
(14), 105 (15), 104 (30), 77 (3
1), 76 (32), 43 (65) From the above analysis values, it was confirmed that the product was N-acetoxyethylphthalimide. The reaction formula of this reaction is as follows.

[0014]

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Example 4 3,5-di-tert-putylphenol 207 mg
(1 mmol), acetyl imidazole 166 mg
(1.5 mmol) was ground well in a mortar and allowed to stand at room temperature for 1 hour. Hexane / ethyl acetate {5/1
(Volume ratio)} as a developing solvent and purification was performed using a silica gel column to obtain 238 mg (yield 96%) of an oily residue. The analysis results of this oily substance were as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 1762, 174
5,1611,1591,1479,1421,136
9, 1228, 1223 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 1.31 (18H, s), 2.28 (3H, s), 6.
69 (2H, s), 7.27 (1H, s) (3) NS [EI, m / e (relative int
(energy)] 248 (M ⁺ , 9), 206 (86), 192 (2
0), 191 (100), 57 (78) From the above results, it was confirmed that the product was 3,5-di-tert-butylphenyl acetate. This reaction is shown by the reaction formula as follows.

[0016]

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Example 5 118 mg (1 mmol) of 1,6-hexanediol,
132 mg (1.2 mmol) of acetylimidazole was thoroughly ground in a mortar and allowed to stand at room temperature for 45 minutes. 85 mg of this was purified using a medium pressure liquid chromatograph using hexane / ethyl acetate {1/1 (volume ratio)} as a developing solvent.
An oily substance (yield 53%) was obtained. The analysis results of this compound are as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 3627,172
8,1367,1252,1221,1216 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 1.2 to 1.35 (4 H, m), 1.35 to 1.5 (2
H, m), 1.5 to 1.7 (2H, m), 2.04 (3
H, s), 3.63 (2H, t, J5), 4.06 (2
H, t, J7) (3) MS [EI, m / e (relative in
intensity)] 121 (42), 119 (99), 117 (M ⁺ -A)
c, 100), 84 (39), 82 (28), 47 (2
9) From the above results, it was confirmed that the product was 6-acetoxyhexanol. This reaction is shown by the reaction formula as follows.

[0018]

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Example 6 Thymol 152 mg (1 mmol) and acetylimidazole 166 mg (1.5 mmol were well ground in a mortar and allowed to stand at room temperature for 1 hour. Further 55 mg (0.5 mm
ol) acetylimidazole was added and ground,
Hexane / ethyl acetate {5/1 (volume ratio)} was used as the developing solvent and purified using a medium pressure liquid chromatograph to 132 m.
g (68% yield) of an oil was obtained. The analysis results of this compound are as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 3019, 175
5,1507,1371, 1220,1216 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 1.19 (3H, d, J6.8), 1.26 (3H,
d, J6.8), 2.3 (6H, s), 2.97 (1
H, septet, J6.8), 6.8 (1H, s),
7.01 (1H, d, J8), 7.18 (1H, d, J
8) (3) NS [EI, m / e (relative int
(energy)] 192 (M ⁺ , 13), 150 (47), 135 (10
0), 91 (13), 43 (19) From the above results, it was confirmed that the product was thymol acetate. This reaction is shown by the reaction formula as follows.

[0020]

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Example 7 Farnesol (198 ml, 1 mmol) and acetylimidazole (166 mg, 1.5 mmol) were ground well in a mortar and allowed to stand overnight at room temperature. After further adding 56 mg (0.5 mmol) of acetylimidazole and mashing, hexane / ethyl acetate {1/1 (volume ratio)} was used as a developing solvent and purified using a medium pressure liquid chromatograph.
92 mg (72% yield) of oil was obtained. The analysis results of this compound are as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 1728,167
0,1447,1383,1239,1023 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 1.6 (6H, s), 1.68 (3H, s), 1.71
(3H, s), 2.05 (3H, s), 1.9 to 2.3
(8H, m), 4.59 (2H, d, J7.1), 5.
1 (2H, br, s), 5.35 (1H, t, J7.
1) (3) MS [EI, m / e (relative int
(energy)] 264 (M ⁺ , 4), 136 (36), 93 (38),
81 (40), 69 (100), 68 (39), 43
(77), 41 (39) From the above results, it was confirmed that the product was farnesyl acetate. This reaction is shown by the reaction formula as follows.

[0022]

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EXAMPLE 8 166 mg (1 mmol) of 2-hydroxymethyl-3,6, dimethylbenzyl alcohol and 133 mg (1.2 mmol) of acetylimidazole were well ground in a mortar and allowed to stand at room temperature for 1 hour. Further, using hexane / ethyl acetate {1/1 (volume ratio)} as a developing solvent, purification was performed using a medium pressure liquid chromatograph to obtain 101 mg (yield 48%) of crystals (melting point 70 ° C.). The analysis results of this compound are as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 3607, 348
9, 1732, 1378, 1239 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 2.06 (3H, s), 2.37 (3H, s), 2.4.
3 (3H, s), 4.76 (2H, s), 5.33 (2
H, s), 7.07 (1H, d, J7.8), 7.12.
(1H, d, J7.8) (3) MS [EI, m / e (relative int
208) (M ⁺ , 2), 148 (100), 147 (6)
9), 119 (23), 105 (26), 91 (1
8), 43 (32) From the above results, it was confirmed that the product was 2-acetoxymethyl 3,6 dimethylbenzyl alcohol. This reaction is shown by the reaction formula as follows.

[0024]

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Example 9 161 mg (0.45 mmol) of monoolein and 133 mg (0.55 mmol) of acetylimidazole were thoroughly ground in a mortar and allowed to stand at room temperature for 1 hour. In addition, 27 mg (0.25 mmo) of acetylimidazole is taken every hour.
l) and 16 mg (0.15 mmol) were added and mashed. Hexane / ethyl acetate {1/1 (volume ratio)} was used as the developing solvent and purified using a medium pressure liquid chromatograph.
Obtained mg (yield 42%) of oil. The analysis results of this compound are as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 3601, 173
6, 1460, 1374, 1220 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 0.88 (3H, t, J6), 1.2 to 1.5 (22)
H, m), 1.5-1.65 (4H, m), 1.95-
2.2 (4H, m), 2.35 (2H, t, J7.
5), 3.66 (2H, br, d), 3.94 (1H,
br, s), 4.1 (2H, m), 5.35 (2H, b
r, s) (3) MS [EI, m / e (relative int
(energy)] 398 (M ⁺ , 0.3), 378 (23), 264 (2
5), 263 (45), 116 (100), 103 (2)
4), 98 (30), 5 (39), 55 (43), 43
(55) From the results above, it was confirmed that the product was 3-acetoxy-1-oleylglycerol. This reaction is shown by the reaction formula as follows.

[0026]

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Example 10 165 mg of 6-tetrahydropyranyloxyhexanol
(0.82 mmol), 136 mg of acetylimidar
Grind (1.23 mmol) well in a mortar and mix at room temperature for 1
Let it stand for a while. Hexane / ethyl acetate {4/1 (volume ratio)} was used as a developing solvent and purified using a medium pressure liquid chromatograph to obtain 167 mg (yield: 84%) of an oily substance. The analysis results of this compound are as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 1728,145
5,1368,1250 (2) ¹ H-NMR [CDCl
₃ , δ (ppm)] 1.4 (3H, m), 1.4 to 2.0 (1H, m),
2.05 (3H, s), 3.4 (1H, m), 3.5
(1H, m), 3.7 (1H, m), 3.9 (1H,
m), 4.06 (2H, t, J6.7), 4.57 (1
H, s) (3) NS [EI, m / e (relative int
(energy)] 201 (M ⁺ -Ac, 7), 101 (23), 85 (1
00), 55 (20), 43 (12) From the above results, it was confirmed that the product was 6-tetrahydropyranyloxyhexyl acetate. This reaction is shown by the reaction formula as follows.

[0028]

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Example 11 4- (p-hydroxyphenyl) -2-butanol 17
0 mg (1 mmol), acetylimidazole 170 m
Grind g (1.5 mmol) well in a mortar and mix at room temperature for 1
I put it in time. Hexane / ethyl acetate {1/1 (volume ratio)} was used as a developing solvent and purified using a medium pressure liquid chromatograph to obtain 145 mg (yield 68%) of an oily substance. The analysis results of this compound are as follows. (1) IR (CHCl ₃ , cm ⁻¹ ) 3607,344
7, 1755, 1507, 1371, 1223, 119
6 (2) ¹ H-NMR [CDCl ₃ , δ (ppm)] 1.22 (3H, d, 6), 1.75 (2H, m),
1.9 (1H, br), 2.26 (3H, s), 2.6
(2H, m), 3.81 (1H, sextet, J
6), 6.98 (1H, d, J8.4), 7.18 (1
H, d, J8.4) (3) NS [EI, m / e (relative int
208) (M ⁺ , 26), 166 (97), 148 (9)
7), 133 (100), 108 (27), 107 (8)
5) From the above results, it was confirmed that the product was 4- (p-acetoxyphenyl) -2-butanol. This reaction is shown by the reaction formula as follows.

[0030]

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[0031]

When the method of the present invention is adopted, the primary alcohol, the secondary alcohol with less steric hindrance, and the acetate derivative of a compound having a phenolic hydroxyl group are highly selective by a much simpler operation than the conventional method. And it can be produced in good yield.

Claims (1)

[Claims] 1. A process for producing an acetic ester, which comprises reacting a compound having a primary alcohol or a phenolic hydroxyl group with acetylimidazole in the substantial absence of a solvent.