**1. Introduction**

Chirality (the ability of an object to exist in the form of non-superimposable mirror copies) is a fundamental property that has numerous manifestations, including various biological effects of enantiomers on a living organism [1]. For this reason, since the beginning of the century, among the new active pharmaceutical ingredients (APIs), chiral substances, represented by a single enantiomer, have dominated [2]. This trend continues to the present. For instance, 45 new drugs have been approved in the USA in 2015, 33 of which were monomeric chiral compounds and, with only one exception, were pure enantiomers [3]. According to the information provided in the review [4], 30 new chiral APIs of a monomeric nature were registered in USA in 2018, of which only two were approved as racemates.

Crystallization, employed in batch or continuous format, is used almost universally for the purification and isolation of solid crystalline APIs [5,6]. Crystallization is widely used for the deracemization of chiral APIs through the separation of their diastereomeric derivatives [7–9]. Compared with the classical methods for the preparation of non-racemic substances [10], direct methods of racemates resolution based on the preferential crystallization of one of the enantiomers from racemic solutions (less often melts) have a number of significant advantages [7,8,11]. The direct methods of resolution of the racemic APIs themselves or their racemic synthetic precursors have been used for quite some time [12]. In the early stages, this approach was applied mainly on an empirical basis. Recently, there has been a steady trend towards turning it into modern technology. This is expressed in the mathematization of the description of the process itself [13–15], in the increasingly sophisticated use of the phase diagram technique [16,17], in the designing of specific reactors for implementing one or another modification of the deracemization process [18,19], finally, in enlarging one-time downloads of racemic raw materials [20]. But with all the modern improvements, an indispensable condition for the implementation of a particular type of direct resolution is the crystallization of the racemic starting material in the form of a conglomerate (i.e., a mixture of enantiopure crystals). Additionally, the search for new conglomerates, in particular, structurally related to bioactive substances, still does not lend itself to strict forecasts.

Expectorant guaifenesin, 3-(2-methoxyphenoxy) propane-1,2-diol, the object of deracemization in [20], as well as in our earlier work [21], refers to chiral glycerol aromatic ethers ArOCH2CH(OH)CH2OH. This series is notable, on the one hand, in that among its representatives there are registered APIs (for example, guaifenesin, mephenesin, chlorphenesin [22]), as well as drug precursors with different activities [12,23–25]. On the other hand, in this series the phenomenon of spontaneous resolution of enantiomers during crystallization is much more common than average [26]. Thus, among the 2,6-, 2,3- and 3,5-dimethylphenyl ethers of glycerol, which serve as the precursors of APIs mexiletine [27], xibenolol [28,29], and metaxalone [30] (Scheme 1), the first two diols crystallize as conglomerates and were obtained by us in an enantiopure form by preferential crystallization.

**Scheme 1.** Chiral drugs, in the synthesis of which dimethyl substituted phenyl glycerol ethers are used.

The object of this study is another dimethylphenyl glycerol ether, 3-(3,4-dimethylphenoxy) propane-1,2-diol **1**, which we used in the synthesis of amino alcohols **2** and **3** (Scheme 2) [31]. Aminopropanol **2** hydrochloride coded as T0502-1048 was reported as a promising β2-adrenoceptor antagonist [32]. Furthermore, there are patent data according to which stereoisomers of 1-(3,4-dimethylphenoxy)-3-(morpholin-4-yl) propan-2-ol **3** show useful activities (but different for the racemate and individual enantiomers) in the treatment of neurodegenerative and neuromuscular disorders, as well as of Friedreich's ataxia [33].

**Scheme 2.** 3,4-Dimethylphenyl ether of glycerol **1** and related bioactive aminopropanols **2** and **3**.

Previously we have obtained diol **1** by Sharpless asymmetric dihydroxylation of 3,4-dimethylphenyl allyl ether [31]. We have noticed that the melting point of diol (*R*)-**1** (96–98 ◦C) was noticeably higher than that of *rac*-**1** (75–77 ◦C). This situation is characteristic of organic compounds prone to spontaneous resolution. For this reason, we decided to study the possibility of direct resolution of its racemate and find out the features of phase behavior for this substance.
