JPS6011696B2 - Method for producing 2-substituted tetrahydropyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2-substituted tetrahydropyridine derivatives.

More specifically, the present invention relates to general formula (1) (wherein R
, R3 and R4 represent a lower alkyl group, and R2 represents an aralkyl group).

The present invention relates to a new method for producing 2-substituted tetrahydropyridines shown in the following.

The object compound (1) of the present invention itself is a promising compound as a drug that acts on the central nervous system, and in one aspect of its utilization, the compound (1) of the general formula (n) (in the formula , R, and R4 are the same as defined above; R represents a substituent).

3-monosubstituted 1,2,314,5,6-hexahydro-6,11-dialkyl-8-hydroxy-2, represented by
6-methano-3-penzazocines are produced.

That is, a manufacturing method has already been established in which the objective compound (1) is converted into the compound represented by the general formula (0) by the route shown in the scheme '1}. Scheme '1' (wherein R., R2, R3 and R4 are the same as defined above, and R represents a substituent).

The compounds represented by the general formula (0) have a remarkable analgesic effect, and in particular, R and R4 are methyl groups,
A compound in which R is 3-methyl-2-putenyl group is a compound having extremely great medical value and is already widely used not only in Japan but also in other countries as a non-narcotic analgesic under the general name pentazocine.

Therefore, the invention of a practical method for synthesizing the compounds (1) of the present invention is
As such, it not only provides drugs for the central nervous system, but also provides important synthetic intermediates for the industrial production of extremely superior analgesics, and thus has great value in the pharmaceutical industry. The compound represented by formula (1), which is the target compound of the present invention, has already been synthesized by several production methods, but
The present invention is completely different from these conventional methods, and is based on the general formula (1
) provides a novel method for synthesizing compounds. Furthermore, the present invention is advantageous in terms of shortening the number of steps, easy availability of raw materials, ease of reaction, yield, etc. Therefore, it will greatly contribute to industrial manufacturing methods that provide excellent analgesics at low prices. .

Each step involved in the method of the present invention is summarized as shown in the scheme (2)'.Scheme '21 (In scheme 2, R,, R3, and R4 represent lower alkyl groups, R
2 represents an aralkyl group.

In addition, the numbers ■, ■, ■, ■, ■, ■, and ■ represent each step). In the above formula '21, the lower alkyl group represented by R, R3 and R4 represents a chain or branched alkyl group having 1 to 4 carbon atoms, and specifically, for example, methyl, ethyl, n-propyl, i -propyl n-butyl, s-butyl, i-butyl, t-butyl and the like. Further, examples of the aralkyl group represented by R2 include penzyl group, substituted penzyl group, phenethyl group, and substituted phenethyl group, and specific examples include methylbenzyl group, methylphenethyl group, chlorobenzyl group, chlorphenethyl group, etc. It is.

The present invention will be specifically explained below by explaining each step in detail.

First, step (2) is a step in which a cyclopropyl pinyl ketone conductor represented by formula (W) is obtained by reacting acetylcyclopropane represented by the compound (dish) with p-alkoxybenzaldehyde under a basic catalyst.

The bases used in this condensation reaction include caustic alkali,
Examples include metal alkoxides and alkyl metals.

Although the reaction temperature cannot be determined unconditionally depending on the solvent used, it is usually about 15 to 15 hours, and a reaction time of 10 to 3 hours is often sufficient. The target product can be collected by known means. Step (2) is a step in which a cyclopropyl ethyl ketone derivative represented by formula (V) is obtained by reducing the double bond portion of the cyclopropyl vinyl ketone derivative represented by formula (W) obtained in step (2) above.

As the reduction method, catalytic reduction using a metal catalyst, high pressure reduction, or a method using a hydrogen metal body is used.

For example, in catalytic reduction or high-pressure reduction, catalysts such as platinum, Raney nickel, and palladium-carbon are used, and Birch reduction using lithium, sodium, etc. can be used to achieve various purposes, but catalytic reduction methods generally give good results. . The solvent used in the reaction is
Examples include water, ethanol, methanol, and liquid ammonia. The reaction temperature is usually around -780 to 100 qo in many cases. A method known per se is employed as a means for collecting the target product in the reaction. Process ■ is
This is a step of obtaining a cyclopropyl 1-bromoethyl ketone derivative represented by the formula (machi) by reacting the cyclopropylethyl ketone derivative obtained in the above step (1) with a brominating agent.

As the brominating agent used in this step, bromine, N-promosuccinimide, etc. are used, but pyridine hydrobromide perbromide gives relatively good results.The reaction is usually carried out in the presence of a suitable solvent. As such a solvent, any solvent may be used as long as it does not participate in the reaction, and specifically, esters such as ethyl ether, tetrahydrofuran, and dioxane, chloroform, methylene chloride, carbon tetrachloride, etc. Examples include halogenated hydrocarbons, and hydrocarbons such as hexane and dimethoxychetane.The reaction temperature is usually around 0 to 10,000 ℃.The reaction time is usually about 1 to 1 hour, which is often sufficient. The purpose of the reaction can be obtained by a known method.Step (2) is a reaction of the cyclopropyl 1-promoethyl ketone derivative of the formula (W) obtained in the above step (2) with an aralkylamine to obtain the formula (skin). ) is a process for obtaining a cyclopropyl 1-substituted aminoethyl ketone derivative.

This reaction is usually carried out by condensing the compound represented by formula (W) with an aralkylamine in a suitable solvent, and any solvent that does not participate in the reaction can be used, such as , methanol, ethanol, tetrahydrofuran, benzene, hexane, ethyl ether and the like.

Of course, the process can proceed without a solvent, and it is often effective to use a deoxidizing agent such as sodium hydrogen carbonate, sodium carbonate, or potassium carbonate, if desired. The reaction temperature is 2
A temperature of about 0°C to 150°C and a reaction time of about 2 to 1 hour are sufficient. As a means for collecting the compound, a method known per se is employed. Step ■ is the formula obtained in step ■ above (skin)
This is a step of converting the cyclopropyl 1-substituted aminoethyl ketone derivative represented by the formula (skin) to the 1-substituted-2-(4-alkoxybenzyl)-4-alkylpiveridin-13-one represented by the formula (skin). .

The purpose of this reaction can be easily achieved by heating the compound represented by the formula (skin), and the heating temperature cannot be unconditionally limited depending on the compound represented by the formula (skin), but it ranges from 30°C to Around 250 pm is sufficient.

The reaction can of course be carried out by heating the compound (skin) in the absence of a solvent, but better results are obtained by allowing the compounds to coexist in an appropriate manner. Such a solvent may be appropriately selected as long as it does not participate in the reaction, such as chloroform, methylene chloride, hexane, benzene, toluene, 1,2-
Examples include dimethoxyethane and acetonitrile.
Although the reaction can easily proceed without a catalyst, depending on the compound, a catalytic amount of an organic acid such as p-toluenesulfonic acid or methanesulfonic acid, or an inorganic salt such as potassium iodide or potassium bromide may be added. It is also possible to make the reaction easier by adding it, and this often gives better results.

The reaction temperature cannot be limited depending on the compound, but is between 300 and 25
A temperature of about 0°C is sufficient. The reaction can also be carried out by heating in a sealed tube, although the purpose can be achieved by overflowing in a solvent or without a solvent. Although the reaction time cannot be determined unconditionally depending on the solvent used, etc., about 10 to 100 hours is sufficient in most cases. The target product of the reaction is collected by known means (eg, evaporation, liquid conversion, concentration, washing, chromatography, crystallization, recrystallization, etc.). Process■
is the 1-substituted-2 represented by the formula (skin) obtained in step ① above.
1-(4-alkoxybenzyl)-4-alkylpiveridin-3-one substituted with 1-3-hydroxy-2-(4-alkoxybenzyl)-3,4-dialkylpiveridine represented by formula (K) This is the process of converting it into The reaction is usually carried out in a solvent by reacting a compound represented by the formula (skin) with an organometallic compound such as a Grignard reagent, an alkyl metal compound, or a Leformaxchi reagent.

Examples of these include alkylmagnesium halides, alkyllithiums, alkylzinc compounds, and the like. The solvents used in this reaction include ethylhenal,
Ether solvents such as tetrahydrofuran and dioxane are suitable. The reaction temperature is about -40°C to about 0°C, and the reaction time is often about 0.1 to 2 hours. After completion of the reaction, the target product of the reaction can be easily collected by methods commonly used in organic chemistry, such as dissolution, liquid conversion, concentration, chromatography, recrystallization, and crystallization. Step (2) is to subject the 1-substituted-3-hydroxy-2-(4-alkoxybenzyl)-13,4-dialkylpiveridine represented by formula (K) obtained in the above step (2) to a dehydration reaction, This is a process for obtaining 1-substituted-2-(4-alkoxybenzyl)-3,4-dialkyltetrahydropyridine represented by formula (1).

This dehydration reaction is usually carried out by treatment with an acid in a solvent.

The acids used in this reaction include mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and polyphosphoric acid, and organic acids such as p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and methanesulfonic acid. Among them, sulfuric acid is preferably used. As a solvent during the reaction, water, an alcoholic solvent such as ethanol, methanol, propanol, or a mixture thereof is used.

The reaction temperature is about 30 o to 200 o'clock, and the reaction time is about 3 to 3 hours in most cases. After completion of the reaction, the 1-substituted 12-(4-alkoxybenzyl)-13,4-dialkyltetrahydropyridine represented by the general formula (1), which is the target product of the reaction, can be purified by known means (for example, conversion). It can be collected by methods such as dissolution, liquid conversion, concentration, chromatography, salt formation, etc.). As described above, the present invention not only provides a compound that itself has a central nervous system effect, but also an important synthetic intermediate for compound (0) of high medical value that exhibits significant analgesic or non-narcotic analgesic activity. (
This method provides a simple synthesis method of 1), and is highly practical and highly useful even in industrial scale production.

Moreover, this new synthetic method is extremely step-wise.
The structures of the compounds and intermediates obtained in the present invention have been clarified by elemental analysis, ultraviolet absorption spectra, infrared absorption spectra, nuclear magnetic resonance spectra, mass spectrometry spectra, and thin layer chromatography. This was elucidated by confirming the identity of what was obtained using the above method.

The present invention will be explained in more detail below with reference to Examples.
It should not be limited to these.

Example 1 Method for producing 11-methylcyclopropyl 2-(4-methoxyphenyl)-vinyl ketone 1-acetyl-1
A mixture of 10.5 parts of methylcyclopropane, 14.6 parts of p-methoxybenzaldehyde, 11 parts of sodium hydroxide, 100 parts of water, and 80 parts of ethanol is stirred at room temperature for 2 hours.

After adding 200 ml of water to the reaction mixture, it was extracted with ether. The ether layer was washed with saturated brine and dried over sodium sulfate, and the solvent was distilled off to obtain a yellow oil. Ultraviolet absorption spectrum Input max (MeOH)n 323
Infrared absorption vector Remax (CHC13) skin-1
1663 (C=○) nuclear magnetic resonance spectrum 6 (CDC
13) 0.63 to 1.53 (mountain day, multiplet, cyclopropane ring) 1.43 (chihito, singlet, 1C ratio) 3.81
(3 days, single line, one OCH3) 6.7-7.64 (each IH, double line, J=14HZ, C
2, 3-H) 6.90, 7.45 (each double line, J=
8HZ, aromatic nucleus proton) mass spectrometry spectrum (m/
e) 216 (molecular ion peak) Elemental analysis C, 4 days, 602・0.2 spot 20 calculated value C
, 76.25; day, 7.54 experimental value C, 76.10;
Sun, 7.39 Example 2 Process for producing 1-methylcyclopropyl 2-(4-methoxyphenyl)-ethyl ketone 1-Methylcyclopropyl 2-(4-methoxyphenyl)-pynyl ketone 18 evenings, Raneynickel (W2) 10 evenings. Suspend in 400% ethanol and shake for 2 hours under a hydrogen stream.

After the reaction, Raney nickel was removed and ethanol was distilled off to obtain a pale yellow oil. This was subjected to vacuum distillation and bpl15o/
0.4 side Hg colorless oil 18 times (Examples 1 to 81.
35%). Infrared absorption spectrum 〃max(C
HC13) Kay-11680 (C=○) Nuclear magnetic resonance spectrum 6 (CDC13) 0.48-1.23 (4 days, multiplet, cyclopropane ring) 1.29 (thin, singlet, -C
Q) 3.72 (bait, singlet, -OCH3) 6.70 7.60 (2 days each, doublet, J=9Hz, aromatic nucleus protoso) Mass spectrometry spectrum (m/e) 218 (molecular ion peak ) Elemental analysis value C, 4 days, 202 Calculated value C, 77.03: days, 8.31 Experimental value C, 76.70; days, 8.36 Example 3 1-Methylcyclopropyl 1-bromo 2-(4 1 obtained in Example 2 of the method for producing -methoxyphenyl)ethyl ketone
monomethylcyclopropyl 2-(4-methoxyphenyl)
Dissolve 50% of ethyl ketone in 200% of ether, and add 7.5% of pyridine hydrobromide perbromide little by little while cooling on ice.

After the addition is complete, stir at the same temperature for another 4 hours.
After the reaction, the reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate water and then with saturated brine, dried over sodium sulfate, and the solvent was evaporated to obtain 7.5 g of yellow oil. Infrared absorption spectrum 〃max (CHC13) Skin-11 Iso 5
(Cni0) Nuclear magnetic resonance spectrum 6 (CDC13)0
．． 6-1.3 (cape, multiplet, cyclopropane ring) 1.3
5 (group, singlet, -C melon) 3.76 (3 days, singlet, one OCH3) 4.47 (IH, quartet, J=6HZ, 9HZ, one CH
Br-) 6.87.1 (each daughter, doublet, J=8HZ, aromatic nucleus p*ton) Mass spectrometry spectrum (m/e) 296 (molecular ion peak) Elemental analysis value C, 4 days, 702Br Calculation Value C, 56. Group: Day, 5.77 Experimental value C, 56.45: Day, 5.87 Example 4 1-Methylcyclopropyl 1-benzylamino-2-(
Example 3 of the method for producing 4-methoxyphenyl)ethyl ketone
The bromo compound obtained in 7.5 hours, the benzylamine 11.3 hours
5. Dissolve the liquid in 200 methanol. During the period, the horse is refluxed.

After the reaction, methanol was distilled off, and the resulting residue was dissolved in 100 g of 10% hydrochloric acid and washed with n-hexane. The mixture is made basic with 10% aqueous ammonia and then extracted with ether. The ether layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain a yellow oil. Purified by silica gel chromatography and extracted from the hexane:benzene = 2:3 effluent fraction as a colorless oil (75.6% from Example 3)
I got it.

Infrared absorption vector Remax (CHC13) Kay-1
1680 (C=○) nuclear magnetic resonance spectrum 6 (CDC
13) 0.5-1.2 (4 days, multiplet, cyclopropane ring) 1.23 (spotted, singlet, -C ratio) 3.8 (3 days, singlet, one OCH3) 6. &7.1 (each doublet, J=8HZ, aromatic nuclear proton) 7.2 (beat, singlet, aromatic nuclear proton) Mass spectrometry spectrum (m/e) 323 (molecular ion peak) Hydrochloric acid of this product The salt is a colorless crystal with a mp of 163 to 1640.

Elemental analysis value C2, day 25N02・HC1・0. Spot 20
Calculated value C, 68.31; Day, 7.38; N, 3.80
Experimental value C, 68.10; day, 7.23; N, 3.83
Example 5 Process for producing 1-penzyl-2-(4-methoxybenzyl)-4-methylpiveridin-3-one Example 4
Hydrobromide salt of pendylamino derivative obtained in 325-9
Potassium tritide 130g is dissolved in acetonitrile and heated in a sealed tube at 140-145°C for 3 days.

After the reaction, inorganic substances were removed and the solvent was distilled off, and the resulting residue was dissolved in 20% 10% hydrochloric acid and washed with n-hexane. 1
The mixture is made basic with 0% aqueous ammonia and then extracted with ether.

The ether layer was washed with saturated sodium thiosulfate and then with saturated brine, dried over sodium sulfate, and the solvent was removed to give a yellow oil. This product is subjected to silica gel force column chromatography and eluted with benzene to obtain a solid substance, which is recrystallized from benzene-hexane to yield a mpl of 04 to 1
It gives 185 females (71.2%) of colorless needles of 05o.
Infrared absorption spectrum 〃max (CHC13) arc-1
1710 (C=〇) Nuclear Magnetic Resonance Spectrum 6 (CDC
13) 1.03 (9th, double line, J = 6.5HZ, 1C
H3) 3.73 (but, singlet, >NCH2Ar) 3.7
8 (crime, single line, -OCH3) 6.7 & 7.03 (each double line, J=9.0HZ,
Aromatic nuclear proton) 7.21 (porridge, singlet, aromatic nuclear proton) Mass spectrometry spectrum (m/e) 323 (molecular ion peak) Elemental analysis value C2, day 2bu02 Calculated value C, 77. Pseudo; day, 7.79 Experimental value C, 78.20: day, 7.73 Example 6 1-benzy-3-hydroxy 2-(4-methoxybenzyl-3,4-dimethylpiveridine production method Example 5) The obtained dry ether solution of 9 of the piberidinone compound 100 was added dropwise to a solution of methylmagnesium iododide (obtained from 85 of magnesium powder and 500 of methyl iododide) dissolved in 5 parts of dry ether.

After the addition is complete, stir at room temperature for another 5 hours. After the reaction, the reaction solution was poured into 10ml of ice water and extracted with ether. The ether layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain a yellow oil. Then, it was subjected to silica gel column chromatography and eluted with benzene-ethyl acetate (95:5) to give 62m9 of a colorless oil.
(59%). The hydrochloride of this product is mp180-18
Gives the final colorless crystal.

Infrared absorption spectrum 〃max (CHC13) arc-1
3500 (1OH) Nuclear Magnetic Resonance Spectrum 6 (CDC
13) 0. We (spot, double line, J=4.0HZ CH3"H<) 1.25 (spot, single line, -CH3) 3.8 (chichi, single line, one OCH3) 6. &7.6 (each doublet, J=8HZ aromatic nucleus proton) 7.65 (square, singlet, aromatic nucleus proton) Elemental analysis value C22 days 2buQ・HC1・0. Field 20 calculated value C,
ship. 64; Sun, 8.06: N, 3.64 experimental value C, 6
8.68: Sun, 7.94: N, 3.71 The instrumental analysis data of this product completely match the standard derived from a known compound.

Example 7 1-Penjiru 1.2.516-Tetrahydro 2-
Hydroxypiveridine compound 30 obtained in Example 6 of the method for producing (4-methoxybenzyl)-3,4-dimethylpyridine
Dissolve 9 in 50% sulfuric acid and stir at 80°C for 2 days.

After the reaction is completed, 10% ammonia water is added to the reaction mixture to make it basic, and the mixture is extracted with ether. The ether layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed to give a yellow oil. This was purified by silica gel thin layer chromatography (petroleum ether = 3:1) to obtain 9 of 23 (81%) as a colorless oil. Nuclear magnetic resonance spectrum 6 (CDC13) 1.63 (set, singlet, Z-CH3
) 3.58 legs, singlet, >NCH2Ar) 3.77 (group, singlet, -OCH3) 6.60 7.08 (each phantom, doublet, J = 9.1 day 2 aromatic nucleus broton) 7 .10 (mother, singlet, aromatic nucleus proton) hydrochloride gives colorless crystals with mp 152-153.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_3 are lower alkyl groups, R_
2 represents an aralkyl group). 1-substituted-2-(4-alkoxybenzyl) represented by
-4-Alkylpiperidin-3-one is reacted with an organic alkyl metal compound, and the general formula ▲ has mathematical formulas, chemical formulas, tables, etc. General formula ▲ Numerical formula, chemical formula, table, etc. characterized by producing 1-substituted-3-hydroxy-2-(4-alkoxybenzyl)-3,4-dialkylpiperidine represented by (representing) and then dehydrating it. A method for producing 1-substituted-2-(4-alkoxybenzyl)-3,4-dialkyltetrahydropyridine represented by ▼ (wherein R_1, R_2, R_3 and R_4 are the same as defined above).