The present invention relates to both the substance definition and synthesis of desoxyscalines with modified mescaline-like action to be used in substance-assisted psychotherapy.
Psychedelics are substances inducing unique subjective effects including dream-like alterations of consciousness, affective changes, enhanced introspective abilities, visual imagery, pseudo-hallucinations, synesthesia, mystical-type experiences, disembodiment, and ego-dissolution (Liechti, 2017; Passie et al., 2008).
Psychedelics, mainly lysergic acid diethylamide (LSD) and psilocin, are currently investigated as potential medications. First clinical trials indicate potential efficacy of LSD and psilocybin in addiction (Bogenschutz, 2013; Bogenschutz et al., 2015; Garcia-Romeu et al., 2019; Garcia-Romeu et al., 2015; Johnson et al., 2014; Johnson et al., 2016; Krebs et al., 2012), anxiety associated with life-threatening illness (Gasser et al., 2014; Gasser et al., 2015), depression (Carhart-Harris et al., 2021; Carhart-Harris et al., 2016a; Davis et al., 2021; Griffiths et al., 2016; Roseman et al., 2017; Ross et al., 2016), and anxiety (Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016). Several trials investigating therapeutic effects of LSD, psilocybin and other psychedelics are also ongoing, as can be seen on www.clinicaltrials.gov. There is also evidence that the psychedelic brew Ayahuasca which contains the active psychedelic substance N,N-dimethyltryptamine (DMT) (Dominguez-Clave et al., 2016) may alleviate depression (de Araujo, 2016; Dos Santos et al., 2016; Palhano-Fontes et al., 2019; Sanches et al., 2016). In contrast, there are no comparable therapeutic studies or elaborated concepts on the use of the psychedelic substance mescaline or related substances to treat medical conditions.
Although no psychedelic is currently licensed for medical use, psilocybin and LSD are used in special therapeutic-use programs (Schmid et al., 2021). Mescaline is a serotonergic psychedelic similar to LSD and psilocybin with comparable acute effects. Mescaline or its derivatives may be equally suitable to treat medical conditions. Specifically, existing psychedelic treatments such as LSD, psilocybin and DMT may not be suitable to be used in all patients considered for psychedelic-assisted therapy. The availability of several substances with different properties is important and the present lack thereof is a therapeutic problem which will further increase with more patients needing psychedelic-assisted therapy and an increase in demand for such treatment once the efficacy of first treatments will be documented in large clinical studies. For example, some patients may react with strong adverse responses to existing therapies such as psilocybin presenting with untoward effects including headaches, nausea/vomiting, anxiety, cardiovascular stimulation, or marked dysphoria. Thus, novel compounds with psychedelic-like action are needed.
Structurally, mescaline is a phenethylamine unlike LSD and psilocybin. LSD, psilocybin, and mescaline are all thought to induce their acute psychedelic effects primarily via their common stimulation of the 5-HT2A receptor. All serotonergic psychedelics including LSD, psilocybin, DMT, and mescaline are agonists at the 5-HT2A receptor (Rickli et al., 2016) and may therefore produce overall largely similar effects. However, there are differences in the receptor activation profiles and in the subsequent signal transduction pathway activation patterns between the substances that may induce different subjective effects. LSD potently stimulates the 5-HT2A receptor but also 5-HT2B/C, 5-HT1 and D1-3 receptors. Psilocin, i.e., the active metabolites present in the human body derived from the prodrug psilocybin, also stimulates the 5-HT2A receptor but additionally inhibits the 5-HT transporter (SERT). Mescaline binds in a similar, rather low concentration range to 5-HT2A, 5-HT2C, 5-HT1A and a2A receptors. In contrast to LSD, psilocybin and mescaline show no affinity for D2 receptors. Taken together, LSD can have greater dopaminergic activity than psilocybin and mescaline, psilocybin can have additional action at the SERT. Mescaline and its derivatives do not interact with the SERT in contrast to psilocybin. Taken together, the pharmacological profiles of LSD, psilocybin and mescaline show some differences, but it is not clear whether these are reflected by differences in their psychoactive profiles in humans. This is currently being investigated in a clinical study (www.clinicaltrials.gov: NCT04227756).
In humans, subjective effects or psychoactive doses of mescaline appear within 30 minutes, peak at 4 hours and dose-dependently last 10-16 hours. The plasma half-life is approximately 6 hours (Charalampous, 1966).
The acute subjective effects of psychedelics are mostly positive in most humans (Carhart-Harris et al., 2016b; Dolder et al., 2016; Dolder et al., 2017; Holze et al., 2019; Schmid et al., 2015). However, there are also negative subjective effects such as anxiety in many humans likely depending on the dose used, personality traits (set), the setting (physical and social environment) and other factors. The induction of an overall positive acute response to the psychedelic is critical because several studies showed that a more positive experience is predictive of a greater therapeutic long-term effect of the psychedelic (Garcia-Romeu et al., 2015; Griffiths et al., 2016; Ross et al., 2016). Even in healthy subjects, a more positive acute response to a psychedelic including LSD has been shown to be linked to more positive long-term effects on well-being (Griffiths et al., 2008; Schmid et al., 2018).
Mescaline has relevant acute side effects to different degrees depending on the subject treated and including increased blood pressure, nausea and vomiting, negative body sensations, and dysphoria. Such side effects of a substance are often linked to its interactions with pharmacological targets. For example, interactions with adrenergic receptors may result untoward clinical cardio-stimulant properties. Additionally, changes in the relative activation profile of serotonin 5-HT receptors and other targets change the quality of the psychoactive effects. Alterations in the binding potency, the binding mode, and the potency in activating the subsequent signaling pathways at 5-HT2A receptors as well as the molecule's lipophilicity may mostly determine the clinical dose to induce psychoactive effects. Alterations changing the metabolic stability of the compounds can also change the duration of action of the substance significantly.
New mescaline-based derivatives are needed to provide substances with an improved effect profile such as, but not limited to, more positive effects, less adverse effects, different qualitative effects, and shorter or longer duration of acute effect.
The present invention provides for a composition of a compound represented by
Ralpha1 and Ralpha2 are, independently, hydrogen, deuteron, methyl, ethyl, deuterated methyl (D1-D3), or deuterated ethyl (D1-D5), and
R′ is
C1-C5 branched or unbranched alkyl with the alkyl optionally substituted with F1-F11 fluorine and/or D1-D11 deuteron substituents up to a fully fluorinated and/or deuterated alkyl,
C3-C6 cycloalkyl optionally and independently substituted with one or more substituents such as F1-F15 fluorine and/or D1-D15 deuteron and/or C1-C2 alkyl,
(C3-C6 cycloalkyl)-C1-C2 branched or unbranched alkyl optionally substituted with one or more substituents such as F1-F15 fluorine and/or D1-D15 deuteron and/or C1-C2 alkyl,
C2-C5 branched or unbranched alkenyl with E or Z or cis or trans double bond configuration, where any of the carbons of the branched or unbranched alkenyl substituent is optionally substituted independently and in any combination with one or more C1-C2 alkyl, with F1-F13 fluorine, with D1-D13 deuteron, with C2 alkenyl or with aryl or heteroaryl bearing no up to any number of ether, thioether, halogen, alkyl, fluorinated alkyl, alkenyl, alkynyl or nitrogen-containing substituents,
C2-C5 branched or unbranched alkynyl where any of the carbons of the branched or unbranched alkynyl substituent is optionally substituted independently and in any combination with one or more C1-C2 alkyl, with F1-F11 fluorine, with D1-D11 deuteron, with C2 alkenyl or with aryl or heteroaryl bearing no up to any number of ether, thioether, halogen, alkyl, fluorinated alkyl, alkenyl, alkynyl or nitrogen-containing substituents,
any halogen or
a nitrogen-containing substituent such as CN or NO2.
The present invention provides a method of changing neurotransmission, by administering a pharmaceutically effective amount of a compound of
The present invention also provides for a method of treating a patient having adverse reactions to psychedelics by administering a desoxyscaline derivative to the patient, and avoiding adverse effects present with psychedelics.
The present invention also provides for a method of changing neurotransmission of an individual, by administering a desoxyscaline derivative, and changing neurotransmission in the individual.
Other advantages of the present invention are readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
The present invention provides for desoxyscaline derivatives. More specifically, the present invention provides for a composition of a compound represented by
Ralpha1 and Ralpha2 are, independently, hydrogen, deuteron, methyl, ethyl, deuterated methyl (D1-D3), or deuterated ethyl (D1-D5), and
R′ is
C1-C5 branched or unbranched alkyl with the alkyl optionally substituted with F1-F11 fluorine and/or D1-D11 deuteron substituents up to a fully fluorinated and/or deuterated alkyl,
C3-C6 cycloalkyl optionally and independently substituted with one or more substituents such as F1-F15 fluorine and/or D1-D15 deuteron and/or C1-C2 alkyl,
(C3-C6 cycloalkyl)-C1-C2 branched or unbranched alkyl optionally substituted with one or more substituents such as F1-F15 fluorine and/or D1-D15 deuteron and/or C1-C2 alkyl,
C2-C5 branched or unbranched alkenyl with E or Z or cis or trans double bond configuration, where any of the carbons of the branched or unbranched alkenyl substituent is optionally substituted independently and in any combination with one or more C1-C2 alkyl, with F1-F13 fluorine, with D1-D13 deuteron, with C2 alkenyl or with aryl or heteroaryl bearing no up to any number of ether, thioether, halogen, alkyl, fluorinated alkyl, alkenyl, alkynyl or nitrogen-containing substituents,
C2-C5 branched or unbranched alkynyl where any of the carbons of the branched or unbranched alkynyl substituent is optionally substituted independently and in any combination with one or more C1-C2 alkyl, with F1-F11 fluorine, with D1-D11 deuteron, with C2 alkenyl or with aryl or heteroaryl bearing no up to any number of ether, thioether, halogen, alkyl, fluorinated alkyl, alkenyl, alkynyl or nitrogen-containing substituents,
any halogen or
a nitrogen-containing substituent such as CN or NO2.
In addition to the aforementioned description of compounds represented by
Ralpha1 and Ralpha2 beyond C2, i.e., longer than methyl or ethyl, are not recommended as they result in compounds that are much less or even completely not pharmacologically active at the target site (5-HT2A receptor).
The compounds represented by
Furthermore, and without loss of generality and elaborating on details, the invention includes any prodrugs, i.e., any chemical modification of the described compounds that is (metabolically) converted to the described compound in the human body (circulation).
The general chemical terms used for
Those skilled in the art will appreciate that certain of the compounds of the present invention have at least one chiral carbon, and can therefore exist as a racemate, as individual enantiomers or diastereomers, and as mixtures of individual enantiomers or diastereomers in any ratio. For example, individual enantiomers of compounds of the invention are illustrated in
Those skilled in the art will also appreciate that certain of the compounds of the present invention have at least one double bond leading, depending on the double bond's substituents, to cis/trans or E/Z configurational isomerism. While it is a preferred embodiment of the invention that the compounds of the invention exist are used as pure configurational isomers, the present invention also contemplates the compounds of the invention existing in individual cis/trans or E/Z mixtures, respectively.
The individual enantiomers and diastereomers can be prepared by chiral chromatography of the racemic or enantiomerically or diastereomerically enriched amine, or fractional crystallization of salts prepared from racemic- or enantiomerically- or diastereomerically-enriched amine and a chiral acid. Alternatively, the free amine can be reacted with a chiral auxiliary and the enantiomers or diastereomers separated by chromatography or crystallization followed by removal of the chiral auxiliary to regenerate the free amine. Furthermore, separation of enantiomers or diastereomers can be performed at any convenient point in the synthesis of the compounds of the invention. The compounds of the invention can also be prepared by application of chiral syntheses. The compound itself is a pharmacologically acceptable acid addition salt thereof.
The individual cis/trans or E/Z configurational isomers can be accessed by either selective synthesis or by separation techniques addressing the different physicochemical properties of the configurational isomers by applying techniques such as chromatography, crystallization, distillation, or extraction.
In patients that have adverse reactions to other psychedelics, desoxyscaline derivatives can be useful as alternative treatments. In some patients, desoxyscalines can also be useful because another experience than made with mescaline, psilocybin or LSD is necessary or because a patient is not suited for therapy with these existing approaches a priori. Thus, desoxyscaline derivatives of
Based on structural relations, the compounds of
This assumption is further emphasized by the only known and described desoxyscaline, a compound named “DESOXY”, which has shown psychoactive effects in human (Shulgin et al., 1991).
The present invention provides compounds of
Therefore, the present invention provides a method of changing neurotransmission, by administering a pharmaceutically effective amount of a compound of
The neuronal interaction of compounds represented in
The intensity and quality of the psychoactive effect including psychedelic or empathogenic effects, the quality of perceptual alterations such as imagery, fantasy and closed or open eyes visuals, and body sensation changes, the pharmacologically active doses, can be different or similar to that of mescaline.
Mescaline and its 4-alkoxy homologs as well as its amphetamine counterparts are known to interact with serotonin 5-HT2A receptors (Kolaczynska, LUthi, Trachsel, Hoener, Liechti,
Some of the invented desoxyscaline compounds represented by
Not only receptor interactions can change by structural modifications represented in
The structure of 4-oxygen-free mescaline derivatives represented in
Desoxyscaline derivatives can include 4-oxygen-free substitution variations of the phenethylamine structure forming “desoxyscalines” or can include the addition of the methylation of the alpha carbon of the phenethylamine structure to form amphetamines also containing the above 3,4,5-substitutions on the phenyl ring to form “3C-desoxyscalines” (Shulgin et al., 1991; Trachsel et al., 2013). Further on, the aforementioned alpha carbon can also be substituted, independently and in any combination, with one or two deuterons, methyl, ethyl, deuterated methyl (D1-D3), or deuterated ethyl (D1-D5) groups. Several new such desoxyscaline derivatives represented in
While all the desoxyscaline derivatives represented in
The synthetic access to 4-substituted 3,5-dimethoxyphenethylamines and their amphetamine counterparts is rather challenging, except for 4-alkoxy derivatives (4-homoscalines) that have been described thoroughly by, e.g., the inventors earlier (provisional patent application entitled: “mescaline derivatives with modified action”, U.S. 63/153,317, filing date 2/24/2021). A general strategy to access some of the compounds of the field of invention has been set up as follows. The direct introduction of the 4-substituent could be achieved by using the ipso substitution method described by Azzena et al. (Azzena et al., 1990). Following this, 3,4,5-trimethoxybenzaldehyde dimethyl acetal was treated with elemental sodium in THF anhydr. For a prolonged time and then the intermediate was allowed to react with an alkyl halide. Acidic hydrolysis of the carbonyl protected intermediate afforded the corresponding benzaldehyde. Another route of access of such benzaldehydes was described by Comins et al. (Comins et al., 1984), wherein an in situ carbonyl protection of the 4-unsubstituted 3,5-dimethoxybenzaldehyde and subsequent ortho-lithiation was applied for introduction of a 4-alkyl substituent. The preparation of the nitroolefins from these 4-alkylated benzaldehydes was achieved by the reaction with nitromethane or nitroethane, generally referred as the Henry reaction, using n-butylamine and acetic acid as well as molecular sieves, an advantageous catalytic system described earlier by the inventors (provisional patent application entitled: “mescaline derivatives with modified action”, U.S. 63/153,317, filing date 2/24/2021). The nitroolefins are reduced to the corresponding desoxyscalines or 3C-desoxyscalines by using lithium aluminum hydride (LAH) or alane generated in situ from LAH and concentrated sulfuric acid, in analogy to earlier works (Shulgin et al., 1991; Trachsel, 2002).
However, the synthetic access invented and described before is not always suitable for accessing compounds represented in
Any of the unsaturated 4-substituent introduced as described before can also be reduced by classical conditions such as the use of hydrogen and a catalyst such as palladium on activated charcoal to access the corresponding 4-alkylated derivatives.
4-fluorinated vinyl or 4-fluorinated alkyl substituted derivatives are yet another type of compounds invented and represented by
The group presented in the preparation section, namely compounds 6a to 6c, 7a to 7d, 11 to 12, 19a to 19b, 20a to 20f, 22a to 22c and 30 to 33, is illustrative of desoxyscaline derivatives represented in
A small selection of the synthesized desoxyscalines and their amphetamine congeners were investigated at the key target for psychoactive effects in vitro (Trachsel, Hoener, Liechti,
Additional receptors such as the serotonergic 5-HT1A and 5-HT2C or dopaminergic D2 receptors are thought to moderate the effects of psychedelics (Rickli et al., 2016). Although some psychedelics like psilocybin do not directly act on dopaminergic receptors, they have nevertheless some dopaminergic properties by releasing dopamine in the striatum (Vollenweider et al., 1999) likely via 5-HT1A receptor activation (Ichikawa et al., 2000). Furthermore, LSD has activity at D2 receptors (Rickli et al., 2016) and some of its behavioral effect may be linked to this target (Marona-Lewicka et al., 2005).
Activity of compounds at monoamine transporters are thought to mediate MDMA-like empathogenic effects (Hysek et al., 2012). Importantly, mescaline is a very weak 5-HT2A receptor ligand and high doses are needed to induce psychoactive effects in humans. However, despite its low potency, mescaline can have extraordinarily strong psychedelic effects in humans at high doses and the same is likely the case for the substances developed within the present invention although 10× to 20× higher potency is also possible in some desoxyscaline compounds, to be evaluated in detail clinically. Key results of the preliminary pharmacological profiling of the compounds described herein were:
Some of the desoxyscaline derivatives represented in
Together, the in vitro profiles of mescaline and its desoxy derivatives represented in
There are several problems when using mescaline that can be solved using the compounds described herein. Namely, high doses of mescaline (200-800 mg) are needed to induce a full psychedelic experience. Derivatives represented in
The compounds represented by
The present invention therefore also provides for a method of treating a patient having adverse reactions to psychedelics by administering a desoxyscaline derivative to the patient, and avoiding adverse effects present with psychedelics.
The group presented in the preparation section, namely compounds 6a to 6c, 7a to 7d, 11 to 12, 19a to 19b, 20a to 20f, 22a to 22c and 30 to 33 (chemical structures see
The compounds according to the invention and represented in
The compounds, according to the invention and represented in
The compounds, according to the invention and represented in
The compounds, according to the invention and represented in
The aforementioned characteristics can be modified in a progressive way by the introduction of one or more fluorine atoms, by one or more deuterium atoms and by one or more alkyl groups, independently as well as in any combination, to the 4-alkyl, 4-cycloalkyl, 4-cycloalkylalkyl, 4-alkenyl or 4-alkynyl group in any position of these substituents (position 4 represented as “R” in
The modified properties can be tailored and applied individually to the patient's need. This is not only targeted by changing the compound's receptor profile but also greatly by the modification of ADME (Absorption, Distribution, Metabolism and Excretion) via the introduction of more, similar or less liable 4-substituents “R” in compounds represented in
A general access to the desoxyscalines and 3C-desoxyscalines is outlined in
Aldehydes containing 4-fluorinated vinyl groups or 4-fluorinated alkylated substituents can also be accessed by the illustrative reaction of 3,5-dimethoxy-4-formyl-benzaldehyde dimethylacetal (23,
The 4-alkylated 3,5-dimethoxybenzaldehydes are then subjected to an aldol condensation, namely the Henry reaction, by mixing any of these aldehydes with a nitroalkane such as nitromethane, nitroethane or 1-nitropropane and a catalyst such as an organic salt or a mixture of an organic base and an organic acid, most favorably n-butylamine and acetic acid (such as illustrated in
As continuation of the illustrative invention, the obtained nitroalkenes are dissolved in an inert solvent such as tetrahydrofuran or diethyl ether and added to a suspension of alane generated in situ from allowing to react lithium aluminum hydride (LiAlH4) with concentrated sulfuric acid (H2SO4) in a similar solvent (such as illustrated in
In order to access alkene derivatives such as represented by compounds 19a-b and 20a-f (illustrated in
To access compounds represented in
Detailed Description of the Chemical Preparation of the Compounds
General. NMR was performed on a Bruker NMR (1H: 300 MHz and 19F: 282 MHz) at ambient temperature. Reaction controls were performed by silica gel TLC (F254; UV detection) and HPLC UV & MS (Agilent 1100, Waters SQD).
General method for the ipso-substitution (4-demethoxy-alkylsubstitution). A solution of 4.00 g (17 mmol) 3,4,5-trimethoxybenzaldehyde dimethyl acetal (2) in 20 mL THF anhydr. Was added within 3 minutes to 1.2 g (52 mmol) freshly cut sodium in 60 mL THF anhydr. Under ice-cooling and a nitrogen atmosphere. The ice bath was removed, and the mixture was stirred for 22 hours whereby the color changed from clear to yellow and progressively to dark red. Next, the mixture was cooled with an ice-bath and 25 mmol neat alkyl halide were added over a course of 5 minutes whereby the color changed towards orange and a fine suspension was formed (NaX). The ice-bath was removed and stirring at ambient temperature was continued for 2 hours. In order to remove most of the remaining sodium solids, the mixture was carefully and quickly decanted to another flask applying a continuous nitrogen stream and further stirred under nitrogen and ice-cooling. Decomposition of excess sodium: the above remaining sodium metal was held under THF anhydr. (40 mL were added) and nitrogen and then were carefully decomposed by dropwise addition of 2.5 mL water in 2.5 mL THF under ice-cooling. After 30 minutes, no more sodium was visible, and the mixture was discarded. In the meantime, the above reaction mixture was quenched by adding dropwise 20 mL water. Next, 50 mL diethyl ether (Et2O) were added and the layers were separated. The org. layer was washed once with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated in vacuo to get the 4-alkyl-3,5-dimethoxybenzaldehyde dimethyl acetal as crude product. This was dissolved in 50 mL of THF/HCl 1M aq. 1:1 and stirred for 4 hours. The mixture was extracted with diethyl ether (3×30 mL) and the combined org. extracts were washed with water (2×30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was either recrystallized or purified by silica gel chromatography.
General method for the nitro olefination (modified Henry reaction). The aryl aldehyde is dissolved in nitromethane or nitroethane under slight warming. Next, molecular sieves 3 Å (where applied), n-butylamine and acetic acid is added, and the mixture is gently stirred at 60-110° C. under an inert atmosphere. When the reaction is complete (monitoring by TLC, i.e., dichloromethane) the mixture is separated from the molecular sieves and concentrated in vacuo. The residue is either recrystallized from an appropriate solvent or purified by dissolving it in a small amount of organic solvent and eluting it with organic solvent through a short-path silica gel column. The eluate obtained is concentrated in vacuo. Usually, the trans-nitroolefin is obtained. In some cases, minor amounts of the cis-nitroolefin were observed as well; upon reduction (see next step) both cis and trans isomers lead to the same products and thus no separation is required.
General method for the alane-promoted reduction of the nitroolefins. To an ice-cooled suspension of lithium aluminum hydride (LiAlH4) in tetrahydrofuran (THF) anhydr. Is added dropwise sulfuric acid (H2SO4) 95-99% under an inert atmosphere and vigorous stirring. When hydrogen evolution has ceased the mixture is stirred for another 5-10 minutes. Next, a solution of the nitroolefin in THF anh. is added under ice-cooling at such a rate that the reaction becomes not too violent, and the reaction temperature stays below 20-30° C. After completion of addition the mixture is brought to a gentle reflux for 3-5 minutes, and then again cooled with an ice-bath. Next, the mixture is cautiously quenched by successive and dropwise addition of anhydr. Isopropanol (IPA) and then 2M sodium hydroxide solution (NaOH). Occasionally, THF is added to keep the mixture stirable. When hydrolysis is complete, the mixture is filtered off and the filter cake is rinsed well with THF. The filtrate is concentrated in vacuo; purging the apparatus can be performed by applying an inert gas such as nitrogen or argon which prevents the formation of any unwanted carbamates.
General method for the hydrochloride salt formations. The base of the desoxyscaline or 3C-desoxyscaline is dissolved in approx. 30-50 times the mass of anhydr. Diethyl ether containing 0.5% anhydr. IPA. The well stirred solution is cautiously neutralized by the addition of 2M anhydr. HCl in diethyl ether or 4M anhydr. HCl in dioxane and occasional cooling; the pH should not be far from neutral in order to not get a sticky mass during processing. The suspension obtained is filtered off, rinsed with diethyl ether, and dried in vacuo to get the final hydrochloride product.
3,4,5-Trimethoxybenzaldehyde dimethyl acetal, 2. To a stirred suspension of 0.60 g ammonium chloride in 80 mL methanol anhydr. And 80 mL trimethyl orthoformate were added 40.0 g (0.204 mol) 3,4,5-trimethoxybenzaldehyde under nitrogen in one portion. The mixture was heated to reflux for 2.5 hours. After cooling to approx. 10° C., 6.0 mL NEt3 was added within 2 minutes, the mixture was further stirred for 5 minutes and then quenched with 200 mL water. The mixture was extracted with Et2O (3×120 mL), and the combined org. extracts were washed with sat. aq. NaHCO3 (1×120 mL) and water (1×120 mL) where the latter step should be performed quickly since there seemed to be a slight temperature increase during washing. The org. layer was dried over Na2SO4 and concentrated in vacuo at up to 60° C. to get 49.54 g (100.2%) crude product as an orangish oil. For further purification this could be distilled at 0.5 mbar (bath 230° C., head temp: 140-145° C.) but for several batches it was proven not to be necessary for the subsequent reactions. 1H-NMR (DMSO-d6; Note: in CDCl3 the product decomposes extremely quickly due to traces of HCl): 3.25 (s, 6H, CH(CH3)2), 3.66 (s, 1 MeO), 3.78 (s, 2MeO), 5.30 (s, CH(Ome)2), 6.67 (s, 2 arom. H).
3,5-Dimethoxy-4-methylbenzaldehyde, 3a. Adapted from (Comins et al., 1984). To a solution of 0.670 mL (6.6 mmol, 1.1 eq) N-methylpiperazine in 20 mL THF anhydr. Were added 2.55 mL (6.3 mmol, 1.05 eq) butyl lithium (BuLi) 2.5M within 2 minutes under nitrogen at −20° C. After stirring for 15 minutes a solution of 1.00 g (6.01 mmol) 3,5-dimethoxybenzaldehyde in 5 mL THF anhydr. Was added within 2 minutes and stirring at this temperature was continued for 20 minutes. Next, 7.2 mL (18.1 mmol, 3 eq) BuLi 2.5M were added within 4 minutes and the clear colorless solution was allowed to stand at −20° C. for 24 hours (freezer). The slight yellowish clear solution was re-submerged into a cooling bath at −20° C., and under stirring 2.25 mL (36.1 mmol, 6 eq) neat methyl iodide was added dropwise (3 minutes) whereby the mixture remained clear. After 30 minutes the cooling bath was removed, and the mixture allowed to reach ambient temperature; during this time, the mixture became gel-like and occasionally was non-stirrable and a sticky mass was formed on the bottom. Next, 50 mL ice-cold HCl 2M and then 30 mL Et2O were added, and the layers were separated. The organic layer was washed subsequently with water (3×20 mL) and brine (1×20 mL), dried over MgSO4 and concentrated in vacuo to get 1.07 g (99%) of a yellowish solid with sufficient purity. 1H-NMR (CDCl3): 2.18 (s, ArCH3), 3.92 (s, 2MeO), 7.08 (s, 2 arom. H), 9.93 (s, CHO).
3,5-Dimethoxy-4-ethylbenzaldehyde, 3b. According to the general method described (ipso-substitution), 3.19 g crude aldehyde were obtained. This was further purified by silica gel chromatography (coated on silica gel using a minimum amount of dichloromethane, elution with hexane/ethyl acetate 9/1). Yield: 1.67 g (50.6%) product 3b as a white solid. 1H-NMR (CDCl3): 1.11 (t, CH2CH3), 2.73 (q, CH2CH3), 3.91 (s, 2MeO), 7.08 (s, 2 arom. H), 9.92 (s, CHO).
3,5-Dimethoxy-4-propylbenzaldehyde, 3c. According to the general method described (ipso-substitution; 1.8 times higher scale), 6.1 g crude aldehyde were obtained. This was further purified by silica gel chromatography (coated on silica gel using a minimum amount of dichloromethane, elution with hexane/ethyl acetate 9/1). Yield: 3.42 g (54.2%) product 3c as a white solid. 1H-NMR (CDCl3): 0.93 (t, CH2CH2CH3), 1.52 (m, CH2CH2CH3), 2.67 (t, CH2CH2CH3), 3.86 (s, 2MeO), 7.05 (s, 2 arom. H), 9.90 (s, CHO).
4-Allyl-3,5-dimethoxybenzaldehyde, 3d. According to the general method described (ipso-substitution; 1.25 times higher scale), 4.56 g crude aldehyde were obtained. This was further purified by silica gel chromatography (coated on silica gel using a minimum amount of dichloromethane, elution with hexane/ethyl acetate 995/5). Yield: 0.40 g (9.4%) product 3d as a yellowish oil. 1H-NMR (CDCl3): 3.48 (dm, ArCH2), 3.92 (s, 2MeO), 4.95-5.04 (m, 2H, H2C═C), 5.93 (m, H2C═CH), 7.10 (s, 2 arom. H), 9.94 (s, CHO).
4-(2,2-Difluorovinyl)-3,5-dimethoxybenzaldehyde, 24. 1.) Preparation of the intermediate 23. A solution of 7.35 g (30.33 mmol) 3,4,5-trimethoxybenzaldehyde dimethyl acetal (2) in 30 mL THF anhydr. Was added within 3 minutes to 2.13 g (92.8 mmol) freshly cut sodium in 130 mL THF anhydr. Under ice-cooling and a nitrogen atmosphere. The ice bath was removed, and the mixture was stirred for 20 hours whereby the color changed from clear to yellow and progressively to dark red. Next, the mixture was cooled with an ice-bath and 3.52 mL neat DMF anhydr. (45.5 mmol) were added over a course of 5 minutes. The ice-bath was removed and stirring at ambient temperature was continued for 1 hour. In order to remove most of the remaining sodium solids, the mixture was carefully and quickly decanted to another flask and further stirred under nitrogen and ice-cooling. Decomposition of excess sodium: the above remaining sodium metal was held under THF anhydr. (60 mL were added) and nitrogen and then were carefully decomposed by dropwise addition of 5 mL water in 5 mL THF under ice-cooling. After some 30 minutes no more sodium was visible, and the mixture was discarded. In the meantime, the above reaction mixture was quenched by adding dropwise 70 mL water. Next, 100 mL tert-butylmethylether (TBME) were added and the layers were separated; to ease phase separation some 50 mL sat. NaHCO3 solution were added. The aq. Layer was extracted with additional TBME (3×50 mL), and the combined org. layers were dried over Na2SO4 and concentrated in vacuo to get 6.33 g yellow solid. This was triturated in 10 mL ice-cold isopropanol, filtered off and the filter cake was rinsed with a minimal amount of additional ice-cold isopropanol and dried in vacuo to get 3.66 g (50.3%) of the intermediate 3,5-dimethoxy-4-formylbenzaldehyde dimethyl acetal (23) as a white solid. 1H-NMR (DMSO-d6; Note: in CDCl3 the product decomposes extremely quickly due to traces of HCl): 3.29 (s, 6H, CH(CH3)2), 3.84 (s, 2MeO), 5.37 (s, CH(Ome)2), 6.73 (s, 2 arom. H), 10.34 (s, CHO). 2.) Preparation of the Wittig reagent (triphenylphosphonio)difluoroacetate (Zheng et al., 2013): In a 250 mL flask, 31.5 g (120 mmol) triphenylphosphine and 25.6 g (120 mmol) potassium bromodifluoroacetate were placed and mixed with DMF anhydr. Under nitrogen at ambient temperature. The solution was stirred for 23 hours whereby a suspension was formed progressively (product plus KBr). The suspension was filtered off, and the solid was washed with DMF (2×10 mL), H2O (2×10 mL) and Et2O (3×20 mL), and finally dried in vacuo at 40° C. for 20 hours to get 34.1 g (79.8%) (triphenylphosphonio)difluoroacetate as a white powder. 1H-NMR (CD3OD) 7.75-7.81 (m, 6H), 7.86-7.98 (m, 9H). 19F-NMR (CD3OD) −96.00 (d, 2F, J=95.9 Hz). 3.) Wittig reaction to access aldehyde 24. A mixture of 1.8 g (7.49 mmol) 3,5-dimethoxy-4-formylbenzaldehyde dimethyl acetal (23) and 5.4 g (15.0 mmol) (triphenylphosphonio)difluoroacetate in 20 mL DMF anhydr. Was heated to 80° C. under nitrogen for 16 hours. Next, the mixture was cooled to ambient temperature and diluted with 150 mL dichloromethane (DCM), washed with water (2×70 mL), half-saturated NaHCO3 solution (1×70 mL) and again with water (1×70 mL). The org. layer was dried over Na2SO4, directly filtered through a small silica gel pad (ca. 1 cm height) and the pad was rinsed with additional DCM. The combined filtrates were concentrated in vacuo to get 6.4 g crude 4-(2,2-difluorovinyl)-3,5-dimethoxybenzaldehyde dimethyl acetal as intermediate to be used directly in the next step. Thus, the residue was dissolved in 50 mL THF, and then 100 mL water and 50 mg pTsOH were added. The mixture was vigorously stirred at 80° C. for 30 min, cooled to ambient temperature and diluted with 150 mL ethyl acetate (EtOAc). The layers were separated, and the org. layer was washed with water (4×50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc, from 95/5 to 7/1) to get 1.68 g (98.2%) product 24 as a white solid. 1H-NMR (CDCl3): 3.93 (s, 2MeO), 5.25 (dd, 3J(H,F)=27 Hz and 3.0 Hz, F2CCH), 7.09 (s, 2 arom. H), 9.93 (s, CHO). 19F-NMR (CDCl3): −74.83 (d, 1F, J=19.7 Hz), −82.27 (d, 1F, J=19.7 Hz).
3,5-Dimethoxy-4-(2,2,2-trifluoroethyl)benzaldehyde, 25. To a solution of 1.54 g (6.75 mmol) 4-(2,2-difluorovinyl)-3,5-dimethoxybenzaldehyde in 7 mL THF anhydr. Were added 7.0 mL 1M tetrabutylammonium fluoride (TBAF) in THF and the mixture was heated to 50° C. under nitrogen. After 1.5 hours another 0.7 mL 1M TBAF in THF were added and heating was continued for another 2.5 hours. Next, the mixture was cooled to ambient temperature, poured into 50 mL water and extracted with EtOAc (1×100 mL). The org. layer was washed with water (2×50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in a minimal amount of DCM and purified by silica gel chromatography (hexane/EtOAc, from 9/1 to 4/1) to get 0.910 g (51.9%) product 25 as a white solid. 1H-NMR (CDCl3): 3.58 (q, 3J(H,F)=10.8 Hz, F3CCH2), 3.92 (s, 2MeO), 7.09 (s, 2 arom. H), 9.94 (s, CHO). 19F-NMR (CDCl3): −64.51 (s, 3F).
3,5-Dimethoxy-4-methyl-β-nitrostyrene, 4a. According to the general method described, from 0.55 g 3a, 0.6 mL nitromethane, 22 μL butylamine, 22 μL acetic acid and 0.30 g molecular sieves, 30 minutes at 90° C. Yield: 0.33 g (48.5%) 4a as a yellow solid. 1H-NMR (CDCl3): 2.15 (s, ArCH3), 3.89 (s, 2MeO), 6.71 (s, 2 arom. H), 7.60 (d, CHNO2), 7.99 (d, CH═CHNO2). A small second signal set (˜4%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002)). Upon reduction, this leads to the same product as the trans-isomer and thus it was not necessary to remove.
1-(3,5-Dimethoxy-4-methylphenyl)-2-nitropropene, 5a. According to the general method described, from 0.48 g 3a, 0.50 mL nitroethane, 204 butylamine, 204 acetic acid and 0.20 g molecular sieves, 90 minutes at 90° C. Yield: 0.34 g (53.9%) 5a as a yellow solid. 1H-NMR (CDCl3): 2.12 (s, ArCH3), 2.49 (d, MeC), 3.85 (s, 2MeO), 6.59 (s, 2 arom. H), 8.07 (s, CH═C). A small second signal set (˜5%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002)). Upon reduction, this leads to the same product as the trans-isomer and thus it was not necessary to remove.
3,5-Dimethoxy-4-ethyl-β-nitrostyrene, 4b. According to the general method described, from 0.92 g 3b, 1.0 mL nitromethane, 364 butylamine, 364 acetic acid and 0.40 g molecular sieves, 40 minutes at 90° C. Yield: 0.96 g (85.5%) 4b as a yellow solid. 1H-NMR (CDCl3): 1.10 (t, CH2CH3), 2.71 (q, CH2CH3), 3.88 (s, 2MeO), 6.71 (s, 2 arom. H), 7.60 (d, CHNO2), 7.99 (d, CH═CHNO2). A small second signal set (˜5%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002)). Upon reduction, this will lead to the same product as the trans-isomer and thus it was not necessary to remove.
1-(3,5-Dimethoxy-4-ethylphenyl)-2-nitropropene, 5b. According to the general method described, from 0.70 g 3b, 0.70 mL nitroethane, 284 butylamine, 284 acetic acid and 0.35 g molecular sieves, 90 minutes at 90° C. Yield: 0.67 g (74%) 5b as a yellow solid. 1H-NMR (CDCl3): 1.09 (t, CH2CH3), 2.49 (d, MeC), 2.68 (q, CH2CH3), 3.84 (s, 2MeO), 6.60 (s, 2 arom. H), 8.07 (s, CH═C). A small second signal set (˜6%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002). Reduction, this leads to the same product as the trans-isomer and thus it was not necessary to remove.
3,5-Dimethoxy-4-propyl-β-nitrostyrene, 4c. According to the general method described, from 2.00 g 3c, 2.0 mL nitromethane, 62 μL butylamine, 62 μL acetic acid and 1.0 g molecular sieves, 40 minutes at 90° C. Yield: 2.04 g (84.6%) 4c as a yellow solid. 1H-NMR (CDCl3): 0.95 (t, CH2CH2CH3), 1.51 (m, CH2CH2CH3), 2.64 (t, CH2CH2CH3), 3.87 (s, 2MeO), 6.68 (s, 2 arom. H), 7.58 (d, CHNO2), 7.97 (d, CH═CHNO2). A small second signal set (˜8%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002)). Upon reduction, this leads to the same product as the trans-isomer and thus it was not necessary to remove.
1-(3,5-Dimethoxy-4-propylphenyl)-2-nitropropene, 5c. According to the general method described, from 1.30 g 3c, 1.3 mL nitroethane, 52 μL butylamine, 52 μL acetic acid and 0.7 g molecular sieves, 105 minutes at 90° C. Yield: 1.09 g (65.8%) 5c as a yellow solid. 1H-NMR (CDCl3): 0.99 (t, CH2CH2CH3), 1.53 (m, CH2CH2CH3), 2.52 (d, MeC), 2.66 (t, CH2CH2CH3), 3.86 (s, 2MeO), 6.62 (s, 2 arom. H), 8.08 (s, CH═C). A small second signal set (˜7%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002)). Upon reduction, this leads to the same product as the trans-isomer and thus it was not necessary to remove.
1-(4-Allyl-3,5-dimethoxyphenyl)-2-nitropropene, 5d. According to the general method described, from 0.38 g 3d, 0.40 mL nitroethane, 15 μL butylamine, 15 μL acetic acid and 0.20 g molecular sieves, 90 minutes at 90° C. Yield: 0.30 g (62.0%) 5d as a yellow solid. 1H-NMR (CDCl3): 2.49 (d, MeC), 3.43 (dm, ArCH2), 3.84 (s, 2MeO), 4.92-5.03 (m, 2H, H2C═C), 5.92 (m, H2C═CH), 6.60 (s, 2 arom. H), 8.06 (s, CH═C). A small second signal set (˜3%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002)). Upon reduction, this leads to the same product as the trans-isomer and thus it was not necessary to remove.
4-Bromo-3,5-dimethoxy-β-nitrostyrene, 9. According to the general method described, from 15.0 g 4-bromo-3,5-dimethoxybenzaldehyde (8; commercially available), 25 mL nitromethane, 0.60 mL butylamine, 0.60 mL acetic acid and 2.5 g molecular sieves, 35 minutes at 90° C. Yield: 16.1 g (89.8%) 9 as a pale-yellow solid. 1H-NMR (CDCl3): 3.98 (s, 2MeO), 6.73 (s, 2 arom. H), 7.62 (d, CHNO2), 7.97 (d, CH═CHNO2). A second signal set (˜20%) was observed and corresponded to the correlative cis-nitroolefin (this phenomenon has been observed and proven earlier by one of the authors (Trachsel, 2002)): 3.94 (s, 2MeO), 6.85 (s, 2 arom. H), 7.62 (d, CHNO2), 8.39 (d, CH═CHNO2). Upon reduction, this leads to the same product as the trans-isomer and thus it was not necessary to remove.
1-(4-Bromo-3,5-dimethoxyphenyl)-2-nitropropene, 10. According to the general method described, from 20.0 g 4-bromo-3,5-dimethoxybenzaldehyde (8; commercially available), 33 mL nitroethane, 0.80 mL butylamine, 0.80 mL acetic acid and 2.5 g molecular sieves, 90 minutes at 90° C. Yield: 20.29 g (81%) 10 as a pale-yellow solid. 1H-NMR (CDCl3): 2.46 (d, MeC), 3.92 (s, 2MeO), 6.59 (s, 2 arom. H), 8.02 (s, CH═C). No cis-nitroolefin was apparent.
4-(2,2-Difluorovinyl)-3,5-dimethoxy-β-nitrostyrene, 26. According to the general method described, from 0.75 g 24, 0.80 mL nitromethane, 24 μL butylamine, 24 μL acetic acid and 0.40 g molecular sieves, 60 minutes at 90° C. Yield: 0.58 g (65.1%) 26 as a yellow solid. 1H-NMR (CDCl3): 3.91 (s, 2MeO), 5.23 (dd, 3J(H,F)=27.3 Hz and 2.7 Hz, F2CCH), 6.72 (s, 2 arom. H), 7.61 (d, CHNO2), 7.98 (d, CH═CHNO2). 19F-NMR (CDCl3): −75.18 (d, 1F, J=19.7 Hz), −82.50 (d, 1F, J=19.7 Hz). No cis-nitroolefin was apparent.
1-(4-(2,2-Difluorovinyl)-3,5-dimethoxyphenyl)-2-nitropropene, 27. According to the general method described, from 0.75 g 24, 0.80 mL nitroethane, 24 μL butylamine, 24 μL acetic acid and 0.4 g molecular sieves, 80 minutes at 90° C. Yield: 0.45 g (48%) 27 as a yellow solid. 1H-NMR (CDCl3): 2.51 (d, MeC), 3.89 (s, 2MeO), 5.23 (dd, 3J(H,F)=27.3 Hz and 2.7 Hz, F2CCH), 6.62 (s, 2 arom. H), 8.07 (s, CH═C). 19F-NMR (CDCl3): −76.19 (d, 1F, J=22.6 Hz), −83.20 (d, 1F, J=22.6 Hz). No cis-nitroolefin was apparent.
3,5-Dimethoxy-4-(2,2,2-trifluoroethyl)-β-nitrostyrene, 28. According to the general method described, from 0.45 g 25, 0.50 mL nitromethane, 13 μL butylamine, 13 μL acetic acid and 0.20 g molecular sieves, 60 minutes at 90° C. Yield: 0.36 g (68.2%) 28 as a yellow solid. 1H-NMR (CDCl3): 3.58 (q, 3J(H,F)=10.5 Hz, F3CCH2), 3.91 (s, 2MeO), 6.74 (s, 2 arom. H), 7.60 (d, CHNO2), 7.98 (d, CH═CHNO2). 19F-NMR (CDCl3): −64.63 (s, 3F). No cis-nitroolefin was apparent.
1-(3,5-Dimethoxy-4-(2,2,2-trifluoroethyl)phenyl)-2-nitropropene, 29. According to the general method described, from 0.45 g 25, 0.50 mL nitroethane, 13 μL butylamine, 13 μL acetic acid and 0.20 g molecular sieves, 2.5 hours at 90° C. Yield: 0.40 g (72.2%) 29 as a yellow solid. 1H-NMR (CDCl3): 2.50 (d, MeC), 3.57 (q, 3J(H,F)=10.5 Hz, F3CCH2), 3.89 (s, 2MeO), 6.62 (s, 2 arom. H), 8.07 (s, CH═C). 19F-NMR (CDCl3): −64.74 (s, 3F). No cis-nitroolefin was apparent.
3,5-Dimethoxy-4-methylphenethylamine hydrochloride (D; Desoxyscaline), 6a. According to the general method described, from 0.32 g 4a, 0.20 g LiAlH4, 0.14 mL H2SO4, 4 mL plus 2 mL THF, 0.85 mL IPA and 0.65 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.16 g (48.3%) product as a white solid. 1H-NMR (D2O): 1.97 (s, ArCH3), 2.91 (t, ArCH2), 3.22 (t, CH2NH3+), 3.79 (s, 2 MeO), 6.61 (s, 2 arom. H).
3,5-Dimethoxy-4-methylamphetamine hydrochloride (3C-D), 7a. According to the general method described, from 0.32 g 5a, 0.19 g LiAlH4, 0.13 mL H2SO4, 4 mL plus 2 mL THF, 0.90 mL IPA and 0.70 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.19 g (57.3%) product as a white solid. 1H-NMR (D2O): 1.34 (d, MeCH), 2.07 (s, ArCH3), 2.94 (d, ArCH2), 3.68 (m, CHNH3+), 3.88 (s, 2 MeO), 6.67 (s, 2 arom. H).
3,5-Dimethoxy-4-ethylphenethylamine hydrochloride (DE; Desoxyescaline), 6b. According to the general method described, from 0.94 g 4b, 0.56 g LiAlH4, 0.39 mL H2SO4, 13 mL plus 5 mL THF, 2.3 mL IPA and 1.8 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.47 g (48.3%) product as a white solid. 1H-NMR (D2O): 1.04 (t, ArCH2CH3), 2.61 (q, ArCH2CH3), 2.99 (t, ArCH2), 3.30 (t, CH2NH3+), 3.87 (s, 2MeO), 6.70 (s, 2 arom. H).
3,5-Dimethoxy-4-ethylamphetamine hydrochloride (3C-DE), 7b. According to the general method described, from 0.67 g 5b, 0.38 g LiAlH4, 0.27 mL H2SO4, 10 mL plus 5 mL THF, 1.57 mL IPA and 1.20 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.50 g (74.1%) product as a white solid. 1H-NMR (D2O): 1.04 (t, ArCH2CH3), 1.33 (d, MeCH), 2.61 (q, ArCH2CH3), 2.93 (d, ArCH2CH), 3.67 (m, CHNH3+), 3.86 (s, 2MeO), 6.66 (s, 2 arom. H).
3,5-Dimethoxy-4-propylphenethylamine hydrochloride (DP; Desoxyproscaline), 6c. According to the general method described, from 2.0 g 4c, 1.13 g LiAlH4, 0.79 mL H2SO4, 25 mL plus 6 mL THF, 4.7 mL IPA and 3.6 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 1.57 g (76.9%) product as a white solid. 1H-NMR (D2O): 0.91 (t, CH2CH2CH3), 1.48 (m, CH2CH2CH3), 2.56 (t, CH2CH2CH3), 2.99 (t, ArCH2), 3.31 (t, CH2NH3+), 3.85 (s, 2MeO), 6.70 (s, 2 arom. H).
3,5-Dimethoxy-4-propylamphetamine hydrochloride (3C-DP), 7c. According to the general method described, from 1.05 g 5c, 0.56 g LiAlH4, 0.39 mL H2SO4, 12 mL plus 5 mL THF, 2.3 mL IPA and 1.8 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.84 g (77.7%) product as a white solid. 1H-NMR (D2O): 0.91 (t, CH2CH2CH3), 1.33 (d, MeCH), 1.47 (m, CH2CH2CH3), 2.56 (t, CH2CH2CH3), 2.93 (d, ArCH2CH), 3.66 (m, CHNH3+), 3.85 (s, 2MeO), 6.67 (s, 2 arom. H).
4-Allyl-3,5-dimethoxyamphetamine hydrochloride (3C-DAL), 7d. According to the general method described, from 0.29 g 5d, 0.16 g LiAlH4, 0.11 mL H2SO4, 4 mL plus 2 mL THF, 0.8 mL IPA and 0.6 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 41 mg (13.7%) product as a white solid. 1H-NMR (D2O): 1.25 (d, MeCH), 2.95 (d, ArCH2CHNH3+), 3.40 (dm, ArCH2CH═CH2), 3.69 (m, CHNH3+), 3.86 (s, 2MeO), 4.86-5.03 (m, 2H, H2C═C), 6.03 (m, H2C═CH), 6.69 (s, 2 arom. H).
4-Bromo-3,5-dimethoxyphenethylamine hydrochloride (DBR; Desoxybromoscaline), 11. According to the general method described, from 16.0 g 9 (added portion wise as a solid), 7.85 g LiAlH4, 5.49 mL H2SO4, 250 mL THF, 32.6 mL IPA and 25 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 11.91 g (72.3%) product as a white solid. 1H-NMR (D2O): 2.92 (t, ArCH2), 3.24 (t, CH2NH3+), 3.83 (s, 2MeO), 6.64 (s, 2 arom. H).
4-Bromo-3,5-dimethoxyamphetamine hydrochloride (3C-DBR), 12. According to the general method described, from 20.2 g 10, 9.52 g LiAlH4, 6.6 mL H2SO4, 200 mL plus 100 mL THF, 39.5 mL IPA and 30.2 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 16.1 g (77.5%) product as a white solid. 1H-NMR (D2O): 1.32 (d, MeCH), 2.93 (m, ArCH2CH), 3.67 (m, CHNH3+), 3.89 (s, 2MeO), 6.63 (s, 2 arom. H).
4-(2,2-Difluorovinyl)-3,5-dimethoxyphenethylamine hydrochloride (DDFV; Desoxydifluorovinylscaline), 30. According to the general method described, from 0.56 g 26, 0.29 g LiAlH4, 0.20 mL H2SO4, 7 mL plus 3 mL THF, 0.50 mL IPA and 0.38 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.237 g (41.0%) product as a white solid. 1H-NMR (D2O): 3.02 (t, ArCH2), 3.32 (t, CH2NH3+), 3.88 (s, 2MeO), 5.26 (dd, 3J(H,F)=27.6 Hz and 2.4 Hz, F2CCH), 6.72 (s, 2 arom. H). 19F-NMR (D2O): −80.38 (d, 1F, J=28.2 Hz), −85.07 (d, 1F, J=28.2 Hz).
4-(2,2-Difluorovinyl)-3,5-dimethoxyamphetamine hydrochloride (3C-DDFV), 31. According to the general method described, from 0.42 g 27, 0.21 g LiAlH4, 0.15 mL H2SO4, 6 mL plus 3 mL THF, 0.50 mL IPA and 0.4 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.30 g (68.2%) product as a white solid. 1H-NMR (D2O): 1.34 (d, MeCH), 2.07 (s, ArCH3), 2.94 (d, ArCH2), 3.69 (m, CHNH3+), 3.87 (s, 2MeO), 5.25 (dd, 3J(H,F)=27.9 Hz and 2.1 Hz, F2CCH), 6.69 (s, 2 arom. H). 19F-NMR (D2O): −80.31 (d, 1F, J=31.0 Hz), −85.03 (d, 1F, J=31.0 Hz).
3,5-Dimethoxy-4-(2,2,2-trifluoroethyl)phenethylamine hydrochloride (DTFE; Desoxytrifluoroescaline), 32. According to the general method described, from 0.35 g 28, 0.171 g LiAlH4, 0.12 mL H2SO4, 4 mL plus 2 mL THF, 0.70 mL IPA and 0.55 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.14 g (38.9%) product as a white solid. 1H-NMR (D2O): 3.03 (t, ArCH2), 3.33 (t, CH2NH3+), 3.60 (q, CH2CF3), 3.89 (s, 2MeO), 6.74 (s, 2 arom. H). 19F-NMR (D2O): −64.59 (s, 3F).
3,5-Dimethoxy-4-(2,2,2-trifluoroethyl)amphetamine hydrochloride (3C-DTFE), 33. According to the general method described, from 0.38 g 29, 0.177 g LiAlH4, 0.12 mL H2SO4, 4 mL plus 2 mL THF, 0.40 mL IPA and 0.31 mL NaOH 2M. Hydrochloride salt formation according to the general method described. Yield: 0.29 g (75%) product as a white solid. 1H-NMR (D2O): 1.34 (d, MeCH), 2.97 (d, ArCH2), 3.61 (q, CH2CF3), 3.66 (m, CHNH3+), 3.88 (s, 2MeO), 6.71 (s, 2 arom. H). 19F-NMR (D2O): −64.92 (s, 3F).
N-Trifluoroacetyl-4-bromo-3,5-dimethoxyphenethylamine, 13. To a solution of 7.40 g (24.94 mmol) 11 and 7.64 mL (54.87 mmol; 2.2 eq) NEt3 in 55 mL MeOH anhydr. Was added dropwise 2.96 mL (27.44 mmol; 1.1 eq) ethyl trifluoroacetate within 1 minutes under nitrogen. After stirring for 1 hour at ambient temperature, the volatiles were removed in vacuo and the residue was redissolved in MTBE (150 mL), washed with aq. HCl 0.5M (2×100 mL) and water (2×50 mL), dried over Na2SO4 and concentrated in vacuo to get 7.58 g (85.3%) product 13 as a beige solid. 1H-NMR (CDCl3) revelated an approx. 90:10 mixture of cis/trans amide mixture (isomers not assigned; major product peak's shifts given first): 2.90/3.07 (t, ArCH2), 3.67 (q (superimposed txd), CH2NH), 3.91/3.89 (s, 2MeO), 6.34 (bs, NH), 6.41/6.58 (s, 2 arom. H).
N-Trifluoroacetyl-4-bromo-3,5-dimethoxyamphetamine, 14. To a solution of 15.50 g (49.9 mmol) 12 and 15.29 mL (109.8 mmol; 2.2 eq) NEt3 in 110 mL MeOH anhydr. Was added dropwise 5.92 mL (54.88 mmol; 1.1 eq) ethyl trifluoroacetate within 1 minute under nitrogen. After stirring 1 hour at ambient temperature, the volatiles were removed in vacuo and the residue was redissolved in MTBE (300 mL) and ethyl acetate (300 mL), washed with aq. HCl 0.5M (2×200 mL) and water (2×100 mL), dried over Na2SO4 and concentrated in vacuo to get 16.26 g (88.0%) product 14 as a beige solid. 1H-NMR (CDCl3): 1.25 (d, MeCH), 2.84 (m, ArCH2), 3.89 (s, 2MeO), 4.30 (m, CHNH), 6.11 (bs, NH), 6.36 (s, 2 arom. H).
N-Trifluoroacetyl-3,5-dimethoxy-4-formylphenethylamine, 15. To a solution of 17 mL (42.14 mmol, 3.0 eq) BuLi 2.5M in 40 mL THF anhydr. At −100° C. (cooling bath: acetone/THF approx. 4/1 mixture, adjusted with liquid N2) under nitrogen was added dropwise (10 minutes) a solution of 5.0 g (14.14 mmol) 13 in 60 mL THF anhydr. In such a manner that a “precooling” on the flask's wall occurred (needle touched the flask's wall). After stirring for 4 minutes, 16.8 mL DMF anhydr. Were added within 5 minutes in a similar way. After completion of addition stirring was continued for 45 minutes and then the mixture was allowed to reach approx. −10° C. Next, the mixture was quenched by a quick addition of 100 mL aq. Saturated NH4Cl solution and 100 mL of citric acid 10%. The mixture was extracted with EtOAc (2×100 mL), and the combined org. extracts were washed twice with water, dried over Na2SO4 and concentrated in vacuo to get 3.9 g of an orange oil that crystallized upon cooling to ambient temperature. The residue was dissolved in 15 mL EtOAc under heating, and the solution was plugged onto a silica gel dry flash column (h: 4 cm, d: 6 cm) preconditioned with hexane/EtOAc 3:1. It was eluted with the same eluent until all the unwanted byproduct (N-trifluoroacetyl-3,5-dimethoxyphenethylamine) was eluted, then it was changed to hexane/EtOAc 1:2 in order to elute the desired product. After pooling and evaporating the corresponding fractions there were obtained 2.21 g (51.5%) product 15 as a beige solid. 1H-NMR (CDCl3) revelated an approx. 90:10 mixture of cis/trans amide mixture (isomers not assigned; major product peak's shifts given first): 2.93/3.11 (t, ArCH2), 3.69 (q (superimposed txd), CH2NH), 3.91/3.92 (s, 2MeO), 6.40/6.64 (s, 2 arom. H), 6.69 (bs, NH), 10.40/10.36 (s, CHO).
N-Trifluoroacetyl-3,5-dimethoxy-4-formylamphetamine, 16. To a solution of 26 mL (64.45 mmol, 3.0 eq) BuLi 2.5M in 60 mL THF anhydr. At −100° C. (cooling bath: acetone/THF approx. 4/1 mixture, adjusted with liquid N2) under nitrogen was added dropwise (10 minutes) a solution of 8.0 g (21.61 mmol) 13 in 90 mL THF anhydr. In such a manner that a “precooling” on the flask's wall occurred (needle touched the flask's wall). After stirring for 5 minutes, 27.5 mL DMF anhydr. Were added within 5 minutes in a similar way. After completion of addition stirring was continued for 45 minutes and then the mixture was allowed to reach approx. −10° C. Next, the mixture was quenched by a quick addition of 150 mL aq. Saturated NH4Cl solution and 150 mL of citric acid 10%. The mixture was extracted with EtOAc (2×150 mL), and the combined org. extracts were washed twice with water (2×150 mL) and with brine (1×150 mL), dried over Na2SO4 and concentrated in vacuo to get 6.64 g of a crude off-white solid. The residue was dissolved in 200 mL EtOAc and 20 mL MeOH. To this solution 18 g silica gel were added and the solvents were removed by rotary evaporation at 45° C. The residue was packed onto a silica gel dry flash column (h: 4 cm, d: 8 cm) preconditioned with hexane/EtOAc 3:1. It was eluted with the same eluent until all the unwanted by-product (N-trifluoroacetyl-3,5-dimethoxyamphetamine) was eluted, then it was changed to hexane/EtOAc 1:2; 1:3; 1:4 and finally pure EtOAc in order to elute the desired product. After pooling and evaporating the corresponding fractions there were obtained 3.33 g (48.3%) product 16 as a beige solid. 1H-NMR (CDCl3): 1.31 (d, MeCH), 2.89 (m, ArCH2), 3.91 (s, 2MeO), 4.37 (m, CHNH), 6.19 (bs, NH), 6.40 (s, 2 arom. H), 10.47 (s, CHO).
N-Trifluoroacetyl-3,5-dimethoxy-4-(2,2-dimethylvinyl)phenethylamine, 17a. To an ice-cooled suspension of 2.62 g (2.3 eq) isopropyltriphenylphosphonium iodide in 25 mL THF anhydr. was added 2.36 mL (2.2 eq) BuLi 2.5M in 25 mL THF anh. during 2 minutes (immediate coloration towards a deep orange). After stirring for 10 minutes at 0° C., a solution of 0.80 g (2.63 mmol) aldehyde 15 in 12 mL THF anhydr. Was added over 3 minutes whereby the reaction mixture did not discolor (and thus, some of the Wittig reagent still was intact, e.g., the excess, and was not “over”-consumed). After stirring for 3 hours at 0° C., the mixture was stirred overnight at ambient temperature. Next, 2 mL acetone were added and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water (50 mL, each), and the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was redissolved in 7 mL DMSO and subjected to preparative HPLC purification (Dynamax SD1, 100 mL/min; UV detection at 210 nm; column: Macherey Nagel, reversed phase C18 Nucleodur Pyramid, 250×32, solvents: A: aqueous formic acid 0.05%, B: acetonitrile, gradient of 80% A and 20% B towards 5% A and 95% B). The collected fractions were roughly concentrated in vacuo to get rid of the acetonitrile. The residue was extracted with ethyl acetate; some brine helped to facilitate phase separation, and the organic layer was dried over Na2SO4 and concentrated in vacuo to get 0.741 g product as an orangish solid. The residue was dissolved in a minimal amount of DCM and added onto a 2 cm silica gel pad (d: 3 cm) preconditioned with ethyl acetate/hexane 1:1. Then it was eluted (approx. 150 mL) with ethyl acetate/hexane 1:1, and the eluate was concentrated in vacuo to get 710 mg (81.8%) product 17a as a beige solid. 1H-NMR (CDCl3) revelated an approx. 90:10 mixture of cis/trans amide mixture (isomers not assigned; only major product peak's shifts given): 1.57 (d, 3H, MeC═), 1.97 (d, 3H, MeC═), 2.89 (t, ArCH2), 3.67 (q (superimposed txd), CH2NH), 3.82 (s, 2MeO), 5.96 (m, ArCH═), 6.34 (bs, NH), 6.39 (s, 2 arom. H).
N-Trifluoroacetyl-4-(Z-buta-1,3-dienyl)-3,5-dimethoxyphenethylamine, 17b. It followed exactly the procedure described for the preparation of compound 17a, by using allyltriphenylphosphonium bromide as the Wittig salt. From 0.80 g (2.63 mmol) aldehyde 15 there were obtained 227.4 mg (26.3%) product 17b as a white solid. 1H-NMR (CDCl3) revelated an approx. 90:10 mixture of cis/trans amide mixture (isomers not assigned; only major product peak's shifts given). For assignment of E/Z isomerism it was followed the comprehensive work of Byrne and Gilheany (Byrne et al., 2012). Z-isomer (exclusively formed or isolated): 2.91 (t, ArCH2), 3.67 (q (superimposed txd), CH2NH), 3.82 (s, 2MeO), 5.11 (dxm, 1H, H2C═), 5.28 (dxm, 1H, H2C═), 6.21-6.43 (m, 3 vinylic H), 6.35 (bs, NH), 6.41 (s, 2 arom. H).
N-Trifluoroacetyl-3,5-dimethoxy-4-vinylamphetamine, 18a. It followed exactly the procedure described for the preparation of compound 17a, by using methyltriphenylphosphonium bromide as the Wittig salt. The crude product was directly purified by classical silica gel chromatography (hexane/EtOAc 3:1). From 0.80 g (2.51 mmol) aldehyde 16 there were obtained 600 mg (75.3%) product 18a as a white solid. 1H-NMR (CDCl3): 1.25 (d, MeCH), 2.82 (m, ArCH2), 3.83 (s, 2MeO), 4.31 (m, CHNH), 5.43 (dxd, 1H, H2C═), 6.04 (dxd, 1H, H2C═), 6.11 (bs, NH), 6.34 (s, 2 arom. H), 6.92 (dxd, 1H, ArCH═).
N-Trifluoroacetyl-3,5-dimethoxy-4-(2,2-dimethylvinyl)amphetamine, 18b. It followed exactly the procedure described for the preparation of compound 17a, by using isopropyltriphenylphosphonium iodide as the Wittig salt. The crude product was directly purified by classical silica gel chromatography (hexane/EtOAc 3:1). From 0.80 g (2.51 mmol) aldehyde 16 there were obtained 580 mg (66.9%) product 18a as a white solid. 1H-NMR (CDCl3): 1.26 (d, MeCH), 1.54 (d, 3H, MeC═), 1.94 (d, 3H, MeC═), 2.84 (m, ArCH2), 3.79 (s, 2MeO), 4.32 (m, CHNH), 5.94 (m, ArCH═), 6.12 (bd, NH), 6.34 (s, 2 arom. H).
E- and Z-isomer of N-trifluoroacetyl-4-(buta-1,3-dienyl)-3,5-dimethoxy-amphetamine, 18c and 18d. It followed exactly the procedure described for the preparation of compound 17a, by using allyltriphenylphosphonium bromide as the Wittig salt. The crude product was first purified by classical silica gel chromatography (hexane/EtOAc 3:1). Next, the pure E/Z-mixture 18c/18d was separated by preparative HPLC applying the same conditions as described under the preparation of 17a. From 0.80 g (2.51 mmol) aldehyde 16 there were obtained 130 mg (15.1%) E-isomer 18c and 360 mg (41.8%) Z-isomer 18d, each as a white solid. For assignment of E/Z isomerism it was followed the comprehensive work of Byrne and Gilheany Byrne and Gilheany (Byrne et al., 2012). 1H-NMR (CDCl3), E-isomer 18c: 1.27 (d, MeCH), 2.85 (m, ArCH2), 3.87 (s, 2 MeO), 4.34 (m, CHNH), 5.12 (dxm, 1H, H2C═), 5.30 (dxm, 1H, H2C═), 6.11 (bd, NH), 6.36 (s, 2 arom. H), 6.53 (m, 1 vinylic H), 6.88 (m, 1 vinylic H), 7.24 (m, 1 vinylic H). Z-isomer 18d: 1.29 (d, MeCH), 2.87 (m, ArCH2), 3.82 (s, 2MeO), 4.35 (m, CHNH), 5.11 (dxm, 1H, H2C═), 5.27 (dxm, 1H, H2C═), 6.14 (bd, NH), 6.21-6.42 (m, 3 vinylic H), 6.38 (s, 2 arom. H).
E- and Z-isomer of N-trifluoroacetyl-3,5-dimethoxy-4-(2-phenylvinyl)-amphetamine, 18e and 18f. It followed exactly the procedure described for the preparation of compound 17a, by using benzyltriphenylphosphonium chloride as the Wittig salt. The crude product was first purified by classical silica gel chromatography (hexane/EtOAc 3:1). Next, the pure E/Z-mixture 18e/18f (0.94 g) was separated by preparative HPLC applying the same conditions as described under the preparation of 17a. From 0.80 g (2.51 mmol) aldehyde 16 there were obtained 400 mg (40.6%) E-isomer 18e and 330 mg (33.4%) Z-isomer 18f, each as a white solid. For assignment of E/Z isomerism it was followed the comprehensive work of Byrne and Gilheany (Byrne et al., 2012). 1H-NMR (CDCl3), E-isomer 18e: 1.27 (d, MeCH), 2.84 (m, ArCH2), 3.88 (s, 2MeO), 4.33 (m, CHNH), 6.12 (bd, NH), 6.38 (s, 2 arom. H), 7.18-7.59 (m, 5 arom. H plus 2 vinylic H). Z-isomer 18f: 1.28 (d, MeCH), 2.84 (d, ArCH2), 3.58 (s, 2MeO), 4.33 (m, CHNH), 6.12 (bd, NH), 6.30 (s, 2 arom. H), 6.41 (d, 1 vinylic H), 6.71 (d, 1 vinylic H), 7.07-7.16 (m, 5 arom. H).
3,5-Dimethoxy-4-(2,2-dimethylvinyl)phenethylamine hydrochloride (Desoxydimethylvinylscaline; DDMV), 19a. To a solution of 700 mg (2.11 mmol) 17a in 120 mL MeOH were added 34.5 mL aq. NaOH 5M under nitrogen. After stirring for 90 minutes, about ½ of the MeOH was roughly removed by using a rotary evaporator (<30° C.), and the mixture was diluted with 100 mL MTBE and washed with 3×30 mL water, dried over Na2SO4 and concentrated in vacuo to get 414 mg product (oil) as free base of 19a. This was dissolved in a few drops of isopropanol anhydr. And 20 mL diethyl ether anhydr. And carefully neutralized under stirring by adding HCl 2M anhydr. In diethyl ether (pH paper was used for check). The white precipitation was filtered off and rinsed with diethyl ether and dried under vacuum to get 426 mg (74.3%) product 19a as an off-white solid. 1H-NMR (D2O): 1.41 (d, 3H, MeC═), 1.83 (d, 3H, MeC═), 2.94 (t, ArCH2), 3.24 (t, CH2NH3+), 3.75 (s, 2MeO), 5.80 (m, ArCH═), 6.62 (s, 2 arom. H).
4-(Z-Buta-1,3-dienyl)-3,5-dimethoxyphenethylamine hydrochloride (Z-Desoxybutadienylscaline; Z-DBD), 19b. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 220 mg 17b and 11.5 mL aq. NaOH 5M in 40 mL MeOH. Yield: 137 mg (76.0%) product 19b as a pale-yellowish solid. 1H-NMR (D2O): 2.95 (t, ArCH2), 3.25 (t, CH2NH3+), 3.75 (s, 2MeO), 5.13 (dxm, 1H, H2C═), 5.30 (dxm, 1H, H2C═), 6.15 (m, 2 vinylic H), 6.36 (m, 1 vinylic H), 6.65 (s, 2 arom. H).
3,5-Dimethoxy-4-vinylamphetamine hydrochloride (3C-DV), 20a. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 600 mg 18a and 25 mL aq. NaOH 5M in 100 mL MeOH. Yield: 420 mg (86.2%) product 20a as a white solid. 1H-NMR (D2O): 1.22 (d, MeCH), 2.82 (d, ArCH2), 3.58 (m, CHNH3+), 3.76 (s, 2MeO), 5.41 (dxd, 1H, H2C═), 5.87 (dxd, 1H, H2C═), 6.55 (s, 2 arom. H), 6.74 (dxd, 1H, ArCH═).
3,5-Dimethoxy-4-(2,2-dimethylvinyl)amphetamine hydrochloride (3C-DDMV), 20b. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 580 mg 18b and 25 mL aq. NaOH 5M in 100 mL MeOH. Yield: 460 mg (95.8%) product 20b as a white solid. 1H-NMR (D2O): 1.22 (d, MeCH), 1.39 (s, 3H, MeC═), 1.79 (s, 3H, MeC═), 2.84 (d, ArCH2), 3.57 (m, CHNH3+), 3.71 (s, 2MeO), 5.76 (s, ArCH═), 6.56 (s, 2 arom. H).
4-(E-Buta-1,3-dienyl)-3,5-dimethoxyamphetamine hydrochloride (E-3C-DBD), 20c. It was exactly followed the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 130 mg 18c and 5 mL aq. NaOH 5M in 20 mL MeOH. Yield: 60 mg (55.8%) product 20c as a yellowish-white solid. 1H-NMR (D2O): 1.22 (d, MeCH), 2.83 (d, ArCH2), 3.57 (m, CHNH3+), 3.78 (s, 2MeO), 5.10 (dxm, 1H, H2C═), 5.26 (dxm, 1H, H2C═), 6.47 (m, 1 vinylic H), 6.54 (s, 2 arom. H), 6.71 (d, 1 vinylic H), 7.07 (m, 1 vinylic H).
4-(Z-Buta-1,3-dienyl)-3,5-dimethoxyamphetamine hydrochloride (Z-3C-DBD), 20d. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 360 mg 18d and 20 mL aq. NaOH 5M in 80 mL MeOH. Yield: 240 mg (80.8%) product 20d as a white solid. 1H-NMR (D2O): 1.23 (d, MeCH), 2.85 (dxd, ArCH2), 3.58 (m, CHNH3+), 3.71 (s, 2MeO), 5.10 (dxm, 1H, H2C═), 5.27 (dxm, 1H, H2C═), 6.11 (m, 2 vinylic H), 6.32 (t, 1 vinylic H), 6.58 (s, 2 arom. H).
3,5-Dimethoxy-4-(E-2-phenylvinyl)amphetamine hydrochloride (E-3C-DPV), 20d. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 400 mg 18e and 20 mL aq. NaOH 5M in 80 mL MeOH. Yield: 185 mg (54.6%) product 20e as a white solid. 1H-NMR (D2O): 1.18 (d, MeCH), 2.77 (m, ArCH2), 3.50 (m, CHNH3+), 3.72 (s, 2MeO), 6.47 (s, 2 arom. H), 7.10-7.45 (m, 5 arom. H plus 2 vinylic H).
3,5-Dimethoxy-4-(Z-2-phenylvinyl)amphetamine hydrochloride (Z-3C-DPV), 20f. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 330 mg 18f and 20 mL aq. NaOH 5M in 80 mL MeOH. Yield: 250 mg (89.3%) product 20f as an off-white solid. 1H-NMR (D2O): 1.22 (d, MeCH), 2.86 (m, ArCH2), 3.53 (s, 2MeO), 3.56 (m, CHNH3+), 6.32 (d, 1 vinylic H), 6.55 (s, 2 arom. H), 6.70 (d, 1 vinylic H), 7.01-7.17 (m, 5 arom. H).
N-Trifluoroacetyl-3,5-dimethoxy-4-vinylphenethylamine, 21a. This procedure has been adapted from (Saa et al., 1992). A mixture of 0.80 g (2.25 mmol) aryl halide 13, 355 mg (1.34 mmol) PPh3, 177 mg (0.267 mmol) PdCl2(PPh3)2 and 0.77 g (18.9 mmol) LiCl anhydr. in 20 mL DMF anhydr. was briefly degassed with N2 using a balloon attached to a syringe/needle. Next, a crystal of BHT (3,5-di-tert-butyl-4-hydroxytoluene) and 0.787 mL (2.69 mmol; d: 1.085 g/mL) vinyltributylstannane was added and the mixture was heated to 120° C. After 1 hour and 9 hours there was added another equal amount of the stannane reagent. After heating for a total of 24 hours the mixture was cooled to ambient temperature, diluted with Et2O/water (150 mL each), the layers were separated and the organic layer was washed once with water, dried over Na2SO4 and concentrated in vacuo. The residue that partially crystallized was dissolved in 7 mL DMSO and subjected to preparative HPLC purification (Macherey Nagel, reversed phase C18 Nucleodur Pyramid, 250×32, 5 μm, solvent: gradient of 80% A: aqueous formic acid 0.05% and 20% B: acetonitrile towards 5% A and 95% B). The collected fractions were roughly concentrated in vacuo to get rid of the acetonitrile. The residue was extracted with ethyl acetate; some brine helped to facilitate phase separation, and the organic layer was dried over Na2SO4 and concentrated in vacuo to get 0.35 g product as a beige solid. 1H-NMR (CDCl3) of this material indicated that still some impurities were contained. Thus, the residue was dissolved in a minimal amount of dichloromethane and placed onto a 2 cm silica gel pad (d: 3 cm) preconditioned with ethyl acetate/hexane 1:1. Then it was eluted (approx. 150 mL) with ethyl acetate/hexane 1:1, and the eluate was concentrated in vacuo to get 340.1 mg (50.0%) product as a white solid. 1H-NMR (CDCl3) revelated an approx. 95:5 mixture of cis/trans amide mixture (isomers not assigned; only major product peak's shifts given): 2.88 (t, ArCH2), 3.65 (q (superimposed txd), CH2NH), 3.86 (s, 2MeO), 5.49 (dxd, 1H, H2C═), 6.07 (dxd, 1H, H2C═), 6.32 (bs, NH), 6.39 (s, 2 arom. H), 6.95 (dxd, 1H, ArCH═).
N-Trifluoroacetyl-3,5-dimethoxy-4-ethynylphenethylamine, 21b. It was exactly followed the procedure described for the preparation of compound 21a, by using ethynyltributylstannane (d: 1.089 g/mL) as the alkylating reagent. From 0.80 g aryl halide 13 were obtained 91.6 mg (13.3%) product as a beige solid. 1H-NMR (CDCl3): 2.92 (t, ArCH2), 3.58 (s, 1H, HC≡), 3.66 (q (superimposed txd), CH2NH), 3.92 (s, 2MeO), 6.33 (bs, NH), 6.39 (s, 2 arom. H).
N-Trifluoroacetyl-4-allyl-3,5-dimethoxyphenethylamine, 21c. It was exactly followed the procedure described for the preparation of compound 21a, by using allyltributylstannane (d: 1.07 g/mL) as the alkylating reagent. From 1.20 g aryl halide 13 were obtained 459 mg (42.9%) product as a beige solid. 1H-NMR (CDCl3) revelated an approx. 90:10 mixture of cis/trans amide mixture (isomers not assigned; only major product peak's shifts given): 2.88 (t, ArCH2), 3.39 (dm, ArCH2CH═CH2), 3.65 (q (superimposed txd), CH2NH), 3.83 (s, 2MeO), 4.98 (m, 2H, H2C═C), 5.95 (m, H2C═CH), 6.32 (bs, NH), 6.38 (s, 2 arom. H).
3,5-Dimethoxy-4-vinylphenethylamine hydrochloride (Desoxvinylscaline; DV), 22a. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 330 mg 21a and 18 mL aq. NaOH 5M in 60 mL MeOH. Yield: 128 mg (48.3%) product 22a as a white solid. 1H-NMR (D2O): 2.92 (t, ArCH2), 3.23 (t, CH2NH3+), 3.80 (s, 2MeO), 5.44 (dxd, 1H, H2C═), 5.90 (dxd, 1H, H2C═), 6.61 (s, 2 arom. H), 6.78 (dxd, 1H, ArCH═).
3,5-Dimethoxy-4-ethynylphenethylamine hydrochloride (Desoxyethynylscaline; DYN), 22b. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 91.6 mg 21b and 5 mL aq. NaOH 5M in 17 mL MeOH. Yield: 14.1 mg (19.2%) product 22b as an off-white solid. 1H-NMR (D2O): 2.95 (t, ArCH2), 3.24 (t, CH2NH3+), 3.84 (s, 2MeO), 3.89 (s, 1H, HCE), 6.62 (s, 2 arom. H).
4-Allyl-3,5-dimethoxyphenethylamine hydrochloride (Desoxyallylscaline; DAL), 22c. It followed exactly the procedure (hydrolysis and hydrochloride salt formation) described for the preparation of compound 19a, by using 440 mg 21c and 23 mL aq. NaOH 5M in 80 mL MeOH. Yield: 315 mg (88.1%) product 22c as a white solid. 1H-NMR (D2O): 2.93 (t, ArCH2), 3.23 (t, CH2NH3+), 3.29 (dxt, ArCH2CH═CH2), 3.77 (s, 2MeO), 4.80 (dxm, 1H, H2C═C), 4.90 (dxm, 1H, H2C═C), 5.93 (m, H2C═CH), 6.62 (s, 2 arom. H).
Number | Date | Country | |
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63280439 | Nov 2021 | US |
Number | Date | Country | |
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Parent | 17987922 | Nov 2022 | US |
Child | 18196992 | US |