CN108239040B - Preparation method of nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride - Google Patents
Preparation method of nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride Download PDFInfo
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a preparation method of 2- (4-methylthiazole-5-yl) ethyl nitrate hydrochloride, which is characterized by comprising the following steps: (1) carrying out nitration reaction on 4-methyl-5- (2-hydroxyethyl) thiazole serving as a starting material to obtain 2- (4-methylthiazol-5-yl) ethyl nitrate; (2) reacting 2- (4-methylthiazol-5-yl) ethyl nitrate with hydrochloric acid in a solvent to prepare a crude product of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride; (3) recrystallizing the crude product of the 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride to obtain a qualified product. The method has the advantages of simple operation, mild reaction conditions, high yield and good product purity, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride.
Background
The compound 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is described in the Journal of Alzheimer' S Disease 2004,6, S75-S84; current Alzheimer Research,2006,3, 237-; neuropsychopharmacology,2007,32, 505-513; pharmacology, Biochemistry and Behavior 2009,91, 495-502; ACS Medicinal Chemistry Letter,2011,2, 656-661; US 20090252704; WO 2014013338. The compound has the code number of GT-1061 in the literature and the molecular formula C6H9ClN2O3S, molecular weight is 224.66, and the structural formula is shown as follows. The literature reports that the nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride has the effect of resisting senile dementia (AD).
GT-1061 document WO2000054756, WO2001049275, WO2005105065, US6310052, Pharmaceutical Chemistry Journal,1999,33, 41-44 reports the synthesis of 2- (4-methylthiazol-5-yl) ethyl nitrate as shown below.
Documents WO2000054756, WO2001049275, WO2005105065 and US6310052 have the condition 1 as the nitration condition, and the yield is low. The literature Pharmaceutical Chemistry Journal,1999,33, 41-44, conditions 2 were adopted as a method for synthesizing 2- (4-methylthiazol-5-yl) ethyl nitrate, and the literature gave no specific experimental details but gave a reaction yield of 82%.
The inventors have verified the literature method, as shown in table 1.
TABLE 1. methods for the synthesis of 2- (4-methylthiazol-5-yl) ethyl nitrate in the validation literature
To summarize:
(1) the actual yield of 2- (4-methylthiazol-5-yl) ethyl nitrate in proof test 1 was 56%, which is higher than 45% of the literature; in the validation experiment 2, the actual yield was 48%.
(2) In the verification test 1, the 4-methyl-5-hydroxyethyl thiazole as the raw material cannot be completely reacted, so that column chromatography purification is required for the reaction, and the yield is low.
(3) In the verification test 2, the 4-methyl-5-hydroxyethyl thiazole serving as the raw material is completely reacted, but the yield is low, and meanwhile, the experimental process involves two temperature control processes of heating and cooling, so that the operation is complicated and the mass production is not facilitated; the raw material urea needs drying treatment, which also increases the production difficulty and cost.
Meanwhile, the document U.S. Pat. No. 2,63, 10052 also reports the nitration of 4-methyl-5-hydroxyethyl thiazole analogues, in which concentrated nitric acid and acetic anhydride are used as nitration reagents, the raw material charge is 0.3g, and the yield is only 32%.
The inventor takes 4-methyl-5-hydroxyethyl thiazole as a raw material to verify the method, takes concentrated nitric acid and acetic anhydride as nitration reagents, adopts the same reaction conditions and post-treatment mode in the literature, and the feeding amount of the raw material 4-methyl-5-hydroxyethyl thiazole is 1.08 g. Test results show that the raw materials are not reacted completely, the product needs column chromatography purification, the operation is complicated, and the yield is only 23 percent. Thus, the process of this patent (US6310052) is not suitable for the preparation of 2- (4-methylthiazol-5-yl) ethyl nitrate.
Although the method shown in table 1 can realize the synthesis of 2- (4-methylthiazol-5-yl) ethyl nitrate, there are significant disadvantages, such as that the 4-methyl-5-hydroxyethylthiazole as the raw material in the verification test 1 cannot react completely, and the product needs column chromatography purification; the reaction operation in the verification test 2 is complicated, and one of the raw materials, namely urea, needs drying pretreatment and the like. The preparation methods reported in the comprehensive literature all have the problems of small preparation amount, complex reaction operation, low yield, poor economy and the like, so that the literature process is not suitable for industrial production of the 2- (4-methylthiazol-5-yl) ethyl nitrate. The preparation of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is not reported in the literature.
Disclosure of Invention
The invention aims to provide a preparation method of nitric acid 2- (4-methylthiazole-5-yl) ethyl ester hydrochloride. The method is suitable for repeated and large-scale industrial preparation, and the produced product can meet the requirement of medicinal quality standard, and has improved operability, yield and environmental compatibility.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the preparation method for preparing 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is characterized by comprising the following steps of:
step (1): 4-methyl-5- (2-hydroxyethyl) thiazole is taken as a starting material to obtain the 2- (4-methylthiazole-5-yl) ethyl nitrate through nitration reaction. The nitration reagent in the reaction is selected from fuming nitric acid and acetic anhydride, the reaction temperature is-10 ℃, the reaction time is 1-5 hours, the reaction solvent is selected from ethyl acetate, acetone, butanone, tetrahydrofuran, acetonitrile, dichloromethane and chloroform, and the reaction solvent comprises the single solvent or a mixed solvent consisting of two or more solvents.
Wherein the preferable reaction temperature is-10 to 5 ℃; further preferably, the reaction temperature is 0-5 ℃;
the preferable reaction time is 1-4 hours; further preferably, the reaction time is 1.5-2.5 hours;
preferably, the reaction solvent is selected from ethyl acetate, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform;
further preferably, the solvent is selected from dichloromethane and chloroform.
Step (2): reacting 2- (4-methylthiazol-5-yl) ethyl nitrate with hydrochloric acid to prepare 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride. The reaction temperature is-10 ℃, the reaction time is 0.5-5 hours, and the hydrochloric acid source is selected from concentrated hydrochloric acid, hydrochloric acid/ethanol solution, hydrochloric acid/ethyl acetate solution and acetyl chloride/ethanol system. The solvent is selected from methanol, ethanol, acetone, toluene, ethyl acetate, N-Dimethylformamide (DMF), tetrahydrofuran, acetonitrile, dichloromethane and chloroform, and can be single solvent or mixed solvent of two or more solvents.
Wherein the preferable reaction temperature is 0-5 ℃;
the preferable reaction time is 0.5-2 hours;
preferably the hydrochloric acid source is selected from hydrochloric acid/ethyl acetate solution, acetyl chloride/ethanol system;
preferably, the solvent used is selected from ethyl acetate, dichloromethane, chloroform.
And (3): recrystallizing 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride in a solvent to obtain a pure product. The recrystallization temperature is 0-30 ℃, and the used solvent is selected from ethyl acetate, acetone, butanone, tetrahydrofuran, acetonitrile, absolute ethyl alcohol, absolute methyl alcohol, isopropanol, methyl tert-butyl ether and the like, and comprises the single solvent or a mixed solvent consisting of two or more solvents.
Wherein the recrystallization temperature is preferably 0-20 ℃; further preferably, the recrystallization temperature is 0-10 ℃;
preferably, the solvent is acetone, ethyl acetate and absolute ethyl alcohol; more preferably, the solvent is absolute ethanol.
The invention has the advantages that:
(1) the 2- (4-methylthiazol-5-yl) ethyl nitrate directly reacts into hydrochloride without concentration treatment after preparation, the operation is simple and convenient, and the explosion risk of nitrate compounds is avoided.
(2) The nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride product is directly separated out from the solvent, the purity is high, and complicated column chromatography separation and purification are avoided.
(3) Mild reaction conditions, low cost, high yield and suitability for industrial production.
Detailed Description
The present invention is further explained with reference to the following examples, which are not intended to limit the scope of the present invention in any way.
Comparative example
Dropwise adding 1.04ml (16.60mmol) of concentrated nitric acid into 8ml (84.66mmol) of acetic anhydride, controlling the temperature to be 25-30 ℃, after dropwise adding, reducing the temperature to be 0-5 ℃, dropwise adding 1.08g (7.52mmol) of 4-methyl-5-hydroxyethyl thiazole, maintaining the internal temperature below 5 ℃, stirring for 45min after dropwise adding, adding 1.8ml of water, stirring for 30min, concentrating, neutralizing the residue with 20ml of saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, drying, concentrating, and purifying by column chromatography to obtain 0.325g of 2- (4-methylthiazol-5-yl) ethyl nitrate, wherein the yield is as follows: 23 percent.
Example 1
Placing 21.46g (0.15mol) of 4-methyl-5-hydroxyethyl thiazole into a 1000ml three-necked bottle, adding 210ml of dichloromethane, cooling by a ice salt bath, adding 56.7ml (0.6mol) of acetic anhydride into the three-necked bottle with the internal temperature below 0 ℃, maintaining the internal temperature below 0 ℃, dropwise adding 25.4ml (0.6mol) of fuming nitric acid, maintaining the temperature of 0-4 ℃ after the addition, reacting for 2 hours, and completing the reaction. Adding 100ml of water into the solution, maintaining the internal temperature below 0 ℃, dropwise adding 60% NaOH (about 120ml) aqueous solution to adjust the pH to be approximately equal to 7-8, separating out an aqueous layer, extracting with dichloromethane (100ml multiplied by 2 times), combining organic layers, washing with water (100ml multiplied by 2 times), washing with saturated salt water (100ml multiplied by 1 times), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 26.33g of 2- (4-methylthiazol-5-yl) ethyl nitrate, wherein the yield is as follows: 93 percent.
Example 2
Placing 7.15g (0.05mol) of 4-methyl-5-hydroxyethyl thiazole into a 500ml three-necked bottle, adding 70ml of dichloromethane, cooling by an ice-salt bath, adding 7.3ml (0.08mol) of acetic anhydride, maintaining the internal temperature below 5 ℃, dropwise adding 8.5ml (0.2mol) of fuming nitric acid, maintaining the internal temperature below 5 ℃ after adding, reacting for 2 hours while maintaining the internal temperature below 5 ℃, completely reacting, adding 33ml of water into the solution, maintaining the internal temperature below 5 ℃, dropwise adding 60% NaOH aqueous solution to adjust the pH to be approximately 7-8, separating out an aqueous layer, extracting with dichloromethane (30ml multiplied by 2 times), combining organic layers, washing with water (30ml multiplied by 2 times), washing with saturated salt (30ml multiplied by 1 times), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon for decolorization, filtering, and concentrating to obtain 9.10g of 2- (4-methylthiazol-5-yl) ethyl nitrate, wherein the yield is as follows: 96.8 percent.
Example 3
Placing 7.15g (0.05mol) of 4-methyl-5-hydroxyethyl thiazole into a 500ml three-necked bottle, adding 35ml of dichloromethane, cooling by an ice salt bath, adding 7.6ml (0.08mol) of acetic anhydride, maintaining the internal temperature below 5 ℃, dropwise adding 8.5ml (0.2mol) of fuming nitric acid, maintaining the internal temperature below 5 ℃ after adding, reacting for 3 hours while maintaining the internal temperature below 5 ℃, completely reacting, maintaining the internal temperature below 5 ℃, dropwise adding 30% NaOH aqueous solution to adjust the pH to 7-8 (about 60ml), separating out an aqueous layer, extracting with dichloromethane (30ml multiplied by 2 times), combining organic layers, washing with water (30ml multiplied by 2 times), washing with saturated salt (30ml multiplied by 1 times), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon to decolor, filtering, concentrating, obtaining 8.94g of 2- (4-methylthiazol-5-yl) ethyl nitrate, and obtaining the yield: 95.1 percent. Dissolving the obtained 2- (4-methylthiazol-5-yl) ethyl nitrate in 55ml of ethyl acetate, adding 2.2g (47.5mmol) of absolute ethyl alcohol, cooling by using a ice salt bath, keeping the internal temperature below 5 ℃, dropwise adding 3.7g (47.5mmol) of acetyl chloride while stirring, separating out a solid, stirring for 30 minutes at room temperature until the solid is completely dispersed, filtering, washing the solid with ethyl acetate, and drying by using an infrared lamp. To obtain 6.9g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, yield: 64.8 percent.
Example 4
Placing 7.15g (0.05mol) of 4-methyl-5-hydroxyethyl thiazole into a 500ml three-necked bottle, adding 35ml of dichloromethane, cooling by an ice salt bath, adding 7.6ml (0.08mol) of acetic anhydride, maintaining the internal temperature below 10 ℃, dropwise adding 8.5ml (0.2mol) of fuming nitric acid, maintaining the internal temperature below 10 ℃ after the addition is finished, reacting for 3 hours while maintaining the internal temperature below 10 ℃, completely reacting, maintaining the internal temperature below 10 ℃, dropwise adding 30% NaOH aqueous solution to adjust the pH to be 7-8 (about 60ml), separating out a water layer, extracting with dichloromethane (30ml multiplied by 2 times), combining organic layers, washing with water (30ml multiplied by 2 times), washing with saturated salt (30ml multiplied by 1 times), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon to decolor, filtering, and concentrating to obtain 8.6g of 2- (4-methylthiazol-5-yl) ethyl nitrate yield: 91.5 percent. Dissolving the obtained 2- (4-methylthiazol-5-yl) ethyl nitrate in 53ml ethyl acetate, adding 2.5g (55.2mmol) of absolute ethyl alcohol, cooling with a ice salt bath, keeping the internal temperature below 5 ℃, dropwise adding 4.3g (55.2mmol) of acetyl chloride while stirring, separating out a solid, stirring for 30 minutes at room temperature until the solid is completely dispersed, filtering, washing the solid with ethyl acetate, and drying by an infrared lamp. To obtain 8.5g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, yield: 96.1 percent.
Table 1 analysis of the influence of reaction temperature and time for the preparation of 2- (4-methylthiazol-5-yl) ethyl nitrate according to the invention:
| examples | Raw material dosage g | Reaction temperature C | Reaction time hr | Yield% |
| 1 | 21.5 | 0～4 | 2 | 93 |
| 2 | 7.15 | <5 | 2 | 96.8 |
| 3 | 7.15 | <5 | 3 | 95.1 |
| 4 | 7.15 | <10 | 3 | 91.5 |
The result shows that when fuming nitric acid/acetic anhydride is used as a nitration reagent, the reaction temperature is lower than 10 ℃, the influence of the adding amount of reaction raw materials and the reaction time on the yield of the product is small, and the yield of the 2- (4-methylthiazol-5-yl) ethyl nitrate is more than 90 percent;
example 5
Placing 7.15g (0.05mol) of 4-methyl-5- (2-hydroxyethyl) thiazole in a 500ml three-necked flask, adding 46ml of dichloromethane, stirring, cooling by using an ice salt bath externally, maintaining the internal temperature below 5 ℃, dropwise adding 7.6ml (0.08mol) of acetic anhydride, dropwise adding 8.4ml (0.2mol) of fuming nitric acid, reacting for 1 hour at the internal temperature below 5 ℃, completely reacting, maintaining the internal temperature below 5 ℃, dropwise adding 33ml of water, dropwise adding 60% NaOH aqueous solution to adjust the pH of the reaction solution to be approximately 11, separating out a water layer, extracting with dichloromethane (20ml multiplied by 2), combining organic layers, washing with water (120ml multiplied by 2), washing with saturated salt water (20ml), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon, filtering, adding 2.72g (0.059mol) of absolute ethyl alcohol, cooling by using an ice salt bath, maintaining the internal temperature below 5 ℃, dropwise adding 4.63g (0.059mol) of acetyl chloride under stirring, the solid was precipitated, stirred at room temperature for 2 hours, filtered, washed with acetone (20 ml. times.2), and dried by infrared lamp to give 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride (7.82 g, yield: 69.6 percent.
Example 6
Placing 7.15g (0.05mol) of raw material 4-methyl-5- (2-hydroxyethyl) thiazole into a 500ml three-necked flask, adding 46ml dichloromethane, stirring, cooling by using an external ice salt bath, keeping the internal temperature below 5 ℃, dropwise adding 7.6ml (0.08mol) acetic anhydride, dropwise adding 8.4ml (0.2mol) fuming nitric acid, reacting for 5 hours at the internal temperature below 5 ℃ after the addition is finished, completely reacting, keeping the internal temperature below 5 ℃, dropwise adding 33ml water, and dropwise adding 60% NaOH aqueous solution to adjust the pH of the reaction solution to be approximately equal to 11. Separating out a water layer, extracting with dichloromethane (20ml × 2), combining organic layers, washing with water (120ml × 2), washing with saturated salt water (20ml), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon for decolorization, filtering, adding 2.72g (0.059mol) of anhydrous ethanol, cooling with a ice salt bath, dropping 4.63g (0.059mol) of acetyl chloride with stirring at an internal temperature of below 5 ℃, separating out a solid, stirring at room temperature for 2 hours, filtering, washing the solid with acetone (20ml × 2), and baking with an infrared lamp to obtain 7.48g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, wherein the yield is as follows: 66.6 percent.
Example 7
Placing 7.15g (0.05mol) of raw material 4-methyl-5- (2-hydroxyethyl) thiazole into a 500ml three-necked flask, adding 46ml dichloromethane, stirring, cooling by using an external ice salt bath, maintaining the internal temperature below 10 ℃, dropwise adding 7.6ml (0.08mol) acetic anhydride, dropwise adding 8.4ml (0.2mol) fuming nitric acid, reacting for 2 hours while maintaining the internal temperature below 10 ℃, completely reacting, maintaining the internal temperature below 5 ℃, dropwise adding 33ml water, and dropwise adding 60% NaOH aqueous solution to adjust the pH of the reaction solution to be approximately equal to 11. Separating out a water layer, extracting with dichloromethane (20ml multiplied by 2), combining organic layers, washing with water (120ml multiplied by 2), washing with saturated salt water (20ml), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon for decolorization, filtering, adding 2.72g (0.059mol) of anhydrous ethanol, cooling with a ice salt bath, dropping 4.63g (0.059mol) of acetyl chloride with stirring at an internal temperature of below 5 ℃, separating out a solid, stirring at room temperature for 2 hours, filtering, washing the solid with acetone (20ml multiplied by 2), and baking with an infrared lamp to obtain 8.26g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, wherein the yield is as follows: 73.5 percent.
Example 8
Placing 7.15g (0.05mol) of raw material 4-methyl-5- (2-hydroxyethyl) thiazole into a 500ml three-necked flask, adding 46ml dichloromethane, stirring, cooling by using an external ice salt bath, keeping the internal temperature below 5 ℃, dropwise adding 7.6ml (0.08mol) acetic anhydride, dropwise adding 8.4ml (0.2mol) fuming nitric acid, reacting for 2 hours at the internal temperature below 5 ℃ after the addition is finished, completely reacting, keeping the internal temperature below 5 ℃, dropwise adding 33ml water, and dropwise adding 60% NaOH aqueous solution to adjust the pH of the reaction solution to be approximately equal to 11. Separating out a water layer, extracting with dichloromethane (20ml multiplied by 2), combining organic layers, washing with water (120ml multiplied by 2), washing with saturated salt water (20ml), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon for decolorization, filtering, cooling with a cold salt bath, keeping the internal temperature below 5 ℃, dropwise adding a hydrochloric acid/ethyl acetate solution to a pH value of approximately 2 under stirring, separating out a solid, stirring at room temperature for 2 hours, filtering, washing the solid with acetone (20ml multiplied by 2), and baking with an infrared lamp to obtain 7.96g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, wherein the yield is as follows: 70.9 percent.
Example 9
Placing 7.15g (0.05mol) of raw material 4-methyl-5- (2-hydroxyethyl) thiazole into a 500ml three-necked flask, adding 46ml dichloromethane, stirring, cooling by using an external ice salt bath, keeping the internal temperature below 5 ℃, dropwise adding 7.6ml (0.08mol) acetic anhydride, dropwise adding 8.4ml (0.2mol) fuming nitric acid, reacting for 2 hours at the internal temperature below 5 ℃ after the addition is finished, completely reacting, keeping the internal temperature below 5 ℃, dropwise adding 33ml water, and dropwise adding 60% NaOH aqueous solution to adjust the pH of the reaction solution to be approximately equal to 11. Separating out a water layer, extracting with dichloromethane (20ml × 2), combining organic layers, washing with water (120ml × 2), washing with saturated salt water (20ml), drying with anhydrous sodium sulfate, adding 0.9g of activated carbon for decolorization, filtering, adding 2.72g (0.059mol) of anhydrous ethanol, cooling with a ice salt bath, dropping 4.63g (0.059mol) of acetyl chloride with stirring at an internal temperature of below 5 ℃, separating out a solid, stirring at room temperature for 5 hours, filtering, washing the solid with acetone (20ml × 2), and baking with an infrared lamp to obtain 8.15g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, wherein the yield is as follows: 72.6 percent.
Example 10
57.2g (0.4mol) of raw material 4-methyl-5- (2-hydroxyethyl) thiazole is placed in a 2000ml three-necked flask, 370ml of dichloromethane is added, the mixture is stirred, the mixture is cooled by an external ice salt bath, the internal temperature is maintained below 5 ℃, 60.5ml (0.64mol) of acetic anhydride is dripped, 67.4ml (1.6mol) of fuming nitric acid is dripped, the reaction is completed when the addition is finished and the internal temperature is below 5 ℃ for 2 hours, the reaction is completed, the internal temperature is maintained below 5 ℃, 267ml of water is dripped, and 60 percent of NaOH aqueous solution is dripped to adjust the pH of the reaction solution to be approximately 11. Separating out the water layer, extracting with dichloromethane (130ml × 2), combining the organic layers, washing with water (130ml × 2), washing with saturated salt water (130ml), drying with anhydrous sodium sulfate, adding 7.5g of activated carbon for decolorization, filtering, adding 21.8g (0.47mol) of anhydrous ethanol, cooling with a ice salt bath, dropping 37.1g (0.47mol) of acetyl chloride with stirring at an internal temperature of less than 5 ℃, stirring for 2 hours at an internal temperature of less than 5 ℃, filtering, washing the solid with acetone (100ml × 2), and vacuum drying at 40 ℃ for 10 hours to obtain 65.8g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, yield: 73.4 percent. Table 2 analysis of the influence of salifying reagent, reaction temperature and time for the preparation of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride according to the invention:
the result shows that in the preparation of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, the 2- (4-methylthiazol-5-yl) ethyl nitrate is directly reacted into hydrochloride without concentration treatment, and the total yield is more than 66%. When the reaction temperature is less than 10, the salifying reagent and the reaction time have little influence on the yield of the product.
The above tables 1 and 2 show that the reaction route has mature and stable conditions, high product yield, high purity and simple post-treatment, and is suitable for industrial production.
Example 11
8.5g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride were placed in a 250ml eggplant type bottle, charged with 128ml EtOAc: C2H5Heating, refluxing and stirring a solvent with OH being 3: 1, adding 1.6g of activated carbon for decolorization after all solids are dissolved, filtering, stirring and crystallizing, filtering, washing the solids with ethyl acetate, and baking to obtain 6.75g of off-white 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, wherein the yield is as follows: 79.4 percent.
Example 12
Placing 11.1g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride into a 500ml eggplant-shaped bottle, adding 42ml of absolute ethyl alcohol, stirring, refluxing, completely dissolving the solid, adding 42ml of ethyl acetate, filtering, adding 84ml of ethyl acetate, stirring, crystallizing, filtering, washing the solid with ethyl acetate for 2 times (25ml +25ml), baking with an infrared lamp for 2 hours, and vacuum-drying in a vacuum drying oven at 60 ℃ for 12 hours to obtain 9.847g of quasi-white 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, wherein the yield is as follows: 88.7 percent.
Example 13
Putting 10g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride into a 1000ml eggplant-shaped bottle, adding 500ml of acetone, stirring and heating, refluxing for 30 minutes until the solid is still not completely dissolved, supplementing 100ml of acetone, stirring and refluxing for 10 minutes until the solid is completely dissolved, adding 1g of activated carbon for decolorization, filtering, evaporating 200ml of solvent out of filtrate, separating out a small amount of solid in the solution, stirring and crystallizing, and standing at room temperature for about 3 hours. The filtrate was washed with acetone and dried to obtain 7.274g of off-white 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride in a yield of 72.7%.
Example 14
10g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is placed in a 250ml eggplant-shaped bottle, 70ml of absolute ethyl alcohol is added, the mixture is stirred and dissolved at the external temperature of 70 ℃, filtered, and the solid is separated out after being placed for one day at the room temperature, filtered, washed by a small amount of absolute ethyl alcohol, vacuumized and dried at the temperature of 60 ℃ in a vacuum drying oven for 10 hours. 6.16g of pseudo-white nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride was obtained, with a yield of 61.6%.
Example 15
Placing 6.58g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride into a 100ml eggplant-shaped bottle, adding 46ml of absolute ethyl alcohol, heating, stirring at an external temperature of 60 ℃, adding 0.66g of activated carbon for decolorization after the solid is completely dissolved, filtering, stirring for 1 hour at a temperature of 0-10 ℃, separating out the solid, filtering, washing the solid with acetone (10ml multiplied by 2), and drying in vacuum for 10 hours at a temperature of 40 ℃ to obtain 5.12g of white-like solid, wherein the yield is as follows: 77.8 percent.
Example 16
Placing 6.58g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride into a 100ml eggplant-shaped bottle, adding 46ml of absolute ethyl alcohol, heating, stirring at an external temperature of 60 ℃, adding 0.66g of activated carbon for decolorization after the solid is completely dissolved, filtering, stirring for 3 hours at a temperature of 0-10 ℃, separating out the solid, filtering, washing the solid with acetone (10ml multiplied by 2), and drying in vacuum for 10 hours at a temperature of 40 ℃ to obtain 5.35g of white-like solid, wherein the yield is as follows: 81.3 percent.
Example 17
Placing 6.58g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride into a 100ml eggplant-shaped bottle, adding 46ml of absolute ethyl alcohol, heating, stirring at an external temperature of 60 ℃, adding 0.66g of activated carbon for decolorization after the solid is completely dissolved, filtering, stirring for 5 hours at a temperature of 0-10 ℃, separating out the solid, filtering, washing the solid with acetone (10ml multiplied by 2), and drying in vacuum for 10 hours at a temperature of 40 ℃ to obtain 5.28g of off-white solid, wherein the yield is as follows: 80.2 percent.
Example 18
Putting 65.8g of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride into a 1000ml eggplant-shaped bottle, adding 460ml of absolute ethyl alcohol, heating, stirring at an external temperature of 60 ℃, adding 6.6g of activated carbon for decolorization after the solid is completely dissolved, filtering, stirring for 1.5 hours at 0-10 ℃, separating out the solid, filtering, washing the solid with acetone (70ml multiplied by 2), and drying in vacuum for 10 hours at 40 ℃ to obtain 52.5g of off-white solid, wherein the yield is as follows: 79.8%, mp: 112-114 ℃, HPLC: 99.826 percent.1H NMR(400MHz,DMSO-d6)δ:9.33(s,1H),4.68(t,J＝6.0Hz,2H),3.26(t,J＝6.0Hz,2H),2.37(s,3H).HRMS(ESI):m/z[M-HCl+H]+calcd for C6H9N2O3S: 189.0328；found:189.0323.
In conclusion, the synthesis method is suitable for preparing the 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride in an industrial scale, can meet the requirements of industrial production, improves the operability, the safety and the yield, and has high product purity.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents and are included in the scope of the present invention.
Claims (5)
1. A method for preparing 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride,
characterized in that the method comprises the following steps:
(1) 4-methyl-5- (2-hydroxyethyl) thiazole is subjected to nitration reaction to obtain 2- (4-methylthiazol-5-yl) ethyl nitrate; wherein, the nitration reagent of the reaction is selected from fuming nitric acid and acetic anhydride, the reaction step is to dissolve a reaction substrate 4-methyl-5- (2-ethoxyl) thiazole in a solvent, then add acetic anhydride, and then add fuming nitric acid;
(2) reacting 2- (4-methylthiazol-5-yl) ethyl nitrate with hydrochloric acid in a solvent to generate 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride;
(3) and (2) directly using the intermediate 2- (4-methylthiazol-5-yl) ethyl nitrate obtained by nitration in the step (1) in the salt forming reaction in the step (2) without purification, and continuously performing the two-step reaction.
2. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the 4-methyl-5- (2-hydroxyethyl) thiazole to the fuming nitric acid is 1:4, the reaction temperature is 0-5 ℃, the reaction time is 1.5-2.5 hours, and the reaction solvent is selected from dichloromethane.
3. The method according to claim 1, wherein in the step (2), the molar ratio of 2- (4-methylthiazol-5-yl) ethyl nitrate to hydrochloric acid is 1: 1.1-1.5, wherein the reaction time is 0.5-2 hours, and the hydrochloric acid source is selected from a hydrochloric acid/ethyl acetate solution and an acetyl chloride/ethanol system; the solvent is selected from ethyl acetate and dichloromethane.
4. The preparation method of claim 1, wherein the 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is subjected to decolorization and recrystallization to obtain a pure product, wherein the recrystallization temperature is 0-30 ℃, and the used solvent is selected from ethyl acetate, acetone, absolute ethyl alcohol and a mixed solvent comprising the above single solvent or two or more solvents.
5. The preparation method according to claim 4, wherein the recrystallization temperature is 0 to 10 ℃, and the solvent is absolute ethanol.
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