CN115850275A - Method for synthesizing zolpidem by utilizing photocatalytic three-component reaction - Google Patents

Method for synthesizing zolpidem by utilizing photocatalytic three-component reaction Download PDF

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CN115850275A
CN115850275A CN202310035013.1A CN202310035013A CN115850275A CN 115850275 A CN115850275 A CN 115850275A CN 202310035013 A CN202310035013 A CN 202310035013A CN 115850275 A CN115850275 A CN 115850275A
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zolpidem
same
reaction
aminopyridine
methyl
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黄雨聪
张�杰
张玉凤
王天骏
江婧瑗
王萧城
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Jiangsu Agri Animal Husbandry Vocational College
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Abstract

The invention discloses a method for synthesizing zolpidem by utilizing a photocatalytic three-component reaction, which takes 5-methyl-2-aminopyridine, 4-methylbenzaldehyde, 3-bromo-N, N-dimethyl-2-propynamide as raw materials and Lewis acid as an additive to react under the action of photocatalysis and under an alkaline condition. Compared with the prior art, the method adopts the strategy of insertion tandem cyclization reaction of free radicals to imine under the synergistic action of Lewis acid and photocatalysis. The method has the advantages of short synthetic route, easily obtained raw materials, no need of pre-synthesis, simple operation, mild conditions, easy implementation and certain industrial application prospect.

Description

Method for synthesizing zolpidem by utilizing photocatalytic three-component reaction
Technical Field
The invention discloses a method for synthesizing zolpidem by utilizing a photocatalytic three-component reaction, belonging to the technical field of medicinal chemistry.
Background
Zolpidem (Zolpidem) was developed by Noneffe, france, and was marketed in France in 1988, and soon received widespread attention from insomnia patients, becoming one of the most popular sedative-hypnotic drugs. In the sale of sedative-hypnotic drugs in domestic hospitals, the leaderboard is always in the leaderboard.
The most mature of the current disclosuresThe synthesis process of zolpidem has long route, seven steps of reaction are required, the total yield is not very high (40%), and a large amount of toxic or highly toxic reagents such as bromine (Br) are required in the process 2 ) Iodomethane (CH) 3 I) And sodium cyanide (NaCN). In addition, 5-methyl-2-aminopyridine and 4-methylbenzaldehyde were reported as raw materials, which were first subjected to dehydration condensation to give aldimine, followed by reaction with CuCl/Cu (OTf) 2 Under the action of a catalytic system, the zolpidem is cyclized with N, N-dimethyl propiolamide in a one-pot reaction mode to generate zolpidem, but the method needs to use a microreactor and operate in a glove box to obtain higher yield, and the yield is obviously reduced when a common reaction bottle is subjected to conventional experimental operation [ Angew.]Thus, it is difficult to realize industrial production. In addition, N-dimethyl-4-oxa-4-p-tolylbutanamide [ j.med.chem.1997,40,3109; org.Prep.proced.int.2011,43,260]Nitroethylene MBH acetate [ org. Lett.2012,14,4580.]And amide group-containing xanthate [ RSC adv.2016,6,63532.]Also reported as starting materials for the synthesis of zolpidem, but the synthetic procedures for these starting materials are complicated. The industrial production is greatly limited.
It is worth mentioning that CN106946876B discloses a method for synthesizing zolpidem by photocatalysis. Compared with the method, the method has the following remarkable advantages: 1) The raw materials are easy to obtain and do not need to be synthesized in advance; 2) The photocatalyst is not limited to metal photocatalysts, but some cheap and easily available non-metal photocatalysts such as Eosin Y are also applicable; 3) The reaction does not need to be carried out in an inert gas atmosphere, and the operation condition is milder; 4) A completely different reaction mechanism is employed: firstly, lewis acid is utilized to activate an imine intermediate generated in situ, and activated imine is subjected to insertion and tandem cyclization through alkynyl free radicals generated by C-Br bond fracture under photocatalysis to synthesize zolpidem. In general, the invention adopts the strategy of the insertion tandem cyclization reaction of free radicals to imine under the synergistic action of Lewis acid and photocatalysis. The raw materials are easy to obtain, the pre-synthesis is not needed, the operation steps are simple, the conditions are mild, the implementation is easy, and the method has a remarkable industrial application prospect.
Disclosure of Invention
The invention aims to solve the technical problems and provides a method for synthesizing zolpidem by using a photocatalytic three-component reaction. The purpose of the invention is realized by the following modes:
a method for synthesizing zolpidem by utilizing a photocatalytic three-component reaction takes 5-methyl-2-aminopyridine, 4-methylbenzaldehyde and 3-bromo-N, N-dimethyl-2-propynamide as raw materials and takes Lewis acid as an additive to react under the action of photocatalysis and under the alkaline condition; the molar ratio of the Lewis acid is 5-20% of that of the 5-methyl-2-aminopyridine, and the molar ratio of the photocatalyst is 1-5% of that of the 5-methyl-2-aminopyridine. The reaction process is as follows:
Figure BDA0004048959040000021
preferably, the above 5-methyl-2-aminopyridine, 4-methylbenzaldehyde, 3-bromo-N, N-dimethyl-2-propynamide is 1. The reaction temperature is preferably 20 to 50 ℃ and the reaction time is preferably 8 to 12 hours.
Preferably, the Lewis acid used is Zn (OTf) 2 、Cu(OTf) 2 、ZnCl 2 Or Zn (OAc) 2 The molar ratio of the 5-methyl-2-aminopyridine is 5-20 percent; more preferably, the amount of 5-methyl-2-aminopyridine used is 10% by mole.
Preferably, the photocatalyst used is Ru (bpy) 3 Cl 2 ·6H 2 O、fac-Ir(ppy) 3 、Ir(ppy) 2 (dtbbpy)PF 6 、Acr + MesClO 4 - Or Eosin Y, more preferably Eosin Y, in a molar ratio of 1% to 5% of 5-methyl-2-aminopyridine; more preferably, the amount of the 5-methyl-2-aminopyridine used is 2% by mole.
Preferably, the base used is triethylamine, potassium carbonate, potassium phosphate or dipotassium hydrogen phosphate, and the molar ratio of the base to the 5-methyl-2-aminopyridine is 2:1-3:1. Further preferably, the molar ratio of the base to 5-methyl-2-aminopyridine is 2.5.
The light source used for photocatalysis is preferably a 5W blue LED lamp or a 5W white LED. The solvent used for the reaction is preferably dimethyl sulfoxide.
After the reaction is finished, water quenching reaction is adopted, and separation is carried out after extraction and reduced pressure concentration. Preferably, the organic solvent used for extraction is ethyl acetate or dichloromethane. Preferably, the separation is performed by column chromatography or recrystallization.
The method for synthesizing zolpidem specifically comprises the following steps:
under the irradiation of visible light, 5-methyl-2-aminopyridine, 4-methylbenzaldehyde, 3-bromo-N, N-dimethyl-2-propynamide, a photocatalyst, lewis acid and alkali react in dimethyl sulfoxide, after the reaction is finished, water quenching reaction is adopted, and the zolpidem is obtained by extraction, reduced pressure concentration and separation.
The method is based on the synergistic effect of the Lewis acid and the photocatalysis, so that in the method, the Lewis acid, the light, the photocatalyst and the alkali are absent, otherwise, no zolpidem product is generated, or the yield is obviously reduced; in addition, the use of too much or too little of Lewis acid, photocatalyst and alkali is not favorable for the improvement of reaction yield.
Compared with the prior art, the method has the following advantages:
1) In the synthesis process, a method of Lewis acid and photocatalysis synergism is used, and the strategy of insertion tandem cyclization reaction of free radicals to imine is applied to efficient synthesis of zolpidem.
2) The raw materials are easily available and are sold in the market, and pre-synthesis is not needed;
3) The method has the advantages of short synthetic route, simple operation steps, mild conditions, easy implementation and certain industrial application prospect.
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be purely exemplary of the invention and are not intended to limit its scope, as various equivalent modifications of the invention will become apparent to those skilled in the art after reading the present invention and fall within the scope of the appended claims.
Example 1
5-methyl-2-aminopyridine (0.54g, 5 mmol), 4-methylbenzeneFormaldehyde (0.60g, 5mmol), 3-bromo-N, N-dimethyl-2-propynylamide (1.75g, 10mmol) were charged in a 100mL reaction flask, and Ru (bpy) was added 3 Cl 2 ·6H 2 O(37.6mg,0.05mol)，Zn(OTf) 2 (90.9mg, 0.25mol), triethylamine (1.01g, 10mmol) and 30mL of dimethyl sulfoxide as a solvent, stirring the mixture for 8 hours at 20 ℃ under the irradiation of a 5W blue LED lamp, adding water to quench the reaction, extracting the reaction product with dichloromethane (60 mL multiplied by 3) and 50mL of saturated saline solution, drying the reaction product with anhydrous sodium sulfate, concentrating the reaction product under reduced pressure, and performing column chromatography to obtain white solid zolpidem, wherein the yield is 73%, and the structural detection data of the synthesized zolpidem are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.93(s,1H),7.52–7.49(m,3H),7.22(d,J＝7.8Hz,2H),7.03(dd,J＝9.2,1.7Hz,1H),4.03(s,2H),2.92(s,3H),2.88(s,3H),2.36(s,3H),2.30(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)167.9,143.5,142.9,137.3,131.0,129.1,128.1,127.6,121.9,121.8,116.0,113.5,37.3,35.6,29.8,21.0,18.2.
example 2
The remaining steps are the same as in example 1, except that: the photocatalyst is fac-Ir (ppy) 3 The yield was 72%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 3
The remaining steps are the same as in example 1, except that: the photocatalyst is Ir (ppy) 2 (dtbbpy)PF 6 The yield was 72%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 4
The procedure is the same as in example 1, except that: the photocatalyst is Acr + MesClO 4 - The yield was 71%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 5
The procedure is the same as in example 1, except that: the photocatalyst was Eosin Y with a yield of 73%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 6
The procedure is the same as in example 1, except that: the Lewis acid being Cu (OTf) 2 The yield was 72%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 7
The procedure is the same as in example 1, except that: the Lewis acid being ZnCl 2 The yield was 70%. The data of the structure detection of the synthesized zolpidem are basically the same as the data of the example 1.
Example 8
The procedure is the same as in example 1, except that: the Lewis acid being Zn (OAc) 2 The yield was 71%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 9
The procedure is the same as in example 1, except that: the base was potassium carbonate in 75% yield. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 10
The procedure is the same as in example 1, except that: the base was potassium phosphate, in 74% yield. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 11
The procedure is the same as in example 1, except that: the base was dipotassium hydrogen phosphate with a yield of 72%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 12
The procedure is the same as in example 1, except that: the reaction temperature was 30 ℃ and the yield was 73%. The data of the structure detection of the synthesized zolpidem are basically the same as the data of the example 1.
Example 13
The procedure is the same as in example 1, except that: the reaction temperature was 50 ℃ and the yield was 72%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 14
The procedure is the same as in example 1, except that: the reaction time was 12 hours, and the yield was 73%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 15
The procedure is the same as in example 1, except that: the reaction time was 10 hours, and the yield was 74%. The data of the structure detection of the synthesized zolpidem are basically the same as the data of the example 1.
Example 16
The procedure is the same as in example 1, except that: the amount of 4-methylbenzaldehyde used was 7.5mmol, and the yield was 77%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 17
The procedure was the same as in example 1, except that: zn (OTf) 2 The amount of (B) was 1mmol, and the yield was 75%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 18
The procedure is the same as in example 1, except that: zn (OTf) 2 The amount used was 0.5mmol, yield 78%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 19
The procedure is the same as in example 1, except that: ru (bpy) 3 Cl 2 ·6H 2 The amount of O used was 0.25mmol, and the yield was 75%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 20
The procedure was the same as in example 1, except that: ru (bpy) 3 Cl 2 ·6H 2 The amount of O used was 0.1mmol, and the yield was 77%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 21
The procedure is the same as in example 1, except that: the amount of triethylamine was 15mmol, and the yield was 74%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 22
The procedure is the same as in example 1, except that: the amount of triethylamine was 12.5mmol, and the yield was 76%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 23
The procedure was the same as in example 1, except that: the illuminant used was a 5W white LED with a yield of 72%. The data of the structure detection of the synthesized zolpidem are basically the same as the data of the example 1.
Example 24
The procedure is the same as in example 1, except that: the extractant was ethyl acetate, yield 74%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Example 25
The procedure was the same as in example 1, except that: the isolation was by recrystallization, with a yield of 72%. The data of the structure detection of the synthesized zolpidem are basically the same as the data of the example 1.
Comparative example 1
The procedure is the same as in example 1, except that: no light is used, so that the yield of the product is 0 and no zolpidem product is generated.
Comparative example 2
The procedure was the same as in example 1, except that: no photocatalyst was added, resulting in a product yield of 0 and no zolpidem product.
Comparative example 3
The procedure is the same as in example 1, except that: no Lewis acid is added, and almost no zolpidem product is generated.
Comparative example 4
The procedure is the same as in example 1, except that: no base was added, resulting in almost no zolpidem product.
Comparative example 5
The procedure is the same as in example 1, except that: the reaction was carried out under a nitrogen atmosphere, yield 66%. The data of the structure detection of the synthesized zolpidem are basically the same as the data of the example 1.
Comparative example 6
The procedure was the same as in example 1, except that: zn (OTf) 2 The amount used was 0.15mmol, 43% yield. The data of the structure detection of the synthesized zolpidem are basically the same as the data of the example 1.
Comparative example 7
The procedure is the same as in example 1, except that: zn (OTf) 2 The amount used was 1.5mmol, yield 61%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Comparative example 8
The procedure is the same as in example 1, except that: ru (bpy) 3 Cl 2 ·6H 2 The amount of O used was 0.025mmol, 39% yield. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Comparative example 9
The procedure is the same as in example 1, except that: ru (bpy) 3 Cl 2 ·6H 2 The amount of O used was 0.3mmol, yield 60%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Comparative example 10
The procedure is the same as in example 1, except that: the amount of triethylamine was 5mmol, yield 44%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Comparative example 11
The procedure is the same as in example 1, except that: the amount of triethylamine was 20mmol, yield 62%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.
Comparative example 12
The procedure is the same as in example 1, except that: the solvent used was acetonitrile, yield 43%. The data of the structure test of the synthesized zolpidem are basically the same as in example 1.

Claims (10)

1. A method for synthesizing zolpidem by utilizing a photocatalytic three-component reaction is characterized in that 5-methyl-2-aminopyridine, 4-methylbenzaldehyde and 3-bromo-N, N-dimethyl-2-propynamide are used as raw materials, lewis acid is used as an additive, and the raw materials are reacted under the action of photocatalysis and under the alkaline condition; the molar ratio dosage of the adopted Lewis acid is 5 to 20 percent of that of 5-methyl-2-aminopyridine, and the molar ratio dosage of the photocatalyst is 1 to 5 percent of that of 5-methyl-2-aminopyridine.
2. The method for synthesizing zolpidem, according to claim 1, characterized in that the molar ratio of 5-methyl-2-aminopyridine, 4-methylbenzaldehyde, 3-bromo-N, N-dimethyl-2-propynamide is 1.
3. The process for the synthesis of zolpidem as claimed in claim 1, characterized in that the Lewis acid employed is Zn (OTf) 2 、Cu(OTf) 2 、ZnCl 2 Or Zn (OAc) 2 。
4. The method for synthesizing zolpidem as claimed in claim 1, wherein the photocatalyst used for the photocatalysis is Ru (bpy) 3 Cl 2 ·6H 2 O、fac-Ir(ppy) 3 、Ir(ppy) 2 (dtbbpy)PF 6 、Acr + MesClO 4 - Or Eosin Y.
5. The method for synthesizing zolpidem of claim 1, wherein the light source used for photocatalysis is a 5W blue LED lamp or a 5W white LED lamp.
6. The method for synthesizing zolpidem as claimed in claim 1, wherein the base used is triethylamine, potassium carbonate, potassium phosphate or dipotassium hydrogen phosphate, and the molar ratio of the base to 5-methyl-2-aminopyridine is 2:1-3:1.
7. The process for the synthesis of zolpidem as claimed in claim 1, wherein the solvent used is dimethyl sulfoxide.
8. The process for the synthesis of zolpidem as claimed in claim 1, wherein after the reaction is finished, the reaction is quenched with water, extracted, concentrated under reduced pressure and then separated.
9. The process for the synthesis of zolpidem as claimed in claim 8, wherein the organic solvent used for said extraction is ethyl acetate or dichloromethane; the separation method adopted by the separation is column chromatography or recrystallization.
10. The method for synthesizing zolpidem as claimed in claim 1, comprising the steps of: under the irradiation of light, 5-methyl-2-aminopyridine, 4-methylbenzaldehyde, 3-bromo-N, N-dimethyl-2-propynamide, a photocatalyst, lewis acid and alkali react in dimethyl sulfoxide, after the reaction is finished, water quenching reaction is adopted, and the zolpidem is obtained by extraction, reduced pressure concentration and separation.
CN202310035013.1A 2023-01-10 2023-01-10 Method for synthesizing zolpidem by utilizing photocatalytic three-component reaction Pending CN115850275A (en)

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