CN115806525B - Method for synthesizing alpha-triarylamine - Google Patents
Method for synthesizing alpha-triarylamine Download PDFInfo
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- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 30
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- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000003054 catalyst Substances 0.000 claims abstract description 37
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 claims abstract description 35
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
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- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- 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
- Y02P20/584—Recycling of catalysts
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Abstract
A method of synthesizing an α -triarylamine comprising: in the presence of a catalyst VO (OR) 3 Mixing a compound shown in a formula I with a compound shown in a formula II in the presence of the catalyst, and reacting to obtain a compound shown in a formula III; the reaction formula is as follows:
. The method takes the formula I and the formula II as raw materials, synthesizes the alpha-triarylamine such as clotrimazole, the flumetsulam and the like in one step, has simple steps, simple operation and short reaction time, does not generate inorganic waste, does not need waste treatment, does not have waste treatment cost, and is more suitable for industrialized preparation of the alpha-triarylamine.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a method for synthesizing alpha-triarylamine.
Background
In the prior art, the synthesis of alpha-triarylamines such as clotrimazole, flumetsulam and the like has the problems of more synthesis steps, more byproducts, large amount of waste, high cost, low yield and the like.
For example, for clotrimazole, clotrimazole (CAS: 23593-75-1) is a widely used broad-spectrum antifungal drug. By inhibiting the synthesis of fungal ergosterol, clotrimazole has good antibacterial effect on various fungi, especially candida albicans, and can be used for treating tinea pedis, vaginal candidiasis, oropharyngeal candidiasis and the like. In addition to antifungal effects, clotrimazole also has shown potential in the study of sickle cell disease, malaria, and some cancers (doi: 10.1111/jam.12554; doi: 10.4172/2161-0444.1000219).
The traditional chemical synthesis method of clotrimazole is a multi-step process, and two routes are more commonly used at present. Route one: o-chlorotoluene is taken as a raw material, and is subjected to chlorination Reaction to obtain O-chlorotoluene, the O-chlorotoluene and anhydrous benzene are subjected to Friedel-Crafts Reaction (Fu Lie Deltaz Reaction) to generate chloro (o-chlorophenyl) diphenylmethane, and the chloro (o-chlorophenyl) diphenylmethane is condensed with imidazole to obtain clotrimazole. The method has the advantages of multiple steps, complex operation, high cost and low yield, and needs to use highly toxic substance benzene, so that a large amount of three wastes are generated in the production process. Route two: o-chlorobenzoic acid is used as a raw material, and clotrimazole is obtained through the reactions such as esterification reaction, format reaction, hydrolysis reaction, chlorination reaction, condensation reaction and the like. The route also has the problems of complicated steps, large amount of waste, high cost and the like.
The existing synthetic route of clotrimazole has the defects of low production efficiency, complicated process steps, complex operation, involving toxic reagents, large amount of inorganic wastes, high production cost and the like. At present, no report on a synthetic method of clotrimazole with simple route, simple operation, safety, environmental protection, high yield and low cost is available.
As another example, for Fluotramazole, fluotramazole (CAS: 119006-77-8) is a topical imidazole antifungal agent with broad-spectrum antimicrobial activity for the treatment of tinea pedis, tinea corporis, tinea cruris, candidiasis, tinea versicolor, etc. caused by sensitive pathogenic fungi such as Trichophyton, epidermophyton, candida and Rhodotorula. The action mechanism of the flumazenil is to inhibit the biosynthesis of ergosterol on fungal cell membranes by inhibiting the activity of fungal cytochrome P-450, damage the fungal cell membranes and change the permeability of the fungal cell membranes, thereby inhibiting the growth of fungi. Fluotramadol was first developed and marketed in Spanish in 1995 in the form of creams, gels and solutions, and then marketed in Chilean, peruvian, argentina, korea, mexico, greece and Italy, respectively. The flutramadol has definite curative effect, small side effect, good tolerance, and rare local irritation and allergy, and is a safe and effective medicament.
The existing route for synthesizing the fluorotramadol is to convert (2-fluorophenyl) (4-fluorophenyl) phenylmethanol to obtain an intermediate product, and then further react with imidazole to obtain the fluorotramadol. The process has the defects of large amount of inorganic waste, related toxic reagents, high production cost and the like. At present, no report on a method for synthesizing the fluorotramadol, which is concise in route, is obtained by directly reacting (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol, is safe and environment-friendly, and has high yield and low cost.
Therefore, the problems of low conversion rate, more byproducts, higher three wastes, higher synthesis cost and the like exist in the prior art about the synthesis method of synthesizing the alpha-triarylamine compounds such as clotrimazole, fluorotramadol and the like, and the problems need to be solved.
Disclosure of Invention
According to a first aspect, in one embodiment, there is provided a method of synthesizing a compound of formula III, comprising: in the presence of a catalyst VO (OR) 3 Mixing a compound shown in a formula I with a compound shown in a formula II in the presence of the catalyst, and reacting to obtain a compound shown in a formula III; the reaction formula is as follows:
in formula I, III, ar 1 、Ar 2 、Ar 3 Independently selected from any one of the following groups, unsubstituted or at least one hydrogen is substituted: aryl, aromatic heterocyclic groups; ar (Ar) 1 、Ar 2 、Ar 3 Has no conjugated relation with each other, or Ar 1 、Ar 2 、Ar 3 Has conjugation relation between at least two groups;
in the formula II, III, R 1 、R 2 Any one selected from the following groups: 1) Hydrogen; 2) An alkyl group; 3) Any one of the following groups, unsubstituted or substituted with at least one hydrogen: aryl, aromatic heterocyclic groups;
the catalyst VO (OR) 3 The structural formula is as follows:
wherein R is selected from alkyl or silane.
According to a second aspect, in one embodiment, a compound VO (OR) is provided 3 The application of the catalyst in synthesizing the compound shown in the formula III;
compound VO (OR) 3 The structural formula is as follows:
r is selected from alkyl or silane;
the structural formula of the compound shown in the formula III is as follows:
in formula III, ar 1 、Ar 2 、Ar 3 Independently selected from any one of the following groups, unsubstituted or at least one hydrogen is substituted: aryl, aromatic heterocyclic groups; ar (Ar) 1 、Ar 2 、Ar 3 Has no conjugated relation with each other, or Ar 1 、Ar 2 、Ar 3 Has conjugation relation between at least two groups;
in formula III, R 1 、R 2 Any one selected from hydrogen, alkyl, unsubstituted or at least one hydrogen substituted: aryl and aromatic heterocyclic groups.
According to the method for synthesizing the alpha-triarylamine, provided by the invention, the synthetic method is simpler in route, simpler in operation, safer and more environment-friendly, and the method is high in yield and low in cost.
In one embodiment, the method takes the formula I and the formula II as raw materials, synthesizes the alpha-triarylamine such as clotrimazole, the flumazenil and the like in one step, has simple steps, simple operation, short reaction time, no inorganic waste generation, no waste treatment cost and suitability for industrialized preparation.
Drawings
FIG. 1 is a schematic diagram of a Dean-Stark apparatus configuration of one embodiment;
FIG. 2 is a single crystal X-ray diffraction pattern of compound 1 of example 13;
FIG. 3 is a single crystal X-ray diffraction pattern of compound 3 of example 13;
FIG. 4 is a single crystal X-ray diffraction pattern of compound 10 of example 13;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the clotrimazole product obtained in example 1;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of the clotrimazole product obtained in example 1;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the fluorotramadol product obtained in example 6;
FIG. 8 is a nuclear magnetic resonance fluorine spectrum of the fluorotramadol product obtained in example 6;
FIG. 9 is a nuclear magnetic resonance carbon spectrum of the fluorotramadol product obtained in example 6.
Detailed Description
The invention will be described in further detail below with reference to the drawings by means of specific embodiments. Wherein like elements in different embodiments are numbered alike in association. In the following embodiments, numerous specific details are set forth in order to provide a better understanding of the present application. However, one skilled in the art will readily recognize that some of the features may be omitted, or replaced by other elements, materials, or methods in different situations. In some instances, some operations associated with the present application have not been shown or described in the specification to avoid obscuring the core portions of the present application, and may not be necessary for a person skilled in the art to describe in detail the relevant operations based on the description herein and the general knowledge of one skilled in the art.
Furthermore, the described features, operations, or characteristics of the description may be combined in any suitable manner in various embodiments. Also, various steps or acts in the method descriptions may be interchanged or modified in a manner apparent to those of ordinary skill in the art. Thus, the various orders in the description and drawings are for clarity of description of only certain embodiments, and are not meant to be required orders unless otherwise indicated.
The numbering of the components itself, e.g. "first", "second", etc., is used herein merely to distinguish between the described objects and does not have any sequential or technical meaning.
As used herein, an "aromatic heterocycle" is a heterocycle having a planar structure in which the atoms in the ring form a conjugated system with a ring closure, the molecule being planar, and the plane having a cyclic delocalized electron cloud on both its upper and lower sides, the number of P electrons in the conjugated system conforming to the scholler rule. Including but not limited to pyridine, furan, thiazole, pyrimidine rings, and the like.
According to a first aspect, in one embodiment, there is provided a method of synthesizing a compound of formula III, comprising: in the presence of a catalyst VO (OR) 3 Mixing a compound shown in a formula I with a compound shown in a formula II in the presence of the catalyst, and reacting to obtain a compound shown in a formula III; the reaction formula is as follows:
in formula I, III, ar 1 、Ar 2 、Ar 3 Independently selected from any one of the following groups, unsubstituted or at least one hydrogen is substituted: aryl, aromatic heterocyclic groups; ar (Ar) 1 、Ar 2 、Ar 3 Has no conjugated relation with each other, or Ar 1 、Ar 2 、Ar 3 Has conjugation relation between at least two groups;
in the formula II, III, R 1 、R 2 Any one selected from the following groups: 1) Hydrogen; 2) An alkyl group; 3) Any one of the following groups, unsubstituted or substituted with at least one hydrogen: aryl, aromatic heterocyclic groups;
catalyst VO (OR) 3 The structural formula is as follows:
wherein R is selected from alkyl or silane.
In one embodiment, catalyst VO (OR) 3 The R group in (2) is selected from isopropyl, ethyl, propyl, 2-methylpropyl, methoxyethyl or silane.
In one embodiment, the catalyst includes, but is not limited to, at least one of triisopropoxyvanadium oxide (CAS number 5588-84-1, also known as triisopropoxyvanadium), triethoxyvanadium oxide (CAS number 1686-22-2, also known as triethoxyvanadium oxide), and the like.
In one embodiment, the molar ratio of the compound of formula I to the compound of formula II is (0.1-10): 1, preferably (0.2 to 10): 1.
In one embodiment, the catalyst is used in an amount of 0.0001 molar equivalents or more, preferably 0.01 to 0.2 molar equivalents, based on the molar amount of the compound of formula II.
In one embodiment, the reaction time is not less than 1min, preferably 4 to 20h.
In one embodiment, the temperature of the reaction system is 20 to 200 ℃, preferably 110 to 180 ℃, preferably 110 to 170 ℃, more preferably 140 to 150 ℃, and also 160 to 170 ℃.
In one embodiment, the reaction system further comprises a solvent.
In one embodiment, the solvent includes, but is not limited to, at least one of acetonitrile, 1,2-DCE, 1,2-DCE, toluene, and the like.
In one embodiment, the reaction is carried out at atmospheric pressure (one atmosphere, about 100 KPa).
In one embodiment, the reaction system is heated to boiling.
In one embodiment, the reaction is carried out under conditions where product water is continuously removed.
In one embodiment, the reaction may be performed in a Dean-Stark apparatus.
In one embodiment, water is removed using a water-absorbing agent.
In one embodiment, the water-absorbing agent includes, but is not limited to, at least one of a 4 a molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, calcium sulfate, activated alumina, and the like.
In one embodiment, the method further comprises purifying the reaction product to obtain a purified product.
In one embodiment, the purification treatment includes, but is not limited to, concentration under reduced pressure and/or column chromatography.
In one embodiment, the compound of formula III includes, but is not limited to, at least one of the following structural formulas:
in one embodiment, compound III is clotrimazole, having the following formula:
in one embodiment, the catalyst used to synthesize clotrimazole is vanadyl triisopropoxide.
In one embodiment, compound III is flutramadol, having the following formula:
according to a second aspect, in one embodiment, a compound VO (OR) is provided 3 The application of the catalyst in synthesizing the compound shown in the formula III; compound VO (OR) 3 The structural formula is as follows:
r is selected from alkyl or silane;
the structural formula of the compound shown in the formula III is as follows:
in formula III, ar 1 、Ar 2 、Ar 3 Independently selected from any one of the following groups, unsubstituted or at least one hydrogen is substituted: aryl, aromatic heterocyclic groups; ar (Ar) 1 、Ar 2 、Ar 3 Has no conjugated relation with each other, or Ar 1 、Ar 2 、Ar 3 Has conjugation relation between at least two groups;
in formula III, R 1 、R 2 Any one selected from hydrogen, alkyl, unsubstituted or at least one hydrogen substituted: aryl and aromatic heterocyclic groups.
In one embodiment, a method of synthesizing clotrimazole is provided, comprising: mixing (2-chlorophenyl) diphenyl methanol with imidazole, and reacting to obtain clotrimazole. The existing method for synthesizing clotrimazole mainly comprises a multi-step process, and has the defects of complicated steps, complex operation, involving toxic reagents, producing a large amount of inorganic wastes, high production cost and the like. In one embodiment, the invention provides a clotrimazole synthesizing method which has the advantages of simpler route, simpler operation, safer and more environment-friendly process, high yield and low cost. The method takes (2-chlorophenyl) diphenyl methanol and imidazole as raw materials, synthesizes clotrimazole in one step, has simple steps, simple operation, short reaction time, no inorganic waste generation, no waste treatment cost and suitability for industrialized preparation.
In one embodiment, the molar ratio of (2-chlorophenyl) diphenylmethanol to imidazole is (0.2-10): 1.
In one embodiment, the reaction system further comprises a catalyst.
In one embodiment, the catalyst includes, but is not limited to, at least one of vanadyl triisopropoxide (CAS number 5588-84-1, also known as triisopropoxyvanadium oxide), vanadium triethoxide (1686-22-2), and the like.
In one embodiment, the catalyst is used in an amount of 0.0001 molar equivalents or more, preferably 0.01 to 0.2 molar equivalents, based on the molar amount of the compound of formula II.
In one embodiment, the reaction time is not less than 1min, preferably 4 to 20h.
In one embodiment, the reaction system further comprises a solvent.
In one embodiment, the solvent includes, but is not limited to, acetonitrile.
In one embodiment, the reaction is carried out at atmospheric pressure (one atmosphere, about 100 KPa).
In one embodiment, the reaction is carried out under heating.
In one embodiment, the temperature of the reaction system is maintained at 110 to 170 ℃, preferably 140 to 150 ℃.
In one embodiment, the reaction system is heated to boiling.
In one embodiment, water absorbing agents are used to absorb water.
In one embodiment, the water-absorbing agent includes, but is not limited to, at least one of a 4 a molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, calcium sulfate, activated alumina, and the like.
In one embodiment, the method further comprises purifying the reaction product to obtain a purified product.
In one embodiment, the purification treatment comprises concentration under reduced pressure and/or column chromatography.
The existing method for synthesizing the flumazenil mainly has the defects of complicated process steps, complex operation, involving toxic reagents, producing a large amount of inorganic wastes, high production cost and the like. In one embodiment, the invention provides a method for synthesizing the fluorotramadol, which has the advantages of simpler route, simpler operation, safer operation, more environmental protection, high yield and low cost. The method takes (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and imidazole as raw materials, synthesizes the fluorotramadol in one step under the catalysis condition, has simple steps, simple operation and short reaction time, has no inorganic waste generation and waste treatment cost, and is more suitable for industrialized preparation.
In one embodiment, a method of synthesizing fluorotramadol is provided comprising: the method is characterized in that (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and imidazole are used as raw materials, acetonitrile is used as a solvent, and the fluorotramadol is synthesized in one step in the presence of a catalyst.
In one embodiment, the molar ratio of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol to imidazole is (1-10): 1.
in one embodiment, the catalyst is used in an amount of 0.001 molar equivalents or more, preferably 0.01 to 0.2 molar equivalents, based on the molar amount of imidazole (i.e., based on the molar amount of substrate used in the reaction).
In one embodiment, the catalyst has the general formula VO (OR) 3 。
In one embodiment, the catalyst includes, but is not limited to, at least one of triisopropoxyvanadium oxide (CAS: 5588-84-1), triethoxyvanadium oxide (1686-22-2), and the like.
In one embodiment, the reaction conditions are heated and stirred at a temperature in the range of 80 to 170 ℃, preferably 160 to 170 ℃.
In one embodiment, the reaction time is ≡1min, preferably 20h.
In one embodiment, the solvent used in the reaction includes, but is not limited to, at least one of acetonitrile, 1,2-DCE, 1,2-DCE, toluene, and the like.
In one embodiment, the reaction for synthesizing the fluorotramadol is as follows:
in one embodiment, (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and imidazole are used as raw materials, the fluorotramadol is directly synthesized in one step, the raw materials are stable and easy to obtain, the synthesis route is simple, the reaction operation is simple, the requirements on production equipment are low, the cost is low, and the yield is high, so that the method is more suitable for industrial production.
In one embodiment, the process only generates water as a byproduct, no inorganic waste is generated, the method is environment-friendly, the waste treatment cost is greatly reduced, and the method is more beneficial to industrial scale-up and mass production.
In the examples below, the yield of each product (also referred to as yield) refers to the percentage of the actual mass yield to the theoretical mass yield of the yield.
Example 1
The embodiment provides a method for synthesizing clotrimazole, the reaction formula is as follows:
the synthesis steps are as follows:
step one: into a dry 15 mL thick-walled pressure-resistant bottle were added 0.2mmol (2-chlorophenyl) of diphenylmethanol (purchased from Shanghai Kai as chemical technology Co., ltd., hereinafter the same) and 0.2mmol of imidazole (purchased from Shanghai Bi as medical technology Co., ltd., hereinafter the same) and a magnetic stirrer.
Step two: 4. 4 mL anhydrous acetonitrile (purchased from Analyst Ji, the same applies below) was added, followed by 0.02 mmol of triisopropoxyvanadium oxide. Acetonitrile served as a solvent for the entire reaction.
Step three: sealing, heating at 140 deg.C, and stopping heating after 20 hr.
Step four: the reaction solution was concentrated under reduced pressure and subjected to column chromatography, whereby the yield was 33%.
Fig. 5 is a nmr spectrum of the clotrimazole product obtained in this example, and fig. 6 is a nmr spectrum of the clotrimazole product obtained in this example, respectively.
Example 2
The embodiment provides a method for synthesizing clotrimazole, which comprises the following steps:
step one: into a dry 15 mL thick-walled pressure-resistant bottle were added 0.6 mmol of (2-chlorophenyl) diphenylmethanol and 0.2mmol of imidazole and a magnetic stirrer.
Step two: 4. 4 mL anhydrous acetonitrile was added, followed by 0.02 mmol of triisopropoxyvanadium oxide.
Step three: sealing, heating at 140 deg.C, and stopping heating after 20 hr.
Step four: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 54%.
Example 3
The embodiment provides a method for synthesizing clotrimazole, which comprises the following steps:
step one: into a dry 15 mL thick-walled pressure-resistant bottle were added 2mmol (2-chlorophenyl) diphenylmethanol and 0.2mmol imidazole and a magnetic stirrer.
Step two: 4. 4 mL anhydrous acetonitrile was added, followed by 0.02 mmol of triisopropoxyvanadium oxide.
Step three: sealing, heating at 140 deg.C, and stopping heating after 20 hr.
Step four: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 80%.
It can be seen that increasing the proportion of (2-chlorophenyl) diphenylmethanol increases the yield without using a Dean-Stark apparatus.
Example 4
The embodiment provides a method for synthesizing clotrimazole, which comprises the following steps:
step one: to a dry 25 mL thick-walled mill tube was added 0.6 mmol (2-chlorophenyl) diphenylmethanol and 0.2mmol imidazole and a magnetic stirrer.
Step two: an acetonitrile solution (11 mL) containing 0.02 mmol of vanadium triisopropoxide was added.
Step three: 500 mg of the 4A molecular sieve was added to the Dean-Stark apparatus.
Step four: the device shown in fig. 1 is arranged, vacuum silicone grease is smeared at each interface, and flowing water is introduced.
Step five: heating to reflux (140 ℃ C.) and after 4h of reaction, stopping heating.
Step six: the reaction solution was concentrated under reduced pressure and subjected to column chromatography, whereby the yield was 75%. Yield refers to the percentage of the actual mass yield of clotrimazole to the theoretical mass yield.
It can be seen that the use of the Dean-Stark apparatus can increase the yield.
Example 5
The embodiment provides a method for synthesizing clotrimazole, which comprises the following steps:
step one: to a dry 25 mL thick-walled mill tube was added 0.6 mmol (2-chlorophenyl) diphenylmethanol and 0.2mmol imidazole and a magnetic stirrer.
Step two: an acetonitrile solution (11 mL) containing 0.02 mmol of vanadium triisopropoxide was added.
Step three: 2g of anhydrous alumina was added to a Dean-Stark apparatus.
Step four: the device shown in fig. 1 is arranged, vacuum silicone grease is smeared at each interface, and flowing water is introduced.
Step five: heating to reflux (140 ℃ C.) and after 4h of reaction, stopping heating.
Step six: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 76%.
Example 6
The embodiment provides a method for synthesizing fluorotramadol, the reaction formula is as follows:
the synthesis steps are as follows:
step one: to a dry 48. 48 mL thick-walled pressure-resistant bottle were added 15 mmol of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol (purchased from Kai chemical, the same applies below) and 5 mmol of imidazole and a magnetic stirrer.
Step two: an acetonitrile solution (20 mL) containing 0.005 mmol of vanadium triisopropoxide was added.
Step three: sealing, heating at 140 deg.C, and stopping heating after 20 hr.
Step four: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 11%.
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in this example, FIG. 8 is a nuclear magnetic resonance fluorine spectrum of the product obtained in this example, and FIG. 9 is a nuclear magnetic resonance carbon spectrum of the product obtained in this example.
Example 7
With reference to example 6, the heating times were varied, in particular 92h, by the following steps:
step one: to a dry 48 mL thick-walled pressure-resistant bottle were added 15 mmol of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and 5 mmol of imidazole, and a magnetic stirrer.
Step two: a solution of 0.005 mmol of vanadium triisopropoxide in acetonitrile (20 mL) was added.
Step three: sealing, heating at 140 deg.C, and stopping heating after 92 hr.
Step four: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 40%.
It can be seen that increasing the reaction time can increase the yield without using a Dean Stark trap.
Example 8
With reference to example 6, the amount of triisopropoxylated vanadium oxide varies, in particular 0.05 mmol, as follows:
step one: to a dry 48 mL thick-walled pressure-resistant bottle were added 15 mmol of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and 5 mmol of imidazole, and a magnetic stirrer.
Step two: 20. 20 mL anhydrous acetonitrile was added, followed by 0.05 mmol of triisopropoxyvanadium oxide.
Step three: sealing, heating at 140 deg.C, and stopping heating after 20 hr.
Step four: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 40%.
It can be seen that without the use of a Dean Stark trap, increased catalyst usage can increase productivity.
Example 9
The procedure was carried out with reference to example 6, using a different apparatus, in particular a Dean Stark trap, with the following specific steps:
step one: to a dry 25 mL thick-walled mill tube was added 0.6 mmol of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and 0.2mmol of imidazole and a magnetic stirrer.
Step two: an acetonitrile solution (15 mL) containing 0.02 mmol of vanadium triisopropoxide was added.
Step three: a Dean Stark trap was placed and connected to running water and heated at 150℃for 20 hours.
Step four: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 62%.
It can be seen that the use of the Dean Stark trap can significantly improve yield.
Example 10
The procedure was carried out with reference to example 6, using a different apparatus, in particular a Dean Stark trap, with the following specific steps:
step one: 15 mmol of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and 5 mmol of imidazole were added to a dry 25 mL thick-walled milling tube with a magnetic stirrer.
Step two: an acetonitrile solution (12 mL) containing 0.5 mmol of vanadium triisopropoxide was added.
Step three: a Dean Stark trap was placed and connected to running water and heated at 170℃for 15 hours.
Step four: the reaction solution was concentrated under reduced pressure and subjected to column chromatography, whereby the yield was 72%.
Example 11
The procedure was carried out with reference to example 6, using a different apparatus, in particular a Dean Stark trap, with the following specific steps:
step one: 15 mmol of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and 5 mmol of imidazole were added to a dry 25 mL thick-walled milling tube with a magnetic stirrer.
Step two: an acetonitrile solution (12 mL) containing 0.5 mmol of vanadium triisopropoxide was added.
Step three: a Dean Stark trap was placed and connected to running water and heated at 170℃for 20 hours.
Step four: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 88%.
Comparative example 1
Reference example 6 was made, but without the use of a catalyst, as follows:
step one: 15 mmol of (2-fluorophenyl) (4-fluorophenyl) benzyl alcohol and 5 mmol of imidazole were placed in a dry 48, mL thick-walled pressure-resistant flask, and a magnetic stirrer was placed therein.
Step two: 20 mL anhydrous acetonitrile was added.
Step three: sealing, heating at 140 deg.C, and stopping heating after 20 hr.
Step four: the yield was 0%.
It can be seen that without using a catalyst, the substrate did not react and no product could be obtained.
Example 12
The embodiment provides a method for synthesizing clotrimazole by using a catalyst of triethoxy vanadium oxide, which comprises the following steps:
step one: to a dry 25 mL thick-walled mill tube was added 0.6 mmol (2-chlorophenyl) diphenylmethanol and 0.2mmol imidazole and a magnetic stirrer.
Step two: an acetonitrile solution (15 mL) containing 0.02 mmol of vanadium triethoxide was added.
Step three: 500 mg of the 4A molecular sieve was added to the Dean-Stark apparatus.
Step four: the device shown in fig. 1 is arranged, vacuum silicone grease is smeared at each interface, and flowing water is introduced.
Step five: heating to reflux (140 ℃ C.) and after 20h of reaction, stopping heating.
Step six: the reaction solution was concentrated under reduced pressure and separated by column chromatography, with a yield of 63%.
Example 13
The reaction formula and the products and yields of this example are as follows:
wherein,, i pr means isopropyl, VO (O) i Pr) 3 Is triisopropoxyvanadium oxide, reflux is heated under reflux, and "10 mol%" is catalyst VO (O) i Pr) 3 The molar amount of (2) is 10% of the molar amount of the compound of formula II.
The percentage after each compound number is the yield of the corresponding compound.
The specific synthesis method is as follows:
step one: to a dry 25 mL thick wall mill tube was added 0.6 mmol of the corresponding triarylmethanol and 0.2mmol of the corresponding amine, and a magnetic stirrer.
Step two: an acetonitrile solution containing 0.02 mmol of vanadyl triisopropoxide (15 mL) was added.
Step three: a Dean Stark water diversion device is arranged, flowing water is connected in, and heating is carried out for 4 hours at 120-130 ℃.
Step four: concentrating the reaction solution under reduced pressure, and separating by column chromatography to obtain the product.
It can be seen that a variety of α -triarylamines can be synthesized based on vanadyl triisopropoxide catalysts.
In one embodiment, the clotrimazole and the flumetrazole synthesized by the invention can be used as antifungal agents and have broad-spectrum antibacterial activity.
In one embodiment, the present invention provides a catalyst-based VO (OR) 3 The method for synthesizing the alpha-triarylamine has the advantages that only water exists in byproducts, no inorganic waste is generated, waste treatment is not needed, waste treatment cost is not needed, and the method is more suitable for industrial preparation.
The foregoing description of the invention has been presented for purposes of illustration and description, and is not intended to be limiting. Several simple deductions, modifications or substitutions may also be made by a person skilled in the art to which the invention pertains, based on the idea of the invention.
Claims (9)
1. A method of synthesizing a compound of formula III comprising: in the presence of a catalyst VO (OR) 3 Mixing a compound shown in a formula I with a compound shown in a formula II in the presence of the catalyst, and reacting to obtain a compound shown in a formula III; the reaction formula is as follows:
the compound shown in the formula III is at least one of the following structural formulas:
the catalyst VO (OR) 3 The structural formula is as follows:
；
r is selected from isopropyl or ethyl.
2. The method of claim 1, wherein the molar ratio of the compound of formula I to the compound of formula II is (0.1 to 10): 1.
3. the process according to claim 1, wherein the catalyst is used in an amount of not less than 0.0001 molar equivalent based on the molar amount of the compound of formula II;
the reaction time is more than or equal to 1min;
the temperature of the reaction system is 20-200 ℃;
the reaction system also contains a solvent;
the solvent comprises at least one of acetonitrile, 1,2-DCE, 1,2-DCE and toluene;
the reaction is carried out at normal pressure.
4. The method of claim 1, wherein heating is to boiling the reaction system;
the reaction is carried out under the condition that the product water in the reaction system is continuously removed.
5. The method according to claim 1, wherein water produced in the reaction system is removed using a water absorbing agent;
the water absorbent comprises at least one of 4A molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, calcium sulfate and active alumina.
6. The method of claim 1, further comprising purifying the reaction product to obtain a purified product;
the purification treatment comprises reduced pressure concentration and/or column chromatography.
7. A method of synthesizing clotrimazole, comprising: in the presence of a catalyst VO (OR) 3 In the presence ofMixing a compound shown in a formula I with a compound shown in a formula II, and reacting to obtain a compound shown in a formula III, wherein the compound III is clotrimazole, and the reaction formula is as follows:
the catalyst VO (OR) 3 The structural formula is as follows:
；
r is selected from isopropyl or ethyl.
8. A method of synthesizing fluorotramadol comprising: in the presence of a catalyst VO (OR) 3 In the presence of a compound shown in a formula I and a compound shown in a formula II, and reacting to obtain a compound shown in a formula III, wherein the compound III is the fluorotramadol, and the reaction formula is as follows:
the catalyst VO (OR) 3 The structural formula is as follows:
；
r is selected from isopropyl or ethyl.
9. Compound VO (OR) 3 The use as catalyst in the synthesis of compounds of formula III, characterized in that,
compound VO (OR) 3 The structural formula is as follows:
r is selected from isopropyl or ethyl;
the reaction formula of the compound shown in the formula III is as follows:
the compound shown in the formula III is at least one of the following structural formulas:
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