WillD

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Introduction
This topic is represented alpha-PVP synthesis way in a medium scale 1-10 kg. There are elaborated video tutorials, which are allowed to produce this substance to anybody. Also, you can find here a list of necessary equipment and reagents.
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Equipment and glassware:
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Reagents:
  • Hydrobromic acid (HBr) 1 kg 48%;
  • Hydrogen peroxide (H2O2) 300 g 35%;
  • Pyrrolidine 1100 ml (CAS 123-75-1);
  • Ethyl acetate 4 L;
  • Sodium carbonate (Na2CO3) 20% aq solution;
  • Diethyl ether (Et2O) 50 ml;
  • EtOH 50 mL;
  • Dibenzoyl-D-tartaric acid 12.7 g, 35.5 mmol;
  • Dichloromethane (CH2Cl2) 830 mL;
  • Hexane 1100 mL;
  • Hydrochloric acid conc. 35% (HCl);
Stage 1. Halogenation.
1. Valerophenone (CAS 1009-14-9) 1 kg is weighed and poured into the reactor.
2. Hydrobromic acid (HBr) 1000 g 48% is added.
3. The reaction mixture is stirred vigorously for 5 minutes.
4. Hydrogen peroxide (H2O2) 300 g 35% is added into the drip funnel and installed onto the reactor neck.
5. A drop funnel tap is opened and hydrogen peroxide is added dropwise with vigorous stirring.
6. Look at the color of the mixture. Color may vary from yellow to red. Hydrogen peroxide is added so that mixture is discolored.
7. The temperature is maintained below 65 ℃. The H2O2 dripping is stopped in case the temperature is risen.
8. The reaction mixture is vigorously stirred for 1.5 h.
9. Distilled water is added and the reaction mixture is stirred for 5 minutes.
10. The stirring is stopped and the reaction mixture is separated into two layers. The target layer is on the bottom, water is on the top layer.
11. The water layer is removed with help of a vacuum pump through the reactor neck.
12. An aqueous alkaline solution is added and stirred for 5 minutes.
13. Steps 9, 10, 11 are repeated.
14. The resulting product is left in the reactor.

Stage 2. Amination.

1. Ethyl acetate 4 L is placed into a reactor with 2'-Bromovalerophenone 1.5 kg and stirred 5 minutes.
2. A drip funnel is installed at the reactor neck and pyrrolidine 1150 ml (CAS 123-75-1) is added into this funnel.
3. A drop funnel tap is opened and pyrrolidine is added dropwise with vigorous stirring.
4. The temperature is maintained below 65 ℃.
5. The reaction mixture is vigorously stirred for 1 hour after completion of the pyrrolidine addition.
8. A reactor vacuum pump and a chiller pump of reflux condenser are turned on.
9. The most part of ethyl acetate is distilled off.
10. A vacuum pump is stopped and acetone is added into the reactor. The stirring is continued.
11. Hydrochloric acid is added into the drip funnel on the reactor neck.
12. Hydrochloric acid is added to pH 5. A small amount of reaction mixture is drained from the bottom reactor tap to control pH with a litmus paper (also, you can use glass rod for this goal). The sample is returned to the reactor.
13. After that, the reaction mixture is poured into a beaker and put into a freezer for 12 hours.

Stage 3. Filtration.
1. A
vacuum filtration system is installed (nutsche filter, filter cloth, vacuum pump).
2. A vacuum pump is turned on.
3. The reaction mixture is poured from the beaker (from step 13 stage 2) to Buchner funnel.
4. The reaction mixture is filtered and pressed until a solid is obtained.
5. A cold acetone is poured into Buchner funnel to cover the whole solid.
6. Acetone is filtered and product is washed. Step 5 is repeated in case the solid substance is not white.
7. The content of Buchner funnel is poured into the Pyrex dish for drying procedure after the acetone filtration and the white solid obtaining.
8. The Pyrex dish is placed in a dry place at room temperature.
9. The product is dried to constant mass. Product is mixed and crushed periodically in order to rise drying speed.

Stage 4. Diastereomeric.

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1. a-PVP HCl 10.0 g, 35.5 mmol is dissolved in minimum volume of distilled water .
2. Na2CO3 20% aq solution is added to reach pH 8-9.
3. The mixture is extracted with Et2O 50 ml.
4. Ether extract is separated in a separatory funnel, then Et2O is distilled off.
5. a-PVP free base is dissolved in EtOH (50 ml).
6. Ethanol solution of a-PVP free base is heated to 70 ℃.
7. Dibenzoyl-D-tartaric acid 12.7 g, 35.5 mmol is added.
8. The solution is refluxed with a reflux condenser for 1 minute and cooled to a room temperature.
9. A solvent is distilled off.
10. The residue is dissolved in CH2Cl2 (530 mL). Hexane (700 mL) is added with stirring.
11. The resulting crystals (9.1 g) are collected by filtration through a Buchner flask and funnel after 3 days.
12. Three consecutive recrystallizations from CH2Cl2/hexane (300/400 mL) are given a single diastereoisomer (6.1 g, 61%);
13. Steps 1, 2, 3 are repeated with salt from step 11.
14. A cold acetone is added.
15. Hydrochloric acid (HCl) is added to reach pH 5.
16. Pruduced crystals from step 15 are filtered and air dried.
 
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BHBlueberry

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Very precise recipe :) Thank you. Could you analyse the Hex-en recipe?
 

ASheSChem

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Pyrrolidine is findable in Europe ?
 

HerrHaber

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Pyrrolidine is findable in Europe ?
ASheSChemeven though it is commercially available and without any reason for it being suspectable (at least not where I am at), surely somebody around here can provide it, moreover it can be obtained from the aminoacid proline by thermal decarboxylation (heating it in a high boiling point solvent but not higher than it actually boils so it does not evaporate out)
 

Morpheus77

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Would love to take a shot at this. Wondering if Cu(II)Br could be used for halogenation rather than HBr though
 

Jamroz

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3l of pyrrolidine for 1kg bromo should be ok?
 

WillD

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FishAndChips

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View previous replies…

baxter192

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where i can find a vendor for pyrrolidin?
 

madmoney69

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I have problems getting it crystalize. What common solutions is for it why I am having problems with getting crystals?
 

🍒cherry

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I have problems getting it crystalize. What common solutions is for it why I am having problems with getting crystals?
madmoney69I think you must freeze the liquid for 2 days then u can see some crystal forming same like hmtd crystal synthesis not sure it might help
⏳⌚ is more important in freezer crystallization
 

komkom

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Hydrochloric acid 20% can be used? (or need >=35%)?
Or, instead of hCl, can be used 1,4-Dioxane (CAS: 123-91-1)? or dioxane hydrochloric acid (20%) ?

 

madmoney69

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Finally my A-PVP synthesis was success.
I had problems to crystalize it and had difficulty to understand what was my mistakes.
But what was needed is to evaporate most of EA, add cold acetone 1:1 and after added enough HCL it started crystalizing almost imediatly.
THNX to the BBgate experts, especially for G.Patton
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K9AZiSPIzx
 

Didi

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Didi

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How much u get gram ??
 

spaggydee

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Finally my A-PVP synthesis was success.
I had problems to crystalize it and had difficulty to understand what was my mistakes.
But what was needed is to evaporate most of EA, add cold acetone 1:1 and after added enough HCL it started crystalizing almost imediatly.
THNX to the BBgate experts, especially for G.Patton View attachment 8118 View attachment 8119
madmoney69I've run into a similar issue a few times - so I appreciate your insight on what solved your issue.

Luckily, somehow, my first synth was smooth sailing and error free - but strangely since then it seems that every other one I've done has weird issues with crystallizing small yields and/or mainly being an oil. I'm not sure where my error is because when I do another synth, it then seems to be successful.

My last synth, for example, is behaving in a way I've never seen before - it crystallizes with heat/air applied and assisted with acetone, however when removed from heat it slowly liquifies back into an oil.

Fingers crossed that my next run doesn't waste further material.
 

madmoney69

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If you still have that material. Try to evaporate all excess solvent add acetone 1:1 cool down all and add more HCL until starts forming crystals.
 
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