27203-92-5

Basic information

• Product Name: Tramadol
• Synonyms: 2-((dimethylamino)methyl)-1-(m-methoxyphenyl)-cyclohexano;cis-(+-)-cyclohexano;TRAMAL;TRANS-(+/-)-2-[(DIMETHYLAMINO)METHYL]-1-(3-METHOXYPHENYL)CYCLOHEXANOL;CRISPIN;Cyclohexanol, 2-(dimethylamino)methyl-1-(3-methoxyphenyl)-, (1R,2R)-rel-;CG 315E;cis-Tramadol
• CAS NO: 27203-92-5
• Molecular Formula: C₁₆H₂₅NO₂
• Molecular Weight: 263.38
• EINECS: 252-950-2
• Product Categories: Tramadol;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 27203-92-5.mol

Chemical Properties

• Melting Point: 178-181 °C
• Boiling Point: 406.62°C (rough estimate)
• Flash Point: 188.5 °C
• Appearance: white to off-white/solid
• Density: 0.9903 (rough estimate)
• Refractive Index: 1.4909 (estimate)
• Storage Temp.: 2-8°C
• PKA: 14.47±0.40(Predicted)
• CAS DataBase Reference: Tramadol(CAS DataBase Reference)
• NIST Chemistry Reference: Tramadol(27203-92-5)
• EPA Substance Registry System: Tramadol(27203-92-5)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 2
• Hazardous Substances Data: 27203-92-5(Hazardous Substances Data)

Usage

Uses

Used in Pain Management:
Tramadol is used as an analgesic for the management of moderate to severe pain. It produces analgesia through two distinct actions: agonist activity at the MOP and KOP receptors, and enhancement of the descending inhibitory systems in the spinal cord by inhibiting noradrenaline reuptake and releasing serotonin from nerve endings.
Used in Urinary Incontinence Treatment:
Tramadol is used as a treatment for urinary incontinence, although the specific application reason is not provided in the materials.
Used in Pharmaceutical Industry:
Tramadol is used in the pharmaceutical industry as an analgesic agent with multiple mechanisms of action, providing pain relief through its interaction with opioid receptors and neurotransmitter reuptake inhibition.
Chemical Properties:
Tramadol is a light yellow oil and is marketed under the brand name Trabar. It is metabolized by cytochrome P450 (CYP2D6 and CYP3A4), and its potency is affected by a patient's CYP genetics. Caution must be exercised in hepatic impairment and in patients receiving monoamine oxidase inhibitors (MAOIs).

Treatment in Particular diseases

In Osteoarthritis: Tramadol with or without acetaminophen has modest analgesic effects in patients with Osteoarthritis. It may also be effective as add-on therapy in patients taking concomitant NSAIDs or COX-2 selective inhibitors. As with opioids, tramadol may be helpful for patients who cannot take NSAIDs or COX-2 selective inhibitors. Tramadol should be initiated at a lower dose (100 mg/day in divided doses) and may be titrated as needed for pain control to a dose of 200 mg/ day. It is available in a combination tablet with acetaminophen and as a sustained-release tablet. Opioid-like adverse effects such as nausea, vomiting, dizziness, constipation, headache, and somnolence are common.

Therapeutic Function

Analgesic

Mechanism of action

Fentanyl is a μ agonist with approximately 80 times greater potency than morphine. Fentanyl has been used in combination with nitrous oxide for “ balanced” anesthesia and in combination with droperidol for “ neurolepalgesia.” The advantages of fentanyl over morphine for anesthetic procedures are its shorter duration of action (1–2 hours) and the fact that it does not cause histamine release on intravenous injection.

Pharmacokinetics

The analgesic activity of tramadol is attributed to a synergistic effect caused by the opioid activity of the (+)-isomer and the neurotransmitter reuptake blocking effect of the (–)-isomer. The (+)-isomer possesses weak μ opioid agonist activity equivalent to approximately 1/3,800 that of morphine. The O-desmethyl metabolite (CYP2D6) of (±)-tramadol has improved μ opioid activity equivalent to 1/35 that of morphine. Affinity for both δ and κ receptors is improved. Despite its higher opioid potency, the contribution of O-desmethlytramedol to the overall analgesic effect has been questioned but not well studied. Individuals who lack CYP2D6 or are taking a CYP2D6 inhibitor have a reduced effect to tramadol. The fact that naloxone causes a decrease in the analgesic potency of tramadol argues strongly for an opioid component to the analgesic activity. (–)-T ramadol possesses only 1/20 the opioid activity of its (+)-isomer, but it has good activities for inhibition of norepinephrine (Ki = 0.78 μM) and serotonin (Ki = 0.99 μM) reuptake. Tramadol's neurotransmitter reuptake activity is approximately 1/20 that of imipramine, a tricyclic antidepressant agent that is used widely in pain management. Although none of the individual pharmacological activities of tramadol is impressive, they interact to give a synergistic analgesic effect that is clinically useful. Tramadol has been used in Europe since the 1980s and was introduced to the U.S. market in 1995. The drug is nonaddicting and, thus, is not a scheduled agent. In addition, tramadol does not cause respiratory depression or constipation.

InChI:InChI=1/C16H25NO2/c1-17(2)12-14-7-4-5-10-16(14,18)13-8-6-9-15(11-13)19-3/h6,8-9,11,14,18H,4-5,7,10,12H2,1-3H3/t14-,16+/m1/s1

Upstream product

• 6651-36-1 1-(Trimethylsilyloxy)cyclohexene 
• 36282-40-3 (3-methoxyphenyl)magnesium bromide 
• 333-27-7 methyl trifluoromethanesulfonate 
• 3188-13-4 ethyl chloromethyl ether 
• 74-88-4 methyl iodide 
• 2398-37-0 3-methoxyphenyl bromide 
• 769092-24-2 2-[(dimethylamino)methyl]cyclohexanone 
• 36282-47-0 tramadol hydrochloride 
• 108-94-1 cyclohexanone 
• 31600-88-1 m-methoxyphenyllithium 
• 502-42-1 cycloheptanone 
• 2082-28-2 1-(m-methoxyphenyl)cycloheptanol 
• 75209-54-0 (E)-1-(3-methoxyphenyl)cyclohept-1-en 
• 124-40-3 dimethyl amine 

Downstream Products

• 2914-78-5 DL-Tramadolhydrochlorid 
• 36282-47-0 tramadol hydrochloride 
• 1206889-11-3 (+)-tramadol-(S)-ibuprofen salt 
• 1112045-11-0 (1R,2R)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (S)-naproxen salt 
• 1112063-73-6 (1S,2S)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (S)-naproxen salt 
• 73986-53-5 (±)-cis-2-[(dimethylamino)methyl]-1-(3-hydroxyphenyl)cyclohexanol 
• 280565-80-2 (-)-cis-tramadol (R)-(-)-mandelate 
• 280565-80-2 (+)-cis-tramadol R-(-)-mandelate 
• 152538-36-8 (-)-tramadol 
• 22204-88-2 (-)-tramadol hydrochloride 
• 280565-80-2 C₁₆H₂₅NO₂*C₈H₈O₃ 
• 2914-77-4 (R,R)-tramadol 

Relevant articles and documents

Catalytic Intramolecular Coupling of Ketoalkenes by Allylic C(sp3)?H Bond Cleavage: Synthesis of Five- and Six-Membered Carbocyclic Compounds

In the presence of a catalytic amount of cobalt(II) acetylacetonate/Xantphos in combination with trimethylaluminum, various ketoalkenes underwent an intramolecular cyclization reaction triggered by cleavage of the allylic C(sp3)?H bond, affording carbocyclic compounds with high regio- and diastereoselectivity. Mono-, bi-, and tricarbocyclic compounds were produced in good yields. One of the products thus obtained was derivatized into tramadol in four simple steps. Notably, these intramolecular cyclizations took place in the absence of a gem-disubstituent on the tethered carbon chain (without the Thorpe-Ingold effect). (Figure presented.).

Continuous-Flow Synthesis of Tramadol from Cyclohexanone

A multioperation, continuous-flow platform for the synthesis of tramadol, ranging from gram to decagram quantities, is described. The platform is segmented into two halves allowing for a single operator to modulate between preparation of the intermediate by Mannich addition or complete the fully concatenated synthesis. All purification operations are incorporated in-line for the Mannich reaction. 'Flash' reactivity between meta-methoxyphenyl magnesium bromide and the Mannich product was controlled with a static helical mixer and tested with a combination of flow and batch-based and factorial evaluations. These efforts culminated in a rapid production rate of tramadol (13.7 g°h -1) sustained over 56 reactor volumes. A comparison of process metrics including E-Factor, production rate, and space-time yield are used to contextualize the developed platform with respect to established engineering and synthetic methods for making tramadol.

Simultaneous chiral separation of tramadol and methadone in tablets, human urine, and plasma by capillary electrophoresis using maltodextrin as the chiral selector

The stereoselective analysis and separation of racemic drugs play an important role in pharmaceutical industry to eliminate the unwanted isomer and find the right therapeutic control for the patient. Present study suggests a maltodextrin-modified capillary electrophoresis method for a single‐run chiral separation of two closely similar opiate pain relief drugs: tramadol (TRA) and methadone (MET). The best separation method possible for the both enantiomers was achieved on an uncoated fused‐silica capillary at 25°C using 100 mM phosphate buffer (pH 8.0) containing 20% (w v?1) maltodextrin with dextrose equivalent of 4–7 and an applied voltage of 16 kV. Under optimal conditions, the baseline resolution of TRA and MET enantiomers was obtained in less than 12 minutes. The relative standard deviations (n = 3) of 20 μg mL?1 TRA and MET were 2.28% and 3.77%, respectively. The detection limits were found to be 2 μg mL?1 for TRA and 1.5 μg mL?1 for MET. This method was successfully applied to the measurement of drugs concentration in their tablets, urine, and plasma samples.

Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.

Optimization of throughput in semipreparative chiral liquid chromatography using stacked injection

An interesting mode of chromatography for preparation of pure enantiomers from pure samples is the method of stacked injection as a pseudocontinuous procedure. Maximum throughput and minimal production costs can be achieved by the use of total chiral column length in this mode of chromatography. To maximize sample loading, often touching bands of the two enantiomers is automatically achieved. Conventional equations show direct correlation between touching-band loadability and the selectivity factor of two enantiomers. The important question for one who wants to obtain the highest throughput is “How to optimize different factors including selectivity, resolution, run time, and loading of the sample in order to save time without missing the touching-band resolution?” To answer this question, tramadol and propranolol were separated on cellulose 3,5-dimethyl phenyl carbamate, as two pure racemic mixtures with low and high solubilities in mobile phase, respectively. The mobile phase composition consisted of n-hexane solvent with alcohol modifier and diethylamine as the additive. A response surface methodology based on central composite design was used to optimize separation factors against the main responses. According to the stacked injection properties, two processes were investigated for maximizing throughput: one with a poorly soluble and another with a highly soluble racemic mixture. For each case, different optimization possibilities were inspected. It was revealed that resolution is a crucial response for separations of this kind. Peak area and run time are two critical parameters in optimization of stacked injection for binary mixtures which have low solubility in the mobile phase.

Biomimetic synthesis of Tramadol

Tramadol has recently been isolated from the roots and bark of Nauclea latifolia. A plausible biosynthetic pathway has been proposed and the product-precursor relationship has been probed by 13C position-specific isotope analysis. By further exploring this pathway, we demonstrate that a key step of the proposed pathway can be achieved using mild conditions that mimic in vivo catalysis.

Comparative performance evaluation and systematic screening of solvents in a range of Grignard reactions

The solvent effect on the Grignard reaction of benzyl, aryl and heteroaromatic substrates has been systematically evaluated based on reaction efficiency, ease of subsequent work-up, safety and greenness. 2-Methyltetrahydrofuran (2-MeTHF), which can be derived from renewable resources, had at least an equal if not a superior overall process most notably in suppressing the Wurtz coupling by-product from the benzyl Grignard reactions. It is therefore a recommended alternative solvent to Et2O and THF for the preparation of most Grignard reagents and their subsequent reactions.

COMPOSITIONS AND METHODS FOR OVERCOMING RESISTANCE TO TRAMADOL

There is disclosed a composition for oral administration of O-desmethyltramadol. There is further disclosed a method for treating disorders modulated by at least opiate receptor activity or monoamine activity, including acute and chronic pain, comprising administering a pharmaceutical formulation comprising O-desmethyltramadol. Compositions and methods are also provided that are effective for overcoming resistance to tramadol in patients.

Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions

This contribution details how a continuous flow reactor was used to react carbonyl compounds with Grignard reagents at room temperature in an efficient and safe manner. Flow rate, residence time and temperature were optimized for the preparation of a small collection of secondary and tertiary alcohols. Excellent yields and general applicability were observed using the set-up protocol. The procedure was also applied for the preparation of Tramadol, an analgesic drug belonging to the opioid group. The developed conditions allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function.

SUBSTITUTED CYCLOHEXANOLS

Disclosed herein are substituted cyclohexanol opioid receptor modulators and/or neurotransmitter reuptake modulators of Formula I or Formula II, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.