JPH034075B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 4'-fluoromethyl-3-amino-2-methyl substituted propiophenone derivatives and pharmacologically acceptable acid addition salts thereof.

More specifically, the present invention relates to the general formula () (In the formula, group A represents a pyrrolidino group, a piperidino group or a morpholino group.) A novel 4'-fluoromethyl-3-amino-2-methyl substituted propiophenone derivative represented by Concerning acceptable acid addition salts.

The compound represented by the general formula () of the present invention can be converted into a pharmacologically acceptable acid addition salt as desired, or from the generated acid addition salt,
It is also possible to liberate the base.

Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula () of the present invention include mineral acid salts such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. , or organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, and tartaric acid.

The novel compound represented by the above general formula () of the present invention
The 4'-fluoromethyl-3-amino-2-methyl substituted propiophenone derivative has the following formula () 4'-fluoromethylpropiophenone, formaldehyde in a solvent, and an amine compound represented by the following general formula () H-A () (wherein, group A has the same meaning as above) Alternatively, it is produced by reacting salts thereof using a method known per se (Mannitzsch reaction).

Examples of formaldehydes used include formaldehyde, its linear or cyclic polymers paraformaldehyde, trioxane, and the like.

Amine compounds are usually used as mineral acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, etc., but when using free amine compounds, sufficient mineral acid should be added to make the reaction system sufficiently acidic. It can be implemented by

Although the reaction equivalent ratio can be selected as appropriate, it is necessary to eliminate the amine compound remaining in the post-reaction treatment, so the reaction equivalent ratio is 1 equivalent of the amine compound represented by the general formula () to 1 equivalent of the amine compound represented by the general formula ().
At least 1 equivalent, preferably 1.1 equivalent, of 4'-fluoromethylpropiophenone and at least 1 equivalent, preferably formaldehyde.
1.5 equivalents.

Solvents used in the reaction include alcohol solvents such as methanol, ethanol, propanol and isopropanol, nitroalkane solvents such as nitromethane and nitroethane, methyl acetate,
Examples include lower fatty acid lower alkyl ester solvents such as ethyl acetate and ethyl propionate, and it is particularly preferable to use lower fatty acid lower alkyl ester solvents.

The reaction is carried out at room temperature to reflux, particularly preferably at the reflux temperature of the solvent used.

Incidentally, 4'-fluoromethylpropiophenone represented by the above formula (), which is a starting material in the method of the present invention, is also a new compound, and its production is described in Reference Examples.

The novel 4'-fluoromethyl-3-amino- represented by the general formula () produced in this way
2-Methyl-substituted propionphenone derivatives and their pharmacologically acceptable acid addition salts have excellent muscle relaxation, spinal reflex suppression, anticonvulsant effects, etc., and are effective against lower back pain, intervertebral disc herniation, and deformity. It is extremely useful as a therapeutic agent for painful muscle spasms associated with musculoskeletal diseases such as spondylosis.

Hereinafter, the present invention will be explained with reference to Examples.

Reference Example 1 4'-Bromomethylpropiophenone 240 ml of carbon tetrachloride, 0.50 g of N-bromosuccinimide and 0.50 g of benzoyl peroxide were added to 43.4 g of 4'-methylpropiophenone, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture is filtered. The liquid is dried under reduced pressure, and 90% aqueous ethanol is added to the resulting residue. Collect the precipitate and obtain 29.37g of the listed compound.
get. Recrystallized from isopropyl ether,
Colorless platelet crystals with a melting point of 58-59° are obtained.

IR spectrum ν (KBr) cm ^-1 : 1685 (C=0) Elemental analysis value C ₁₀ H ₁₁ BrO Theoretical value C, 52.89; H, 4.88 Experimental value C, 52.71; H, 5.07 Reference example 2 4'-Fluoromethyl Propiophenone 44.6 g of potassium fluoride and 80 ml of diethylene glycol were added to 35.0 g of 4'-bromomethylpropiophenone obtained in Reference Example 1, and the mixture was heated and stirred at 140° for 1 hour. After cooling, water was added to the reaction mixture, and the mixture was extracted with ether. The ether layer is washed with water and dehydrated. The solvent is distilled off. The obtained residue is distilled under reduced pressure, and the boiling point is 100~
Compound 13.3 described as a colorless liquid at 101° (6 mmHg)
get g.

IR spectrum ν (film) cm ^-1 : 1690 (C=0) Example 1 4'-Fluoromethyl-2-methyl-3-piperidinopropiofenone 4'-Fluoromethylpropioff obtained in Reference Example 2 To a solution of 4.98 g of enone in 10 ml of isopropanol are added piperidine, 3.52 g of hydrochloride, and 1.35 g of paraformaldehyde, and the mixture is heated under reflux for 4 hours. After the reaction, the solvent was distilled off, and the residue was extracted with an aqueous hydrochloric acid solution.
Separate the aqueous layer. After washing the aqueous layer with ether, it is made alkaline with potassium carbonate and extracted with ether. The ether layer is washed with water and dehydrated. Distill the solvent,
After dissolving the resulting residue in ether, 15% ethanolic hydrochloric acid is added. Take the precipitated crystals. The sample was recrystallized from a mixture of ethanol and ether,
3.05 g of the hydrochloride salt of the title compound are obtained as colorless needles with a melting point of 172-173°.

IR spectrum ν (KBr) cm ^-1 : 1680 (C=0) Elemental analysis value C ₁₆ H ₂₂ FNO・HCl Theoretical value C, 64.10; H, 7.73; N, 4.67 Experimental value C, 64.11; H, 7.63; N , 4.66 Example 2 4'-Fluoromethyl-2-methyl-3-pyrrolidinopropiophenone To a solution of 4.00 g of 4'-fluoromethylpropiophenone obtained in Reference Example 2 in 15 ml of ethyl acetate,
Pyrrolidine hydrochloride 2.50g, paraformaldehyde 1.10g and 22% acetic acid ethyl ester hydrochloric acid 0.5g
ml and heated under reflux for 4 hours. After the reaction, add an aqueous hydrochloric acid solution, shake, and separate the aqueous layer. The aqueous layer is made alkaline with potassium carbonate and extracted with ether. The ether layer is washed with water and dehydrated. After evaporating the solvent and dissolving the resulting residue in ether, 40% ethanolic hydrochloric acid is added. Take the precipitated crystals.
The residue was recrystallized from a mixture of ethanol and ether to give 3.20 g of the hydrochloride of the title compound as colorless plate crystals with a melting point of 151-152°.

IR spectrum ν (KBr) cm ^-1 : 1680 (C=0) Elemental analysis value C ₁₅ H ₂₀ FNO・HCl Theoretical value C, 63.04; H, 7.41; N, 4.90 Experimental value C, 63.16; H, 7.49; N , 4.94 Example 3 4'-Fluoromethyl-2-methyl-3-morpholinopropiophenone Into a 20 ml solution of 4.50 g of 4'-fluoromethylpropiophenone obtained in Reference Example 2 in ethyl acetate,
Morpholine 2.20g and paraformaldehyde 1.20
Add g. Next, while cooling and stirring, hydrogen chloride gas was introduced to make the mixture acidic, and the mixture was heated under reflux for 4 hours. The hydrochloride of the title compound was then treated in the same manner as in Example 2.
Obtain 3.71g. Recrystallization from a mixture of ethanol and ether gives colorless needles with a melting point of 157-158°.

IR spectrum ν (KBr) cm ^-1 : 1680 (C=0) Elemental analysis value C ₁₅ H ₂₀ FNO ₂・HCl Theoretical value C, 59.70; H, 7.01; N, 4.64 Experimental value C, 59.84; H, 7.14; N, 4.59

Claims (1)

[Claims] 1. General formula (In the formula, the group A represents a pyrrolidino group, a piperidino group or a morpholino group.) 4'-Fluoromethyl-3-amino-2
-Methyl-substituted propiophenone derivatives and pharmacologically acceptable acid addition salts thereof.