CN115232022B - Preparation method of acetaminophen dimer derivative - Google Patents

Preparation method of acetaminophen dimer derivative Download PDF

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CN115232022B
CN115232022B CN202210920666.3A CN202210920666A CN115232022B CN 115232022 B CN115232022 B CN 115232022B CN 202210920666 A CN202210920666 A CN 202210920666A CN 115232022 B CN115232022 B CN 115232022B
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CN115232022A (en
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韩小华
宋磊
杨石
王忠义
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Tlc Nanjing Pharmaceutical Research And Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a acetaminophen dimer derivative and a preparation method thereof. The derivative is a metabolite of acetaminophen, has important significance for drug metabolism research, and has great application value in clinical pharmacokinetics research. The preparation method provided by the invention has reasonable process design and strong operability, and provides necessary technical support for future industrial production. The prepared acetaminophen dimer derivative has high purity and higher yield, and provides an important basis for scientific evaluation of quality, safety and efficacy of acetaminophen.

Description

Preparation method of acetaminophen dimer derivative
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of a acetaminophen dimer derivative.
Background
Acetaminophen (Acetaminophen), chemical name N- (4-hydroxyphenyl) acetamide, CAS 103-90-2, acetaminophen, commodity name paracetamol, belongs to acetanilide antipyretic analgesic. Synthesized first by Morse in 1878 and used first in clinic by VonMering in 1893. In 1955, the medicine became an over-the-counter medicine, and production began in China at the end of the 50 s of the 20 th century. Clinically, the traditional Chinese medicine composition is mainly used for treating fever, headache, light and moderate pains and the like caused by cold, such as arthralgia, myalgia, neuralgia, migraine, dysmenorrhea, cancerous pain, postoperative pain and the like; can also be used for patients allergic to aspirin, intolerance or inapplicability to aspirin, and patients with light peptic ulcer and gastritis; in addition, it can be used for synthesizing medicine pamphlet pain, and as organic synthesis intermediate, photographic chemical and stabilizer of hydrogen peroxide.
With the progress of the age and the improvement of the technology level, people have more fully recognized the importance of scientific evaluation of quality, safety and efficacy of medicines before the medicines are marketed, wherein the control of medicine impurities is closely related to the quality of medicines. Impurities often have a direct relationship with drug safety. The pharmacopoeia of each country strictly prescribes the content and the kind of the drug impurities.
The compound name of the acetaminophen dimer derivative (compound VII) prepared by the application is N- (5-acetamido-2-hydroxyphenol) -N- (4-hydroxyphenol) acetamide, and the molecular formula is C 16 H 16 N 2 O 4 The derivative is a dimerization product of the acetaminophen, is a metabolite of the acetaminophen, has important significance for drug metabolism research, and has great application value in clinical pharmacokinetics research. There is no report in the literature on the synthesis of this compound, journal of the Chemical society. Perkin transformations I,1990,12, (3339-3344) provides a method that produces trace amounts of product, but in very low yields, without providing detailed information. The preparation method disclosed by the invention has the advantages of reasonable process design and strong operability, and provides necessary technical support for future industrial production.
Disclosure of Invention
The invention aims to: a acetaminophen dimer derivative and its preparation method are provided.
The technical scheme is as follows: the preparation method of the acetaminophen dimer derivative comprises the following steps:
(1) Dissolving the compound I and the compound II in DMF, adding a catalyst and alkali, and reacting to obtain a compound III;
(2) Dissolving the compound III in acetic acid, adding an acetylating reagent, and reacting to obtain a compound IV;
(3) Dissolving the compound IV in a solvent, adding benzyl bromide and alkali, and reacting to obtain a compound V:
(4) Dissolving the compound V in tertiary butanol, adding an acetylating reagent, a catalyst and alkali, and reacting to obtain a compound VI;
(5) Dissolving the compound VI in methanol, adding a palladium-carbon catalyst, and reacting to obtain a compound VII;
preferably, in the step (1), the catalyst is selected from cuprous iodide and cuprous chloride, preferably cuprous iodide; the base is selected from potassium phosphate, potassium carbonate, potassium hydroxide, preferably potassium phosphate.
Preferably, in the step (1), the compound I is 1 equivalent, and the compound II is 1 to 3 equivalents, preferably 2 equivalents; the catalyst is 0.05 to 0.3 equivalent, preferably 0.1 equivalent; the reaction temperature is 25-100 ℃, preferably 80 ℃; the reaction time is 3 to 24 hours, preferably overnight.
Preferably, in the step (2), the acetylating agent is selected from acetic anhydride, acetyl chloride and glacial acetic acid, preferably acetyl chloride.
In the step (2), the compound III is 1 equivalent, and the acetylating agent is 1 to 3 equivalents, preferably 2 equivalents; the reaction temperature is 25-100 ℃, preferably 70 ℃; the reaction time is 3 to 24 hours, preferably overnight.
In step (3), the organic solvent is selected from acetonitrile, acetone, DMF, preferably acetone; the base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, potassium hydroxide, preferably potassium carbonate.
In step (3), the compound IV is 1 equivalent, and benzyl bromide is 1 to 3 equivalents, preferably 1.1 equivalents; the base is 1 to 3 equivalents, preferably 2 equivalents; the temperature is room temperature and the reaction time is 3 to 24 hours, preferably overnight.
In step (4), the catalyst is selected from Pd 2 (dba) 3 、Pd(dba) 2 、Pd(PPh 3 ) 4 Pd (PPh) is preferred 3 ) 4 The method comprises the steps of carrying out a first treatment on the surface of the The base is selected from potassium phosphate, potassium carbonate, potassium bicarbonate, preferably potassium phosphate; the acetylating agent is selected from acetic anhydride, acetyl chloride, ammonium acetate, preferably ammonium acetate.
In the step (4), the compound V is 1 equivalent, and the catalyst is 0.005-0.1 equivalent, preferably 0.05 equivalent; the reaction temperature is 25-140 ℃, preferably 110 ℃; the reaction time is 5 to 72 hours, preferably 48 hours.
In the step (5), the compound VI is 1 equivalent, and the catalyst is 0.05 to 0.2 equivalent, preferably 0.1 equivalent; the reaction time is 2 to 24 hours, preferably overnight.
The beneficial effects are that: the synthesis process has reasonable design and strong operability, and the purity can reach 99 percent and the yield can reach 68 percent by the characteristics of nuclear magnetism, mass spectrum, liquid phase and the like. The acetaminophen dimer derivative obtained by the application can provide a test sample and a control sample for quality control of acetaminophen serving as a raw material drug, and has important application value in drug declaration. Meanwhile, the derivative is a metabolite of acetaminophen, has great significance for drug metabolism research and has great application value in clinical pharmacokinetics research. The preparation method has reasonable process design and strong operability, and provides necessary technical support for future industrial production.
Drawings
FIG. 1 is a synthetic scheme of the present invention.
FIG. 2 is an MS of the compound III synthesized according to the present invention.
FIG. 3 is an MS of compound V synthesized according to the present invention.
FIG. 4 shows a compound VI obtained by synthesis according to the invention 1 H-NMR chart.
FIG. 5 shows a compound VII obtained by synthesis according to the invention 1 H-NMR chart.
FIG. 6 is an HPLC chart of compound VII synthesized in the present invention.
FIG. 7 is an MS of a compound VII synthesized according to the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are given by way of illustration only and are not intended to limit the scope of the invention in any way.
Example 1
A process for the preparation of a acetaminophen dimer derivative comprising the steps of:
(1) Preparation of Compound III
Compound I (150.00 g,0.570 mol) and compound II (163.69 g,1.14 mol) were dissolved in DMF (750.0 mL), cuprous iodide (10.86 g,0.057 mol) and potassium phosphate (121.00 g,0.570 mol) were added, the reaction was stirred at 80C overnight, and the TLC detection was complete. Concentrating under reduced pressure to obtain crude product. The crude product was eluted with a mixture of dichloromethane and methanol to give compound III (52.00 g) by silica gel column chromatography in an MS as shown in FIG. 2 in 58% yield.
(2) Preparation of Compound IV
Compound III (52.00 g,0.160 mol) was dissolved in acetic acid (282.0 mL) and acetyl chloride (25.06 g,0.319 mmol) was added. The reaction was stirred overnight at 70℃and the reaction was completed by TLC. Concentrating under reduced pressure to obtain crude product.
The crude product is subjected to silica gel column chromatography by using a mixed system of dichloromethane and methanol, and then is recrystallized by using normal hexane to obtain a compound IV (25.83 g), wherein the mass spectrum number is 367.10, and the yield is 44%.
(3) Preparation of Compound V
Compound IV (25.83 g,70.2 mmol) was dissolved in acetone (258.0 mL) and benzyl bromide (13.21 g,77.2 mmol), potassium carbonate (19.41 g,140.4 mmol) was added under ice-bath. The reaction was stirred overnight at room temperature and TLC was complete. Suction filtering, concentrating the filtrate under reduced pressure to obtain crude product.
The crude product was eluted with a mixture of petroleum ether and methylene chloride by silica gel column chromatography to give compound V (18.33 g) whose MS is shown in FIG. 3 in 57% yield.
(4) Preparation of Compound VI
Compound V (18.33 g,40.0 mmol) was dissolved in t-butanol (236.7 mL) and acetamide (3.54 g,60.0 mmol), potassium phosphate (12.74 g,60.0 mmol), tetrakis (triphenylphosphine) palladium (0.23 g,0.20 mmol) was added. The reaction was stirred at 110℃for 48 hours, and the reaction was essentially complete by TLC. Concentrating under reduced pressure to obtain crude product.
The crude product was subjected to silica gel column chromatography using a mixed system of dichloromethane and methanol, and recrystallized from n-hexane to give compound VI (14.42 g) whose 1H-NMR is as shown in FIG. 4 in 75% yield.
(5) Preparation of Compound VII
Compound VI (2.00 g,4.2 mmol) was dissolved in methanol (20 mL) and a 10% palladium on charcoal catalyst (0.20 g) was added under nitrogen. The reaction was stirred overnight at room temperature and TLC was complete. Suction filtering, concentrating the filtrate under reduced pressure to obtain crude product. The crude product was dissolved in methanol and recrystallized from isopropyl ether to give compound VII (0.85 g), 1H-NMR thereof shown in FIG. 5 and MS thereof shown in FIG. 7. The yield thereof was found to be 68%. As shown in FIG. 6, the purity of the product is up to 99% by HPLC.
Example 2
A process for the preparation of a acetaminophen dimer derivative comprising the steps of:
(1) Preparation of Compound III
Compound I (75.00 g, 0.284 mol) and compound II (81.85 g,0.570 mol) were dissolved in DMF (375.0 mL), cuprous iodide (5.43 g,0.029 mol) and potassium carbonate (39.39 g, 0.284 mol) were added, and the reaction was stirred overnight at 80℃and the reaction was completed by TLC. Concentrating under reduced pressure to obtain crude product.
The crude product was eluted with a mixture of dichloromethane and methanol to give compound III (41.05 g) in 44% yield by silica gel column chromatography. Its MS is the same as in example 1.
(2) Preparation of Compound IV
Compound III (41.00 g,0.126 mol) was dissolved in acetic acid (222.3 mL) and acetic anhydride (25.73 g,0.252 mmol) was added. The reaction was stirred overnight at 70℃and the reaction was completed by TLC. Concentrating under reduced pressure to obtain crude product.
The crude product was subjected to silica gel column chromatography using a mixed system of dichloromethane and methanol as an eluent, and recrystallized from n-hexane to give compound IV (6.49 g) in a yield of 14%.
(3) Preparation of Compound V
Compound IV (6.46 g,17.6 mmol) was dissolved in acetone (64.6 mL) and benzyl bromide (6.02 g,35.2 mmol), potassium carbonate (4.86 g,35.2 mmol) was added under ice-bath. The reaction was stirred overnight at room temperature and TLC was complete. Suction filtering, concentrating the filtrate under reduced pressure to obtain crude product.
The crude product is eluted with petroleum ether and dichloromethane mixture to obtain compound V (4.59 g) in 57% yield. Its MS is the same as in example 1.
(4) Preparation of Compound VI
Compound V (4.50 g,9.8 mmol) was dissolved in t-butanol (58.5 mL) and acetamide (0.87 g,14.7 mmol), potassium phosphate (3.12 g,14.7 mmol), pd was added 2 (dba) 3 (0.45 g,0.49 mmol). The reaction was stirred at 110℃for 72 hours, and the reaction was completed by TLC. Concentrating under reduced pressure to obtain crude product.
The crude product was subjected to silica gel column chromatography using a mixed system of dichloromethane and methanol, and recrystallized from n-hexane to give compound VI (2.88 g) in a yield of 61%. Its 1H-NMR was the same as in example 1.
(5) Preparation of Compound VII
Compound VI (2.88 g,6.0 mmol) was dissolved in methanol (28.8 mL) and a 10% palladium on charcoal catalyst (0.29 g) was added under nitrogen. The reaction was stirred at room temperature for 2 hours, and the reaction was essentially complete by TLC. Suction filtering, concentrating the filtrate under reduced pressure to obtain crude product. The crude product was dissolved in methanol and recrystallized from isopropyl ether to give compound VII (1.08 g) in 60% yield. Its 1H-NMR and MS were the same as in example 1.
Example 3
A process for the preparation of a acetaminophen dimer derivative comprising the steps of:
(1) Preparation of Compound III
Compound I (150.00 g,0.570 mol) and compound II (163.69 g,1.14 mol) were dissolved in DMF (750.0 mL), cuprous chloride (11.28 g,0.114 mol) was added, potassium phosphate (242.00 g,1.14 mol) was added, and the reaction was stirred overnight at 80℃and the reaction was completed by TLC. Concentrating under reduced pressure to obtain crude product.
The crude product was eluted with a mixture of dichloromethane and methanol to give compound III (52.00 g) in 28% yield by silica gel column chromatography. Its MS is the same as in example 1.
(2) Preparation of Compound IV
Compound III (52.00 g,0.160 mol) was dissolved in acetic acid (282.0 mL) and acetyl chloride (39.28 g,0.500 mmol) was added. The reaction was stirred overnight at 50℃and TLC checked for small amounts of starting material remaining. Concentrating under reduced pressure to obtain crude product.
The crude product was subjected to silica gel column chromatography using a mixed system of dichloromethane and methanol as an eluent, and recrystallized from n-hexane to give compound IV (14.67 g) in 25% yield.
(3) Preparation of Compound V
Compound IV (12.91 g,35.1 mmol) was dissolved in acetonitrile (129.1 mL) and benzyl bromide (6.60 g,38.6 mmol), potassium carbonate (14.55 g,105.3 mmol) was added under ice-bath. The reaction was stirred overnight at room temperature and TLC was complete. Suction filtering, concentrating the filtrate under reduced pressure to obtain crude product.
The crude product is eluted with petroleum ether and dichloromethane mixture to obtain compound V (7.23 g) in 45% yield. Its MS is the same as in example 1.
(4) Preparation of Compound VI
Compound V (7.00 g,15.3 mmol) was dissolved in t-butanol (91.0 mL) and acetamide (1.35 g,23.0 mmol), potassium phosphate (1.05 g,23.0 mmol), tris (dibenzylideneacetone) dipalladium (0.44 g,0.77 mmol) was added. The reaction was stirred at 100℃for 24 hours, and the reaction was essentially complete by TLC. Concentrating under reduced pressure to obtain crude product.
The crude product was chromatographed on a silica gel column using a mixture of dichloromethane and methanol as eluent to give compound VI (1.10 g) in 15% yield. Its 1H-NMR was the same as in example 1.
(5) Preparation of Compound VII
Compound VI (1.10 g,2.3 mmol) was dissolved in methanol (11.0 mL) and 10% palladium on charcoal catalyst (0.055 g,0.05 equiv) was added under nitrogen. The reaction was stirred overnight at room temperature and TLC was complete. Suction filtering, concentrating the filtrate under reduced pressure to obtain crude product. The crude product was dissolved in methanol and recrystallized from isopropyl ether to give compound VII (0.45 g) in 65% yield. Its 1H-NMR and MS were the same as in example 1.
The foregoing description is only exemplary of the present invention and is not intended to limit the scope of the invention, as any equivalent structure or equivalent flow transformation or direct or indirect application of other related technical fields are included in the scope of the present invention.

Claims (7)

1. A process for the preparation of a acetaminophen dimer derivative comprising the steps of:
(1) Dissolving a compound I and a compound II in DMF, adding a catalyst and alkali, and reacting to obtain a compound III;
(2) Dissolving the compound III in acetic acid, adding an acetylating reagent, and reacting to obtain a compound IV;
(3) Dissolving the compound III in a solvent, adding benzyl bromide and alkali, and reacting to obtain a compound V;
(4) Dissolving a compound V in tertiary butanol, adding an acetylating reagent, a catalyst and alkali, and reacting to obtain a compound VI;
(5) Dissolving the compound VI in methanol, adding a palladium-carbon catalyst, and reacting to obtain a compound VII:
in the step (1), the catalyst is selected from cuprous iodide or cuprous chloride; the base is selected from potassium phosphate, potassium carbonate or potassium hydroxide;
in the step (2), the acetylating agent is selected from acetic anhydride, acetyl chloride or glacial acetic acid;
in the step (4), the catalyst is Pd 2 (dba) 3 、Pd(dba) 2 Or tetrakis (triphenylphosphine) palladium; the base is selected from potassium phosphate; the acetylating agent is selected from acetamides.
2. The method of manufacture of claim 1, wherein: in the step (1), the compound I is 1 equivalent, the compound II is 1-3 equivalents, the catalyst is 0.05-0.3 equivalent, the reaction temperature is 25-100 ℃, and the reaction time is 3-24 hours.
3. The method of manufacture of claim 1, wherein: in the step (2), the compound III is 1 equivalent, the acetylating agent is 1 to 3 equivalents, the reaction temperature is 25 to 100 ℃, and the reaction time is 3 to 24 hours.
4. The method of manufacture of claim 1, wherein: in step (3), the organic solvent is selected from acetonitrile, acetone or DMF; the base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or potassium hydroxide.
5. The method of manufacture of claim 1, wherein: in the step (3), the compound IV is 1 equivalent, the benzyl bromide is 1 to 3 equivalents, the alkali is 1 to 3 equivalents, the reaction temperature is room temperature, and the reaction time is 3 to 24 hours.
6. The method of manufacture of claim 1, wherein: in the step (4), the compound V is 1 equivalent, the catalyst is 0.005-0.1 equivalent, the reaction temperature is 25-140 ℃, and the reaction time is 5-72 hours.
7. The method of manufacture of claim 1, wherein: in the step (5), the compound VI is 1 equivalent, the catalyst is 0.05 to 0.2 equivalent, and the reaction time is 2 to 24 hours.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4424150A (en) * 1982-04-02 1984-01-03 Syva Company Acetaminophen analogs, antigens, and antibodies

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4424150A (en) * 1982-04-02 1984-01-03 Syva Company Acetaminophen analogs, antigens, and antibodies

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chuanzhou Liang et al..Mechanism for primary transformation of acetaminophen in a soil/water system.Water Research.2016,第98卷215-224. *
Magoichi Sako et al..Photochemical Oxygenation of Phenols by pyrimido[5,4-g]pteridine N-Oxide. Comparative Studies with Pyridazine and Isoalloxazine N-Oxides.Journal of the Chemical Society. Perkin Transaction 1.1990,3339-3344. *

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