JPS638945B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, X represents a halogen atom.) The present invention relates to a method for producing 2-cyclohexyl-r-2-phenyl-t-4-piperidinomethyl-1,3-dioxolane methyl halide. The compound represented by the general formula () is the general formula (′) (In the formula, X represents a halogen atom) 2-cyclohexyl-2-phenyl-
4-piperidinomethyl-1,3-dioxolane
It is a stereoisomer of methyl halide, 1,3
-The phenyl group and the piperidinomethyl group are in a trans configuration in the dioxolane ring. Compound (') has a strong anti-acetylcholine effect, especially the compound (') where X is iodine. 2-cyclohexyl-2-phenyl-
4-piperidinomethyl-1,3-dioxolane
Methiodide has excellent effects, and the isomer of compound (') with a high melting point is currently being used as an autonomous diameter blocker. The compound represented by the general formula (') is 2,2,4-trisubstituted-1,3-
Since it is a dioxolane derivative, there are two types of stereoisomers, but the production method is described in Japanese Patent Publication No. 41
-6585, it is synthesized by the route shown in the following formula. However, their three-dimensional structures have not been studied at all. Furthermore, as for the production method of compound ('), it is synthesized by the route shown in the following formula as described in Japanese Patent Publication No. 45-16475, and furthermore, the mixture of stereoisomers of compound (') is synthesized by trichlene treatment. The three-dimensional structure is unknown, but an isomer with a high melting point and an isomer with a low melting point were obtained. In this production method, the synthetic intermediate 2-cyclohexyl-2-phenyl-4-bromomethyl-
1,3-dioxolane () and 2-cyclohexyl-2-phenyl-4-piperidinomethyl-
Attempts have been made to separate the mixture of stereoisomers of 1,3-dioxolane (') by fractional distillation, fractional recrystallization, or column chromatography, but all have failed, and in the end, the compound (') was treated with trichlene to separate isomers, but its 3D structure has not been clarified. Furthermore, the fact that the production ratio of isomers in this production method is approximately 50:50 is industrially disadvantageous for obtaining isomers with high melting points that are used as pharmaceuticals. As a result of various studies under these circumstances, the present inventors have already synthesized purely the trans isomer () of compound ('), which could not be separated by conventional production methods, by the route shown in the formula below, and We succeeded in synthesizing the trans isomer () of compound (') by reacting it with methyl iodide, and the compound () obtained at this time has a higher molecular weight than that of compound (') obtained by conventional production methods. Since the melting point and instrumental analysis data completely matched the isomer having a melting point, we were able to clarify the three-dimensional structure of the isomer of compound ('), which is a pharmaceutical product. Compound (') can also be obtained by the route shown in the formula below.
It was found that the isomer with a high melting point can be obtained in pure form. Furthermore, this time, we have added a general formula () that was difficult to separate isomers and could not be isolated using conventional production methods. (In the formula, X represents a halogen atom) 2-cyclohexyl-2- which is unknown in the literature
We succeeded in purely synthesizing the trans isomer of phenyl-4-halogenomethyl-1,3-dioxolane, which was then reacted with piperidine to form the formula () 2-cyclohexyl-r-2-phenyl-t-4-piperidinomethyl-1,3-dioxolane represented by is obtained, and the thus obtained compound () is quaternized with methyl halide to obtain the general formula ( ) (wherein, X represents a halogen atom) It was discovered that 2-cyclohexyl-r-2-phenyl-t-4-piperidinomethyl-1,3-dioxolane methyl halide can be obtained, and the compound () It has been found that the compound () can also be obtained by reacting with N-methylpiperidine. First, 2-cyclohexyl-r-2-phenyl-t-4-halogenomethyl-1,3-dioxolane (), which is an important intermediate of the present invention, is obtained by the method of Inch et al. −
2-Phenyl-t-4-para-tolylsulfonyloxymethyl-1,3-dioxolane () [Reference: J.Chem.Soc.(C). 1970, 263] can be obtained in high yield by reacting with an inorganic halide. Inorganic halides include lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, sodium iodide,
Potassium chloride, potassium bromide, potassium iodide,
Calcium chloride, calcium bromide, calcium iodide, magnesium chloride, magnesium bromide, magnesium iodide, etc. are used, and the solvents are methanol, ethanol, dimethylformamide,
dimethylacetamide, dimethyl sulfoxide,
Diethylene glycol, ether, acetone, methyl ethyl ketone, water, etc. are used. The reaction temperature is about 0 to 200°C, and the reaction time is about 10 minutes to 48 hours. Compound () is treated by known processing means,
For example, it can be purified by distillation, recrystallization, column chromatography, etc. Compound () can then be synthesized by reacting compound () with piperidine. The reaction is carried out without a solvent or using a suitable organic solvent, but any solvent may be used as long as it does not inhibit the reaction, such as methanol, ethanol, isopropanol, butanol, benzene,
Toluene, xylene, petroleum ether, hexane,
Ligroin, ether, tetrahydrofuran, dioxane, methyl acetate, ethyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, etc. are used. The reaction temperature is room temperature to 150℃, and the reaction time is 1 to 48℃.
It takes about an hour. In this case, use excess piperidine to neutralize the hydrogen halide formed during the reaction, or add an equivalent amount of piperidine to sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, monosodium phosphate, disodium phosphate. The reaction may be carried out in the presence of a base such as trisodium phosphate. By quaternizing the thus obtained compound () with methyl halide, a purely trans isomer compound () can be synthesized. Any solvent may be used as long as it does not inhibit the reaction, such as methanol, ethanol, isopropanol, butanol, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, ether, tetrahydrofuran, dioxane, petroleum ether, hexane, ligroin, Methyl acetate, acetone, methyl ethyl ketone, acetonitrile, etc. are used, the reaction temperature is about -20 to 100°C, and the reaction time is about 30 minutes to 48 hours. Furthermore, by reacting compound () with N-methylpiperidine, compound () can be synthesized in one step. The reaction conditions are the same as those for the reaction of compound () with piperidine, and compound () can be purified by known processing means such as recrystallization, column chromatography, etc. As described above, by using 2-cyclohexyl-r-2-phenyl-t-4-para-tolylsulfonyloxymethyl-1,3-dioxolane () as an intermediate, it has been possible to 2-Cyclohexyl-r-2-phenyl-t-4-halogenomethyl-1,3-dioxolane (), which could not be released, can be easily obtained, and the compound () can also be used to exhibit anti-acetylcholine effects. 2-cyclohexyl-2-phenyl-4-piperidinomethyl-1,3
-Dioxolane Although it was possible to synthesize the trans isomer of methyl halide in a pure manner, the synthesis method according to the present invention is useful for the pharmaceutical drug 2-cyclohexyl-2-phenyl-4-piperidinomethyl-1,
This can be said to be an industrially valuable production method for producing the trans isomer of 3-dioxolane methiodide. Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto. Example 1 2-cyclohexyl-t-4-iodomethyl-
Method for producing r-2-phenyl-1,3-dioxolane 2-cyclohexyl-r-2-phenyl-t-
4-para-tolylsulfonyloxymethyl-1,
3-dioxolane 1.04g, sodium iodide 3.0
A mixture of g and 10 ml of acetone was refluxed for 30 hours,
After evaporating the solvent, water is added to the residue and extracted with chloroform. After washing the chloroform layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from acetone to give 754 mg of colorless plate-like crystals with a melting point of 85-86°C.
(81.1%). Elemental analysis value C ₁₆ H ₂₁ IO ₂ Calculated value: C, 51.63; H, 5.69 Experimental value: C, 51.66; H, 5.65 Nuclear magnetic resonance spectrum δ (CDCl ₃ ) 3.10-4.37 (5H, multiplet, -CH ₂ I and

[Formula]) Example 2 2-cyclohexyl-r-2-phenyl-t-
Method for producing 4-piperidinomethyl-1,3-dioxolane 2-cyclohexyl-t-4-iodomethyl-
r-2-phenyl-1,3-dioxolane 558mg,
A mixture of 0.45ml piperidine and 10ml toluene
After refluxing for 25 hours and allowing to cool, the toluene layer was washed with water and dried. The solvent was distilled off under reduced pressure, and the resulting brown oil was subjected to silica gel column chromatography to yield 436 mg (88.4%) of a colorless oil using benzene-ethanol (100:2). Nuclear magnetic resonance spectrum δ ( _CDCl3 ) 2.23-2.73 (6H, multiplet,

【formula】) 3.43~4.30 (3H, multiplet,

[Formula]) Example 3 2-cyclohexyl-r-2-phenyl-t-
4-Piperidinomethyl-1,3-dioxolane Production of methiodide (1) 2-cyclohexyl-t-4-iodomethyl-r-2-phenyl-1,3-dioxolane
A mixture of 200 mg and 1.2 ml of N-methylpiperidine is stirred at 120-125°C for 6 hours, and after cooling, water is added and extracted with chloroform. After washing the chloroform layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from monochlorobenzene to determine the melting point.
Obtained 130 mg (51.4%) of colorless crystals at 210-212 °C.
This product is an isomer with a high melting point of 2-cyclohexyl-2-phenyl-4-piperidinomethyl-1,3-dioxolane methiodide obtained by a conventional method, has a melting point, an infrared absorption spectrum,
The nuclear magnetic resonance spectra were completely consistent. (2) 2-cyclohexyl-r-2-phenyl-t
296 mg of -4-piperidinomethyl-1,3-dioxolane is dissolved in 2 ml of methanol, 0.12 ml of methyl iodide is added thereto, the solution is tightly stoppered, and the solution is left at room temperature overnight. The residue obtained by distilling off the solvent and excess methyl iodide under reduced pressure was recrystallized from monochlorobenzene to obtain 358 mg (84.4%) of colorless crystals with a melting point of 210-212°C. The melting point, infrared absorption spectrum, and nuclear magnetic resonance spectrum of this substance completely matched those of 2-cyclohexyl-r-2-phenyl-t-4-piperidinomethyl-1,3-dioxolane methiodide obtained in (1).

Claims (1)

[Claims] 1 Formula () By reacting 2-cyclohexyl-γ-2-phenyl-t-4-para-tolylsulfonyloxymethyl-1,3-dioxolane represented by the formula with iodomethyl, the formula () (In the formula, X represents an iodine atom.) Synthesize 2-cyclohexyl-γ-2-phenyl-t-4-iodomethyl-1,3-dioxolane, and then react the compound of formula () with piperidine. Let, expression () After synthesizing 2-cyclohexyl-γ-2-phenyl-t-4-piperidinomethyl-1,3-dioxolane represented by formula (), the compound of formula () is further reacted with iodomethyl. A method for producing 2-cyclohexyl-γ-2-phenyl-t-4-piperidinomethyl-1,3-dioxolane methiodide.