Ab initio calculation of the optimal solvent system for crystallization for the Ugi product intermediate of praziquantel

Researcher: Andrew Lang


Introduction

An precursor of praziquantel can be prepared by a four component Ugi reaction . The goal of this study is to predict an optimal solvent for synthesis. The following calculations are based upon the Abraham general solvation model assuming that the reaction is run under conditions where the carboxylic acid (cyclohexanecarboxylic acid / 1-cyclohexanoic acid) is a solid[1].

Reaction Scheme

reactionscheme.png
Amine [r.t. phase - liquid]
Name: 2,2-dimethoxyethanamine / aminoacetaldehyde dimethylacetal
SMILES: O(C)C(OC)CN
CSID: 80987

Aldehyde [r.t. phase - liquid]
Name: formaldehyde
SMILES: O=C
CSID: 692

Imine Intermediate [r.t. phase - unknown]
Name: 2,2-dimethoxy-N-methylideneethanamine
SMILES: COC(CN=C)OC
CSID: N/A

Isonitrile [r.t. phase - liquid]
Name: 2-phenylethyl isocyanide / (2-isocyanoethyl)benzene
SMILES: [C-]#[N+]CCc1ccccc1
CSID: 378400

Carboxylic acid [r.t. phase - solid but see[1].]
Name: cyclohexanecarboxylic acid / 1-cyclohexanoic acid
SMILES: O=C(O)C1CCCCC1
CSID: 7135

Ugi Product [r.t. phase - solid]
Name: N-(2,2-dimethoxyethyl)-N-{2-oxo-2-[(2-phenylethyl)amino]ethyl}cyc​lohexanecarboxamide
SMILES: O=C(N(CC(=O)NCCc1ccccc1)CC(OC)OC)C2CCCCC2
CSID: 9906289

Reaction Attempts

The reaction has been attempted by both the Bradley lab[2], the Todd lab[3, 4], and Domling[5]. Lee et. al. also made the product but did not use the Ugi reaction[6].

Abraham Descriptors

Abraham descriptors were calculated for the carboxylic acid, imine, and Ugi product using Absolv - part of the ACD Labs ADME Suite 5.0. The r.t. water solubility of the acid was taken as the average of two literature values[7, 8]. The water solubility of the imine and Ugi product were calculated as the average of the values from ACD LogS, VCC LogS, and Abraham LogS. The primary solvent for Ugi reactions is methanol, so the methanol solubility is also noted in the table below. It was calculated by averaging the values from the Abraham descriptors prediction and solubility model 4 .

Summary of descriptors
Solute
A
B
S
E
V
LogS
methanol (M)
acid
0.57
0.38
0.71
0.39
1.0607
-1.625
5.77*
imine
0.00
0.62
0.37
0.25
0.9873
-0.676
6.65
product
0.26
1.78
2.80
1.50
3.0697
-3.736
0.51

*The solubility of the acid in liquid phase has been measured in methanol to be 8.06M [9].

Summary of predicted water solubilities
Solute
ACD LogS
VCC LogS
Abraham LogS
acid
lit. [7, 8]
N/A
N/A
imine
-0.14
-1.13
-0.757
product
-2.9
-3.79
-4.517

Summary of predicted methanol solubilities
Solute
model 4
Abraham
acid
4.815
6.717
imine
6.294
7.010
product
0.163
0.855

Solvent Selection

The solubility of the acid, imine, and Ugi product have been predicted in 70 additional solvents using the Abraham descriptors. These values have been stored in Google spreadsheets: acid , imine , Ugi product . Typical solvent selection requires a solvent with a boiling point less than 100C where the solubility of the product is less than 0.03M and the solubilities of the reactants are greater than 0.3M. Scanning the summary spreadsheet we see that there is no solvent that matches all these criteria. Relaxing the boiling point constraint, we see that only one solvent matches the solubility conditions, namely dibutyl ether (boiling point 142.1C), where the solubility of the acid, imine, and product are predicted to be 0.82M, 2.25M, and 0.01M respectively.

It is intriguing that all the reactants are liquids just above room temperature. This lends itself to the idea of attempting the reaction in a solvent where the product is almost insoluble, maybe an alkane, at a temperature where all the reactants are liquids, say 35C. One consideration here would be the phase / solubility of the intermediate imine. The predicted solubility of the product in pentane, hexane, and heptane is 0.0003M, 0.0004M, and 0.0003M respectively. Whereas the predicted solubility of the imine in pentane, hexane, and heptane is 2.7M, 3.4M, and 4.0M. Thus an alkane may actually be a good solvent choice.

Pure methanol is not predicted as the optimal solvent for crystallization but a water/methanol mixture may be a good choice. Fitting a simple linear model to the predicted solubilities for the acid, imine, and product, we see that the product is predicted to precipitate from a water/methanol mixture with a water percent mol fraction of at least 41%, asuming the reaction is run at 0.3M.
linearmodel.gif
Linear fit to methanol/water predicted solubilities.

So a third possibility is attempting the reaction in a water/methanol mixture with the fairly high percent mol fraction of water. The reaction may also run faster in a water/methanol mixture[10]. To improve predictions in cosolvents the solubility of the reactants and product should be measured in different ratios of water and methanol and the data fitted to a Jouyban-Acree model[11]. Of course this is not possible initially when the product has yet to be synthesized.

Conclusion

Based upon the analysis, we recommend attempting the reaction in either dibutyl ether at 2M, a 50:50 water/methanol mixture at 2M with slow addition of water to precipitate the product after the reaction has run its course (as done in the German patent), or in an alkane (e.g. hexane) at 2M and at 35C.

Improved Predictions

To improve predictions, once the product has been isolated, solvent optimization can be reworked using measured product solubility values, see draft .


References

1. Melting point of cyclohexanecarboxylic acid is 29-32C. http://www.alfa.com/en/GP100w.pgm?DSSTK=A14693
2. UsefulChem (Bradley Lab) Open Notebook. Exp258
3. OurExperiment (Todd Lab) Open Notebook. MW36
4. OurExperiment (Todd Lab) Open Notebook. MW36X (optimization by varying temperature, acidic catalyst, and stoichiometry).
5. “Novel Synthesis of Praziquantel“ A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.
6. Kim, J.,H.; Lee, Y., S.; Kim, C., S.; Heterocycles, 48; 11; 1998; 2279- 2285; 1998 (doi:10.3987/COM-98-8293)
7. The Merck Index. Thirteenth Edition 2001
8. Niyazov A.N.; Namatov B.; Atlyev Kh. lzv. Akad. Nauk Turkn. SSR; Ser. Fiz.Tekh.; Khim. Geol. Nauk 1974
9. Solubility of cyclohexanecarboxylic acid in methanol. ONSChallange Exp022
10. Pirrung, M. C.; Sarma, K. D. (2004). "Multicomponent Reactions Are Accelerated in Water". Journal of the American Chemical Society 126 (2): 444–445. doi:10.1021/ja038583a. PMID 14719923.
11. Fakhree, M.A.A.; Acree, W.E.; Jouyban, A. Solubility of phenanthree in binary mixtures of c1-c4 alcohols at 298.2K. J. Chem. Eng. Data 2010, 55, 531-534