Introduction
This synthesis is a good option in case you have unavailable phenylacetone for further amphetamine or methamphetamine synthesis. BMK glycidate can be easily turn into P2P by hydrolysis. This reaction have some pros and cons. The main disadvantage that reaction is very sensitive to water. You have to use absolutely dry glassware and reagents. Make sure that your reagents was dried and purified before synthesis. Water traces decline the yield. Also, it is worth to carry out this reaction in an inert atmosphere (N2) to increase its yield. There are advantages such as quite high yield, short reaction time. Moreover, the reaction doesn't take any solvents.
Equipment and glassware:
- 2 L batch reactor (or flask) with a reflux condenser, top stirrer and water jacket (water bath) in a set-up;
- Retort stand and clamp for securing apparatus;
- 1 L Drip funnel;
- Conventional funnel;
- Laboratory grade thermometer (up to -10 - 100 °С);
- Glass rod;
- Silicone hoses;
- Measuring cylinder for 1 L;
- Vacuum source;
- Laboratory scale (1-200 g is suitable);
- Cold water bath sours for reflux condenser and water pump (in case of chiller absense);
- Buchner flask and funnel;
- 2 L; 1 L x2; 500 ml x2 Beakers;
- Plastic spoon or spatula;
- Freezer;
- Circulating pump chiller (optional);
- Pyrex dishes for product (or other containers);
Reagents:
- Benzaldehyde 200 g (cas 100-52-7);
- Methyl 2-chloropropionate 350 g (cas 17639-93-9);
- Anhydrous sodium sulfate (Na2SO4);
- Sodium hydroxide (NaOH) 200 g or potassium hydroxide (KOH) 265 g;
- Distilled water ~2 L;
- Sodium ethylate 200 g (EtONa);
Synthesis
Substitution nucleophilic reaction between benzaldehyde and methyl 2-chloropropionate.
The glass reactor is equipped with a jacket connected to a circulating pump chiller with the 0°С coolant temperature set. If you use a flask or a single layer reactor, you have to use an ice-water cooling bath. The reaction flask (reactor) must be perfectly dry inside, without water drops and condensate.
1. Pour benzaldehyde 200 g into a beaker.
2. Add methyl 2-chloropropionate 350 g. The benzaldehyde and methyl methyl 2-chloropropionate mixture is stirred.
Note: If the reagents are fresh and stored in suitable conditions, use them directly by loading into the reactor. If not or for the prevention purpose (to be sure), you may additionally dry the benzaldehyde and methyl 2-chloropropionate mixture with a desiccant. In this case, anhydrous sodium sulfate (Na2SO4) is used.
3. Anhydrous Na2SO4 is added to the mixture so that it completely covers the glass bottom (approximate amount). The mixture is stirred.
Note: Na2SO4 collecting the remaining water, forming crystalline hydrates and settling onto the vessel bottom without stirring. Water adsorption occurs quite quickly. Visually it looks as a transparent reagents mixture formation.
4. The settled, dehydrated by sodium sulfate, mixture is decanted into the reaction vessel. Make sure that the sediment (crystalline hydrates) does not get into the reactor.
Note: The all formed sodium sulfate crystalline hydrates and unreacted sodium sulfate precipitates are settled onto the vessel bottom. It is decanted quite easy. You can use additional filtration or install a pre-filter in the reactor funnel in order to be sure.
5. The sodium sulfate crystalline hydrates precipitate is easily separated. Then, it is disposed off. Prepare sodium ethoxide for an addition.The stirrer is turned on.
Note: Set the stirring speed so that the mixture is well stirred, but at the same time, it isn’t splashed too much on the reactor (flask) walls.
6. The reaction mixture (RM) is cooled to 0-10°С by the cooled reactor jacket. The temperature is maintained at the same level and checked with a temperature probe during the reaction. The temperature is measured by a temperature probe immersion. An immersion thermometer or IR thermometer for the flask can be used.
7. An aqueous solution of alkali (sodium or potassium hydroxide) is prepared in advance. Sodium hydroxide 200 g (or potassium hydroxide 265 g) is poured into a beaker. Distilled cold water 0.8-1 l is added. The mixture is stirred until a NaOH is dissolved completely. The solution gets very hot. Then, alkali solution is left in a cold place so that the mixture is cooled to room temperature. After that, alkali solution can be put into a refrigerator.
8. When RM is cooled down to 0°С inside the reactor, dry sodium ethylate 200 g (EtONa) addition is started. The addition have to be carried out in small portions with breaks in order to maintain the reaction temperature below 10°С. A too fast addition and large portions of EtONa may cause a sharp mixture heat up and even RM boiling, the reaction yield will be reduced in this case. EtONa have to be dosed with a plastic or silicone spoon; metal spoon cannot be used.
Note: Other metal alcoholates such as sodium methoxide, potassium tert-butoxide, sodium isopropoxide, etc. can be used. In addition, sodium hydride, sodium amide can be used as well. RM is heated up and thickened a little during the EtONa addition, an external cooling is applied.
The mixture is thickened, color is turned yellow, then brick red and brown subsequently. The temperature have to be always maintained in the range of 0-10°С. The more sodium ethylate is added, the thicker the mixture is become. The stirring is maintained by an adjustment of the stering speed.
Note: If the reaction is carried out in a reaction flask on a magnetic stirrer, then one anchor may not be enough. A hand stirrer or an overhead stirrer should be used.
9. RM is stirred and maintained in the range of 0-10°С for 1 h after complete EtONa addition.
10. Then, external cooling is removed and RM is stirred at room temperature for 12 h.
Optional: As an option, an external gradual heating is set up to 60°С. With this method, the reaction yield will be reduced. A reflux condenser is installed on the reactor. RM is stirred at 60°С for additional 1 h. A heating is carried out with help of a reactor jacket and a thermostat.
11. After 1 h, the external heating is turned off. The mixture is slowly cooled to room temperature with constant stirring.
12. A drip funnel with 1 l cold distilled water is installed onto the reactor. Water is added dropwise with a vigorous stirring. The thick RM is turned liquid.
13. The stirrer is turned off. RM is separated into two layers. The top layer is methyl glycidic ester (BMK methyl glycidate), the lower layer is water with unnecessary reaction salts, which are dissolved in it. The lower layer is discarded, the top glycidic ester layer is used in the further reactions.
14. BMK-glycidate methyl ester is left in the reactor. It can be vacuum distilled to produce the purer ester in case you want to sale it as a product. Approximate ester amount is around 400 g. As an option, the ester is used in the next reaction to obtain the sodium or potassium salt of glycidic acid.
2. Add methyl 2-chloropropionate 350 g. The benzaldehyde and methyl methyl 2-chloropropionate mixture is stirred.
Note: If the reagents are fresh and stored in suitable conditions, use them directly by loading into the reactor. If not or for the prevention purpose (to be sure), you may additionally dry the benzaldehyde and methyl 2-chloropropionate mixture with a desiccant. In this case, anhydrous sodium sulfate (Na2SO4) is used.
3. Anhydrous Na2SO4 is added to the mixture so that it completely covers the glass bottom (approximate amount). The mixture is stirred.
Note: Na2SO4 collecting the remaining water, forming crystalline hydrates and settling onto the vessel bottom without stirring. Water adsorption occurs quite quickly. Visually it looks as a transparent reagents mixture formation.
4. The settled, dehydrated by sodium sulfate, mixture is decanted into the reaction vessel. Make sure that the sediment (crystalline hydrates) does not get into the reactor.
Note: The all formed sodium sulfate crystalline hydrates and unreacted sodium sulfate precipitates are settled onto the vessel bottom. It is decanted quite easy. You can use additional filtration or install a pre-filter in the reactor funnel in order to be sure.
5. The sodium sulfate crystalline hydrates precipitate is easily separated. Then, it is disposed off. Prepare sodium ethoxide for an addition.The stirrer is turned on.
Note: Set the stirring speed so that the mixture is well stirred, but at the same time, it isn’t splashed too much on the reactor (flask) walls.
6. The reaction mixture (RM) is cooled to 0-10°С by the cooled reactor jacket. The temperature is maintained at the same level and checked with a temperature probe during the reaction. The temperature is measured by a temperature probe immersion. An immersion thermometer or IR thermometer for the flask can be used.
7. An aqueous solution of alkali (sodium or potassium hydroxide) is prepared in advance. Sodium hydroxide 200 g (or potassium hydroxide 265 g) is poured into a beaker. Distilled cold water 0.8-1 l is added. The mixture is stirred until a NaOH is dissolved completely. The solution gets very hot. Then, alkali solution is left in a cold place so that the mixture is cooled to room temperature. After that, alkali solution can be put into a refrigerator.
8. When RM is cooled down to 0°С inside the reactor, dry sodium ethylate 200 g (EtONa) addition is started. The addition have to be carried out in small portions with breaks in order to maintain the reaction temperature below 10°С. A too fast addition and large portions of EtONa may cause a sharp mixture heat up and even RM boiling, the reaction yield will be reduced in this case. EtONa have to be dosed with a plastic or silicone spoon; metal spoon cannot be used.
Note: Other metal alcoholates such as sodium methoxide, potassium tert-butoxide, sodium isopropoxide, etc. can be used. In addition, sodium hydride, sodium amide can be used as well. RM is heated up and thickened a little during the EtONa addition, an external cooling is applied.
The mixture is thickened, color is turned yellow, then brick red and brown subsequently. The temperature have to be always maintained in the range of 0-10°С. The more sodium ethylate is added, the thicker the mixture is become. The stirring is maintained by an adjustment of the stering speed.
Note: If the reaction is carried out in a reaction flask on a magnetic stirrer, then one anchor may not be enough. A hand stirrer or an overhead stirrer should be used.
9. RM is stirred and maintained in the range of 0-10°С for 1 h after complete EtONa addition.
10. Then, external cooling is removed and RM is stirred at room temperature for 12 h.
Optional: As an option, an external gradual heating is set up to 60°С. With this method, the reaction yield will be reduced. A reflux condenser is installed on the reactor. RM is stirred at 60°С for additional 1 h. A heating is carried out with help of a reactor jacket and a thermostat.
11. After 1 h, the external heating is turned off. The mixture is slowly cooled to room temperature with constant stirring.
12. A drip funnel with 1 l cold distilled water is installed onto the reactor. Water is added dropwise with a vigorous stirring. The thick RM is turned liquid.
13. The stirrer is turned off. RM is separated into two layers. The top layer is methyl glycidic ester (BMK methyl glycidate), the lower layer is water with unnecessary reaction salts, which are dissolved in it. The lower layer is discarded, the top glycidic ester layer is used in the further reactions.
14. BMK-glycidate methyl ester is left in the reactor. It can be vacuum distilled to produce the purer ester in case you want to sale it as a product. Approximate ester amount is around 400 g. As an option, the ester is used in the next reaction to obtain the sodium or potassium salt of glycidic acid.
Alkaline hydrolysis to BMK sodium glycidate
15. An alkali solution, which was prepared in advance, is poured into a drip funnel. The stirrer is turned on. A dropwise addition of cooled NaOH (or KOH) aqueous solution at room temperature is started.
In our case, self-heating of the mixture is allowed. After the alkaline addition, the thermostat is set to 60°С in order to speed up the salt obtaining process. The mixture is stirred for addition 2 h.
Note: If you want to get a higher yield of the product, then add the alkaline solution with external cooling. Further, RM is stirred for additional 12 h at room temperature. The mixture is thickened rather quickly (glycidic acid sodium salt precipitates) during alkaline addition without cooling. In case the mixture is thickened too much, stirring speed is increased.
Caution! Methyl alcohol is obtained in this reaction from the BMK methyl glycidate.
16. The mixture is turned transparent during a heating. The resulting glycidic acid sodium salt is soluble in water. Shortly thereafter, the reactor is prepared for cooling to crystallize the glycidic salt. As an option, the thermostat can be turned off and the mixture is gradually cooled to room temperature.
The mixture is started to crystallize during gradual cooling. It becomes more cloudy, glycidic salt is precipitated, the mixture is thickened. A mixture of BMK glycidic acid sodium salt is obtained.
17. The mixture is vacuum filtered on a Buchner flask and funnel. The dry product 300 g 79% yield (cas 5449-12-7) is obtained.
In our case, self-heating of the mixture is allowed. After the alkaline addition, the thermostat is set to 60°С in order to speed up the salt obtaining process. The mixture is stirred for addition 2 h.
Note: If you want to get a higher yield of the product, then add the alkaline solution with external cooling. Further, RM is stirred for additional 12 h at room temperature. The mixture is thickened rather quickly (glycidic acid sodium salt precipitates) during alkaline addition without cooling. In case the mixture is thickened too much, stirring speed is increased.
Caution! Methyl alcohol is obtained in this reaction from the BMK methyl glycidate.
16. The mixture is turned transparent during a heating. The resulting glycidic acid sodium salt is soluble in water. Shortly thereafter, the reactor is prepared for cooling to crystallize the glycidic salt. As an option, the thermostat can be turned off and the mixture is gradually cooled to room temperature.
The mixture is started to crystallize during gradual cooling. It becomes more cloudy, glycidic salt is precipitated, the mixture is thickened. A mixture of BMK glycidic acid sodium salt is obtained.
17. The mixture is vacuum filtered on a Buchner flask and funnel. The dry product 300 g 79% yield (cas 5449-12-7) is obtained.
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