A run through of the synthesis on different solvents and optimum reagent ratios.

[Rush-Benzo]

Hi. When carrying out the synthesis in Benzene / Toluene / Xylene / DCM, it is sufficient to dissolve BK4 in whichever solvent mentioned, add methylamine 40% in water and then heat together with maximum vigorous stirring for 3h at 60 degrees C? (2h and 40 degrees for DCM)

Finally, separate the aqueous layer from the organic layer. Rinse the organic one a few times with water and you can get down to acidification?

Is this the process or have I missed something?

By the way, so as not to start a second topic, question no. 2.

What are the starting proportions of the reagents (temperature and reaction time above), how many L of solvent and how many L of m40 per 1kg of BK4 to be optimal?

Question 3. After washing the organic phase, instead of adding an equal volume of Acetone and then liquefying with concentrated hydrochloric acid 35-37% in water to pH 5.5-6, can I use IPA or ethyl acetate instead of Acetone?

Thank you for your time and valuable advice

 

[Rush-Benzo]

I forgot to add, and I can't edit the topic anymore....

What do you say about these proportions:
1kg BK4 - 4.5L Benzene / Toluene / Xylene / DCM - 1.85L M40 in water.

I calculated the proportions from a certain 4MMC synthesis table that circulates on the web and describes the reaction time/temperature depending on the solvent and the impurities formed.

 

[Mellym]

Proportions looks ok to me. But the total scale you are going to run would be a hardwork))

 

[Mellym]

In general the process is right. One more thing you could do is to wash organic layer with brine at the end. This would remove any leftover water, leaving more clear layer.


Ethylacetate does work. Haven't used IPA. My advice is don't dilute your freebase solution. Just add dropwise and carefully HCL. Bear in mind it will get hot, so better keep it on ice bath or let cool time after time. Then the pH is good, product will start to precipitate. At this moment just pour acetone or ethylacetate and it'll crush whole product instantly.

 

[Rush-Benzo]

How do you prepare such a brine solution?

After washing the organic layer, should I add HCL 35-37% drop by drop, cooling the whole thing down to pH 5.5-6, and only when I have this PH should I add an equal volume of Ethyl Acetate or Acetone?

Is there any difference to the + side by first adding HCL and then diluting, instead of diluting and only adding HCL?

Thank you for your reply

 

[Mellym]

Brine is saturated NaCl water solution. You can prepare it at fist place by dissolving table salt in water. Maximum concentration of NaCl is 36g/100ml water. Take 1lit. of water, put it on mild heat, and start adding salt. It should take about 400grams to dissolve in hot water. After cooling to room temp. some precipitate would fall back, that's ok. You can just pour it away.

After you wash your freebase solution with water, wash it with brine. Pour some amount, so it forms a separate layer. And when just swirl gently, don't shake. You should see your organic solution becomes clearer, less cloudy. Wait for layers to settle and separate. This could be repeated if needed.

Well could be some minor differences depending on how you acidify on final step. In general it just comes to proportion mishaps. Like too much solvent left, or some you got residual water- you wont see your product crush out. You'll have to wait, leaving it overnight to crystallise, or try to evaporate excess solvent... That's just takes time and patience, basically.

 

[Mellym]

Oh, and just another advice on acidifying step. Before you start, divide your freebase solution in two halfs. Or at least leave some ammount. This could be really a savior in case. If you somehow happen to overshoot too much acid, just add this extra freebase and this will fix your mistake, rollback the pH.

That's a good practice for any drug salt formation step, not just meph.

 

[Rush-Benzo]

Thank you very much. Your advice will certainly come in handy.

According to you, will the ratio of 1kg BK4, 4.4L solvent and 1.85L M40 pass the test?

When acidifying after washing the organic layer how much acetone / ethyl acetate should I add? An equal volume or, for example, half of it?

 

[HerrHaber]

It is advisable to hold about a quarter of your final freebase solution in solvent aside from the one in which you drop the acid so as to be able to correct the pH if it falls below the limit... you will end up pouring it all in and then carefully drop more acid to reach your desired pH (you will get better or rather more attentive as you progress). Acetone has great precipitating properties in this context, and also has the advantage of being water miscible therefore dilutes the water found in the acid and in your solvent thus helping the salt material (your product) to precipitate (come out of solution/crystalize) simultaneously. Adding half the volume of your mixture is a bit in the upper end since I fear too much would also cause impurities to precipitate, also doing an acetone wash after vacuum filtration (either in the funnel or in a separate container) promisses a much faster drying of your solid product.

 

[Rush-Benzo]

Thank you very much for your professional way of interpreting. I am grateful for that. I will therefore stay with Acetone.

Simply put if I have 5L of free base already after washing, it is best to add 2.5L of Acetone to it and slowly add hydrochloric acid until PH 5.5-6.

Have I understood this correctly? Is it better to add less than half, e.g. 2L of Acetone, per 5L of free washed base? Do you have any experience with this?

As for setting some aside in case the PH drops much too low - noted and will probably be used in reality.

 

[StarWars]

U can use acetone IPA alkohol ethyl acetate or water to get 4mmc HCl
And of cours acid HCl can use 30%
Is much way how to get out 4mmc form freebase

 

[Rush-Benzo]

I understand this perfectly well. I mean something completely different.

How much solvent (acetone, ethyl acetate, IPA), for example, per 5L of free, washed alkali, should I add before starting to add hydrochloric acid 35-37% up to pH 5.5-6?

 

[StarWars]

The same how much u have freebase if u have 500ml freebase u use the same acetone or IPA alkohol or ethyl acetate.
They u throw slow HCl and check all the time pH then u know how much HCl u need simple

 

[Rush-Benzo]

So acetone / IPA / ethyl acetate I add as much as I have free base. This is also what I read somewhere, no less a colleague a few posts above wrote that half this volume may be too much, so opinions are divided. No less I have to try it out. Thank you

 

[StarWars]

Made and u will see

 

[StarWars]

pH 6