CN1224618C - 1-methyl-3-substituted piperazine like compound and its preparation method - Google Patents

Abstract

The present invention provides a kind of general formula: a kind of convenient preparation method of the piperazine compound of the right formula, wherein _R represents H, substituted or non-substituted alkyl, alkoxy, aryl, alkyl or aryl acyl, Alkyl or arylsulfonyl; R ₂ represents H, substituted or unsubstituted alkyl, alkoxy, aryl, arylalkyl; R ₃ represents phenyl or substituted phenyl, aromatic heterocycle and The compound is obtained by condensation of α-halogenated arylate and diethylamine, and then reacted with halide benzyl or substituted halide benzyl, and then the target compound is obtained through reduction, methylation and debenzylation.

Description

A kind of preparation method of substituted piperazine compound

technical field

The present invention relates to piperazine compounds and an improved method for preparing piperazine compounds, and more particularly relates to an improved preparation method for substituted piperazine compounds.

Background technique

Mirtazapine (US 4062848) is an antidepressant drug developed by Organon Corporation of the United States, and it is a selective serotonin reuptake inhibitor (SSRI). The piperazine derivative 1-methyl-3-phenylpiperazine is a key intermediate for the preparation of mirtazapine, but the existing methods have disadvantages such as high cost, low reaction yield, complicated post-treatment and separation. Such as Roderick, W.R.et al.J.Med.Chem 1966, 9, 181-185 and Schmiesing, R.J.Hetercycles 1989, 29, 359-363 methylation with methyl iodide in the last step, high cost, many by-products, and difficult to purify the product . WO 00163185 has longer reaction steps.

Contents of the invention

The purpose of the present invention is to provide a new method for preparing substituted piperazine compounds including 1-methyl-3-phenylpiperazine with cheap raw materials, high reaction yield and simple separation and purification. Compounds involved in the present invention can be represented by the following formula:

in:

_R represents H, alkyl, benzyl, alkoxy;

_R represents H, alkyl, benzyl, alkoxy;

R3 represents phenyl or substituted phenyl. These compounds are important intermediates in the preparation of many useful drugs such as the antidepressant mirtazapine.

Compounds of the present invention are implemented through the following main steps:

X is a leaving group such as chlorine or bromine.

A. Compound 1 was obtained by condensation of α-halogenated arylate and diethylamine in a polar protic or aprotic solvent under strong base conditions such as sodium alkoxide or potassium alkoxide.

B. Compound 1 was reacted with benzyl halide or substituted benzyl halide in a non-polar solvent, such as toluene, benzene; organic base, such as triethylamine, pyridine, etc., or inorganic base, such as potassium carbonate, sodium carbonate, to obtain compound 2.

C. Compound 2 is reduced in an anhydrous non-polar solvent, such as tetrahydrofuran, diethyl ether, etc., with a negative hydrogen ion reducing agent such as lithium tetrahydrogen to obtain compound 3.

D. Compound 3 was refluxed methylated with formaldehyde and formic acid to obtain compound 4.

E. Compound 4 uses palladium carbon or Raney-Ni as a catalyst to catalytic hydrogenolysis in alcohol, acetic acid or water to remove benzyl or replace benzyl to obtain compound 5.

The present invention is implemented through the following more detailed steps

step a.

R3 can be phenyl or substituted phenyl, aromatic heterocycle, X=Cl, Br. The reaction solvent is a polar protic solvent such as ethanol, methanol, isopropanol, etc., preferably ethanol. The strong base used in the reaction is sodium alcoholate or potassium alcoholate, preferably sodium ethylate. The reaction temperature is from room temperature to solvent reflux temperature, preferably 60-70°C, and the reaction time is generally 3-10 hours. Acetone, ethyl acetate or their mixed solvents can be used for recrystallization, and the preferred solvent is acetone.

Step B.

R2 represents substituted or unsubstituted alkyl, alkoxy, aryl, arylalkyl, X=Cl, Br. As the reaction solvent, benzene, toluene, acetone, etc. can be used, preferably toluene. The base can be an organic base such as triethylamine, pyridine, diethylamine, etc., an inorganic base such as potassium carbonate, sodium carbonate, etc., and the best is triethylamine. The reaction temperature may be from room temperature to the solvent reflux temperature, preferably at the solvent reflux temperature. The reaction time is 3-10 hours, preferably 5-6 hours.

Step C.

The reducing agent is a negative hydrogen ion reducing agent such as lithium aluminum hydride, potassium borohydride or sodium borohydride plus zinc chloride, etc., preferably lithium aluminum hydride. The solvent is anhydrous inert ether solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., preferably anhydrous tetrahydrofuran. The reaction temperature is from 0°C to the solvent reflux temperature, and the optimum reaction temperature is the solvent reflux temperature. The reaction time is from 1 hour to 48 hours. Compound 3 can be used in the next reaction without purification.

Step D.

The formaldehyde/formic acid method is selected for the methylation of compound 3. Compared with the methylation with methyl iodide, this method can avoid side reactions such as the formation of quaternary ammonium salts, and the reaction yield is improved. The reaction temperature is from room temperature to the reflux temperature of the formaldehyde/formic acid mixed solvent. Product purification is to use 37% concentrated hydrochloric acid to form a salt. After removing the solvent, use ethanol, methanol, isopropanol, acetone, ethyl acetate, chloroform, dichloromethane, benzene, toluene, n-hexane, n-heptyl Alkanes or their mixed solvents of two or more components in appropriate proportions for recrystallization, the preferred recrystallization solvents are ethanol and ethyl acetate (volume ratio is 1:1). The molar ratio of compound 3 and formaldehyde/formic acid can range from 1:2 to 1:20.

StepE.

The catalyst for catalytic hydrogenolysis can be selected 10% or 5% palladium carbon or other palladium-containing catalysts, or Raney-Ni, and the preferred catalyst is 10% palladium carbon. The solvent can be selected from lower alkyl alcohols such as methanol, ethanol, isopropanol, etc., or other solvents such as acetic acid or water, preferably methanol. The reaction time can be from 1 hour to no longer absorbing hydrogen. The reaction temperature may be from room temperature to 40°C, preferably room temperature. The reaction pressure can range from normal pressure to tens of atmospheric pressure, and the best condition is normal pressure. The recrystallization solvent is recrystallized with ethanol, methanol, isopropanol, acetone, ethyl acetate, chloroform, methylene chloride, benzene, toluene, n-hexane, n-heptane or their mixed solvents of two or more components in appropriate proportions. For crystallization, the preferred recrystallization solvents are ethanol and ethyl acetate (volume ratio 1:1).

Detailed ways

The following examples illustrate the present invention, but the present invention is not limited to this example.

The melting point was determined by the capillary method, and the thermometer was not corrected; the nuclear magnetic resonance instrument was Gemini-2000 (300MHz).

Example 1 2-oxo-3-phenyl-piperazine [J.Med.Chem., 9,181]

To a mixture of ethylenediamine (68ml) and ethyl bromophenylacetate (122g) in ethanol (750ml) was added dropwise a sodium ethoxide solution (11.5g of sodium metal reacted with 100ml of ethanol) at room temperature. After dripping, react at 60-70°C for 5 hours, distill off ethanol and excess ethylenediamine under reduced pressure, extract the residue with hot acetone four times, combine the acetone solution with activated carbon to decolorize, concentrate part of the acetone, and place it for recrystallization to obtain 2 -Oxo-3-phenyl-piperazine (35.3 g). Yield 40%. Mp138-140℃. ¹ H-NMR (CDCl ₃ , δ): 3.06(m, 1H); 3.15(m, 1H); 3.37(m, 1H); 3.52ppm(m, 1H); 4.58(s, 3H ); 7.26-7.43(m, 5H).

Example 2 2-oxo-3-phenyl-4-benzylpiperazine

At room temperature, 3-oxo-2-phenylpiperazine (102 g), benzyl bromide (109.7 g), triethylamine (242 ml), and toluene (1000 ml) were mixed, and the suspension was heated to reflux for 6 hours and filtered set of solids. The solid was suspended in water (300 ml), stirred for 1 hour and then filtered. The solid was washed with water and dried to obtain a white powdery solid (131.3 g). Mp>210°C. Yield 85.2%. ¹ H-NMR (CDCl ₃ , δ): 2.53 (m, 1H); 3.01 (m, 1H); 3.23 (m, 2H); 3.54 (m, 1H); 3.76 (m, 1H); 1H); 7.19-7.31(m, 5H); 7.37-7.40(m, 3H); 7.55(d, J=, 2H).

Example 3 1-benzyl-2-phenylpiperazine

Lithium aluminum hydride (28.5 g) was suspended in dry tetrahydrofuran (600 ml) under cooling in an ice-water bath, and 2-oxo-3-phenyl-4-benzylpiperazine (80 g) was added in batches. Return to room temperature, react at room temperature for 1 hour and then reflux for 20 hours. Excess lithium aluminum hydride was decomposed with water (28.5 ml) and 20% sodium hydroxide solution (117 ml) in an ice-water bath. After filtering and distilling off the solvent, the crude product of 2-phenyl-1-benzylpiperazine was obtained. The next reaction can be carried out without purification.

Example 4 1-benzyl-2-phenyl-4-methylpiperazine hydrochloride

Formaldehyde (63.4 ml) and formic acid (88.8 ml) were added to the above crude product under cooling in an ice-water bath, and heated to reflux for 12 hours until no bubbles were released. After cooling to room temperature, 37% concentrated hydrochloric acid (50 ml) was added dropwise. After the drop was completed, the reaction was stirred for 1 hour, formic acid and excess formaldehyde were evaporated under reduced pressure, and the residue was recrystallized with a mixed solvent of ethanol/ethyl acetate (1:1). White short needle crystals (89.2 g) were obtained. Mp > 200 ° C two-step total yield of 98%. Mp>200°C. ¹ H-NMR (CDCl ₃ , δ): 2.17 (t, J=10.8Hz, 1H); 2.28 (s, 3H); 2.30 (m, 1H); 2.80 (m, 1H); 2.84 -2.90(m, 4H); 3.46(dd, J=2.93Hz, 10.52Hz, 1H); 3.81(d, J=13.55Hz, 1H); 7.20(m, 1H); 7.22-7.30(m, 5H) ;7.35(t, J=6.96Hz, 2H); 7.50(d, J=6.59Hz, 2H).

Example 5 1-methyl-3-phenylpiperazine hydrochloride

At room temperature, 1-methyl-3-phenyl-4-benzylpiperazine hydrochloride (89.2 grams), 10% palladium carbon (4.0 grams), and methanol (500 milliliters) were mixed and hydrogenated at the same temperature for 5 Hydrogen is no longer absorbed after hours. Filtrate, distill off the filtrate solvent to obtain a solid, which is recrystallized from a mixed solvent of ethanol/ethyl acetate = 1:1 to obtain 1-methyl-3-phenylpiperazine hydrochloride (59.7 g) as a white short needle-like solid. Yield 95.3%. Mp>200°C. ¹ H-NMR (CDCl ₃ , δ): 2.38 (s, 3H); 2.52 (m, 2H); 2.93 (m, 2H); 3.08 (m, 2H); 4.07 (dd, J= 10.71Hz, 2.74Hz, 1H); 7.26-7.34(m, 3H); 7.47(m, 2H).

Claims (9)

1, the preparation method of a class with substituted-piperazinyl compounds of following general formula comprises the steps:

Wherein:

R ₁Represent H, alkyl, benzyl, alkoxyl group;

R ₂Represent H, alkyl, benzyl, alkoxyl group;

R ₃Represent the phenyl of phenyl or replacement;

Chemical equation is as follows:

A, alpha-halogen aryl esters and diethylamine condensation in polar protic or aprotic solvent obtain compound 1 under sodium alkoxide or potassium alcoholate highly basic condition;

The halogen benzyl of B, compound 1 and halogen benzyl or replacement is at non-polar solvent, organic bases, or react in the mineral alkali compound 2;

C, compound 2 obtain compound 3 with the reduction of Lithium Aluminium Hydride negative hydrogen ion reductive agent in non-aqueous non-polar solvent;

D, compound 3 usefulness formaldehyde and formic acid reflux methylate compound 4;

E, compound 4 usefulness palladium carbon or Raney-Ni do catalyzer catalytic hydrogenolysis debenzylation or substituted benzyl in alcohol or acetate or water and get compound 5.

2, the preparation method of substituted piperazidine compounds according to claim 1 is characterized in that the steps A reaction solvent is an ethanol, methyl alcohol, Virahol polar protic solvent; Highly basic is adopted in reaction, temperature of reaction from room temperature to the solvent refluxing temperature.

3, the preparation method of substituted piperazidine compounds according to claim 2 is characterized in that it is sodium alkoxide or potassium alcoholate that highly basic is adopted in the steps A reaction.

4, the preparation method of substituted piperazidine compounds according to claim 1 is characterized in that step B reaction solvent is benzene, toluene, acetone, and organic bases is selected from triethylamine, pyridine, diethylamine, mineral alkali and is selected from salt of wormwood, yellow soda ash.

5, the preparation method of substituted piperazidine compounds according to claim 1 is characterized in that non-aqueous non-polar solvent is tetrahydrofuran (THF) or ether among the step C.

6, the preparation method of substituted piperazidine compounds according to claim 1, it is characterized in that it is reductive agent that step C adopts Lithium Aluminium Hydride, POTASSIUM BOROHYDRIDE or sodium borohydride to add zinc chloride, solvent is ether, tetrahydrofuran (THF), dioxane anhydrous inert ether solvent; Temperature of reaction from 0 ℃ to the solvent refluxing temperature, the reaction times was from 1 hour to 48 hours.

7, the preparation method of substituted piperazidine compounds according to claim 1 is characterized in that the step D selection formaldehyde/formic acid that methylates makes methylating reagent; The mol ratio of compound 3 and formaldehyde/formic acid can be by within 1: 2 to 1: 20 scope; Temperature of reaction is by the reflux temperature of room temperature to formaldehyde/formic acid mixed solvent.

8, the preparation method of substituted piperazidine compounds according to claim 7 is characterized in that the thick product of step D gained makes the mixed solvent recrystallization that hydrochloride is used ethanol, methyl alcohol, Virahol, acetone, ethyl acetate, chloroform, methylene dichloride, benzene, toluene, normal hexane, normal heptane or their two components or polycomponent suitable proportion again.

9, the preparation method of substituted piperazidine compounds according to claim 1, the catalyzer that it is characterized in that the step e catalytic hydrogenolysis is that palladium or carbon or other contain the catalyzer of palladium, or Raney-Ni, solvent is low alkyl alcohol, or acetate or water; Reaction pressure is from normal pressure to tens normal atmosphere.