The methanol and ethanol solvates of 4-glutarato-N,N-diisopropyltryptamine

The structures of two solvates of the zwitterionic prodrug of the psychedelic 4-HO-DiPT are reported.


Chemical context
Psychedelic compounds continue to be a major research focus for treating conditions including depression, post-traumatic stress disorder (PTSD), Alzheimer's disease, and chronic pain (Carhart-Harris & Goodwin, 2017;Krediet et al., 2020;Vann Jones & O'Kelly, 2020;Ramaekers et al., 2021). Tryptamine compounds with chemical structures resembling that of the active product of magic mushrooms, psilocin (4-hydroxy-N,Ndimethyltryptamine; 4-HO-DMT), are of particular interest. This is due not just to their structural similarities to the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), but because many have desirable drug characteristics including oral availability, lowered susceptibility to monoamine oxidase (MAO) degradation, and short duration of action (Kuypers et al., 2019). The synthesis of prodrugs that undergo hydrolysis to produce 4-hydroxy derivatives of dialkyltryptamines are of increasing interest (Klein et al., 2021;Chadeayne et al., 2019a;Chadeayne, Pham, Reid et al., 2020;Naeem et al., 2022). 4-Hydroxy-N,N-diisopropyltryptamine (4-HO-DiPT) is one example of a psilocin analog, first synthesized in 1977, in which both methyl groups on the ethylamino moiety of psilocin are replaced with isopropyl groups (Repke et al., 1977). In early 2022, 4-HO-DiPT along with four other psychedelics were part of a proposal issued by the US Drug Enforcement Administration (DEA), requesting comments on reclassifying these compounds to Schedule I of the Controlled Substance Act. Due to a strong public response, the DEA withdrew the proposal before the hearing, which was scheduled for August (US DEA, January 14 & July 6, 2022a,b). 4-HO-DiPT is a serotonin-2A (5-HT 2A ) receptor agonist that, like psilocin, produces a head-twitch response (HTR) in mice, indicating its competence in producing psychedelic effects (Halberstadt et al., 2020). 4-HO-DiPT also interacts with the serotonin transporter (SERT) with IC 50 values in the low micromolar range, similar to 3,4-methylenedioxymethamphetamine (MDMA) (Rickli et al., 2016). 4-HO-DiPT has been reported as orally active at a 15-20 mg dose, with its profound psychedelic effects beginning within 15 minutes and lasting about 2-3 h (Shulgin & Shulgin, 2017).
4-HO-DiPT glutarate, a 'hemiester' prodrug of 4-HO-DiPT has been reported in the patent literature (Bryson, 2022). We have previously published work characterizing tryptamine compounds, highlighting the importance of single-crystal X-ray diffraction studies when characterizing tryptamine salts because they can occur in a variety of forms that are often not appreciated by other means of characterization (Chadeayne et al., 2019a,b;Sammeta et al., 2020;Pham et al., 2021;Naeem et al., 2022). To this end, we synthesized 4-glutarato-N,N-diisopropyltrypamine and report herein two crystalline forms of the compound as both its methanol and ethanol solvates.

Structural commentary
In the solid state, the compound exists as a zwitterion, with a protonated tertiary ammonium group and a deprotonated carboxylate of the glutarato group. Both of the solvate structures possess one zwitterionic molecule and one alcohol molecule in the asymmetric unit (Fig. 1). In the ethanol solvate, the alcohol molecule is disordered over two orientations in a 0.531 (11):0.469 (11) ratio. Both solvates have near planar indole units with r.m.s. deviations from planarity of 0.009 and 0.016 Å for the methanol and ethanol solvates, respectively. The glutarato units are also close to planar with r.m.s. deviations of only 0.061 and 0.071 Å . In both cases, the glutarato unit is nearly orthogonal to the indole plane, showing plane-to-plane twists of 90.99 (6) and 94.21 (8) . Likewise, the ethylamino arms are nearly orthogonal to the indole plane with C7-C8-C9-C10 angles of 90.2 (2) and 86.1 (3) . Both ethylamino arms demonstrate anti configurations, with C8-C9-C10-N2 angles of 179.92 (14) and 180.0 (2) . In both structures, the glutarato and ethylamino arms are turned to opposite sides of the indole. This differs from the structures observed in other zwitterionic indoles where intramolecular hydrogen bonding leads to two groups being on the same side of the aromatic rings (Naeem et al., 2022). The nature of the groups in this compound only allows for intermolecular interactions (vide infra) and having the groups on opposite sides of the indole is sterically preferred.

Supramolecular features
In both crystals, the zwitterionic molecules and alcohol solvents are held together by N + -HÁ Á ÁO À and O-HÁ Á ÁO hydrogen bonds that produce infinite two-dimensional networks parallel to the (100) plane. The most significant hydrogen bonds are N2-H2Á Á ÁO4 bonds between the diisopropyltryptammonium cation and the carboxylate anion of another zwitterionic molecule. These interactions form centrosymmetrical dimers, which form rings with graph-set notation of R 2 2 (28) (Etter et al., 1990). These dimers are shown in Fig. 2 The ring formed by the dimerization of two zwitterionic 4-glutarato-N,Ndiisopropyltryptamine molecules with graph set notation of R 2 2 (28). The image shown is from the methanol solvate. Hydrogen bonds are shown as dashed lines. H atoms not involved in hydrogen bonding are omitted for clarity. Symmetry code: (i) 1 À x, 1 À y, 1 À z.
The powder was recrystallized from boiling methanol to yield single crystals of the methanol solvate suitable for X-ray diffraction analysis. Slow evaporation of an ethanol solution of the powder produced single crystals of the ethanol solvate suitable for X-ray diffraction analysis.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. In the methanol solvate, hydrogen atoms H1, H2 and H5A were found in a difference-Fourier map and in the ethanol solvate, hydrogen atoms H1 and H2 were found in a difference-Fourier map. These hydrogens were refined isotropically, using DFIX restraints with N-H(indole) distances of 0.87 (1) Å , N-H(ammonium) distances of 0.90 (1) Å , and O-H distances of 0.99 (1) Å . Isotropic displacement parameters were set to 1.2U eq of the parent nitrogen atoms and 1.5U eq of the parent oxygen atom.   Table 1 Hydrogen-bond geometry (Å , ) for the methanol solvate.

Figure 3
The crystal packing of the methanol solvate (left) and the ethanol solvate (right) of 4-glutarato-N,N-diisopropyltryptamine, both shown along the a-axis.

5-[(3-{2-[Bis(propan-2-yl)azaniumyl]ethyl}-1H-indol-4-yl)oxy]-5-oxopentanoate methanol monosolvate (I)
Crystal data (7)   Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

5-[(3-{2-[Bis(propan-2-yl)azaniumyl]ethyl}-1H-indol-4-yl)oxy]-5-oxopentanoate ethanol monosolvate (II)
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (