阅读说明：本技术 制备1-(4-氨基苯基)-4-(4-羟基苯基)哌嗪的方法 (Process for preparing 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine ) 是由 王复平 田志国 王学民 于 2021-09-28 设计创作，主要内容包括：本发明涉及一种制备式(I)化合物的方法,其特征在于,包括以下步骤：a)使式(II)化合物依次与式(III)化合物和式(IV)化合物在碱的存在下在溶剂中进行反应,得到式(V)化合物；b)使式(V)化合物在催化剂和还原剂的存在下在溶剂中进行反应,得到式(I)化合物；式(II)中和式(V)中,R为苄基、对甲氧基苄基或对硝基苄基；式(III)和式(IV)中,X各自独立地为卤素。本发明方法的原料价格便宜、反应条件温和、环境友好、容易实现、收率高、污染低,最终产品成本明显降低。(The invention relates to a method for preparing a compound of formula (I), which is characterized by comprising the following steps: a) reacting a compound of formula (II) with a compound of formula (III) and a compound of formula (IV) in sequence in a solvent in the presence of a base to obtain a compound of formula (V); b) reacting a compound of formula (V) in a solvent in the presence of a catalyst and a reducing agent to obtain a compound of formula (I); in the formula (II) and the formula (V), R is benzyl, p-methoxybenzyl or p-nitrobenzyl; in the formulae (III) and (IV), X is independently halogen. The method has the advantages of cheap raw materials, mild reaction conditions, environmental friendliness, easy realization, high yield, low pollution and obvious reduction of the final product cost.)

1. A process for the preparation of a compound of formula (I) comprising the steps of:

a) reacting a compound of formula (II) with a compound of formula (III) and a compound of formula (IV) in sequence in a solvent in the presence of a base to obtain a compound of formula (V);

b) reacting a compound of formula (V) in a solvent in the presence of a catalyst and a reducing agent to obtain a compound of formula (I);

in the method, the method comprises the following steps of,

the base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, or mixtures thereof;

the catalyst is selected from Raney nickel, palladium carbon, palladium hydroxide or a mixture thereof;

the reducing agent is hydrogen;

each solvent is independently water, alcohol, or a mixture thereof;

in the formula (II) and the formula (V), R is benzyl, p-methoxybenzyl or p-nitrobenzyl; in the formulae (III) and (IV), X is independently halogen.

2. The process according to claim 1, wherein the reaction of step a) is a one-pot reaction.

3. The process according to claim 1, wherein the reaction of step b) is a one-step reaction.

4. The method according to claim 1, wherein the molar ratio of the compound of formula (II), the compound of formula (III) and the compound of formula (IV) is in the range of 1 (0.8-1.5) to (0.8-1.4), preferably in the range of 1 (0.9-1.2) to (0.9-1.3), more preferably in the range of 1 (1-1.1) to (1-1.2);

the molar ratio of compound of formula (III) to base is in the range of 1:1 to 1:3, preferably in the range of 1:1.5 to 1:2.5, more preferably in the range of 1:1.7 to 1:2.3, for example in the range of 1: 1.97;

the molar ratio of the compound of formula (IV) to the base is in the range of 1:0.8 to 1:2, preferably in the range of 1:0.9 to 1:1.5, more preferably in the range of 1:0.95 to 1:1.3, most preferably in the range of 1:1 to 1: 1.2; and/or

The mass fraction ratio of the compound of formula (V) to the catalyst is in the range of 1:0.05 to 1:0.5, preferably in the range of 1:0.06 to 1:0.3, more preferably in the range of 1:0.07 to 1:0.2, most preferably in the range of 1:0.1 to 1: 0.15.

5. The process according to claim 1, wherein the reaction temperature of step a) is in the range of 20 ℃ to 120 ℃, preferably in the range of 30 ℃ to 110 ℃, more preferably in the range of 40 ℃ to 100 ℃, most preferably in the range of 50 ℃ to 90 ℃; and/or

The reaction temperature of step b) is in the range of 20 ℃ to 80 ℃, preferably in the range of 25 ℃ to 75 ℃, more preferably in the range of 50 ℃ to 70 ℃.

6. The process according to claim 1, wherein the reaction time of step a) is in the range of 10-80 hours, preferably in the range of 20-70 hours, more preferably in the range of 30-60 hours; most preferably in the range of 40-50 hours; and/or

The reaction time of step b) is in the range of 3 to 12 hours, preferably in the range of 5 to 11 hours, more preferably in the range of 8 to 10 hours.

7. The process of claim 1, wherein step a) is carried out at atmospheric pressure; and/or

Step b) is carried out under pressure, preferably in the range of from 0.1 to 2MPa, more preferably in the range of from 0.2 to 1.0MPa, most preferably in the range of from 0.3 to 0.7 MPa.

8. The process according to claim 1, wherein the compound of formula (IV) is added after cooling after the reaction of the compound of formula (II) and the compound of formula (III) is completed, preferably the compound of formula (IV) is added together with a base.

9. The process of claim 1, wherein after completion of the reaction in step a), the reaction mixture is cooled to room temperature and stirred further, and when the precipitate does not increase further, suction filtration is carried out to obtain the compound of formula (V),

preferably, the compound of formula (V) obtained by suction filtration is added with twice the amount of solvent and stirred at room temperature, and when the precipitate does not increase any more, suction filtration is carried out, and drying is carried out to obtain the pure compound of formula (V).

10. The process of claim 1, wherein after the reaction of step b) is completed, the reaction mixture is cooled to room temperature and stirred further, when the precipitate does not increase further, suction filtration is carried out, the filtrate is adjusted to pH 3 with an acid solution, a solid is precipitated, suction filtration is carried out to obtain a wet product, the wet product is adjusted to pH 8 with an alkali solution, suction filtration is carried out, and drying is carried out to obtain the pure compound of formula (I).

Technical Field

The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a preparation method of a posaconazole intermediate compound 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.

Background

Posaconazole is a second-generation triazole antifungal drug marketed by FDA in the united states in 2006, is a derivative of itraconazole, and is widely applied to fungal infections caused by severe immunodeficiency or other drug resistance. Posaconazole (chemical name: 4- [4- [4- [4- [ [ (3R,5R) -5- (2, 4-difluorophenyl) -5- (1,2, 4-triazol-1-ylmethyl) oxolan-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S,3S) -2-hydroxypentan-3-yl ] -1,2, 4-triazol-3-one) having the structural formula:

1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine is one of indispensable important intermediate compounds for synthesizing posaconazole bulk drugs, and the structural formula is as follows:

disclosure of Invention

The inventor finds that the existing preparation method has one or more of the following problems: the raw materials, reagents and/or solvents are expensive, the reaction temperature is too high, the use of high-corrosivity raw materials causes great environmental pollution, a great number of side reactions, low yield, strict requirements on equipment, high difficulty in reaction operation, safety risk and the like.

The present invention provides a process for the preparation of a compound of formula (I),

the method is characterized by comprising the following steps:

a) reacting a compound of formula (II)

Wherein R is benzyl, p-methoxybenzyl or p-nitrobenzyl;

in turn with a compound of formula (III) and a compound of formula (IV)

Wherein each X is independently a halogen;

in the presence of a base in a solvent to give a compound of formula (V)

Wherein R is as defined for compounds of formula (II);

b) reacting a compound of formula (IV) in a solvent in the presence of a catalyst and a reducing agent to obtain a compound of formula (I);

in the method, the method comprises the following steps of,

the base is selected from alkali metal hydroxides, alkali metal amides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, or mixtures thereof;

the catalyst is selected from Raney nickel, palladium carbon, palladium hydroxide or a mixture thereof;

the reducing agent is hydrogen;

the solvents are each independently water, alcohol, or a mixture thereof.

The method of the invention has one or more of the following advantages: the raw materials, reagents and/or solvents are cheap, the reaction conditions are mild, the environment is friendly, the pollution is low, the method is easy to realize, the yield is high, and the safety risk is low.

Drawings

FIG. 1 is a scheme of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine¹H-NMR spectrum.

FIG. 2 is a scheme of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine¹H-NMR spectrum.

Detailed Description

As used herein, the term "halogen" generally includes fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), stone field (Ts), and the like. Specifically, halogen means fluorine, chlorine, bromine or iodine; more specifically, halogen means fluorine, chlorine or bromine; most particularly, halogen means fluorine or chlorine.

As used herein, the term "alkali metal hydroxide" generally includes lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, and the like. Specifically, the alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, or a mixture thereof.

As used herein, the term "alkali metal carbonate" generally includes lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, and the like. In particular, the alkali metal carbonate is selected from sodium carbonate, potassium carbonate, or mixtures thereof.

As used herein, the term "alkali metal bicarbonate" generally includes lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, rubidium bicarbonate, cesium bicarbonate, and the like. In particular, the alkali metal bicarbonate is selected from sodium bicarbonate, potassium bicarbonate, or a mixture thereof.

As used herein, the term "alkali metal phosphate" generally includes lithium phosphate, sodium phosphate, potassium phosphate, rubidium phosphate, cesium phosphate, and the like. Specifically, the alkali metal phosphate is selected from sodium phosphate, potassium phosphate, or a mixture thereof.

As used herein, the term "acid" is typically a mineral acid. Specifically, the acid is selected from hydrochloric acid, phosphoric acid, or a combination thereof; more specifically, the acid is hydrochloric acid.

As used herein, the term "alcohol" refers to a class of compounds formed by replacing a hydrogen on a saturated carbon atom with a hydroxyl group (-OH) in a hydrocarbon molecule having 1 to 12 carbon atoms. Specifically, the alcohol is selected from methanol, ethanol, propanol, isopropanol, tert-butanol, or a mixture thereof; more specifically, the alcohol is selected from methanol, ethanol, isopropanol, or mixtures thereof; most particularly, the alcohol is selected from methanol, ethanol, or mixtures thereof.

The weight percent (w/v) as referred to herein is expressed in grams of each component per 100ml of final volume based on the final volume of the formulation when present in liquid form.

In a particular embodiment, the reaction of step a) is a one-pot reaction.

In a particular embodiment, the reaction of step b) is a one-step reaction.

In a particular embodiment, the base in step a) is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, or mixtures thereof; preferably, the base in step a) is selected from an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, or a mixture thereof; more preferably, the base in step a) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a mixture thereof.

In a particular embodiment, the base in step a) is added in portions at different reaction time points; preferably, one or part of the base in step a) is added after the addition of the compound of formula (III) and the other or another part of the base in step a) is added after the addition of the compound of formula (IV); more preferably, an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide) is added after the addition of the compound of formula (III), and an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate) or alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate) is added after the addition of the compound of formula (IV).

In a particular embodiment, the catalyst in step b) is selected from raney nickel, palladium on carbon, palladium hydroxide, or mixtures thereof; preferably, the catalyst in step b) is raney nickel.

In a particular embodiment, the reducing agent in step b) is hydrogen.

In a particular embodiment, the solvents in steps a) and b) are each independently water, alcohol, or a mixture thereof; preferably, the solvent in step a) is water, the solvent in step b) is an alcohol, such as methanol, ethanol, isopropanol, more preferably the solvent in step b) is methanol or ethanol, most preferably the solvent in step b) is methanol.

In a particular embodiment, the molar ratio of the compound of formula (II), the compound of formula (III) and the compound of formula (IV) in step a) is in the range of 1 (0.8-1.5) to (0.8-1.4), preferably in the range of 1 (0.9-1.2) to (0.9-1.3), more preferably in the range of 1 (1-1.1) to (1-1.2).

In a particular embodiment, the molar ratio of the compound of formula (III) to the base in step a) is in the range of from 1:1 to 1:3, preferably in the range of from 1:1.5 to 1:2.5, more preferably in the range of from 1:1.7 to 1:2.3, for example in the range of from 1: 1.97.

In a particular embodiment, the molar ratio of the compound of formula (IV) to the base in step a) is in the range of from 1:0.8 to 1:2, preferably in the range of from 1:0.9 to 1:1.5, more preferably in the range of from 1:0.95 to 1:1.3, most preferably in the range of from 1:1 to 1: 1.2.

In a particular embodiment, the mass fraction ratio of compound of formula (V) to catalyst in step b) is in the range of from 1:0.05 to 1:0.5, preferably in the range of from 1:0.06 to 1:0.3, more preferably in the range of from 1:0.07 to 1:0.2, most preferably in the range of from 1:0.1 to 1: 0.15.

In a particular embodiment, the reaction temperature of step a) is in the range of 20 ℃ to 120 ℃, preferably in the range of 30 ℃ to 110 ℃, more preferably in the range of 40 ℃ to 100 ℃, most preferably in the range of 50 ℃ to 90 ℃, such as 60 ℃, 70 ℃ or 80 ℃.

In a particular embodiment, the reaction temperature of step b) is in the range of from 20 ℃ to 80 ℃, preferably in the range of from 25 ℃ to 75 ℃, more preferably in the range of from 50 ℃ to 70 ℃, e.g. 60 ℃.

In a particular embodiment, the reaction time of step a) is in the range of 10 to 80 hours, preferably in the range of 20 to 70 hours, more preferably in the range of 30 to 60 hours, most preferably in the range of 40 to 50 hours, e.g. 42 hours.

In a particular embodiment, the reaction time of step b) is in the range of 3 to 12 hours, preferably in the range of 5 to 11 hours, more preferably in the range of 8 to 10 hours.

In a particular embodiment, step a) is carried out at atmospheric pressure.

In a particular embodiment, step b) is carried out under pressure, preferably in the range of from 0.1 to 2MPa, more preferably in the range of from 0.2 to 1.0MPa, most preferably in the range of from 0.3 to 0.7MPa, e.g.0.5 MPa.

In a particular embodiment, the compound of formula (IV) is added after cooling (e.g. to 30-35 ℃) after completion of the reaction of the compound of formula (II) and the compound of formula (III), preferably the compound of formula (IV) is added together with a base, such as an alkali metal carbonate.

In a particular embodiment, after completion of the reaction of step a), the reaction mixture is cooled to room temperature (typically in the range of from 10 to 30 ℃, preferably in the range of from 13 to 26 ℃, more preferably in the range of from 14 to 22 ℃, e.g. 20 ℃) and stirred further, and when the precipitate does not increase further, it is filtered off with suction and dried to give the compound of formula (V);

preferably, the compound of formula (V) obtained by suction filtration is added to a twice the amount of solvent (e.g., a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is in the range of (15-25):1, preferably in the range of (18-22):1, e.g., 20:1) and stirred at room temperature (typically in the range of 10-30 ℃, preferably in the range of 15-28 ℃, more preferably in the range of 23-27 ℃, e.g., 25 ℃) until the precipitate does not increase any more, suction filtration is carried out and drying is carried out to obtain the pure compound of formula (V).

In a particular embodiment, after completion of the reaction in step b), the reaction mixture is cooled to room temperature (typically in the range of from 10 to 30 ℃, preferably in the range of from 13 to 26 ℃, more preferably in the range of from 14 to 22 ℃, e.g. 20 ℃) and stirred further, suction filtration is carried out until the precipitate does not increase further, the filtrate is adjusted to pH 3 with an acid (e.g. an inorganic acid such as hydrochloric acid) solution (e.g. acid concentration of 2N), solids are precipitated, suction filtration is carried out to obtain a wet product, the wet product is adjusted to pH 8 with a base (e.g. an alkali metal carbonate or alkali metal bicarbonate) solution (e.g. a base concentration of 5 to 15% w/v, e.g. 10% w/v), suction filtration is carried out and drying is carried out to obtain the pure compound of formula (I).

The various embodiments or different preferred grades of embodiments described herein can be combined in any combination, unless otherwise indicated.

The present invention is illustrated below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The compounds or reagents used in the following examples are commercially available or prepared by conventional methods known to those skilled in the art; the laboratory instruments used are commercially available.

Examples

Example 1

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Simian Seisaku industries Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, performing suction filtration to obtain a crude product, and drying at the temperature of below 60 ℃ to obtain 1127 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 1006g of a pale yellow solid in 83% yield.

¹H NMR(400MHz，DMSO)δ8.08(d，2H)，7.43(d，2H)，7.38(t，2H)，7.32(t，1H)，7.10(d，2H)，6.94(m，4H)，5.04(s,2H),3.61(t,4H),3.16(t,4H)。

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 60 ℃, the reaction was carried out for 8 hours under the pressure of 0.5MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain 157g wet product, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain 128g solid with yield of 93%.¹H NMR(400MHz，DMSO)δ8.73(s，1H)，6.82(m，2H)，6.73(m，2H)，6.66(m，2H)，6.51(d，2H)，4.73(s，2H)，3.05(m，8H)。

Example 2

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 666g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Xian's Cisco Seisakusho industries, Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 1097 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered under suction, and dried to give 966g of a pale yellow solid in 80% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 40g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 60 ℃, the reaction was carried out for 8 hours under the pressure of 0.5MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain 149g wet product, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain 121g solid with yield of 88%.

Example 3

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 527g of parafluoronitrobenzene (purchased from Xian's Cisco Seisakusho industries Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at the temperature of below 60 ℃ to obtain 1106g of crude product. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 986g of a pale yellow solid in 81% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 10g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 60 ℃, the reaction was carried out for 8 hours under the pressure of 0.5MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain wet product 155g, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain solid 125g with yield 91%.

Example 4

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 832g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added into a 5L four-neck flask at room temperature, the temperature was raised to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 570g of parafluoronitrobenzene (purchased from Xian's Cisco Seisakusho industries Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at the temperature of below 60 ℃ to obtain 1055 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 933g of a pale yellow solid in 77% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 30g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 60 ℃, the reaction was carried out for 8 hours under the pressure of 0.5MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain 157g wet product, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain 126g solid with yield of 92%.

Example 5

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 56g of sodium hydroxide/56 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from western Ancisco Seisakusho Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 1027 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 905g of a pale yellow solid in 75% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine, 20g of palladium carbon, 1L of methanol, three times of nitrogen replacement at 0.3MPa and three times of hydrogen replacement at 0.3MPa are added into a 2L high-pressure reaction kettle at room temperature, the temperature is raised to 60 ℃, the reaction is carried out for 8h under the pressure of 0.5MPa, and TLC detection (dichloromethane: methanol 5: 1) cooling to room temperature after no raw material is left, performing suction filtration, adjusting the pH of the filtrate to 3 with 2N hydrochloric acid, precipitating a solid, performing suction filtration to obtain 153g of a wet product, adjusting the pH of the wet product to 8 with 10% w/v sodium carbonate, performing suction filtration, and drying to obtain 119g of the solid with the yield of 87%.

Example 6

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 430g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Simian Seisaku industries Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 1012 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to yield 896g of a pale yellow solid in 74% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of palladium hydroxide, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave at room temperature, the mixture was heated to 60 ℃, and the reaction was carried out for 8 hours under a pressure of 0.5MPa, followed by TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no raw material is left, performing suction filtration, adjusting the pH of the filtrate to 3 with 2N hydrochloric acid, precipitating a solid, performing suction filtration to obtain 155g of a wet product, adjusting the pH of the wet product to 8 with 10% w/v sodium carbonate, performing suction filtration, and drying to obtain 122g of a solid with a yield of 89%.

Example 7

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 90g of potassium hydroxide/90 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 396g of sodium carbonate solid and 440g of parafluoronitrobenzene (purchased from Simian Seisaku industries Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) when no raw material remains, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 1057 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to yield 943g of a pale yellow solid in 78% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of raney nickel, 1.2L of ethanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 60 ℃, the reaction was carried out for 8 hours under the pressure of 0.5MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain 147g wet product, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain 118g solid with yield of 86%.

Example 8

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 90g of potassium hydroxide/90 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 374g of potassium bicarbonate solid and 440g of parafluoronitrobenzene (purchased from Simian Seisaku industries Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 967 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered under suction and dried to give 861g of a pale yellow solid in 71% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of raney nickel, 1.1L of isopropanol, three times of nitrogen substitution at 0.3MPa, three times of hydrogen substitution at 0.3MPa, heating to 60 ℃, reacting for 8 hours under the pressure of 0.5MPa, and detecting by TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no raw material is left, performing suction filtration, adjusting the pH of the filtrate to 3 with 2N hydrochloric acid, precipitating a solid, performing suction filtration to obtain 125g of a wet product, adjusting the pH of the wet product to 8 with 10% w/v sodium carbonate, performing suction filtration, and drying to obtain 94g of the solid with a yield of 68%.

Example 9

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added into a 5L four-neck flask at room temperature, the temperature was raised to 80 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was left by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Simian Seisaku industries Co., Ltd.), heating to 60 ℃, reacting for 36 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, performing suction filtration to obtain a crude product, and drying at the temperature of below 60 ℃ to obtain 1018 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 926g of a pale yellow solid in 76% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 50 ℃, the reaction was carried out for 8 hours under the pressure of 0.7MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain wet product 137, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain solid 109g with yield 79%.

Example 10

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added into a 5L four-neck flask at room temperature, the temperature was raised to 100 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was left by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Simian Seisaku industries Co., Ltd.), heating to 60 ℃, reacting for 20 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, performing suction filtration to obtain a crude product, and drying at the temperature of below 60 ℃ to obtain 1033 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 957g of a pale yellow solid in 79% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 70 ℃, the reaction was carried out for 10 hours under the pressure of 0.3MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain wet product 131g, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain solid 103g with yield of 75%.

Example 11

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was found by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 35 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Simian Seisaku industries Co., Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 1012 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to yield 896g of a pale yellow solid in 74% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 60 ℃, the reaction was carried out for 9 hours under the pressure of 0.5MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain 157g wet product, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain 128g solid with yield of 93%.

Example 12

Preparation of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

620g of 4- (benzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added into a 5L four-neck flask at room temperature, the temperature was raised to 80 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and no residual material was left by TLC (dichloromethane: methanol ═ 10: 1). Cooling to 35 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from western Ancisco Seisakusho Co., Ltd.), heating to 70 ℃, reacting for 20 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, performing suction filtration to obtain a crude product, and drying at 60 ℃ to obtain 1018 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 926g of a pale yellow solid in 76% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-benzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 25g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa and three times of hydrogen substitution at 0.3MPa were added to a 2L autoclave, the temperature was raised to 60 ℃, the reaction was carried out for 8 hours under the pressure of 0.5MPa, and TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain 157g wet product, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain 128g solid with yield of 93%.

Example 13

Preparation of 1- (4-4-methoxybenzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

714g of 4- (4-methoxybenzyloxy) aniline (from Beijing carbofuran, Inc.), 580g of bis (2-chloroethyl) amine hydrochloride (from Beijing carbofuran, Inc.), and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and the raw material was checked by TLC (dichloromethane: methanol 10: 1) for almost no residue. Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Xian's Cisco Seisakusho industries, Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 1097 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered, and dried to give 992g of a pale yellow solid in 76% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-4-methoxybenzyloxy) phenyl) -4- (4-nitrophenyl) piperazine prepared in the above step, 20g of raney nickel, 1L of methanol, three times of nitrogen substitution at 0.3MPa, three times of hydrogen substitution at 0.3MPa, heating to 60 ℃, reacting for 8 hours under the pressure of 0.5MPa, and detecting by TLC (dichloromethane: methanol 5: 1) cooling to room temperature after no raw material remains, performing suction filtration, adjusting the pH of the filtrate to 3 with 2N hydrochloric acid, precipitating a solid, performing suction filtration to obtain 127g of a wet product, adjusting the pH of the wet product to 8 with 10% w/v sodium carbonate, performing suction filtration, and drying to obtain 109g of the solid with the yield of 85%.

Example 14

Preparation of 1- (4-4-nitrobenzyloxy) phenyl) -4- (4-nitrophenyl) piperazine

760g of 4- (4-nitrobenzyloxy) aniline (purchased from Beijing carbofuran, Tech., Ltd.), 580g of bis (2-chloroethyl) amine hydrochloride (purchased from Beijing carbofuran, Tech., Ltd.) and 2.4L of tap water were added to a 5L four-neck flask at room temperature, the mixture was heated to 90 ℃ for reaction, 64g of sodium hydroxide/64 g of aqueous solution was added after three hours, one batch was added every three hours, four batches were continuously added, the reaction was continued for three hours, and the raw material was checked by TLC (dichloromethane: methanol: 10: 1) to be substantially free from residue. Cooling to 30 ℃, stirring for reaction, adding 516g of potassium carbonate solid and 440g of parafluoronitrobenzene (purchased from Xian's Cisco Seisakusho industries, Ltd.), heating to 60 ℃, reacting for 24 hours, detecting by TLC (dichloromethane: methanol 10: 1) that no raw material is left, cooling to 20 ℃, stirring for 1 hour, precipitating a large amount of solid, filtering to obtain a crude product, and drying at 60 ℃ to obtain 1097 g. The crude product was slurried with twice the mass of solvent at 25 deg.C (petroleum ether: ethyl acetate: 20:1) for 1 hour, filtered with suction, and dried to give 987g of a pale yellow solid in 73% yield.

Preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine

At room temperature, 200g of 1- (4-4-nitrobenzyloxy) phenyl) -4- (4-nitrophenyl) piperazine, 20g of raney nickel, 1L of methanol, three times of nitrogen replacement at 0.3MPa and three times of hydrogen replacement at 0.3MPa are added into a 2L high-pressure reaction kettle, the temperature is raised to 60 ℃, the reaction is carried out for 8 hours under the pressure of 0.5MPa, and TLC detection (dichloromethane: methanol 5: 1) cooling to room temperature after no material remains, vacuum filtering, adjusting pH of the filtrate to 3 with 2N hydrochloric acid, precipitating solid, vacuum filtering to obtain 122g wet product, adjusting pH of the wet product to 8 with 10% w/v sodium carbonate, vacuum filtering, and drying to obtain 100g solid with yield of 81%.

Obviously, many modifications, substitutions, and alterations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims and their equivalents. The person skilled in the art will appreciate that the individual features of the inventive solutions described in the present application can be combined as appropriate as required.