JPH03200749A - Production of phenoxypropylamine - Google Patents

Abstract

PURPOSE:To obtain the title compound efficiently by reacting 1-(2,6- dimethylphenoxy)-2-propanol with phthalimide compound in the presence of azodicarboxylic diester and tertiary phoshine and then removing phthaloyl group. CONSTITUTION:Phenoxypropanol shown by formula I is reacted with a phthalimide compound shown by formula IV (X<1> to X<4> are H, alkyl, halogen or nitro) or formula V (X<5> and X<6> are H or halogen) in the presence of an azodicarboxylic diester shown by formula II (R<1> is alkyl) and a tertiary phoshine shown by formula III (R<2> to R<4> are alkyl, aryl, alkylaryl, alkyloxy, aryloxy or alkylaryloxy) to give a phenoxyphthaloylaminopropane shown by formula VI or formula VII. Finally phthaloyl group is eliminated to give 1-(2,6- dimethylphenoxy)-2-aminopropane. This compound is useful for ventricular arrhythmia.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention has a beneficial effect in ventricular arrhythmia conditions and is particularly useful in the treatment of ischemic heart disorders, myocardial infarction, ventricular fibrillation and tachycardia. The present invention relates to an efficient method for producing physiologically active 1-(2,6-dimethylphenoxy)-2-aminopropane.

C. Prior Art Regarding the production of 1-(2,6-dimethylphenoxy)-2-aminopropane, see British Patent Specification No. 120595.
The enemy method is disclosed in No. 8. The conventional technology described here had various problems, but the
Significant improvements were made by the method disclosed in No. 3-38979.

According to this method, the desired product is produced by reducing the compound of formula (V]II).

According to Japanese Patent Publication No. 63-38979, the compound of formula (■) is a compound of 1-(2,6-dimethylphenoxy)-2-propanol represented by formula (1) expressed by general formula (IX). It can be produced by converting the compound H3A (in the formula, A represents a leaving group) and further reacting it with an alkali metal azide.

(Problems to be Solved by the Invention) The above production method requires three steps to produce the desired product from the raw material 1-(2,6-dimethylphenoxy)-2-propanol, and is not efficient. Lacks sex.

Furthermore, this method still has sufficient 1-
Problems remain regarding the production of (2,6-dimethylphenoquino)-2-aminopropane. Therefore 1-(2,
There is a need for an efficient method for producing 6-dimethylphenoxy)-2-aminopropane.

An object of the present invention is to provide a method for producing 1-(2,6-dimethylphenoxy)-2-aminopropane efficiently and with a yield close to quantitative yield, and furthermore, In terms of safety, our goal is to provide a highly safe manufacturing method.

[Means to solve the problem]

The present invention solves the above-mentioned problems regarding the method for producing 1-(2,6-dimethylphenoxy)-2-aminopropane, and is a more excellent method for producing 1-(2,6-dimethylphenoxy)-2-aminopropane.

That is, the present invention provides 1-(2,6-dimethylphenoxy)-2-aminopropane.
6-dimethylphenoxy)-2-propatool with azodicarboxylic acid diester represented by the general formula (If) and R'0CON=NCOOR' (I
I) (in the formula, R' represents an alkyl group) - Funato (■
) Tertiary phosphine R"-P-R' (Ill) 3 (wherein R", R3, and R' each independently represent an alkyl group,
Aryl group, alkylaryl group, alkyloxy group,
(representing an aryloxyl group or an alkylaryloxy group), a phthalimide compound represented by the general formula (IV) or (V) (wherein (V), x' and xh independently represent a hydrogen atom or a halogen (representing an atom), phenoxyphthaloylaminopropane (hereinafter referred to as blank space) represented by -form (VI), (■) (However, in formula (IV), X', (in the formula (Vl), x', x", x', and x' independently represent a hydrogen atom, an alkyl group, a halogen atom, or a nitro group) Represents an atom or a nitro group.

In the formula (■), ) (S, This is a method for producing (enoxy)-2-aminopropane.

The alkyl group referred to herein is preferably a straight chain or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group,
Examples include n-propyl group, isopropyl group, n-butyl group, isobutyl group, neobutyl group, and tertiary butyl group.

Similarly, the aryl group is preferably an aromatic substituent having 6 to 14 carbon atoms, such as a phenyl group, a naphthyl group, an anthranyl group, and the like.

The alkylaryl group represents an aryl group substituted at any position with an alkyl group, and the alkyl group and aryl group can be the same as those mentioned above.

Examples of the alkyloxy group include oxygen atoms substituted with the aforementioned alkyl groups.

Examples of the aryloxy group include oxygen atoms substituted with the above-mentioned 7-aryl group, and examples of the alkylaryloxy group include oxygen atoms substituted with the above-mentioned furkylaryl group.

Further, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and the like.

The azodicarboxylic acid diesters represented by the general formula (It) used in the production method of the present invention include dimethyl azodicarboxylate, diethyl azodicarboxylate, di-n-propyl azodicarboxylate, diisopropyl azodicarboxylate, and diisopropyl azodicarboxylate. -n-butyl, diisobutyl abdicarboxylate, dineobutyl azodicarboxylate, di-tert-butyl abdicarboxylate, and the like. -Sailor (III
) Examples of the tertiary phosphine represented by trimethylphosphine, triethylphosphine, triisopropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, trineobutylphosphine, triphenylphosphine, dimethylphenylphosphine, diethylphenylphosphine ,
Propylphenylphosphine, dibutylphenylphosphine, diphenylmethylphosphine, diphenylethylphosphine, diphenylpropylphosphine, diphenylbutylphosphine, tritolylphosphine, dimethyltolylphosphine, diethyltolylphosphine, dipropyltolylphosphine, dibutyltolylphosphine, trinaphthylphosphine, trimethyl Examples include phosphite, triethyl phosphite, tripropyl phosphite, tributyl phosphite, triphenyl phosphite, trinaphthyl phosphite and the like.

Further, examples of the phthalimide derivatives represented by -Funenin (IV) and (V) include phthalimide, chlorophthalimide, 3,4,5,6-titrachlorophthalimide, nitrophthalimide, bromophthalimide, bromophthalimide,
3.4.5.6-titrabromophthalimide, naphthalimide, 3,8-dichloronaclimide and the like.

Next, the production of phenoxyphthaloylaminopropane will be described.

1-(2,6-dimethylphenoxy)-2-propanol and azodicarboxylic acid diester represented by general formula (II), -C tertiary phosphine represented by formula (III), -I formula (IV The reaction molar ratio of the phthalimide compounds represented by ) and (V) is usually 1.0 to l(2,6-dimethylphenoxy)-2-propatol, respectively.
~2. O1 is preferably 1.0 to 1.5. Here, since the azodicarboxylic acid diester and the tertiary phosphine both form a condensing agent at a mixing ratio of 1:1, the reaction molar ratio of both is preferably equimolar, and the molar ratio is 1-(2,6
-dimethylphenoxy)-2-propatool,
It is 1.0-2.0, preferably 1.0-1.5.

The reaction temperature is usually -70 to 100'C, preferably 0 to 100'C.
It is 30'C.

The reaction time is about 5 minutes to 20 hours.

This reaction is carried out without a solvent or in a solvent such as a halogenated hydrocarbon, R, ethers, aromatic hydrocarbons, or a polar solvent.

Examples of halogenated hydrocarbons include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, 1,4-dioxane, diglyme, and the like. Examples of aromatic hydrocarbons include benzene and toluene. Examples of polar solvents include N, N-
Dimethylformamide, dimethyl sulfoxide and the like can be mentioned.

In this reaction, it is preferable to use a dry solvent because the reactant used is unstable with respect to water, and the product is usually separated and purified using a silica gel column method.

Next, the production of the desired product, 1-(2,6-dimethylphenoxy>-2-aminopropane), will be described.

The present compound is produced by removing the phthaloyl group of the obtained phenoxyphthaloylaminopropanes represented by general formulas (Vl) and (■) by a known method (see TJ, Greene "Protective
Groups in Organic 5ynthes
is″JJi ley&S.

ns: New York, 1981. p265) -
Removal of this phthaloyl group is preferably carried out by treatment with hydrazine.

-i The reaction molar ratio of phenoxyphthaloylaminopropane and hydrazine represented by formulas (Vl) and (■) is usually 1.0 to phenoxyphthaloylaminopropane.
-10.0, preferably 1.0-5.0.

The reaction temperature is usually 50 to 150°C, and the reaction time is usually about 10 minutes to 20 hours.

This reaction is carried out without a solvent or in a solvent such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, or polar solvents.

Examples of halogenated hydrocarbons include methylene chloride, chloroform, carbon tetrachloride, and the like.

Examples of ethers include diethyl ether, tetrahydrofuran, 1,4-dioxane, and the like. Examples of aromatic hydrocarbons include benzene and toluene. Examples of polar solvents include ethanol, methanol, propatool, butanol, and the like.

〔Example〕

The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples in any way.

(Example 1) Method for producing 1-(2,6-dimethylphenoxy)-2-phthaloylaminopropane (1) 1-(2,6-dimethylphenoxy)-2-propatol 9.01 g (0.05 mol) of the above, 65 g (0.052 Ilol) of Phthalai Rendoa, 14.43 g (0.055 mol) of triphenylphosphine
50 #f of anhydrous tetrahydrofuran. Thereto, 9.58 g (0,055+5 ol) of diethyl azodicarboxylate dissolved in 50H1 anhydrous tetrahydrofuran was added dropwise. After − hours, the reaction solution was concentrated to dryness, and the concentrated residue was separated and purified using silica gel column chromatography. The target fractions were collected and concentrated to dryness to obtain 14.93 g (96.5%) of 1-(2,6-dimethylphenoxy)-2-7taloylaminopropane 1 as an oil.

IR (NaCI) veaax 2920.177
5.17G8.1469.1384゜1369.120
0.781 cm-''H-NMR (CDCh)
δ 1.55 (d, 3H), 2.19 (s, 6) 1).

4.85 (a, IH), 6.8-6.9 (+++, 3H
)7.7~7.9 (m, 4H) Elemental analysis Cr q H+ *CHN as NOs Calculated value (%) 73.7? 6.19 4.53
Analysis value (%)? 2.16 5.95 4.29 (
Example 2) Production method of 1-(2,6-dimethylphenoxy)-2-aminopropane hydrochloride 1-(2,6-dimethylphenoxy)-2-phthaloylaminopropane i12 .32 g (0,039 Ilo
l), hydrazine-water salt 10. Og (0.2 mol)
was circulated in 500 d of ethanol for 1 hour. The reaction solution in which a large amount of cloud-like substances had precipitated was cooled, filtered, and the filtrate was concentrated to dryness. The condensation residue was dissolved in 200af of chloroform and washed twice with 100d of water each time. The chloroform layer was dried over sodium sulfate and concentrated to dryness to obtain 6.94 g (92.6%) of 1-(2,6-dimethylphenoxy)-2-aminopropane as an oil.

'H-NMR (CDCl2) 61.18 (d, 3H
), 1.70 (brs, 2H).

2.27 (s, 311), 2.33 (s, 31 () 3.
25-3.65 (s, 3H), 6.94 (m, 3H) Elemental analysis C++H + tN0・1/2 CHN as H, O Calculated value (%) 70.18 9.64 7.44 Analysis value (%) ? 0.33 9゜38 7.15 Dissolve 6.94 g of this 1-(2,6-dimethylphenoxy)-2-aminopropane in 10-methanol and add 10%
After adding 20 ml of HCl-methanol, the mixture was concentrated to dryness to obtain 7.29 g (100%) of crystals of 1-(2,6-dimethylphenoxy)-2-aminopropane hydrochloride.
This was recrystallized from isopropanol ether.

mp 202-203°C IR (KBr) vmax 3000,2910
, 1600.14B2, 1267°12031092.
1040cm Elemental analysis C+ + H17No・HCI as HNCI total]; [Id! (%) , 61.25 8.4
1 6.49 16.43 Analysis value (%) 61.
42 8.25 6.48 16.25 [Effects of the Invention] The production method of the present invention produces 1-(2,6-dimethylphenoxy)-2-aminopropane, which exhibits beneficial effects in ventricular arrhythmia conditions.・Can be used in the production method of hydrochloride.

The first advantage of the production method of the present invention is that the reaction proceeds under mild conditions and in a short time with almost quantitative yield.

The second advantage is that the reaction steps are shorter than conventional production methods and can be used industrially.

A third advantage is that the starting materials and all reactants are easy to handle and are not harmful to health.

A fourth advantage is that the conversion of the compounds of -Funenin (VI) and (■) to amines can be carried out in a fairly quantitative manner under mild conditions, resulting in the production of pure compounds.

As described above, the production method of the present invention greatly contributes to the production method of 1-(2,6-dimethylphenoxy)-2-aminopropane hydrochloride.

Claims (1)

[Claims] Phenoxypropanol represented by the formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) An azodicarboxylic acid diester represented by the general formula (II) and R^1OCON=NCOOR^1( II) (In the formula, R^1 represents an alkyl group.) General formula (III)
There are mathematical formulas, chemical formulas, tables, etc. of the tertiary phosphine represented by Represents an alkyloxy group, aryloxy group or alkylaryloxy group.) Phthalimide compounds represented by general formulas (IV) and (V) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (IV) (However, ( IV) In the formula, X^1, X^2, X^3, and X^4 each independently represent a hydrogen atom, an alkyl group, a halogen atom, or a nitro group.) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (V ) (However, in formula (V), X^5 and X^6 each independently represent a hydrogen atom or a halogen atom.) Propane ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) (In formula (VI), X^1, X^2, X^3, X^4 are each independently represents a hydrogen atom, an alkyl group, a halogen atom, or a nitro group. In formula (VII), X^5 and X^6 each independently represent a hydrogen atom or a halogen atom.) A method for producing 1-(2,6-dimethylphenoxy)-2-aminopropane, which comprises eliminating a group.