Ugi+Product+Intermediate+of+Praziquantel

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

 * 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

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

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

**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. 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.