PMK Ethyl Glycidate, also known as MDP2P, is a chemical compound with a wide range of applications, particularly in the pharmaceutical and fragrance industries. Its versatile properties and diverse uses make it a valuable substance in various manufacturing processes. In this article, we delve into the intricacies of PMK Ethyl Glycidate, its uses, and its significance in modern industry.
PMK Ethyl Glycidate (CAS -16-7) is a synthetic compound derived from piperonal, a natural substance found in various plants. It is commonly used as a precursor in the synthesis of pharmaceuticals, fragrances, and other organic compounds. PMK Ethyl Glycidate is a clear, colorless liquid with a faint odor, making it suitable for a wide range of applications.
Pharmaceuticals: One of the primary uses of PMK Ethyl Glycidate is in the pharmaceutical industry. It serves as a key intermediate in the synthesis of certain medications, including those used to treat conditions such as Parkinson's disease and attention deficit hyperactivity disorder (ADHD). PMK Ethyl Glycidate's role as a precursor allows for the efficient production of pharmaceutical compounds with high purity and efficacy.
Fragrances: PMK Ethyl Glycidate is also utilized in the fragrance industry for the production of perfumes, colognes, and other scented products. Its pleasant aroma and chemical stability make it an ideal ingredient in fragrance formulations, providing long-lasting and appealing scents. PMK Ethyl Glycidate contributes to the complex olfactory profiles of many popular fragrances, enhancing their overall appeal to consumers.
Organic Synthesis: In addition to its pharmaceutical and fragrance applications, PMK Ethyl Glycidate is used in various organic synthesis reactions. It serves as a versatile building block for the creation of diverse organic compounds, including those used in agrochemicals, dyes, and flavorings. PMK Ethyl Glycidate's reactivity and compatibility with other chemicals make it an invaluable tool for chemists and researchers in the development of new materials and compounds.
- Versatility: PMK Ethyl Glycidate's versatility allows it to be used in a wide range of applications across multiple industries, making it a valuable asset for manufacturers and researchers.
- Efficiency: As a key intermediate in the synthesis of pharmaceuticals and fragrances, PMK Ethyl Glycidate enables efficient production processes, leading to cost savings and increased productivity.
- Purity: High-quality PMK Ethyl Glycidate is readily available, ensuring consistent performance and reliable results in manufacturing processes.
- Stability: PMK Ethyl Glycidate exhibits excellent chemical stability, allowing for long-term storage and use in various applications without degradation or loss of effectiveness.
As industries continue to innovate and evolve, the demand for PMK Ethyl Glycidate is expected to grow. Its importance as a precursor in pharmaceutical and fragrance synthesis, as well as its versatility in organic chemistry, positions it as a key ingredient in numerous manufacturing processes. Ongoing research and development efforts aim to further explore the potential applications of PMK Ethyl Glycidate and optimize its production methods for enhanced efficiency and sustainability.
In conclusion, PMK Ethyl Glycidate is a valuable chemical compound with diverse applications in pharmaceuticals, fragrances, and organic synthesis. Its versatility, efficiency, and stability make it an indispensable ingredient in modern manufacturing processes, driving innovation and advancement across industries. As the demand for high-quality PMK Ethyl Glycidate continues to rise, suppliers and manufacturers play a crucial role in meeting the needs of their customers and supporting ongoing research and development efforts.
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MDMA is increasingly used in clinical research, but no cGMP process has yet been reported. We describe here the first fully validated cGMP synthesis of up to 5 kg (&#;30 000 patient doses) of MDMA in a four-step process beginning with a noncontrolled starting material. The overall yield was acceptable (41&#;53%, over four steps), and the chemical purity of the final product was excellent, exceeding 99.9% of the peak area by HPLC in each of the four validation trials. The availability of cGMP-compliant MDMA will facilitate ongoing clinical trials and provide for future therapeutic use, if encouraging results lead to FDA approval.
Indeed, prior to a recently completed Phase 3 trial for PTSD, 8 it is likely that few even contemplated a need for cGMP-compliant MDMA. As a Schedule I substance, it officially had no recognized medical utility up until now. As a well-known compound with a lengthy history in the public domain and a short treatment regimen, it also had little apparent commercial value. 24
To date, none of the synthetic explorations into MDMA appear to have considered cGMPs. While intended for pharmaceutical production, Merck&#;s early investigations occurred less than a decade after the FDA was founded, and well before its cGMP rules were developed. Some clandestine labs reliably produce large quantities of high-quality MDMA; 23 however, these facilities necessarily operate outside of regulatory frameworks and certainly do not report or document cGMP-compliant procedures. Most other synthetic explorations of MDMA have been geared toward the production of MDMA as a research chemical, usually for small-scale studies in animals or for forensic analysis ( ).
Clandestine chemists preparing MDMA for the black market have additionally developed a number of synthetic routes from readily available starting materials like catechol ( 7 ), 19 eugenol ( 8 ), 19 isosafrole ( 9 ), 20 and piperine ( 10 ), 21 though most still approach MDMA through a safrole 22 or (less frequently) piperonal 21 intermediate. These synthetic methods often rely on chemicals readily available to ordinary consumers, in an effort to circumvent controlled substance precursor regulations. Most of these clandestine syntheses are well-documented, both by anonymous chemists, in online forums, and by forensic scientists, who often identify clandestine production methods by their distinct impurity profiles. 20
Unlike many drug candidates, MDMA ( 1 ) enjoyed a robust synthetic history prior to receiving any serious consideration as a pharmaceutical substance. MDMA was first synthesized by Merck, in , as an intermediate to the styptic compound methylhydrastitine. 13 Scientists periodically explored its pharmacological effects over the intervening half-century, both at Merck and in the United States Army, 14 but MDMA does not appear in either the patent or the chemical literature again until , when Biniecki and Krajewski published a synthesis identical to Merck&#;s in Poloniae Pharmaceutica 15 (it is unlikely that they were aware of the Merck patent). This synthetic route proceeded via hydrobromination of the natural product safrole ( 2 ), yielding the Markovnikov adduct 3 , which was then converted to MDMA using methylamine in methanol. A variety of synthetic approaches from methyl piperonyl ketone ( 4 ), which was commercially available at the time, and which can be easily prepared either from safrole&#;typically via Wacker oxidation&#;or piperonal ( 5 )&#;typically by reducing its nitroalkene derivative 6 with iron in hydrochloric acid&#;were summarized by Shulgin, in . 16 A novel approach from piperonal, via Curtius rearrangement, was reported by Schulze, in , 17 and a handful of asymmetric syntheses of (S)-MDMA, some relying on alternate starting materials, have also appeared in the literature ( Scheme 1 ). 18
As the research environment grows steadily more supportive of clinical exploration, and as successful clinical trials open the door for fully approved treatments, the need for pharmaceutically acceptable MDMA continues to expand. To ensure that patients receive safe, effective drugs, the manufacture of pharmaceutical substances is closely regulated by the FDA, under a structure called Current Good Manufacturing Practice (cGMP). 11 These rules delineate standards for every aspect of the manufacturing process, including facility design, establishment and documentation of operating procedures, process monitoring, and chemical analysis. Because only small samples of each pharmaceutical batch are submitted for (destructive) quality control testing, a well-controlled manufacturing process is the best-known way to ensure that all drugs distributed to consumers are of predictably high quality, consistency, and efficacy. cGMP-compliant synthetic processes are typically developed for drug candidates in tandem with progressing clinical trials. 12
This second wave of so-called psychedelic studies more expansively includes compounds like entactogen 3,4-methylenedioxymethamphetamine (MDMA). Like traditional psychedelics, MDMA had previously enjoyed a brief period of encouraging early-stage exploration, in the s and s, which was similarly curtailed by social and regulatory backlash. In contrast to psychedelics like LSD and psilocybin, however, the addition of MDMA to the U.S. Drug Enforcement Administration&#;s (DEA) Schedule I appeared to be largely related to MDMA&#;s popularity as an illicit &#;party drug,&#; 5 rather than to significant concerns regarding either contemporary research efforts or its therapeutic utility. 6 Indeed, in clinical trials conducted since the U.S. Food and Drug Administration (FDA) and DEA first granted research approval, in , 7 MDMA has shown promise as a psychotherapeutic aid for patients suffering from PTSD, 8 autism-related social anxiety, 9 and alcoholism. 10
Interest in the clinical utility of psychedelic compounds has increased dramatically in recent years. Although medical usage of these substances, in tandem with psychotherapy, was briefly&#;and controversially 1 &#;explored, in the s and s, 2 increased regulatory oversight and social disapprobation effectively eliminated such research until the late s, when tentative efforts to revive it commenced. 3 Promising early results very slowly stimulated additional engagement, both experimentally and culturally, provoking recent regulatory shifts that have further stimulated engagement by making research chemicals more accessible and expanding the permissible scope of clinical studies. 4
We report here the first cGMP synthesis of MDMA and its hydrochloride salt (MDMA·HCl), which is used in pharmaceutical formulations. In this fully validated, four-stage process, up to 5 kg of MDMA·HCl was reproducibly synthesized, with an overall yield of 41.8&#;54.6% and a minimum purity of 99.4% (w/w) by HPLC assay. Over a minimum of four consecutive trials, for each stage, the established targets for yields and impurity profiles were achieved&#;and, in most cases, exceeded. Chemical impurities in the final product (MDMA·HCl) averaged 0.04% of the total peak area, by HPLC, and no single impurity ever exceeded 0.03% of the total peak area. Of all of the organic solvents used in the production process, only isopropanol (Class 3, 409&#;509 ppm), tetrahydrofuran (Class 2, <7 ppm), methanol (Class 2, <6 ppm), and n-heptane (Class 3, <67 ppm) were detected in the final product&#;all in concentrations well below the permitted daily exposure (PDE) per FDA guidance. 25 The scale and reliability of this cGMP process will improve access to MDMA for ongoing and future clinical trials&#;and potentially for licensed therapeutic use, pending FDA approval.
Increased demand for pharmaceutical-grade MDMA encouraged us to develop a cGMP-compliant production process, both to supply our own Phase III clinical trials, for PTSD, and to ameliorate existing supply constraints for the broader research community. While large-scale clandestine production is common, to the best of our knowledge, no multi-kilogram synthesis of pharmaceutical-grade MDMA has yet been reported in the literature. We therefore needed to develop a practicable synthetic route while simultaneously addressing cGMP requirements.
MDMA is not a particularly complex molecule, and many synthetic pathways have been reported. Most begin from either safrole or piperonal, which are highly regulated and consequently difficult to obtain; for the sake of convenience and efficiency, we elected to avoid these. We identified 5-bromo-1,3-benzodioxole (11), which does not appear on any geopolitical entity&#;s list of controlled substance precursors, as a useful starting material for our synthesis. The 1,3-benzodioxole moiety appears in a variety of natural products, including oils,26 spices,27 and traditional plant-based medicines.28 Many compounds containing this structural feature are known to interact with cytochrome P450 enzymes in mammals, producing a range of clinically notable effects, both pharmacologically useful and neurotoxic.29 Compound 11 is synthesized via the bromination of benzodioxole with NBS; analysis of multiple batches, from a range of suppliers, indicated that the only significant impurities present in the batch are 5,6-dibromo-1,3-benzodioxole and succinimide, which is insoluble in Compound 11 and consequently present in only very trace amounts. We additionally screen for the presence of 4-bromo-1,3-benzodioxole, which would likely present separation challenges during production, but we have never observed this isomer in the starting material. At the levels observed, neither of the two significant impurities interfered with the downstream chemistry.
Compound 11 has been previously used in at least two (reported) approaches to MDMA: as a starting material in the asymmetric synthesis of (S)-MDMA, through a protected aziridine intermediate,30 and as a precursor to safrole, via Grignard reaction with allyl bromide (Scheme 2).19,31
Instead of approaching MDMA conventionally, via safrole, we elected to generate a 2-propanol substituent via ring-opening addition between the same aryl Grignard reagent used to synthesize safrole, above, and 1,2-propylene oxide (12), which is both inexpensive and readily available. Reactions of Grignard reagents and epoxides are well-known,32 but&#;to the best of our knowledge&#;this particular synthetic pathway has not previously been used to produce MDMA. Our familiarity with this type of reaction made us optimistic that scale-up would proceed smoothly&#;and it did. Although Grignard formation is slow, the bulk reaction can be expedited via initiation with a small amount of previously prepared Grignard reagent. The 5,6-dibromo-1,3-benzodioxole impurity present in the starting material does not undergo Grignard formation and is removed during workup as part of the organic layer. The workup at this stage was quite efficient, and distillation via a wiped-film evaporator (two to three passes) yielded 1-(3,4-methylenedioxy-phenyl)-2-propanol (13) in excess of 96% chemical purity by HPLC. The adjusted yield, based on HPLC assay, was 79.22&#;87.39% (w/w) over five trials.
The next three steps relied on well-known synthetic transformations. 13 was oxidized to methyl piperonyl ketone (4) with a biphasic (DCM/H2O) TEMPO/KBr/bleach reagent system, which was followed by aqueous workup and filtration to remove remaining solids. The solvent was removed via a rotatory evaporator, and the crude product was of sufficient purity to proceed to the next process stage, without an additional purification step (100.2&#;108.2% yield over four trials; 84.98&#;90.01% w/w by HPLC assay). Stage 3, reductive amination of 4, was accomplished with aqueous methylamine and NaOH/NaBH4. Workup was somewhat complex, using an acid/base treatment to remove the vast majority of impurities, followed by acidification with HCl in isopropanol which yielded 71.6&#;75.8% MDMA·HCl (14), over eight trials, with chemical purity exceeding 99.26% of peak area, by HPLC. Recrystallization in isopropanol (Stage 4) yielded 85.5&#;86.2% of a white, crystalline solid, with a minimum purity of 99.95% by HPLC and a minimum assay of 99.40% (w/w), also by HPLC (Table 1).
MDMA·HCl was previously known to form one major crystal form (Form I) and at least four hydrates that incorporate 0.25&#;1 waters of hydration.16 Our polymorphic screening process identified two new anhydrous crystal forms (Forms II and III) and established Form I as the most stable of the three. Form II can be reproducibly produced from a variety of alcoholic solvents, as well as in the presence of ethyl acetate and an ethereal antisolvent. Unlike Form III, which spontaneously converted to Form I after 2.5 weeks at ambient conditions, and could not be reproduced, Form II is shelf-stable, though it will convert to Form I under competitive equilibration conditions. Interestingly, both Form I and Form II reversibly convert into the known monohydrate; upon dehydration, the monohydrate formed from Form I will revert back to Form I, and the monohydrate formed from Form II will revert back to Form II. If crystallized from a concentrated aqueous solution with no form memory, the monohydrate will thermally dehydrate exclusively into Form I. X-ray powder diffraction spectra for all three forms are shown in .
To maintain compliance with cGMP regulations, all reagents were visually inspected and tested, prior to use. Conformance to established specification(s) was documented, reagents were labeled with identifying raw material numbers, and these identifying numbers were recorded whenever a reagent was used, in-process. Organic reagents were typically confirmed by FT-IR, as well as by other methods specific to their chemical identity and various process needs (e.g., Karl&#;Fischer titration to establish water content, etc.), in accordance with established procedures. Inorganic reagents were confirmed by appropriate chemical identification tests. Reagents that failed to meet all established specifications were not used at any stage of the process.
Another concern for cGMP manufacturing is the presence of residual solvents, which must be below solvent-specific concentration thresholds defined in USP <467>. The limits set for residual solvent concentrations are based on anticipated daily exposure to a pharmaceutical product. In clinical use, MDMA is never recommended for daily&#;or even regular&#;consumption; instead, it is ingested during a small number of therapy sessions, spread over weeks or months. Nevertheless, our monograph utilizes the USP <467> PDE limits as acceptance criteria&#;and our process yielded residual solvent concentrations significantly below these limits, over four consecutive validation trials (Table 2). The limit of detection for all tested solvents was 1 ppm; solvents detected in concentrations below the quantitation limit were reported as such.
In addition to meeting residual solvent concentration limits, cGMP pharmaceuticals must have acceptable impurity profiles. Any single impurity exceeding 0.1% must be both characterized and quantified. Over four trials, our process yielded MDMA·HCl with chemical purity in excess of 99.9% of peak area by HPLC; no single impurity ever exceeded 0.05% of the total peak area. While impurity characterization was consequently not required, we routinely screened for two known impurities ( ), both of which were generated via low-level electrophilic addition during the Stage 2 oxidation of 13. Chlorination was only significant when the bleach was overcharged, and the reaction conditions used in Stage 2 prevent this. Bromination, which also increased with excess bleach, was a more significant side reaction, but it was successfully minimized using KBr in catalytic, rather than stoichiometric, quantities. Neither impurity was ever found in excess of 0.03% of the total peak area, by HPLC, in any of the four Stage 4 validation trials.
Heavy metal impurities in finished pharmaceutical products are also an area of potential concern. As with residual solvents, cGMP-compliant limits are established with the assumption that a medication will be consumed on a daily basis, a usage pattern that we do not anticipate will ever be in effect for clinically administered MDMA. Nevertheless, we used the oral daily dose PDEs from USP &#;232&#; when determining acceptability parameters. As shown in Table 3, the greatest quantifiable amount of any heavy metal impurity was 97% less than the permissible daily intake limit&#;and most were well below that level.
To validate this cGMP process, each stage was successfully completed at the 8 kg scale (based on the starting charge of benzodioxole) at least four consecutive times, in accordance with the documented procedures. All reagents, products, intermediates, common impurities, and (as required) reaction end points were validated using cGMP-compliant analytical methods, some of which were specifically developed for this synthetic process. Any deviations from the documented procedures or parameters were noted, and the anticipated impact on the final product&#;if any&#;was characterized. No documented deviation appeared to affect either the final product or the outcome of the Stage 4 recrystallization step, which yielded remarkably consistent results throughout the validation process (Table 1). We are confident that our cGMP protocols are sufficient to reliably produce enough pharmaceutically acceptable MDMA to meet expanding research and therapeutic needs.
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