CN113636990A - Method for preparing diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone - Google Patents
Method for preparing diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 39
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 27
- DIQSYMRVTOVKQT-UHFFFAOYSA-N n-(3-acetyl-4-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(O)C(C(C)=O)=C1 DIQSYMRVTOVKQT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 11
- 239000000376 reactant Substances 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims abstract description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims abstract description 9
- 229940031826 phenolate Drugs 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 239000007791 liquid phase Substances 0.000 claims abstract description 6
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 5
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 100
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000010992 reflux Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000002270 dispersing agent Substances 0.000 claims description 2
- 230000001678 irradiating effect Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000010438 heat treatment Methods 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 230000008707 rearrangement Effects 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 230000021736 acetylation Effects 0.000 abstract description 2
- 238000006640 acetylation reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 238000005618 Fries rearrangement reaction Methods 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 15
- UJAOSPFULOFZRR-UHFFFAOYSA-N (4-acetamidophenyl) acetate Chemical compound CC(=O)NC1=CC=C(OC(C)=O)C=C1 UJAOSPFULOFZRR-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- AWOGXJOBNAWQSF-UHFFFAOYSA-N diacetolol Chemical compound CC(C)NCC(O)COC1=CC=C(NC(C)=O)C=C1C(C)=O AWOGXJOBNAWQSF-UHFFFAOYSA-N 0.000 description 4
- 229950003563 diacetolol Drugs 0.000 description 4
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical class CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- BKGANAFEDBCHTO-UHFFFAOYSA-N 1-[5-(butylamino)-2-hydroxyphenyl]ethanone Chemical class CCCCNC1=CC=C(O)C(C(C)=O)=C1 BKGANAFEDBCHTO-UHFFFAOYSA-N 0.000 description 2
- 229960002122 acebutolol Drugs 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
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- 238000010523 cascade reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- -1 phenol ester Chemical class 0.000 description 2
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- 206010020772 Hypertension Diseases 0.000 description 1
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- 125000002252 acyl group Chemical group 0.000 description 1
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- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
- C07D301/28—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms by reaction with hydroxyl radicals
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
- C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.
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Abstract
The invention belongs to the field of organic photochemistry and medicine intermediate chemistry, and particularly relates to a method for synthesizing a diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone by acetylation-photochemical rearrangement series reaction. The efficient continuous acetylation synthesis process includes mixing p-aminophenol and acetic anhydride, water separating reaction with water carrying agent, distilling to eliminate water carrying agent, cooling the reactant, adding polar organic solvent, photochemical Fries liquid phase rearrangement reaction, Fries rearrangement with UV-visible light of certain wavelength, and heating to evaporate solvent to obtain intermediate 2-acetyl-4-acetamidophenol. Adding sodium hydroxide to prepare phenolate, and then reacting with epoxy chloropropane to prepare an intermediate 5-acetamido-2- (2, 3-epoxy propoxy) acetophenone. The tandem type synthetic method is simple and easy to implement, and low-toxicity, high-efficiency and cheap green chemical reagents are used in the synthetic process.
Description
Technical Field
The invention belongs to the field of organic photochemistry and pharmaceutical chemistry, and particularly relates to a method for synthesizing a diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone by acetylation-photochemical rearrangement series reaction.
Background
Description of the background of the inventionthe art to which the present invention pertains is presented solely for the purpose of illustration and understanding the context of the present invention and is not to be construed as an admission or admission that the applicant is aware or appreciates that such prior art forms part of the present invention as the first filing date of the present application.
With the rapid development of environmental protection chemistry, photochemical synthesis has attracted wide attention as a green chemical method, and the intermediate of photochemical reaction has the characteristic of ground-state electronic configuration different from that of the conventional intermediate of thermochemical reaction. The activation energy of the induced chemical transformation is very low, so that the photoreaction can often occur efficiently at room temperature. And the light reaction has great difference with the transition state performance of the traditional thermochemical reaction, so that the chemical conversion which is difficult to realize by the thermochemical reaction can be realized. In solution, the phenol ester undergoes photolysis and the acyl group migrates to the ortho/para position to form a mixture of phenolic ketones, known as photoFries rearrangement. It undergoes a carbon-oxygen bond cleavage in an excited state to form a radical pair, which is recombined in a (polar) solvent cage to form the product.
Diaceolol (diacetool) is a metabolite of Acebutolol (Acebutolol), a commonly used cardiovascular drug beta receptor blocker, has a blocking effect on beta receptors (beta 1 receptors) of heart, and also has a blocking effect on beta receptors (beta 2 receptors) of bronchial and vascular smooth muscle, and can be used for treating hypertension, myocardial infarction, arrhythmia and other diseases. The 5-acetamido-2- (2, 3-epoxy propoxy) acetophenone is an important intermediate for synthesizing diacetolol, and the green and efficient synthesis of the 5-acetamido-2- (2, 3-epoxy propoxy) acetophenone is realized, so that the method has important application value.
The photochemical synthesis of 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone, which is a diacetolol intermediate, is not reported, while 2-acetyl-4-acetaminophenol, which is a further step, is an analogue of 2-acetyl-4-n-butylaminophenol, which is an acebutolol intermediate, and the latter is related to U.S. Pat. Nos. 3726919, 3857952 and 3928601, and a solid-phase solvent-free synthesis method related to 2-acetyl-4-n-butylaminophenol is also reported in the prior patent application CN1970529A, but the post-treatment is more complicated, and the toxicity and pollution of reagents in the related methods are higher and the cost is higher. Methods for photochemical synthesis of natural heterocyclic compounds and pharmaceutical intermediates based on a series developed in previous work by the applicant (Tetrahedron Letters 2017,58, 329. 332; Tetrahedron Letters 2017,58, 2127. 2130; org. biomol. chem.2018,16, 2406. 2410). The green photochemical synthesis method is tried to be popularized and applied to the preparation reaction of 2-acetyl-4-acetaminophenol and 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone, so that the synthesis of the drug intermediate is further environment-friendly and green. The method can be performed spontaneously under the irradiation of ultraviolet-visible light without a high-temperature and high-pressure environment, and related preparation methods are successfully applied in laboratories. Based on the work, the thermochemistry-photochemistry series reaction technology is further popularized and applied to the actual synthesis of the diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone.
Disclosure of Invention
The invention aims to solve the problems of high toxicity and pollution of used reagents, high cost, complex reaction operation and the like in the prior art, and provides a method for preparing a diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone.
In order to solve the technical problems, the technical scheme of the invention is as follows: a method for preparing 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone, which is a diacetolol intermediate, comprises the following steps:
the method comprises the following steps: adding acetic anhydride and p-aminophenol into a reactor, performing reflux reaction by using a water-carrying agent, and distilling at normal pressure to recover the water-carrying agent; cooling the reactant, adding a polar organic solvent as a dispersing agent, performing a photochemical Fries liquid phase rearrangement reaction, irradiating the photoreaction vessel with ultraviolet-visible light with a certain wavelength, and stirring for a certain time to obtain an intermediate 2-acetyl-4-acetaminophenol;
step two: adding a certain amount of sodium hydroxide solution into a certain amount of the product 2-acetyl-4-n-butylamidophenol obtained in the first step to prepare phenolate, adding epoxy chloropropane to perform ring-opening coupling reaction, pouring the reactant into water, filtering, recrystallizing with a mixed solvent, filtering, and drying to obtain the diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone.
In a preferred embodiment, the molar ratio of the acetic anhydride to the p-aminophenol is 1:2 to 1: 4;
in a preferred embodiment, the molar ratio of acetic anhydride to p-aminophenol is 1: 2.2.
In a preferred embodiment, the water-carrying agent is toluene.
In a preferred embodiment, the photochemical Fries liquid phase rearrangement reaction temperature is 25 ℃, and the adopted laser wavelength is 200 nm-350 nm.
As a preferred embodiment, the weight ratio of the organic solvent to the p-aminophenol is 5: 1-12: 1.
in a preferred embodiment, the polar organic solvent is tetrahydrofuran, pyridine or 1, 4-dioxane.
As a preferred embodiment, the mixed solvent is a mixture of toluene and ethanol, and the volume ratio of the mixture is 5: 1-15: 1.
the beneficial effects obtained by adopting the technical scheme are as follows:
1. the synthesis method is simple and easy to implement, the reaction is carried out under the conventional reaction conditions, and the atom-economical thermochemical acetylation and photochemical Fries liquid phase rearrangement Tandem reaction (Tandem reaction) synthesis methods are used.
2. The synthesis process of the invention uses low-toxicity, low-pollution and cheap green chemical reagents, does not need high temperature and high pressure conditions, and has environment-friendly post-treatment process of the reaction product, namely the diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone and the intermediate, and simple and convenient purification operation.
3. The product obtained by the invention meets the requirement of the intermediate, and the synthesis method of the intermediate is successfully prepared by gram-level mini-preparation in a laboratory; further optimization can be carried out, and medium-scale production can be realized. The invention provides a green chemical synthesis method with advantages and development prospects for the synthesis of a cardiovascular drug diacetolol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a schematic diagram of a first step reaction process;
FIG. 2 is a schematic diagram of the reaction process of the second step.
Detailed Description
The following further describes embodiments of the present invention with reference to the drawings. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
In the description of the present application, it is to be understood that the terms "center," "longitudinal," "lateral," "length," "width," "thickness," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," "outer," "clockwise," "counterclockwise," and the like are used in the orientations and positional relationships indicated in the drawings for convenience in describing the present application and for simplicity in description, and are not intended to indicate or imply that the referenced devices or elements must have a particular orientation, be constructed in a particular orientation, and be operated in a particular manner, and are not to be construed as limiting the present application. Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, features defined as "first", "second", may explicitly or implicitly include one or more of the described features. In the description of the present application, "a plurality" means two or more unless specifically limited otherwise.
Example 1
Step one, adding 2.10g of acetic anhydride, 1.09g of p-aminophenol and 3.40g of toluene into a reaction bottle, and heating, refluxing and dehydrating. Refluxing was carried out for about 9 hours, and the toluene was recovered by atmospheric distillation. After about 80% of the toluene amount was recovered, the reaction mixture was distilled under reduced pressure to remove toluene, thereby obtaining N- (4-acetoxyphenyl) acetamide. Then, 5.5g of tetrahydrofuran was added to the above product, and after sufficient dissolution, the mixture was irradiated with ultraviolet-visible light, preferably ultraviolet light having a wavelength of 254nm, stirred for 24 hours, heated to evaporate the solvent, and then recrystallized, filtered and dried to obtain 1.44g of needle-like white crystals of 2-acetyl-4-acetaminophenol in a yield of 75.1%.
And step two, adding 1.0g of sodium hydroxide solution with the mass concentration of 20% into 0.96g of the product 2-acetyl-4-n-butylamidophenol obtained in the step one to obtain phenolate, adding 0.46g of epoxy chloropropane to react for 12 hours, pouring the reactant into water to be filtered, then recrystallizing by using 10mL of mixed solvent of toluene/ethanol (the volume ratio is 10:1), filtering and drying to obtain 0.88g of 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone as a diacalol intermediate, wherein the yield is 70.4%.
Example 2
Step one, adding 2.10g of acetic anhydride, 1.09g of p-aminophenol and 3.40g of toluene into a reaction bottle, and heating, refluxing and dehydrating. Refluxing was carried out for about 9 hours, and the toluene was recovered by atmospheric distillation. After about 80% of the toluene amount was recovered, the reaction mixture was distilled under reduced pressure to remove toluene, thereby obtaining N- (4-acetoxyphenyl) acetamide. Then 6.0g of pyridine is added into the product, after the pyridine is fully dissolved, an ultraviolet-visible light irradiation light reaction container is adopted, ultraviolet irradiation with the preferable wavelength of 254nm is adopted, stirring is carried out for 24 hours, the solvent is heated and evaporated, then recrystallization is carried out, filtering and drying are carried out, 1.04g of needle-shaped white 2-acetyl-4-acetaminophenol crystals are obtained, and the yield is 53.8%.
And step two, adding 2.0g of sodium hydroxide solution with the mass concentration of 20% into 0.96g of the product 2-acetyl-4-n-butylamidophenol obtained in the step one to obtain phenolate, adding 0.46g of epoxy chloropropane to react for 12 hours, pouring the reactant into water to be filtered, then recrystallizing by using 10mL of mixed solvent of toluene/ethanol (the volume ratio is 10:1), filtering and drying to obtain 0.92g of 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone as a diacalol intermediate, wherein the yield is 72.2%.
Example 3
Step one, adding 2.10g of acetic anhydride, 1.09g of p-aminophenol and 3.40g of toluene into a reaction bottle, and heating, refluxing and dehydrating. Refluxing was carried out for about 12 hours, and the toluene was recovered by atmospheric distillation. After about 80% of the toluene amount was recovered, the reaction mixture was distilled under reduced pressure to remove toluene, thereby obtaining N- (4-acetoxyphenyl) acetamide. Then 6.0g of 1, 4-dioxane was added to the above product, and after sufficient dissolution, the reaction vessel was irradiated with ultraviolet-visible light, preferably ultraviolet light having a wavelength of 254nm, and stirred for 24 hours, the solvent was evaporated by heating and then recrystallized, filtered and dried to obtain 1.20g of needle-like white crystals of 2-acetyl-4-acetaminophenol in 62.1% yield.
And step two, adding 2.0g of sodium hydroxide solution with the mass concentration of 20% into 0.96g of the product 2-acetyl-4-n-butylamidophenol obtained in the step one to obtain phenolate, adding 0.92g of epoxy chloropropane to react for 12 hours, pouring the reactant into water to be filtered, then recrystallizing by using 10mL of mixed solvent of toluene/ethanol (the volume ratio is 10:1), filtering and drying to obtain 0.98g of 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone as a diacalol intermediate, wherein the yield is 78.4%.
Example 4
Step one, adding 2.10g of acetic anhydride, 1.09g of p-aminophenol and 3.40g of toluene into a reaction bottle, and heating, refluxing and dehydrating. Refluxing was carried out for about 15 hours, and the toluene was recovered by atmospheric distillation. After about 80% of the toluene amount was recovered, the reaction mixture was distilled under reduced pressure to remove toluene, thereby obtaining N- (4-acetoxyphenyl) acetamide. Then 9.0g of 1, 4-dioxane was added to the above product, and after sufficient dissolution, the reaction vessel was irradiated with ultraviolet-visible light, preferably ultraviolet light having a wavelength of 254nm, and stirred for 36 hours, the solvent was evaporated by heating and then recrystallized, and filtered and dried to obtain 1.05g of needle-like white crystals of 2-acetyl-4-acetaminophenol in a yield of 54.4%.
And step two, adding 2.0g of sodium hydroxide solution with the mass concentration of 20% into 0.96g of the product 2-acetyl-4-n-butylamidophenol obtained in the step one to obtain phenolate, adding 0.69g of epoxy chloropropane to react for 10 hours, pouring the reactant into water to be filtered, then recrystallizing by using 10mL of mixed solvent of toluene/ethanol (the volume ratio is 12:1), filtering and drying to obtain 0.95g of 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone as a diacalol intermediate, wherein the yield is 75.2%.
Example 5
Step one, 4.2g of acetic anhydride, 2.2g of p-aminophenol and 8.0g of toluene are put into a reaction bottle, and the temperature is increased, the reflux is carried out and the dehydration is carried out. Refluxing was carried out for about 12 hours, and the toluene was recovered by atmospheric distillation. After about 80% of the toluene amount was recovered, the reaction mixture was distilled under reduced pressure to remove toluene, thereby obtaining N- (4-acetoxyphenyl) acetamide. Then 12.0g of 1, 4-dioxane was added to the above product, and after sufficient dissolution, the reaction vessel was irradiated with ultraviolet-visible light, preferably ultraviolet light having a wavelength of 254nm, and stirred for 24 hours, the solvent was evaporated by heating and then recrystallized, filtered and dried to obtain 2.08g of needle-like white crystals of 2-acetyl-4-acetaminophenol in 53.8% yield.
And step two, adding 5.0g of sodium hydroxide solution with the mass concentration of 20% into 1.93g of the product 2-acetyl-4-n-butylamidophenol obtained in the first step to obtain phenolate, adding 1.90g of epoxy chloropropane to react for 12 hours, pouring the reactant into water to be filtered, then recrystallizing by using 20mL of mixed solvent of toluene/ethanol (the volume ratio is 10:1), filtering and drying to obtain 1.98g of 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone as a diacalol intermediate, wherein the yield is 79.5%.
Example 6
Step one, 4.2g of acetic anhydride, 2.2g of p-aminophenol and 8.0g of toluene are put into a reaction bottle, and the temperature is increased, the reflux is carried out and the dehydration is carried out. Refluxing was carried out for about 12 hours, and the toluene was recovered by atmospheric distillation. After about 80% of the toluene amount was recovered, the reaction mixture was distilled under reduced pressure to remove toluene, thereby obtaining N- (4-acetoxyphenyl) acetamide. Then, 8.0g of tetrahydrofuran was added to the above product, and after sufficient dissolution, the mixture was irradiated with ultraviolet-visible light, preferably ultraviolet light having a wavelength of 254nm, stirred for 24 hours, heated to evaporate the solvent, and then recrystallized, filtered and dried to obtain 2.37g of needle-like white crystals of 2-acetyl-4-acetaminophenol in a yield of 61.2%.
And step two, adding 7.0g of sodium hydroxide solution with the mass concentration of 20% into 1.93g of the product 2-acetyl-4-n-butylamidophenol obtained in the first step to obtain phenolate, adding 2.20g of epoxy chloropropane to react for 12 hours, pouring the reactant into water to be filtered, then recrystallizing by using 20mL of mixed solvent of toluene/ethanol (the volume ratio is 10:1), filtering and drying to obtain 1.92g of 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone as a diacalol intermediate, wherein the yield is 77.1%.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.
Claims (8)
1. A method for preparing a diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone is characterized by comprising the following steps: the method comprises the following steps:
the method comprises the following steps: adding acetic anhydride and p-aminophenol into a reactor, performing reflux reaction by using a water-carrying agent, and distilling at normal pressure to recover the water-carrying agent; cooling the reactant, adding a polar organic solvent as a dispersing agent, performing a photochemical Fries liquid phase rearrangement reaction, irradiating the photoreaction vessel with ultraviolet-visible light with a certain wavelength, and stirring for a certain time to obtain an intermediate 2-acetyl-4-acetaminophenol;
step two: adding a certain amount of sodium hydroxide solution into a certain amount of the product 2-acetyl-4-n-butylamidophenol obtained in the first step to prepare phenolate, adding epoxy chloropropane to perform ring-opening coupling reaction, pouring the reactant into water, filtering, recrystallizing with a mixed solvent, filtering, and drying to obtain the diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone.
2. The process of diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone according to claim 1, characterized in that: the molar ratio of the acetic anhydride to the p-aminophenol is 1: 2-1: 4.
3. The process of diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone according to claim 2, characterized in that: the molar ratio of the acetic anhydride to the p-aminophenol is 1: 2.2.
4. The process of diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone according to claim 1, characterized in that: the water-carrying agent is toluene.
5. The process of diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone according to claim 1, characterized in that: the photochemical Fries liquid phase rearrangement reaction temperature is 25 ℃, and the adopted laser wavelength range is 200-350 nm.
6. The process of diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone according to claim 1, characterized in that: the weight ratio of the organic solvent to the p-aminophenol is 5: 1-12: 1.
7. the process of diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone according to claim 1, characterized in that: the added polar organic solvent is tetrahydrofuran, pyridine or 1, 4-dioxane.
8. The process of diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone according to claim 1, characterized in that: the mixed solvent is a mixture of toluene and ethanol, and the volume ratio of the mixed solvent is 5: 1-15: 1.
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