CN117756750A - Preparation method of 1-acetyl-4- (4-hydroxyphenyl) piperazine - Google Patents
Preparation method of 1-acetyl-4- (4-hydroxyphenyl) piperazine Download PDFInfo
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- AGVNLFCRZULMKK-UHFFFAOYSA-N 1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1C1=CC=C(O)C=C1 AGVNLFCRZULMKK-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 238000003756 stirring Methods 0.000 claims abstract description 21
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims abstract description 20
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- YHHKEXPNBPDPOW-UHFFFAOYSA-N 2-bromo-n-(2-bromoethyl)ethanamine;hydrobromide Chemical compound Br.BrCCNCCBr YHHKEXPNBPDPOW-UHFFFAOYSA-N 0.000 claims abstract description 12
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 239000012044 organic layer Substances 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 238000007039 two-step reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 208000031888 Mycoses Diseases 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 4
- 206010017533 Fungal infection Diseases 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000002538 fungal effect Effects 0.000 description 4
- 229960004125 ketoconazole Drugs 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 241000233866 Fungi Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000008686 ergosterol biosynthesis Effects 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 229960004130 itraconazole Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 241000104952 Xanthophyllum eurhynchum Species 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- -1 phenolic ester Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- KUJFKFWQVGCSAR-UHFFFAOYSA-M sodium;ethyl acetate;hydrogen carbonate Chemical compound [Na+].OC([O-])=O.CCOC(C)=O KUJFKFWQVGCSAR-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 1-acetyl-4- (4-hydroxyphenyl) piperazine, which comprises the steps of preparing a compound III from bis (2-bromoethyl) amine hydrobromide (compound II) through two-step reaction in a reaction kettle, adding a reaction solvent and the compound II, stirring, adding alkali 1 in batches, controlling the internal temperature, and dropwise adding a solution of acetyl chloride and the reaction solvent until the reaction is complete; adding water, stirring, standing, layering, and leaving an organic layer in a kettle; in the step of preparing the compound I from the compound III, adding alkali 2, tetrabutylammonium iodide and p-aminophenol into a reaction kettle under the protection of nitrogen, stirring and heating until the reaction is complete; post-treatment gives 1-acetyl-4- (4-hydroxyphenyl) piperazine (compound I). The method has the advantages of simple reaction, easy operation, high yield, total yield up to 88%, purity more than 99.5%, no high-risk reaction, and suitability for industrial production.
Description
Technical Field
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of 1-acetyl-4- (4-hydroxyphenyl) piperazine.
Background
Fungal infections are more common in dermatology and can cause superficial mycoses and deep mycoses after clinical infection with fungi. In recent years, the incidence of fungal infections has increased year by year, and especially deep fungal infections are increasingly threatening the health and life of patients. Ketoconazole is an imidazole broad-spectrum antifungal agent that inhibits the biosynthesis of ergosterol on fungal cell membranes by highly selectively interfering with the activity of cytochrome P-450 in fungi. Is effective for superficial and deep fungal infection, and can inhibit fungal growth and transformation of spores into mycelium, and prevent further infection. The itraconazole is artificially synthesized triazole broad-spectrum antifungal agent, exerts antibacterial activity by changing the permeability of fungal cell membranes, has antibacterial activity on pathogenic bacteria infected by superficial and deep fungi, has wider and stronger antibacterial spectrum than ketoconazole, and can inhibit the synthesis of ergosterol of the fungal cell membranes, thereby exerting antifungal effect.
1-acetyl-4- (4-hydroxyphenyl) piperazine (compound 1) is a key intermediate for synthesizing itraconazole and ketoconazole, and has important significance in researching the preparation method of 1-acetyl-4- (4-hydroxyphenyl) piperazine.
Patent CN1257163C discloses a synthesis method of 1-acetyl-4- (4-hydroxyphenyl) piperazine as follows:
reagents and conditions: (a) acetone, 40% hbr, yield: 51.2%; (b) MeOH, n-butanol, acetone, para-aminoanisole, anhydrous NaCO 3 Yield: 60% -66%; (c) acetone, 40% hbr, yield: 78.6%; (d) EtOH, K 2 CO 3 Acetic anhydride, yield: 85%.
This route has the following problems: step a and step c use 40% HBr, which is very corrosive; the total yield of the compound I obtained by the synthesis method is only 21-23%, the yield is low, the method is not suitable for large-scale production, and meanwhile, the method can cause great pollution to the environment.
The following synthetic methods are reported in the literature in the autumn, liu Lilin, wang Xiaoyan, lv Jiaguo, sun Chang, & Zhang Huanxiang et al (1984) for the synthesis of the antifungal ketoconazole:
reagents and conditions: (e) P-nitrochlorobenzene, anhydrous potassium carbonate, n-butanol, dilute hydrochloric acid, 40% naoh, yield: 75%; (f) 95% etoh, pyridine, acetic anhydride, yield: 90%; (g) ethanol, 85% hydrazine hydrate, active nickel, yield: 84%; (h) 7.5% sulfuric acid, sodium nitrite, copper nitrate, copper powder, naHCO 3 Ethyl acetate, yield: 57%.
The method has the advantages of multiple steps, complex operation, high-risk reaction, harsh reaction conditions, large equipment investment, potential safety hazard, hydrazine genotoxic impurity risk and low overall yield.
Disclosure of Invention
The invention aims to: in order to overcome the defects in the prior art, the invention discloses a preparation method of 1-acetyl-4- (4-hydroxyphenyl) piperazine, which is carried out in a reaction kettle, has short steps and is simple and convenient to operate; high-risk reaction does not exist, and the investment of large equipment cost is avoided; through the route design, the production of phenolic ester impurities and hydrazine genotoxic impurities is avoided, the purity is improved, the requirements of the medicine industry are met, the yield can reach 88%, and the method can be used for industrial production.
The invention is realized by the following technical means:
in the method, in the step of preparing a compound III from a compound II through two-step reaction in a reaction kettle, a reaction solvent and bis (2-bromoethyl) amine hydrobromide are added, stirring is carried out, alkali 1 is added in batches, the internal temperature is controlled, and the solution of acetyl chloride and the reaction solvent is dropwise added until the reaction is complete; adding water, stirring, standing, layering, and leaving an organic layer in a reaction kettle; in the step of preparing the compound I from the compound III, adding alkali 2, tetrabutylammonium iodide and p-aminophenol into a reaction kettle under the protection of nitrogen, stirring and heating until the reaction is complete; and (3) carrying out post-treatment to obtain the compound I.
In the preparation method of the 1-acetyl-4- (4-hydroxyphenyl) piperazine, the reaction solvent is one of methyl tertiary butyl ether and 2-methyltetrahydrofuran.
In the step of preparing the compound III from the compound II, the alkali 1 is one of sodium carbonate and potassium carbonate.
Further, in the step of preparing the compound III from the compound II, the molar ratio of the compound II, the alkali 1 and the acetyl chloride is 1:1.3-1.6:1.1-1.3.
In the step of preparing the compound III from the compound II, when the solution of acetyl chloride is dripped, the internal temperature is controlled to be 0-10 ℃, the reaction temperature is controlled to be 10-35 ℃ after the dripping is finished, and the reaction is carried out for 4-8 hours.
Further, in the step of preparing the compound I from the compound III, the alkali 2 is one of sodium carbonate, sodium bicarbonate and potassium bicarbonate.
Further, in the step of preparing the compound I from the compound III, the molar ratio of the compound III, the para-aminophenol, the tetrabutylammonium iodide and the base 2 is 1:1 to 1.2:0.03 to 0.1:1.5 to 5.
In the step of preparing the compound I from the compound III, the reaction temperature is 60-90 ℃ and the reaction time is 8-26 h.
In the step of preparing the compound I from the compound III, the post-treatment step is that the solvent is removed by reduced pressure distillation; adding water, cooling, filtering, recrystallizing the filter cake with 95% ethanol, and vacuum drying to obtain the compound I.
Advantageous effects
The bis (2-bromoethyl) amine hydrobromide (compound II) is used as a starting material, and the compound III is obtained by reaction; then reacts with p-aminophenol to obtain 1-acetyl-4- (4-hydroxyphenyl) piperazine (compound I). The total yield of 2 steps of the preparation of the compound I can reach 89.1 percent, and the purity can be more than 99.5 percent. The method is carried out in a reaction kettle, has short steps and is simple and convenient to operate; high-risk reaction does not exist, the investment of large equipment cost is avoided, and the method is suitable for industrial production. The invention solves the defects of complex operation, large equipment investment, potential safety hazard and the like in the existing known synthesis process.
Drawings
FIG. 1 is a HPLC purity profile for example 1, 1-acetyl-4- (4-hydroxyphenyl) piperazine;
FIG. 2 is a hydrogen spectrum of example 1, 1-acetyl-4- (4-hydroxyphenyl) piperazine.
Detailed Description
The following detailed description is provided for further details of the purposes, technical solutions and advantageous effects of the present application, and it should be understood that the following description is only a detailed description of the present application, and is not intended to limit the scope of the present application.
Example 1:
methyl tertiary butyl ether (800 mL) and bis (2-bromoethyl) amine hydrobromide (155.9 g,0.5mol,1.0 e.q.) are added into a dry reaction kettle equipped with a thermometer, a stirring and a reflux condenser, stirring is started, sodium carbonate (68.9 g,0.65mol,1.3 e.q.) is added in portions, the internal temperature is controlled to be 0-10 ℃, acetyl chloride (43.2 g,0.55mol,1.1 e.q.) and 45mL of methyl tertiary butyl ether solution are added dropwise, the mixture is reacted at 25 ℃ for 8 hours after TLC, and the raw material reaction is completed; adding water (250 mL), stirring, standing, layering, and leaving an organic layer in a kettle; sodium bicarbonate (126.0 g,1.5mol,3 e.q.), tetrabutylammonium iodide (5.54 g,0.015mol,0.03 e.q.), and para-aminophenol (54.6 g,0.5mol,1 e.q.) were added under nitrogen protection, stirred, heated, and reacted at 60℃for 20 hours under thermal insulation, TLC control, and the reaction of the starting materials was complete; recovering methyl tertiary butyl ether by reduced pressure distillation; water (600 mL) was added, cooled, filtered off with suction, the filter cake recrystallized from 95% ethanol and dried under vacuum to give 98.7g of white crystals with 99.7% HPLC purity and 89.6% yield (calculated as bis (2-bromoethyl) amine hydrobromide). 1-ethylThe HPLC purity chart of the acyl-4- (4-hydroxyphenyl) piperazine is shown in figure 1; the hydrogen spectrum of the 1-acetyl-4- (4-hydroxyphenyl) piperazine is shown in figure 2, 1 HNMR(400MHz,DMSO-d 6 )δ：8.90(s,1H),6.82-6.78(m,2H),6.68-6.64(m,2H),3.56-3.52(m,4H),2.95-2.86(m,4H),2.02(s,3H)。
example 2:
2-methyltetrahydrofuran (800 mL) and bis (2-bromoethyl) amine hydrobromide (155.9 g,0.5mol,1.0 e.q.) are added into a dry reaction kettle equipped with a thermometer, a stirring and a reflux condenser, stirring is started, sodium carbonate (68.9 g,0.65mol,1.3 e.q.) is added in portions, the internal temperature is controlled to be 0-10 ℃, acetyl chloride (43.2 g,0.55mol,1.1 e.q.) and 45mL of 2-methyltetrahydrofuran solution are added dropwise, the dropwise reaction is carried out at 35 ℃ for 4 hours, TLC is controlled in center, and the raw materials are reacted completely; adding water (250 mL), stirring, standing, layering, and leaving an organic layer in a kettle; sodium bicarbonate (84.1 g,1.0mol,2 e.q.), tetrabutylammonium iodide (9.24 g,0.025mol,0.05 e.q.), and para-aminophenol (57.3 g,0.525mol,1.05 e.q.) were added under nitrogen protection, stirred, heated, and reacted at 80℃for 12 hours under thermal insulation, TLC was controlled, and the reaction of the starting materials was complete; recovering 2-methyltetrahydrofuran by reduced pressure distillation; water (600 mL) was added, cooled, filtered off with suction, the filter cake recrystallized from 95% ethanol and dried under vacuum to give 97.5g of white crystals with 99.6% HPLC purity and 88.5% yield (calculated as bis (2-bromoethyl) amine hydrobromide).
Example 3:
methyl tertiary butyl ether (800 mL) and bis (2-bromoethyl) amine hydrobromide (155.9 g,0.5mol,1.0 e.q.) are added into a dry reaction kettle equipped with a thermometer, a stirring and a reflux condenser, stirring is started, potassium carbonate (110.6 g,0.8mol,1.6 e.q.) is added in portions, the internal temperature is controlled to be 0-10 ℃, acetyl chloride (51 g,0.65mol,1.3 e.q.) and 45mL of methyl tertiary butyl ether solution are dropwise added, the mixture is reacted at 25 ℃ for 8 hours after the dropwise addition, TLC is controlled, and the raw materials are completely reacted; adding water (350 mL), stirring, standing, layering, and leaving an organic layer in a kettle; under the protection of nitrogen, potassium bicarbonate (250.3 g,2.5mol,5 e.q.), tetrabutylammonium iodide (18.5 g,0.05mol,0.1 e.q.), and para-aminophenol (60.0 g,0.55mol,1.1 e.q.) are added, stirred, heated, and the reaction is carried out at 60 ℃ for 26 hours, TLC is controlled, and the raw materials are completely reacted; recovering methyl tertiary butyl ether by reduced pressure distillation; water (1000 mL) was added, cooled, filtered off with suction, the filter cake recrystallized from 95% ethanol and dried under vacuum to give 97.7g of white crystals with 99.6% HPLC purity and 88.7% yield (calculated as bis (2-bromoethyl) amine hydrobromide).
Example 4:
2-methyltetrahydrofuran (800 mL) and bis (2-bromoethyl) amine hydrobromide (155.9 g,0.5mol,1.0 e.q.) are added into a dry reaction kettle equipped with a thermometer, a stirring and a reflux condenser, stirring is started, sodium carbonate (68.9 g,0.65mol,1.3 e.q.) is added in portions, the internal temperature is controlled to be 0-10 ℃, acetyl chloride (43.2 g,0.55mol,1.1 e.q.) and 45mL of 2-methyltetrahydrofuran solution are added dropwise, the dropwise reaction is carried out at 10 ℃ for 8 hours, TLC is controlled in center, and the raw materials are reacted completely; adding water (250 mL), stirring, standing, layering, and leaving an organic layer in a kettle; sodium carbonate (79.5 g,0.75mol,1.5 e.q.) tetrabutylammonium iodide (9.24 g,0.025mol,0.05 e.q.) and para-aminophenol (65.5 g,0.6mol,1.2 e.q.) were added under nitrogen protection, stirred, heated, kept at 90 ℃ for 8 hours, TLC was used for controlling, and the reaction of the raw materials was completed; recovering 2-methyltetrahydrofuran by reduced pressure distillation; water (600 mL) was added, cooled, filtered off with suction, and the filter cake recrystallized from 95% ethanol and dried under vacuum to give 98.1g of white crystals with 99.5% HPLC purity and 89.1% yield (calculated as bis (2-bromoethyl) amine hydrobromide).
Claims (9)
1. A process for the preparation of 1-acetyl-4- (4-hydroxyphenyl) piperazine comprising:
in the method, in the step of preparing a compound III from a compound II through two-step reaction in a reaction kettle, a reaction solvent and bis (2-bromoethyl) amine hydrobromide are added, stirring is carried out, alkali 1 is added in batches, the internal temperature is controlled, and the solution of acetyl chloride and the reaction solvent is dropwise added until the reaction is complete; adding water, stirring, standing, layering, and leaving an organic layer in a reaction kettle; in the step of preparing the compound I from the compound III, adding alkali 2, tetrabutylammonium iodide and p-aminophenol into a reaction kettle under the protection of nitrogen, stirring and heating until the reaction is complete; and (3) carrying out post-treatment to obtain the compound I.
2. The process for preparing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1, wherein in the step of preparing compound III from compound II, the base 1 is one of sodium carbonate and potassium carbonate.
3. The process for producing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1 or 2, wherein in the step of producing compound iii, the molar ratio of compound ii, base 1 and acetyl chloride is 1:1.3 to 1.6:1.1 to 1.3.
4. The process for producing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1, wherein in the step of producing compound III, the internal temperature is controlled to be 0 to 10℃and the reaction temperature is controlled to be 10 to 35℃after the completion of the dropwise addition of the solution of acetyl chloride, and the reaction is carried out for 4 to 8 hours.
5. The method for preparing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the reaction solvent is one of methyl tert-butyl ether and 2-methyltetrahydrofuran.
6. The process for preparing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1, wherein in the step of preparing compound i from compound iii, the base 2 is one of sodium carbonate, sodium bicarbonate and potassium bicarbonate.
7. The process for preparing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1 or 6, wherein in the step of preparing compound i from compound iii, the molar ratio of compound iii, p-aminophenol, tetrabutylammonium iodide to base 2 is 1:1 to 1.2:0.03 to 0.1:1.5 to 5.
8. The process for producing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1, wherein in the step of producing compound i from compound iii, the reaction temperature is 60 to 90 ℃ and the reaction time is 8 to 26 hours.
9. The process for preparing 1-acetyl-4- (4-hydroxyphenyl) piperazine according to claim 1, wherein in the step of preparing compound i from compound iii, the post-treatment step is to remove the solvent by distillation under reduced pressure, then add water, cool, suction filter, recrystallize the filter cake with 95% ethanol, and vacuum-dry to obtain compound i.
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