JP3487067B2 - Method for producing 3-amino-2-hydroxyacetophenone salt - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 3-amino-2-hydroxyacetophenone useful as a pharmaceutical intermediate .
Sulfate or 3-amino-2-hydroxyacetophenone
And a method for producing a hydrogen halide salt thereof.

[0002]

Methods for producing BACKGROUND ART 3-Amino-2-hydroxyacetophenone or acid addition salts thereof, various methods have been proposed. For example, JP-A-3-951
Japanese Patent Laid-Open No. 44-44 proposes a method shown by the following route. The method for producing 3-amino-2-hydroxyacetophenone shown in the above route is an advantageous method because it is superior in positional characteristics at the time of introducing an acetyl group or a nitro group, as compared with the methods by other routes. The 3-amino-2-hydroxyacetophenone obtained by this method becomes a hydrogen halide salt of 3-amino-2-hydroxyacetophenone by hydrogen halide generated by catalytic reduction, as can be seen from the above route diagram. However ,
The crystals of the hydrogen halide salt obtained by the method described in JP-A-3-95144 have poor efficiency in isolation operations such as filtration and drying or transfer operations therefor, and industrially, improvement of this point is sought. There is. It is also possible to take out this hydrogen halide salt as neutral 3-amino-2-hydroxyacetophenone after neutralization.
No. 4, gazette, but free 3-amino-2
Not only is there a problem in the stability of -hydroxyacetophenone itself, but this method is industrially problematic because another complicated or inefficient operation of concentrating the solvent is required.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is 3-amino-2-hydroxyacetophenone, which is industrially easy to handle, particularly has a low crystal bulk and improved fluidity.
Sulfate or 3-amino-2-hydroxyacetopheno
It is to provide a method for producing a hydrogen halide salt of benzene.

[0004]

The present inventors have continued to study a method for producing 3-amino-2-hydroxyacetophenone by catalytic reduction via 2-hydroxy-3-nitroacetophenone. As a result, 3-amino-2-hydroxyacetophenone was added to sulfuric acid in a non-aqueous solvent.
The reaction solution obtained by reacting with
Mino-2-hydroxyacetophenone sulfate, and 3
-Halogenation of amino-2-hydroxyacetophenone
Mixture obtained by reacting hydrogen salt with sulfuric acid in a non-aqueous solvent
3-Amino-2-hydroxyacetate obtained by cooling and crystallization of the liquid
Tophenone hydrohalide and sulphate mixtures are
These crystals bulk is low, fluidity is extremely high, the
The inventors of the present invention have found that the problems of the prior art described above are solved and have reached the present invention. The present invention provides: (a) 3-amino-2-hydroxyacetophenone in a non
Cool the reaction solution obtained by reacting sulfuric acid in an aqueous solvent.
Consists of analysis, the crystal bulk is low, the preparation of fluidity improved 3-amino-2-hydroxyacetophenone sulfate, and, (ii) 3-amino-2-hydroxyacetophenone Ha
It was obtained by reacting hydrogen halide with sulfuric acid in a non-aqueous solvent.
The crystal bulk is low, which consists of cooling and crystallization of the mixed liquid
And 3-amino-2-hydroxyl with improved fluidity
Preparation of hydrogen halide and sulfate mixtures of cetophenone
It provides a construction method .

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
3-amino-2-hydroxyacetophenone (1) or its hydrogen halide salt has the general formula (1) (In the formula, X represents a halogen atom or a hydrogen atom) and can be obtained by catalytically reducing the nitro compound.

This catalytic reduction reaction is usually carried out in the presence of a solvent. Typical examples of the solvent used in the reaction include alcohols such as methanol, ethanol and isopropanol ; aromatic hydrocarbons such as benzene, toluene, xylene and ethylbenzene ; methylene chloride, chloroform, carbon tetrachloride and the like. halogenated hydrocarbons; tetrahydrofuran, dioxane, ethers such as diethyl ether; N, N-dimethylformamide, acetic acid, acetic anhydride, or the like thereof a mixture of two or more solvents. The solvent used in the reaction is preferably
They are alcohols, aromatic hydrocarbons , or a mixed solvent of two or more thereof. The amount of the solvent used is usually 2 to 10 times by weight, preferably 3 to 6 times by weight based on the nitro compound (1).

Examples of the catalytic reduction catalyst used include palladium carbon, palladium black, palladium alumina, palladium silica, palladium, platinum dioxide, platinum carbon, nickel and Raney nickel. The amount of the catalytic reduction catalyst used is usually 0.001 to 1% by weight, preferably 0.01 to 0.2, relative to the nitro compound (1).
It is 5% by weight. The hydrogen pressure is usually not less than atmospheric pressure and is not particularly limited, but is preferably 0 to ²⁰ kg / cm ² G. The reaction temperature is generally -20 ° C to 100 ° C, preferably 10 ° C to 60 ° C.

By the above reaction , the nitro compound (1) is converted into
When X is a hydrogen atom, 3-amino-2-hydroxyacetophenone is produced, and the nitro compound (1) is converted to
When X is a halogen atom, 3-amino-2-hi
A hydrogen halide salt of droxyacetophenone is produced . After the completion of the reaction, the catalytic reduction catalyst used in the reaction is usually removed by filtration. The catalyst removal is usually,
X is a halogen atom in the two Toro Compound (1),
And, when the solvent is a solvent such as a non-aqueous solvent such as alcohols and aromatic hydrocarbons in which a hydrogen halide salt of 3-amino-2-hydroxyacetophenone is precipitated, it is usually a base in the reaction solution in advance. 3-amino-
It is made by dissolving 2-hydroxyacetophenone as a free form in a solvent and then filtering. In this case 3
-Inorganic halides such as sodium chloride, ammonium chloride and potassium bromide are deposited in the reaction liquid instead of amino-2-hydroxyacetophenone, so that the catalyst and the inorganic halides are removed at the same time.

Examples of the base used when the base acts include, for example, alkyl metal carbonates and alkyl metal
Bicarbonate, hydroxide of alkali metal; an alkaline earth metal carbonate, alkaline earth metal bicarbonates, alk
Examples thereof include hydroxides of alkaline earth metals ; organic fatty acid salts and organic bases. Specifically, carbonates of metals such as lithium, sodium, potassium, magnesium and calcium ; lithi
Um, sodium, potassium, magnesium, calciu
Bicarbonates of metals such as aluminum ; lithium, sodium, potassium
Hydroxides of metals such as um, magnesium and calcium
Or triethylamine, pyridine, picoline, ammonium
And organic bases such as a. The amount of base added is
The amount may be at least the amount required to dissolve 3-amino-2-hydroxyacetophenone, but is usually 0.1 to 3 equivalents, preferably 0.5 to 1.2 equivalents. When the base is allowed to act, the temperature is usually -20 ° C to 100 ° C or the boiling point of the solvent, preferably 10 ° C to 60 ° C. The temperature in catalyst filtration is usually -20 ° C to 100 ° C.
℃ or up to the boiling point of the solvent, preferably 10 ℃ ~ 6
It is 0 ° C. Thus obtained 3-amino-2-hydroxyacetophenone or 3-amino- 2-hydroxya
The hydrogen halide salt of cetophenone can be isolated by subjecting it to a treatment such as solvent removal and recrystallization, but usually, the solution from which the catalyst has been removed can be used as a raw material for the production method of the present invention. The nitro compound (1) is, for example,
It can be produced according to the method described in JP-A-3-95144.

In the present invention (a) , 3-amino-2
-Crystallization of a reaction solution obtained by reacting hydroxyacetophenone with sulfuric acid in a non-aqueous solvent produces 3-amino-2-hydroxyacetophenone sulfate having low crystal bulk and improved fluidity. . Also, the present invention
In (b), 3-amino-2-hydroxyaceto
Sulfuric acid was prepared from phenone hydrohalide in a non-aqueous solvent.
By cooling and crystallization of the resulting mixed solution
3-amino-2- having a low crystal bulk and improved fluidity
Mixture of Hydroxyacetophenone Hydrochloride and Sulfate
Is manufactured. In these production methods, the sulfuric acid used, usually, also sulfuric acid aqueous solution of 30 to 98% concentration
The include fuming sulfuric acid, preferably, Ru include aqueous solutions of sulfuric acid 70 to 98% concentration <br/>. A method of reacting 3-amino-2-hydroxyacetophenone with sulfuric acid, or 3-a
As a method for causing sulfuric acid to act on the hydrogen halide salt of mino-2-hydroxyacetophenone , 3-amino-2-
Method of adding sulfuric acid to a solution of hydroxyacetophenone
And 3-amino-2-hydroxyacetophenone halogen
And a method of adding sulfuric acid to a suspension solution of emissions hydrogen salt. Examples of the non-aqueous solvent used include alcohols such as methanol, ethanol and isopropanol ; aromatic hydrocarbons such as benzene, toluene, xylene and ethylbenzene ; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride ; tetrahydrofuran. , ethers such as dioxane and diethyl ether; N, N - dimethylformamide; acetic acid; acetic anhydride, also, Ru mentioned two kinds or more mixed solvents and the like. Further, it is also possible to use the solution of 3-amino-2-hydroxyacetophenone, which has been subjected to the catalyst removal treatment after the above-mentioned catalytic reduction reaction, as it is.

The amount of sulfuric acid used is 3-amino-2-hydroxyacetophenone or 3-amino-2- hydroxy acetic acid.
Usually 1 mol based on the hydrogen halide salt of cetophenone
10 to 10 times , preferably 2 to 4 moles
It is a double range . The amount of non-aqueous solvent will depend on the solvent used and is typically 3-amino-2-hydroxyacetophenone or 3-amino-2-hydroxyacetophenone.
To hydrogen halide salt of emissions, it is appropriately selected in a range of 2 to 10 times by weight. The temperature at which sulfuric acid acts is usually -2.
0 ° C. to 100 ° C. or is up to the boiling point of the nonaqueous solvent, preferably in the range of 10 ° C. to 60 ° C.. After adding sulfuric acid,
If necessary, it can be aged for about 1 to 3 hours.

The solvent is 3-amino-2-hydroxyacetophenone sulfate or 3-amino -2-hydroxyl.
From sheet aceto of Fe non-halogen crystals KaOsamu of hydrogen salt point, alcohols, solvents consisting hydrocarbons and halogenated hydrocarbons, and the like, or to use a solvent containing them 70% by weight or more preferably.

[0013] While the crystal was processed sulfate is separated from the solvent by filtration, the solvent separation is advantageous in order to increase the yield of more, low temperature crystallization, the industrial, usually -
It is carried out at about 20 ° C to 20 ° C. Examples of the method for filtering crystals include vacuum filtration, pressure filtration, centrifugal filtration, and natural filtration . The filtration method of the crystal, the industrial pressure filtration or centrifugal filtration perborate are preferred. The crystal separated from the solvent by filtration can be made into a dried product by a usual drying treatment such as reduced pressure drying or ventilation drying. 3-amino-2-hydroxyacetophenone sulfate obtained or
3-amino-2-hydroxyacetophenone halogenated
Crystals hydrogencarbonate low crystallinity bulk, the value measured by measuring the weight of the crystals of a certain capacity, usually 0.
5-10 ml / g, preferably from 0.5~6ml / g, more preferably 0.5~4ml / g. Also , 3-
Poor fluidity of amino-2-hydroxyacetophenone in hydrochloride or the like is also improved, and the angle of repose when measured by a known repose angle measuring device is usually 55 ° or less, preferably 50 ° or less. The angle of repose measurement method used in the present invention is an injection method, and as a measuring device, a device of Hosokawa Micron PT-N or Tsutsui Rikagaku Kikai Co., Ltd. is generally used.

[0014]

INDUSTRIAL APPLICABILITY According to the present invention, 3-amino-2-hydroxyacetate , which is useful as an intermediate for pharmaceuticals and has a small crystal volume and good fluidity, is obtained by an extremely simple treatment.
Tophenone sulfate or 3-amino-2-hydroxyacetate
Tophenone hydrogen halide salt can be obtained, and these
The salt of (1) has remarkably excellent productivity and operability, and is industrially advantageous .

[0015]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. The nitro compound (1) used in the present invention was synthesized according to the method described in JP-A-3-95144. Examples 1 to 8 [Production of 3-amino-2-hydroxyacetophenone sulfate ] (1) In 200 g of the reaction solvent shown in Table 1, 5-chloro-
2-hydroxy-3-nitroacetophenone 40 g, 5
% Palladium carbon (water content 55%) 1.75 g,
Catalytic reduction was performed at 25 ° C. to 50 ° C. under a hydrogen atmosphere at normal pressure. When the completion of the reduction reaction was confirmed, the reaction solution became a slurry solution of 3-amino-2-hydroxyacetophenone hydrochloride. 0.9 equivalent of the base shown in Table 1 was added to this reaction liquid with respect to 5-chloro-2-hydroxy-3-nitroacetophenone, and the mixture was stirred at 50 ° C. for 30 minutes, and then the precipitated catalyst and inorganic halide were removed by filtration. did. (2) 56.1 g of 98% sulfuric acid was added dropwise to the above filtrate at 50 ° C. for 1 hour, then kept at 50 ° C. for 1 hour, and then gradually cooled to 0 ° C. to precipitate crystals, which were precipitated by the cooling crystallization. did
The sulfate crystals were collected by filtration at 0 ° C. The obtained crystals were dried under reduced pressure, and the volume of the crystals was measured with a quantitative container. The angle of repose as an index of fluidity was measured using a repose angle measuring instrument manufactured by Tsutsui Rikagaku Kikai. The results are shown in Table 1. In addition, MTA, ETA and IPA in Table 1 are respectively
, Methanol, ethanol and i-propyl alcohol
Represents

[0016]

[Table 1]

Example 9 In 200 g of ethanol, 34 g of 2-hydroxy-3-nitroacetophenone and 5% palladium carbon (water content: 5
5%) 1.75 g was added, and catalytic reduction was carried out at 25 ° C. under a hydrogen atmosphere at atmospheric pressure. After completion of the reduction reaction, the catalyst was filtered off at 40 ° C. 56.1 g of 98% sulfuric acid was added dropwise to the filtrate at 40 ° C. for 1 hour, then the temperature was kept at 50 ° C. for 1 hour, then gradually cooled to 0 ° C., and 3-amino-2-hydroxy precipitated by the cooling crystallization. Acetophenone / sulfate crystals at 0 ℃
It was collected by filtration. The obtained crystals were dried under reduced pressure. Gain:
38.4 g, crystal bulk: 2.1 ml / g, angle of repose: 40
It was °.

Comparative Examples 1 to 3 [Production of 3-amino-2-hydroxyacetophenone hydrochloride] (1) Implemented except that the base shown in Table 2 was added in an amount of 0.9 equivalent to 3-amino-2-hydroxyacetophenone. Example 1
The same process as (1) was performed. (2) 28.9 g of 35% hydrochloric acid was added to the obtained filtrate at 50 ° C. for 1 hour.
After dropping over a period of time, the temperature was kept at 50 ° C. for 1 hour, then gradually cooled to 0 ° C., and the precipitated crystals were collected by filtration at 0 ° C.
The obtained crystals were dried under reduced pressure, and the bulk of the crystals and the angle of repose as an index of fluidity were measured in the same manner as in Example 1.
The results are shown in Table 2. In addition, ETA in Table 2 represents ethanol.

[0019]

[Table 2]

Example 10 (1) A slurry solution consisting of 20 g of 3-amino-2-hydroxyacetophenone hydrochloride and 100 g of ethanol was charged into a reactor and heated to 50 ° C., and 98% sulfuric acid was added to the reactor at the same temperature for 1 hour.
It dripped over time. After dropping, keep it at the same temperature for 1 hour,
After that, it was cooled to 2 ° C., and sulfuric acid precipitated by the cooling crystallization.
The salt and the mixed crystal of the hydrochloride salt were collected by filtration at 2 ° C. The obtained crystals were dried under reduced pressure, and the bulk of the crystals and the angle of repose as an index of fluidity were measured in the same manner as in Example 1. The bulk of the crystals was 3.1 ml / g, the angle of repose was 51 °, and the yield was 85%.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroaki Hibino 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture Sumitomo Chemical Co., Ltd. (72) Etsuko Fukuda 2-1-1 Tsukahara, Takatsuki City, Osaka Prefecture Sumitomo Within Kagaku Kogyo Co., Ltd. (56) Reference JP-A-3-95144 (JP, A) JP-A-3-77852 (JP, A) JP-A-6-92916 (JP, A) (58) Fields investigated ( Int.Cl. ⁷ , DB name) C07C 221/00 C07C 225/22

Claims (9)

(57) [Claims] 1. Amino-2-hydroxyacetopheno
The reaction solution obtained by reacting sulfuric acid with sulfuric acid in a non-aqueous solvent
Cooling crystallization to Rukoto preparation of 3-amino-2-hydroxyacetophenone sulfate, wherein. 2. 3-Amino-2-hydroxyacetopheno
Of action of sulfuric acid in a non-aqueous solvent emissions hydrogen halide salt of
And cooling and crystallization of the obtained mixture 3
-Halogenation of amino-2-hydroxyacetophenone
Method for producing hydrogen salt and sulfate mixture . 3. The amount of sulfuric acid is 3-amino-2-hydroxyacetophenone or 3-amino-2-hydroxyaceto
And to hydrogen halide salt of phenone, Process according to claim 1 or 2 is 1 to 10 mol times <br/>. 4. A non-aqueous solvent, Process according to any one of claims 1 to 3 of A alcohol ethers or aromatic hydrocarbons. 5. A crystalline bulk or 3-amino-2-hydro of the obtained 3-amino-2-hydroxyacetophenone sulfate.
The crystal bulk of the xyacetophenone hydrogen halide salt is 0.
It is 5-6 ml / g, The manufacturing method in any one of Claims 1-4. 6. 3-Amino-2-hydroxyacetophenone and / or 3-amino-2-hydroxyacetophenone phenol
Emissions hydrohalide of the following formula (1) (Wherein, X is also halogen atom represents a hydrogen atom.) A process according to any one of claims 1-5 is obtained by catalytic reduction of the nitro compound represented by the. 7. A 3-amino-2-hydroxyacetophenone and / or 3-amino-2-hydroxyacetophenone phenol
The method according to claim 6, wherein the hydrogen halide salt of benzene is obtained by catalytically reducing the nitro compound represented by the above formula (1) and then removing the catalyst used. 8. The production method according to claim 7, wherein the catalyst is removed after the catalytic reduction and after the reaction with a base. 9. The base is an alkali metal carbonate or alkali.
Metal hydrogen carbonates, alkali metal hydroxides; alkaline earth metal carbonates, alkaline earth metal bicarbonates, A
The method according to claim 8, which is a hydroxide of a alkaline earth metal ; an organic fatty acid salt or an organic base.