JPS6028826B2 - Method for producing benzylamine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of the general formula (1) [wherein R1
, R2 are the same or different and represent a hydrogen atom, a lower alkylcarbonyl group or a penzoyl group, and R3 is a hydrogen atom, a lower alkyl or lower alkenyl group which may have a hydroxyl group, phenyl group or morpholinocarbonyl group as a substituent. , represents a lower alkylcarbonyl group or a penzoyl group which may have a mercapto or morpholino group as a substituent.

x indicates a halogen atom] The present invention relates to a method for producing a penzylphumine derivative represented by the following. More specifically, the present invention provides a pendylamine derivative of general formula (1), which is characterized by halogenating a compound represented by general formula (0) [wherein R1, R2 and R3 have the same meanings as above]. Regarding manufacturing methods.

In each of the above formulas, the lower alkylcarbonyl group represented by RI and R2 is an alkyl group having 1 to 3 carbon atoms, such as acetyl, propionyl, butyryl group, etc.
Examples include lower alkylcarbonyl groups, which are lower alkyl groups.

Examples of the lower alkyl group or lower alkenyl group represented by R3 include methyl, ethyl, propyl, and isof. Lopyl, butyl, isobutyl, tert-butyl,
Examples include straight chain and branched groups having about 1 to 6 carbon atoms, such as sec-butyl, allyl, bentyl, and hexyl groups.
When these groups further have a hydrogen group, phenyl group or morpholinocarbonyl group as a substituent, one or more of these substituents may be substituted at any position of the group represented by R3. good. Examples of the phenyl-substituted alkyl when the substituent is a phenyl group include aralkyl groups such as verzyl and phenethyl groups. R3
When the lower alkyl group represented by has a hydroxyl group as a substituent, specific examples of these substituents include, for example,
Hide. oxymethyl'B-hydro. Examples include hydroxyalkyl groups such as xyethyl and dihydroxypropyl. The lower alkylcarbonyl represented by R3 is R
1, the same alkyl moiety as shown in R2 has 1 carbon number
An example is an alkylcarbonyl group which is a lower alkyl group of about 3 to 30%. When the lower alkylcarbonyl group represented by R3 further has a mercapto or morpholino group as a substituent, one to two or more of these substituents may be substituted at any position of the lower alkylcarbonyl group represented by R3. It's okay to do so. Specific examples of lower alkylcarbonyl groups having these substituents include mercaptoacetyl, mercaptoacyl such as 8-lcaptopropionyl, morpholinoacetyl, 8-morpholinopropionyl, and the like. The halogen atoms indicated by x are chlorine, bromine, iodine and fluorine atoms, with bromine and chlorine atoms being particularly preferred. The method of the present invention is carried out by reacting the compound of general formula (b) with a halogenating agent.

As the halogenating agent that can be used in the reaction, any one that can be used in the halogenation reaction of aromatic rings can be used. For example, halogen itself such as chlorine and bromine, bromochloride (Br+CI -),
Chlorfuromide (C
rBr), etc. The reaction is usually carried out in an inert solvent. Examples of inert solvents used in the reaction include aromatic hydrocarbons such as benzene and toluene;
Petroleum benzine, n-hexane, etc. and, for example, carbon tetrachloride, chloroform, dichloromethane, etc. Examples of the hydrogenated hydrocarbons include organic carboxylic acids such as acetic acid and propionic acid. Among these, organic carboxylic acids and halogenated hydrocarbons are preferred as the reaction solvent. As the reaction temperature, a temperature of about 1,200 to about 140° can be used as appropriate, but the reaction can be particularly advantageously carried out at room temperature. The amount of halogenating agent used is usually about 2 to about 20 molar equivalents per 1 mol of starting compound (0), but 2 mol equivalents or a slight excess thereof per 1 mol of compound (B). It is preferable to use The target compound (1) is produced in a free form or as a hydrohalide salt corresponding to the halogenating agent used, and both are purified by conventional methods such as chromatographic distillation or recrystallization. When the target compound (1) obtained in this way is a free base, a known method using a physiologically acceptable inorganic or organic acid, for example, an alcoholic solution of the acid is mixed with 1 to 3 molar equivalents of the compound (1). By reacting, it can be converted into the corresponding acid addition salt. Examples of acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as lactic acid, citric acid, tartaric acid, and maleic acid. In addition, the object compound (1) of the present invention can also be produced by the synthesis method shown by the following formula.

[In the formula, R3 and carried out under the same conditions.

[In the formula, R1, R2, R3 and X have the same meanings as above.] The ketone group in this step is reduced by reduction with a fluorinated metal hydride.

Examples include lithium aluminum hydride, sodium aluminum hydride, sodium boron hydride, etc. As a solvent, anything that does not inhibit the reaction can be used, such as ethers such as ether'tetrahydrofuran dioxane, and hydrocarbons such as benzene and n-hexane. . Also, the temperature is between 15 and 120q.
It is carried out until o. [In the formula, R1, R2, R3 and may also be used.

Compound (1) can be produced by heating this mixture to 120 to 200 qo. [In the formula, R1
, R2, R3 and × have the same meanings as above, RI' and R
2' represents the same lower alkylcarbonyl group or penzoyl group as shown by R1 and R2] The acylation reaction in this step is carried out in the step (B) in the production of the starting compound (b) of the present invention, which will be described later. ) is carried out under the same conditions as the acylation reaction of compound (0').

[In the formula, R1, R2, and × have the same meanings as above, 1 represents a halogen atom such as chlorine or bromine, and R3' represents the definition of R3 excluding a hydrogen atom] Substitution reaction of this step is a starting compound (
b) to obtain (1), the solvent is:
Examples include alcohols, ketones, hydrocarbons, halogen hydrocarbons, and dimethyl formaldehyde, and the reaction temperature is 0 to 120 qo.

Furthermore, R3' Kazuya1 is usually used in an equimolar amount or in a slightly excess amount relative to (b). The target compound (1) or a salt thereof produced according to the method of the present invention is a novel compound having respiratory tract fluid secretion promoting action, antihistamine action and/or anti-dust bonito action, and is an airway fluid secretion promoting agent (removal of lacquer). It can be used as a medicine such as an antihistamine agent or an anti-salt bonito agent.

When compound (1) or a salt thereof is used as a pharmaceutical for these purposes, a pharmaceutically acceptable diluent, excipient, excipient, solubilizing agent, etc. Mixed with chapters, tablets, capsules, powders, granules,
It can be administered orally or parenterally in various dosage forms such as solutions, syrups, aerosols, ointments, injections, and suppositories. Among these, the acid addition salt of compound (1) is soluble in water and is particularly suitable for use as an injection or aqueous solution. The dosage of compound (1) or a salt thereof varies depending on the target disease, the type of compound, etc., but when used as the above-mentioned medicine, the usual dose for adults is about 5 to 200 o/day. Note that the raw material compound (0) of the present invention is, for example, available from Journal of Chemical Society (JomMi of
It can also be produced according to the method described in Chemical Society), p. 1722 (19th year), and by the steps shown below. [In the formula, R1, R2, R
3 has the same meaning as above, and X' represents a halogen atom similar to
ety) page 39 (192 Uroko) or a method analogous thereto.

The reaction in the process is carried out by reacting compound a' and compound {b), and the amount of compound 'b} used is the same as that of compound (
It is usually about 1 to 3 molar equivalents per mol of a'.

The reaction is usually carried out in a solvent, such as alcohols (e.g. methanol, ethanol, propanol), halogenated hydrocarbons (e.g. carbon tetrachloride, chloroform, dichloromethane), ketones (e.g. acetone,
Methyl ethyl ketone), dimethyl formaldehyde, etc. The reaction temperature is usually 0 to 120 qo, and when a solvent is used, it is around the boiling point of the solvent. The reaction in step 'B' is carried out by first reducing the compound 'c' obtained in the process.

Any reducing agent used in the reaction can be used as long as it can reduce the nitro group of the aromatic ring to an amino group.
Examples include catalytic reduction in the presence of a catalyst such as Ranenitzker, platinum oxide, palladium on carbon, etc.; reduction using sodium hydrogen sulfide; and reduction using Ranenitzker-hydratine hydrate. Reaction conditions vary depending on the reducing agent used. In catalytic reduction, the reaction usually proceeds at room temperature,
Reduction using sodium hydrosulfide is carried out near the boiling point of the alcohol (eg, methanol, ethanol, propanol) used as a solvent. In reactions using Raney nickel hydratisohydrate, the solvent is usually
Although the reaction itself is carried out using the above-mentioned alcohol, etc.
It is an exothermic reaction and does not require heating. Preferably about 50
The reaction is carried out at ˜70°. In the general formula (0), the compound (ro'') in which RI and/or R2 are lower alkylcarbonyl or penzoyl groups is
2-aminobenzylpiverazine derivative (0') (wherein R3 has the same meaning as above) obtained by the reduction reaction of B} is produced by acylation of the amine/group at the 2-position.

The acylation reaction is carried out by reacting the 2-aminobenzylpiverazine derivative (2') with an acylating agent. The corresponding reactive conductors of lower aliphatic or aromatic carboxylic acids (e.g., acid halides such as acetyl chloride and benzoyl chloride, acid anhydrides such as acetic anhydride and benzoic anhydride, and mixed acid anhydrides of these acids) can give. The amount of the acylating agent used is usually about 1 to 4 molar equivalents per 1 mol of compound (b'). The reaction is usually carried out in a solvent, and examples of the solvent include esters such as ethyl acetate and butyl acetate, and ethers such as tetrahydrofuran and dioxane.
The reaction temperature is usually about 0 to 12,000 ℃. The thus obtained 21(monoacylamino)1 or 21(
diacylamino)-penzylpiverazine derivative (RO'')
is one of the acyl groups (lower alkylcarbonyl group or penzoyl group) of this mono or diacylamino group,
Or, if desired, both can be removed by a conventional hydrolysis method using scale acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and conversely, 2-(monoacylamino)-penzylpiverazine derivative (0'') can be further subjected to the above-mentioned acylation reaction to lead to the 2-(diacylamino)-benzylpiverazine derivative (0'').

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

Example 1 N,-methyl-N4-(2-amino-3,5-dipromobenzyl)piverazine hydrochloride acetic acid 10 on top of N,-methyl-N4-(2-aminobenzyl)piverazine 0.81
Dissolve the 0.32% bromine in a pestle, add 0.32% bromine at room temperature, and allow to react for 30 minutes.

Then, the solvent is removed from the reaction solution under reduced pressure, and the resulting residue is made alkaline with concentrated aqueous ammonia and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and the chloroform is distilled off. 18% of the resulting oil
When the crystalline substance obtained by the ethanol-hydrochloric acid treatment is recrystallized from methanol, pale yellow crystals are obtained. Melting point 182
~185q C Analytical value C, 2 days, 7N3Br2・HC1・day 20 Theoretical value C 34.51: day 4.82: N IO. 06 Experimental value C 34.42; Sun 5.31:N 9.75 Example 2 In the same manner as in Example 1, the following compounds are obtained from the corresponding aminobenzylpiverazine derivatives.

N,-Hydrogen-N4-(2-amino-3,5-dibromobenzyl)piverazine hydrochloride (melting point 194-19600
), N,1n-propyl-N4-(2-amino-3,5
-dibromobenzyl)piverazine hydrochloride (melting point 167
~16900), N,1penzyl-N4-(2-amino-3,5-dibromobenzyl)-piverazine hydrochloride (melting point 215-220°C), N,1[(morpholinocarbonyl)-methyl]-N4 -(2-amino-3,5
-dibromobenzyl)-piverazine hydrobromide (melting point 201~204oo), N,1(8-hydroxyethyl)-N4-(2-amino-3,5-dibromobenzyl)piverazine hydrochloride (melting point 148~ 150pm ○),
N,1[(morpholinomethyl)-carbonyl]-N
4-(2-amino-3,5-dibromobenzyl)piverazine hydrochloride (melting point 224-227q0), N,-isopropyl-N4-(2-amino-3,5-dibromobenzyl)piverazine hydrochloride (melting point 205-227q0) 20900)
, N,-mercaptoacetyl-N4-(2-amino-3
,5-difurobenzyl)piverazine hydrochloride (melting point 1
82-18600 (decomposition)), N,1-acetyl-N4-(2-diacetylamino-3,5-dibromobenzyl)
Piverazine hydrochloride (melting point 140-14yo), N,1penzoyl-N4-(2-monobenzoylamino-3,
5-dibromobenzyl)piverazine hydrochloride (melting point 15
3-155o0), N,-cinnamyl-N4-(2-
Amino-3,5-dibromobenzyl)piverazine hydrochloride (melting point 208-210qo (decomposed)) N. -(morpholinocarbonylmethyl)-N4-(2-diacetylamino-3,5-dibromobenzyl)piverazine hydrochloride (melting point 163-165o0), N,1(morpholinocarbonylmethyl)-N4(2'-monobenzoyl) Minnow 3,
5-dibromobenzyl)piverazine hydrochloride (melting point 162
~164℃), N,1 (morpholinocarbonylethyl)
-N4-(2-amino-3,5-dibromobenzyl)piverazine hydrochloride (melting point 150-154 2○ (decomposition)) Reference example 1 {1) N,-methyl-N4-(2-nitrobenzyl)
Manufacture of Piverazine 0 Nitrobenzyl chloride 2.1
Dissolve 60% of ethanol in 20% of ethanol, and then add N- to this.
Add 1.02 hours of methylpiverazine and 1.3 hours of potassium carbonate, and react under reflux for 1 hour.

Then, the reaction solution was heated in a furnace, and the solvent was distilled off from the mother liquor under reduced pressure.
The resulting residue is extracted with water-ether (1:1).
The ether layer is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain a brown oil. Infrared absorption spectrum (liquid film) skin-1:1610,1538.
Nuclear magnetic resonance spectrum (deuterochloroform) ppm: 2.
25 (narrow, 1 lane), 2.40 (4 days, 1 double line), 3.
73 (2nd, single line), 7.2-7.9 (cape, multiple line)
(2) N,-methyl-N4-(2-aminobenzyl)
Preparation of Piverazine 1.87 g of N,-methyl-N4(2-nitrobenzyl)-piverazine is dissolved in 30 g of ethanol and then 3.0 g of Lanenickel is added thereto.

To this, 3.0 g of hydratine hydrate was further added and reacted at room temperature for 2 hours. After the reaction, Fune nickel is separated from the reaction mixture in a furnace, soot is distilled off from the mother liquor under reduced pressure, and the resulting oil is recrystallized from water-containing methanol to obtain pale yellow crystals. Melting point 78-7900 Elemental analysis C, 2 days, bu 3 Theoretical value C 70.20; days 9.33; N 2
0.47 Experimental value C 70.01; Sun 9.69:N
20.40 Reference Example 2 In the same manner as in Reference Example 1, nitrobenzyl chloride and pibeheracin or the corresponding N-
The following compounds can be obtained from the substituted piperazine derivatives.

N, monohydrogen-N4-(2-aminobenzyl)piverazine (melting point 127-128qo), N. -n-propyl-N4-(2-aminobenzyl)piverazine hydrochloride (melting point 215-220°C), N,-penzyl-N4-(2-
aminobenzyl) piperazine (melting point 92-93q○)
,N,1 [((morpholinocarbonyl)-methyl]
-N4(2-aminobenzyl)-piverazine (melting point 1
58-160℃), N,1(8-hydroxyethyl)
-N4-(2-aminobenzyl)-piverazine maleate (melting point 152-153°C), N. -Cinnamyl-N4-(2-aminobenzyl)-piverazine (melting point 185-187°C), N,1-isopropyl-N4-(
2-ami/penzyl)-piverazine oil.

Nuclear magnetic resonance absorption spectrum (deuterochloroform) skin: 1.
03 (Bait, double line J=7), 2.50 (Chichi, 1 lane), 2. Ship (IH, 2 lanes J=7), 3.46 (but, 1
lane), 6.4-7.2 (cape, multiplet) N, one (morpholinomethylcarbonyl) one N4 one (2-aminobenzyl) piperazine, oil.

Nuclear magnetic resonance absorption spectrum (NMR) (deuterochloroform) trace: 2.3 to 2.8 (mother's day, multiplet). 3.20 (group, 1 lane), 3.43 (but, 1 lane), 3.4-3.9
(Mother's Day, multiplet), 5.0 (ga), 6.4-7.2 (4
day, multiplet), N, one (mercaptomethylcarbonyl)
-N4-(2-aminobenzyl)piverazine, hot crystal form. NM Nagi (heavy chloroform) skin: 2.1-2.7 (4 days, multiplet), 3.3-3.9 ((''day, multiplet), 3.
43 (2 days, single line), 3.50 (spot, 1 perpendicular line). 6.
5-7.4 (4 days, multiplet) N,1(morpholinocarbonylethyl)-N4-(2-aminobenzyl)piverazine (melting point 65-670〇)
- Reference example 3N. -(morpholinocarbonylmethyl)-N4-(2-aminobenzyl)piverazine 100 nails 9 pyridine 3. [Add 9 of penzoyl chloride 62 to the solution and leave it at room temperature overnight.

Then, the pyridine was removed under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate to obtain N,1(morpholinocarbonylmethyl) as an oil.
-N4-(2-monobenzoylaminobenzyl)piverazine is obtained. NMR (heavy chloroform) Yanagi: 2.4
0 (cape, 1 perpendicular), 2.80 (4 days, 1 double line), 3.0
3, 3.18 (each IH, broad single line), 3.53 (
Spotted, single line), 3.60 (8th, Broad 1 lane), 6
．． 8-8.3 ■ days, multiplet). In a similar manner, the following compound is obtained from the corresponding 2-aminobenzylpiverazine derivative and an acylating agent.

N,1(morpholinocarbonylmethyl)-N4-(2-diacetylaminobenzyl)-piverazine, oil.

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom, a lower alkylcarbonyl group, or a benzoyl group, and R^ 3 is a hydrogen atom, a lower alkyl or lower alkenyl group which may have a hydration group, phenyl group or morpholinocarbonyl group as a substituent, a lower alkylcarbonyl group which may have a mercapto or morpholino group as a substituent or a benzoyl group] is characterized by halogenating a compound ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1
, R^2 and R^3 have the same meanings as above, and X represents a halogen atom].