JPS62116548A - Aminoketone derivative - Google Patents

Abstract

NEW MATERIAL:2-Amino-4'-isobutylpropiophenone expressed by formula I and an acid addition salt thereof. USE:A synthetic intermediate for ibuprofen [2-(4'-isobutylphenyl)propionic acid] useful as an anti-inflammatory agent. PREPARATION:A 2-halogeno-4'-isobutylpropiophenone expressed by formula II (X is halogen) is reacted with ammonia in an inert organic solvent, e.g. N,N- dimethylformamide, to give the aimed compound expressed by formula I or a novel compound expressed by formula III (R is lower alkyl) is reacted with trifluoroacetic acid in the presence or absence of an inert organic solvent and water is added thereto. Alternatively the compound expressed by formula III is dissolved or suspended in a hydrous inert organic solvent and trifluoroacetic acid is reacted therewith to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Field of Application The present invention deals with ibuprofen (2-(4'-isobutylphenyl)propio), which is widely used as an anti-inflammatory agent.
This invention relates to novel aminoketone derivatives useful as intermediates for the synthesis of acids].

Conventional technology of ibuprofen! 8! Many proposals have been made regarding construction methods. Among them, the following example is known as a method utilizing 1,2-aryl transfer of propiophenone derivatives.

1) Method via acetal of 2-hydroquine-4'-isobutylpropiophenone [hereinafter referred to as compound (a)] (JP-A-57-67531, JP-A-57-67535)
No.) 2) Method via acetal of 2-halogeno-4'-isobutylpropiophenone (hereinafter referred to as compounds) (JP-A-56-135423) 3) 2-halogeno-4'-
A method involving isobutylpropiophenone [hereinafter referred to as compound (C)] (J, chem, Sac, Perki
n Trans, 1.235 (1982)] 1), compound (C) is treated with sodium methylate in methanol to obtain compound (a) as a raw material, and then the hydroxy group of compound (a) is removed once. 2-(4'-inbutylphenyl)propionic acid ester [hereinafter referred to as compound (d)] by heat treatment with, for example, an aqueous calcium carbonate solution, and by hydrolyzing this compound (d), ibuprofen is produced. There is.

In this synthesis method, from compound (C) to ibuprofen, 4
It requires a process.

In method 2), compound (C) is reacted with alcohol in the presence of an acid to obtain the starting compound (b), and then compound (b) is reacted in the presence of a Lewis acid to produce compound (d).
Ibubrofen is obtained by hydrolyzing this. This synthesis method also requires three steps from compound (C) to ibuprofen.

In method 3, silver nitrate is used for compound (C) to form compound (
d) and is hydrolyzed to produce ibuprofen.

In this synthetic method, ibuprofen is obtained from compound (C) in two steps, but a stoichiometric amount of expensive silver nitrate, which is not suitable for industrialization, is used.

Furthermore, since all of the above three synthesis methods obtain ibuprofen as an ester, it is necessary to hydrolyze it.

Problems to be Solved by the Invention There is a need for a method for obtaining ibuprofen from compound (C) in a short process and in good yield.

Means for Solving the Problems The present invention provides 2-amino-4'-isobutylpropiophenone represented by formula (1) [hereinafter referred to as compound (1)]. The same applies to compounds of other formula numbers] and acid addition salts thereof.

Compound (I) and its acid addition salt are novel compounds derived from compound (C) in step (1), and can be easily converted into 1.2-
Aryl rearrangement occurs and leads to ibuprofen (Reference Example 2).

Acid addition salts of compound (I) include hydrochloride, sulfate, nitrate, phosphate, hydroiodide, hydrobromide, perchlorate,
It includes inorganic acid salts such as perbromate, and organic acid salts such as methanesulfonate, ethanesulfonate, toluenesulfonate, gamphersulfonate, and trifluoroacetate.

Compound (1) can be produced by the method shown below.

[Manufacturing method - Δ]

Compound (1) can be obtained by reacting 2-halogeno-4'-isobutylpropiophenone represented by the formula ([) (wherein X is a halogen atom) with ammonia in an inert organic solvent. I can do it. Specifically, a method is used in which ammonia gas is introduced into a solution in which the compound (n) is dissolved or suspended in an organic solvent.

The halogen atom of X in formula (II) includes chlorine, bromine, iodine and the like. Inert organic solvents include N,N-dimethylformamide, dimethylacetamide, etc., and may be used alone or as a mixed solvent.

The amount of ammonia gas introduced is 2 for compound (n).
．． The amount is 0 to 50 times by mole, and particularly preferably 5.0 to 8.0 times by mole. The reaction temperature can be selected within the range of -50 to 50°C, preferably -20 to 0°C. The reaction time in this case is 0.61 to 10 hours, usually 0.5 to 2.0 hours.
It is 0 hours.

Isolation and purification of compound (I) from the reaction mixture is carried out, for example, by pouring the reaction mixture into a large amount of water, extracting with chloroform, and distilling off the solvent from the extract at a low temperature. Further, the acid addition salt of compound (I) can be prepared by adding an acid to the above chloroform extract to precipitate it as crystals.

[Manufacturing method-B]

Compound (1) is a fine water obtained by reacting a compound represented by I[[] (wherein R is a lower alkyl group) with trifluoroacetic acid in the absence or presence of an inert organic solvent. or add the compound ([[>
It can be obtained by dissolving or suspending in a water-containing inert organic solvent and treating the solution with trifluoroacetic acid.

If an inert organic solvent is not used, trifluoroacetic acid can also serve as a solvent. Inert organic solvents used include ethanol, tetrahydrofuran, dioxane, and the like.

The moisture content is usually 10 to 50%. The amount of trifluoroacetic acid used is a catalytic amount (for example, 0.5
double mole) is sufficient.

The reaction temperature can be selected within the range from 0°C to the boiling point of the solvent. Preferably it is 20-80°C. The reaction time varies depending on the reaction temperature, but is usually 1 to 50 hours.

Isolation and purification of compound (1) from the reaction mixture is carried out by concentrating the reaction mixture under reduced pressure, neutralizing with an aqueous alkaline solution, extracting with chloroform, and distilling off the solvent from the extract at low temperature. Further, the acid addition salt of compound (1) can be obtained by adding an acid to the above chloroform extract to precipitate it as crystals.

In this reaction, if an optically active substance is used as compound (III), optically active compound (I) can be obtained.

Compound (III) as a starting material is also a new compound, and can be easily synthesized by the Friedel-Crach reaction of an aranine derivative and isobutylbenzene according to the method shown below (Reference Example 1).

Examples and reference examples of the present invention are shown below.

Example 1 2-bromo-4'-isobutylpropiophenone 10,
8 g was dissolved in 80 ml of dimethylformamide (DMF), and 10.4 g of ammonia gas was added at -10°C under stirring and cooling.
g over 60 minutes.

Immediately after blowing, the reaction solution was poured into 2 OQml of water,
The produced 2-amino-4'-isobutylpropiophenone was extracted four times with 5 Qml of chloroform each time. Next, 5. 35% hydrochloric acid water was added to the extracted chloroform solution. Q
ml was added and stirred, and the precipitated crystals were separated, washed with a small amount of acetone, and then dried to obtain 8.4 g of colorless flaky crystals.

Melting point: 216.2°C (decomposition) 'H-NMR (in DMSO); δ (ppm) 0.87 (
d, 6H), 1.47 (d, 3H), 1.71-2
．． 0Hm, IH).

5.04 (q, IH), 7.29 (d, 2H), 7.9
2 (d, 2H), 8.59 (s, 3H) Elemental analysis value (% as C13H20ON C12) Actual value C64,6588,41N5.72 Cj 1
4.57 Calculated value C64,5988,34N5.79
CI 14.66 From the above physical property values, the above crystal is 2-
It was identified as amino-4'-isobutylpropiophenone monohydrochloride.

Example 2 0.5 g of 2-ethoxycarbonylamino-4'-isobutylpropiophenone was dissolved in 25 ml of trifluoroacetic acid and reacted at room temperature for 20 hours.

After concentrating the reaction solution under reduced pressure, 20ml of water was added, and 4N and N
After adjusting the pH to 9.5 with aOH water, add 20ml of chloroform.
Extracted three times. When 20ml of concentrated hydrochloric acid is added to the chloroform layer, crystals begin to precipitate. When the crystals are filtered and dried, 2-
0.35 g of amino-4'-isobutylpropiophenone monohydrochloride was obtained.

Melting point: 215.5°C (decomposition) 'H-NMR (in DMSO) Consistent with that obtained in Example 1.

Elemental analysis value (% as CH3H200N Cj!) Actual value C64,52H8JON5.72 C114,7
5 Calculated value C64, 59H8, 34N5.79 C1
14,66 Reference Example I 12.9 g of N-ethoxycarbonylalanine was dissolved in 20 Qml of methylene chloride, and 3 Qml of oxalyl chloride was added over about 10 minutes at 0 to 5°C. Approximately 10% of the reaction solution
Concentrate under reduced pressure to 20 Qml of isobutylbenzene.
ml was added and cooled to -5°C. Anhydrous aluminum chloride 2
2.7 g was added in about 5 minutes. It turned brown and transparent in about 15 minutes. The reaction solution was heat aged at -5°C for 30 minutes and then mixed with 20 Q of water.
ml and separated. The organic layer was dehydrated over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 32 g of a yellow oil. When the concentrated residue - is distilled under reduced pressure, 1-(4'-
18.8 g of isobutylphenyl)-2-ethoxycarbonylamino-1-propanone were obtained.

Boiling point: 120-125℃ (0.2mmHg)'H-NM
R (CD (in l); δ (ppm) 0.82 (d, 6H)
, 1.10 (t, 3H), 1.29 (dm, 3H)
.

1,82 (m, IH), 2.46 (d, 2H),
4.00 (q, 2H).

5.20 (m, IH), 5.82 (d, 1) 1), 7
．． 0 to 7.8 (dd, 4H) elemental analysis value (CI6H
% as 2303N) Actual value C69,9887,6
5N 13.72 Calculated value C69°93 8 7.
59 N 13.76 Reference Example 2 2-Amine-4'-isobutylpropiophenone 1.2
g was suspended in 50 ml of tetrahydrofuran and 10 ml of glacial acetic acid. 3.5 g of sodium nitrite was slowly added at 20-30°C. After reacting at the same room temperature for 1 hour, the mixture was concentrated under reduced pressure to remove the solvent. 20 Qml of ethyl acetate was added to the residue, extracted twice with 20 ITll of water, and washed with water.

The ethyl acetate layer was dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane:ethyl acetate 3:1) to obtain 0.86 g of pure ibuprofen.

Melting point: 146-146.5°C Effects of the Invention By passing through the intermediate of the present invention, ibuprofen can be obtained in a shorter process and with higher yield than in conventional methods.

Claims (2)

[Claims] (1) 2-amino-4'-isobutylpropiophenone and its acid addition salt. (2) Acid addition salts are hydrochloride, sulfate, nitrate, phosphate,
Patent for hydroiodide, hydrobromide, perchlorate, perbromate, methanesulfonate, ethanesulfonate, toluenesulfonate, gamphersulfonate or trifluoroacetate A compound according to claim 1.