An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.
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Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil
Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil
Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K, Communication
DOI: 10.1039/C6GC02623K, Communication
Shivam Maurya, Dhiraj Yadav, Kemant Pratap, Atul Kumar
We developed a post-sulfoxidation protocol for the synthesis of Modafinil that exhibits improved sustainability credentials, utilizing the recyclable heterogeneous catalyst Nafion-H.
We developed a post-sulfoxidation protocol for the synthesis of Modafinil that exhibits improved sustainability credentials, utilizing the recyclable heterogeneous catalyst Nafion-H.
Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil
*Corresponding authors
aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
E-mail: dratulsax@gmail.com, atul_kumar@cdri.res.in
E-mail: dratulsax@gmail.com, atul_kumar@cdri.res.in
bAcademy of Scientific and Innovative Research, New Delhi 110001, India
Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K
Atul Kumar
Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI
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Selection and justification of starting materials: new Questions and Answers to ICH Q11 published
The ICH Q11 Guideline describing approaches to developing and understanding the manufacturing process of drug substances was finalised in May 2012. Since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experience has shown that there is some need for clarification. Thus the Q11 Implementation Working Group recently issued a Questions and Answers Document.
The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.
On 30 November 2016 the ICH published a Questions and Answers…
View original post 2,105 more words
Lumefantrine
lumefantrine
- Molecular FormulaC30H32Cl3NO
- Average mass528.940 Da
- Benflumetol
- dl-Benflumelol
UNIIF38R0JR742
CAS number82186-77-4
(±)-2-(Dibutylamino)-1-((9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl)ethanol
(±)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-α-((dibutylamino)methyl)fluorene-4-methanol
(9Z)-2,7-Dichloro-9-[(4-chlorophenyl)methylene]-α-[(dibutylamino)methyl]-9H-fluorene-4-methanol
120583-70-2 [RN]
120583-71-3 [RN]
2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]-9H-fluoren-4-yl]ethan-1-ol
| (±)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-α-((dibutylamino)methyl)fluorene-4-methanol |
| 2-Dibutylamino-1-[2,7-dichloro-9-(4-chloro-benzylidene)-9H-fluoren-4-yl]-ethanol |
| 2-Dibutylamino-1-{2,7-dichloro-9-[1-(4-chloro-phenyl)-meth-(Z)-ylidene]-9H-fluoren-4-yl}-ethanol |
| Benflumetol |
| dl-Benflumelol |
UNII F38R0JR742
CAS number 82186-77-4
Weight Average: 528.94
Monoisotopic: 527.154947772
Chemical Formula C30H32Cl3NO
Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term “co-artemether” is sometimes used to describe this combination.[1] Lumefantrine has a much longer half-life compared to artemether and so is therefore thought to clear any residual parasites that remain after combination treatment.[2]
Lumefantrine, along with pyronaridine and naphtoquine, were synthesized in course of the Project 523 antimalaria drug research initiated in 1967; these compounds are all used in combination antimalaria therapies.[3][4][5]
Lumefantrine is an antimalarial drug chemically known as 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4- chlorobenzylidene)-9H-floren-4-yl] ethanol, which is used in the prevention and treatment of Malaria in worm blooded animals. Lumefantrine is using the combination of β-Artemether in the treatment of Malaria
SYN
Synthetic Reference
Beutler, Ulrich; Fuenfschilling, Peter C.; Steinkemper, Andreas. An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part II. Organic Process Research & Development. Volume 11. Issue 3. Pages 341-345. 2007.
SYN 2
Synthetic Reference
Rao, Dharmaraj Ramachandra; Kankan, Rajendra Narayanrao; Phull, Manjinder Singh. Process for preparation of lumefantrine as antimalarial agent with improved method. Assignee Cipla Co., Ltd., India. CN 1865227. (2006).
SYN 3
Synthetic Reference
Sethi, Madhuresh Kumar; Gonuguntla, Anantavena Rani; Arikatla, Siva Lakshmi Devi; Mulukutla, Suryanarayana; Yerramalla, Rajakrishna; Bontalakoti, Jaganmohanarao; Vemula, Lakshminarayana; Thirunavukarasu, Jayaprakash. Synthesis and characterization of novel related substances of Lumefantrine, an anti-malarial drug. Pharma Chemica. Volume 8. Issue 3. Pages 91-100. 2016.
SYN4
Synthetic Reference
Mathur, Prafull; Mathur, Suvigya; Vishwanath, Kannan; Mishra, Anand Kumar. Preparation of lumefantrine. Assignee Aanjaneya Lifecare Limited, India. IN 2013MU00611. (2015).
SYN 5
Synthetic Reference
Wu, Guang-liang; Dai, Ying-jie; Kang, Cong-min; Zi, Yan. A new synthetic technology of anti-malarial drug lumefantrine. Zhongguo Xinyao Zazhi. Volume 21. Issue 24. Pages 2944-2947. 2012.
SYN 6
Synthetic Reference
Krishna, Bettadapura Gundappa; Verma, Sudhakar; Krishna, Sujatha; Naik, Gajanan; Arulmoli, Thangavel. A process for preparation of lumefantrine. Assignee SeQuent Scientific Limited, India. IN 2012CH00470. (2012).
SYN 7
Synthetic Reference
Bansi, Lal; Genbhau, Gund Vitthal; Prabhakar, Bapat Chintamani; Popat, Bochiya Pravin; Banshi, Punde Dnyanadeo; Venkata, Reddy Prabhakar Gorla. Improved one pot process for the synthesis of lumefantrine. Assignee Calyx Chemicals and Pharmaceuticals Ltd., India. IN 2009MU01437. (2010).
SYN 8
Synthetic Reference
Shailesh, Singh; Dhaval, Vashi; Vinod, Gaikwad; Sanjay, Chowkekar; Sanjay, Bute. Process for the preparation of lumefantrine. Assignee Ajanta Pharma Ltd., India. IN 2008MU01677. (2010).
SYN 9
Synthetic Reference
Rawalnath, Sakhardande Rajiv; Kanji, Khatri Navin; Nilkanth, Firake Pandharinath; Vasant, Panchal Rajesh; Nagesh, Babrekar Chandan; Madhukar, Mohite Dhanaji. Preparation of lumefantrine. Assignee Saxena, Alok, India. IN 2006MU00260. (2007).
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PATENT
https://patents.google.com/patent/CN107501316A/en
Embodiment 1：The synthesis of (the chloro- 2- of 2- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) ethyoxyl) trimethyl silane
2,7- dichloro fluorenes -4- oxirane (100g, 0.368mol), zinc oxide are sequentially added in 1000ml there-necked flasks (2.94g, 0.036mol) and 500ml dichloromethane, TMSCl (43g, 0.4mol) are added drop-wise in above-mentioned reaction solution, room temperature reaction 2h.Filtering, a small amount of dichloromethane washing of filter cake, filtrate washing, organic phase anhydrous sodium sulfate drying, filtering, filtrate are rotated to analysis After going out solid, stop revolving, stand and separate out a large amount of yellow solids, filtering, drain to obtain (the chloro- 2- of 2- (2,7- bis- chloro- 9H- fluorenes- 4- yls) ethyoxyl) trimethyl silane yellow solid 102g, yield 73%.δ(1HNMR,CDCl3)：7.78-7.80(m,1H), 7.56(s,1H),7.48(s,1H),7.41(s,1H),7.32-7.35(m,1H),5.64-5.67(m,1H),4.03-4.11(m, 2H),3.84(m,2H),0.63(s,9H),ppm。
Embodiment 2：N- butyl-N- (1- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) -2- (trimethylsiloxy group) ethyl) butyl – The synthesis of 1- amine：
(the chloro- 2- of 2- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) ethyoxyl) trimethyl silicane is sequentially added in 1000ml there-necked flasks Alkane (100g, 0.26mol), di-n-butylamine (67g, 0.52mol), potassium carbonate (71.65g, 0.52mol) and 800ml acetonitriles.Put It is changed to nitrogen system, back flow reaction 16h.After being down to room temperature, filtering, a small amount of acetonitrile of filter cake washs, and filtrate is evaporated to obtain fourth containing N- The crude yellow oil of base-N- (1- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) -2- (trimethylsiloxy group) ethyl) butyl -1- amine. Crude product is directly used in be synthesized in next step, without purifying.MS:479(MH+)
Embodiment 3：The synthesis of 2- dibutyl aminos -2- [the chloro- 9H- fluorenes -4- bases of 2,7- bis-] ethanol
By-the N- of butyl containing N- obtained in the previous step (1- (the chloro- 9H- fluorenes -4- bases of 2,7- bis-) -2- (trimethylsiloxy group) second Base) crude yellow oil of butyl -1- amine is dissolved in 500ml tetrahydrofurans, concentrated hydrochloric acid (1ml), nitrogen protection, heating is added dropwise To 50 DEG C of reactions, TLC tracing detections to raw material have reacted completely, cool, and separate out solid, filtering, the washing of filter cake tetrahydrofuran, take out Dry, filtrate is abandoned, and filter cake is transferred in beaker, adds 200ml dichloromethane, and saturated aqueous sodium carbonate is adjusted pH=8, separated Machine phase, water layer are extracted once with 200ml dichloromethane again, merge organic phase, are washed, and are dried, are concentrated to give yellow oil 68g, two step yields 64%.δ(1HNMR,CDCl3)：7.80(s,1H),7.56(s,1H),7.38(m,2H),7.25(s,1H), 4.7(brs,1H),4.03-4.11(m,2H),3.99(m,1H),3.56(m,2H),2.42-2.85(m,4H),1.44-1.48 (m,4H),1.23-1.28(m,4H),0.86-0.91(m,6H).ppm。
Embodiment 4：(RS, Z) -2- dibutyl aminos -2- [bis- chloro- 9- of 2,7- (4- chlorobenzenes methylene) -9H- fluorenes -4- bases] second The synthesis of alcohol
2- dibutyl aminos -2- [the chloro- 9H- fluorenes -4- bases of 2,7- bis-] ethanol (68g, 0.167mol) is dissolved in 200ml ethanol In, 4-chloro-benzaldehyde (28.2g, 0.2mol) and sodium hydroxide (2.68g, 0.067mol) are added, nitrogen protection, is heated to reflux anti- Answer 1h.Room temperature is down to, watery hydrochloric acid, which is added dropwise, makes product be filtered into salting out, and the washing of filter cake ethanol, drains to obtain yellow solid, shifts Into beaker, 200ml dichloromethane is added, adds saturated aqueous sodium carbonate to dissociate, be layered, aqueous phase uses 200ml dichloromethane again Extraction once, merges organic phase, washing, and anhydrous sodium sulfate drying 6h is filtered, and filtrate is concentrated to give (RS, Z) -2- dibutyl aminos -2- [2,7- bis- chloro- 9- (4- chlorobenzenes methylene) -9H- fluorenes -4- bases] ethanol be yellow foam shape solid 74g, yield 83%, 0-5 DEG C Preserve.δ(1HNMR,CDCl3)：7.75(brs,1H),7.66(s,1H),7.55(s,1H),7.44-7.48(m,5H),7.28- 7.29(m,1H),7.30-7.31(m,1H),4.7(brs,2H),3.88-3.89(m,2H),2.71-2.72(m,2H),2.60- 2.63(m,2H),1.44-1.48(m,4H),1.23-1.31(m,4H),0.86-0.90(m,6H).ppm。
PATENT
Process for high purity lumefantrine Dr KrishnaSarma Pathy,Ramesh.D,P atchutaramaiah,Ch Sivasubramanyam Abstract. The present invention relates to Process for the preparation of lumefantrine Lumefantrine is a dichlorobenzylidine derivative effective for the treatment of various types of malaria. Chemically lumefantrine is 2-Dibutylamino-1-[ 2, 7-dichloro-9-(4- chlorobenzylidene)-9H-fluoren-4-yl]-Ethanol (racemate) The antimalarial agent is active against multi-drug resistant strains of Plasmodium falciparum. In combination with artemether, the drug is also used for the treatment of uncomplicated falciparum malaria. It has primary action as blood schizontocidal and secondary action as inhibition of nucleic acid and protein synthesis within the malarial parasite thus having a longer duration of anti malarial action. Thus, today lumefantrine is a drug of choice in antimalarial treatment against P. faliciparum. Therefore, development of an appropriate analytical procedure for the quantitative analysis of lumefantrine is of considerable importance to pharmaceutical industry. The spectroscopic techniques were used to confirm the identity of lumefantrine. The IR spectra, showed strong absorption band at 3404.67 cm-1(OH), 2953.28 cm-1(aliphatic and aromatic CH), 1757.31 cm-1(-C=C-), 933 cm-1(alkanes) and 696.37-373.22 cm-1 (Cl). Thus, IR spectra confirmed the presence of these functional groups in the structure of lumefantrine. The mass spectrum showed a sharp molecular ion peak at 528.0 m/z in Q1 MS (m/z, parent ion) parameter at negative polarity confirming the molecular weight of lumefantrine. The NMR spectra observed triplet at 0.943-0.989 (methyl protons of alkyl chain); a multiplet at 1.372-1.498 (methylene protons of alkyl chains); a multiplet at 2.449-2.909 (methylene protons of alkyl chain); broad singlet at 4.573 (OH proton); and multiplet at 7.314-7.733 (aromatic proton), thus confirming identity of lumefantrine. Summary of the process Stage1 Cl Cl 2,7-dichloro-9H-fluorene ClCl O Cl 2-chloro-1-(2,7-dichloro-9H-fluoren-3-yl)ethanone AlCl3 Chloroacetyl chloride In a 1 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser450.0 ml MDC cool to 0C.Start addition of 59.4 gm chloro acetyl chloride at 0-5C and stir for 15 min.Start addition of aluminium chloride at 0-5C. Stir for 30.0 min at same temp.Start addition of 2,7-dichloro fluorene soln. preprepared in 300.0 ml MDC d 150.0 ml saturated brine for washing and stir for 15-20 min. at 50-55 C.Allow to settle the layers at 50- 55C for 30.0 min.Separate the ORGANIC LAYER. at 50-55C.Again repeat Abovestep. for one time.Collect ORGANIC LAYER. and distill out dibutyl amine under vac. At 60- 90C.Disconnect vac. And cool reaction mass to 60C add 400.0 ml methanol and reflux to 30.0 min. After maintaining the reaction mass cool reaction mass to 50C.Seed the reaction mass by adding 500 mg stage 2 material at . 50C.Cool reaction mass to 30- 35C.Stir reaction mass further at same temp. fot 2 hrs.Filter reaction mass at 30- 35C.Suck dry and wash with 50.0 ml methanol at 30-35C.Suck dry and unload. Dry at 50-55C. Wt. of wet cake : 139.0 gm Wt. of dry material : 123.0 gm . . . a b c . . . a b c M.P: 72-76C Stage3: ClCl N OH + Cl COH ClCl N OH Cl 2,7-dichloro-alpha-[(dibutyl amino) p-chloro benzaldehyde methyl]-9H-fluoren-4-yl]oxirane Mol. Wt. 406 Lumefantrine Mol. Wt. 140.5Mol. Wt. 528.5 Under Nitrogen In a 2 liter 3-necked flask, equipped with stirrer, thermometer and reflux.Charge 840.0 ml ethanol at 30-35C.Chrge 120.0gm stage2 material at 30-35C.Charge 27.96 gm sodium methoxide in 30 min. at 30C exothermobserved temp. rise to 45C.Charge 41.52 gm p- Chloro benzaldehyde .Maintain reaction mass temp. 30-35C for 24 hrs. Check TLC a : Stage 2 b : Co spot c : reaction mass Mobile phase Hexane : Ethyl acetate 9 : 1 If TLC complies 1) 2) 3) Filter reaction mass at 30-35C. Suck dry and wash with 100.0 ml methanol. Suck dry and unload wet cake. Dry material at 50-55 C . . . a bc Wt. of wet cake : 184.0 gm Wt. Of dry material : 141.0 gm M.P : 122-126C Purification : In a 1 liter 3-necked flask, equipped with stirrer, thermometer and reflux .Charge 700.0 ml ethyl acetate at 30-35C.Chrge crude 141.0 gm material at 30-35C.Heat reaction mass to refluxand main for 30.0 min. to dissolve the material.Filter reaction mass at 75-80C.Collect filtrate cool to reaction mass to 0- 5C.Maintain reaction mass at same temp. for 30.0 min.Filter the reaction mass at 0- 5C.Suck dry and wash with 100.0 ml ethyl acetate at 0-5C.Suck dry and unload. Dry material at 50-55 C Wt. of wet cake : 100.0 gm Wt. Of dry material : 70-80 gm
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].
M.P: 128-132C RESULTS:= Lumefantrine 99.15% (by HPLC) 128 – 130 Purity Melting Pointo C Liquid chromatography HPLC-UV investigation of the impurity profiles was performed on a HPLC-PDA apparatus consisting of a Waters Alliance 2695 separation module and a Waters 2998 photodiode array detector with Empower 2 software for data acquisition . For PDA detection, the UV spectrum was recorded at 190-400 nm. Quantification was performed at 266 nm. The positive ion ESI and the collision-induced dissociation (CID) mass spectra were obtained from the LC-UV/MS apparatus consisting of a Spectra System SN4000 interface, a Spectra System SCM1000 degasser, a Spectra System P1000XR pump, a Spectra System AS3000 autosampler, and a Finnigan LCQ Classic ion trap mass spectrometer in positive ion mode mass to charge range m/z 100 to m/z 2000 at unit resolution and with a peak width of 0.25 daltons/z, equipped with a Waters 2487 dual wavelength UV detector and Xcalibur 2.0 software (Thermo) for data acquisition. ESI was conducted using a needle voltage of 4.5 kV. Nitrogen was used as sheath and auxiliary gas with the heated capillary set at 250C. UV-detection was used for quantification (at 266 nm), while ESI-ion trap MS detection was used for identification. LC determination of impurities in lumefantrine samples was performed using a Purospher STAR RP-18 endcapped (150 4.6 mm, 5 m particle size) column (Merck, Darmstadt, Germany) with guard column at 30C under isocratic conditions with a mobile phase consisting of ammonium acetate (pH 4.9; 0.1 M) and acetonitrile (10:90, v/v). The flow rate was set at 2.0 mL/min (minimal run time: 30 min.). The injection volume was 10 l. Under these conditions, lumefantrine elutes at approximately 22 min. System suitability tests (SSTs) were established as the plate number on lumefantrine (N 8.2 103) and the oxidative stress degradation product (N 2.4 103), the signal-to-noise ratio of 0.5% l.c. lumefantrine solution (S/N 30), the peak area ratio of the 0.5% l.c. versus 100% l.c. (between 0.4 and 0.6) and the relative position of the in-situ prepared N-oxide by H2O2 treatment (RRTbetween 0.12 and 0.22). The LC method was validated for the determination of lumefantrine and its related impurities. The selectivity of the developed chromatographic method was established by the separation of lumefantrine and its impurities. A correlation coefficient (r2) of 0.9998 for lumefantrine (0.0006 to 0.01 mg/ml) and 1.0 for impurity A and DBK (0.001 to 0.1 mg/ml) demonstrated that the HPLC method is linear in the lower range. LOD/LOQ values for lumefantrine, DBK and impurity A were calculated (S/N = 3 resp. 10): 0.004 mg/mland 0.026 mg/ml for lumefantrine (0.004% respectively 0.026% l.c.), 0.011 mg/ml and 0.040 mg/ml for DBK (0.012% respectively 0.042% l.c.) and 0.110 mg/ml and 0.393 mg/ml for impurity A (0.115% respectively 0.409% l.c.). The analytical stability of lumefantrine, impurity A and DBK was confirmed over a storage period of 24 hours at 5C, i.e. the sample compartment temperature. Accuracy and precision were evaluated by repeated analysis (n = 6), with 102.6% l.c. recovery and 2.1%, respectively 2.86%, for repeatability, respectively intermediate precision. Structural information for the observed and/or reported lumefantrine related impurities # Compound [formula, mono-isotopic mass]Structure Origin # Compound [formula, mono-isotopic mass]Structure Origin Alkaline stress Oxidative stress Oxidative stress Metabolite 1Desbenzylketo N-oxide [C23H27NO3Cl2, MW 435.14] 2 Lumefantrine (mono-)desbutyl derivative [C26H24NOCl3, MW 473.09] 3Lumefantrine N-oxide [C30H32NO2Cl3, MW 543.15] Oxidative stress Degradation 4 2,7-dichloro-4-[2-(di-n-butylamino)-1-hydroxyethyl]- 9H-fluoren-9-one; Desbenzylketo derivative (DBK) [C23H27NO2Cl2, MW 419.14] Oxidative stress Acidic stress Degradation 5 2-(di-n-butylamino)-1-[2,7-dichloro-9H-fluoren-4- yl]ethanol; Desbenzyl derivative [C23H29NOCl2,405.16] Synthesis 6 Synthesis impurity found in lumefantrine API; Lumefantrine oxide [C30H32NO2Cl3, MW 543.14] Synthesis 7 Synthesis impurity found in lumefantrine API; Lumefantrine oxide [C30H32NO2Cl3, MW 543.14] Synthesis 8 (RS,Z)-2-(Dibutylamino)-2-(2,7-dichloro-9-(4- chloro-benzylidene)-9H-fluoren-4-yl)ethanol (isomeric compound); Impurity A (Ph. Int./USP Salmous) [C30H32NOCl3, MW 527.15] Synthesis 9 Synthesis
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].
mpurity found in lumefantrine API; Lumefantrine oxide [C30H32NO2Cl3, MW 543.14] Synthesis 10 (1S,3R,5R)-1,3-bis((EZ)-2,7-Dichloro-9-(4- chlorobenzyl-idene)-9H-fluoren-4-yl)-2,6- dioxabicyclo[3.1.0]hexane; Impurity BA(USP Salmous) [C44H24Cl6O2, 797.39] 2-((EZ)-2,6-Dichloro-9- (4-chlorobenzylidene)-9H- fluoren-4-yl)-3′-((EZ)-2,7-dichloro-9-(4- chlorobenzylidene)-9H-fluoren-4-yl)-2,2′-bioxirane; Impurity BB (USP Salmous) [C44H24Cl6O2, 797.39] Percentage maximum actual levels of lumefantrine related impuritiesobserved(1) Synthesis 11 Synthesis # CompoundAPIFPP Unstressed Stressed Release Accelerated Stressed 1.39 0.560.11 21.32 1 Desbenzylketo N-oxide 2 Monodesbutyl derivative 3 Lumefantrine N-oxide 4 Desbenzylketo derivative 5 Desbenzyl derivative 6Lumefantrine oxide (RRT ~ 0.49) 7Lumefantrine oxide (RRT ~ 0.52) 8 Impurity A 9Lumefantrine oxide (RRT ~ 0.59) (1) RT: reporting threshold = 0.10% 0.60 0.12 0.34 0.86 4.26 HPLC characteristics of lumefantrine related impurities # CompoundRT(1)RRT(2) Most abundant m/z observed 436.14 474.00 544.08 420.13 406.09 544.12 544.12 528.10 544.12 528.10 1 Desbenzylketo N-oxide 2 Monodesbutyl derivative 3.25 3 Lumefantrine N-oxide 4 Desbenzylketo derivative 7.41 5 Desbenzyl derivative 6 Lumefantrine oxide 7 Lumefantrine oxide 8 Impurity A 9 Lumefantrine oxide L Lumefantrine (1) Retention time (min.) (2) Relative retention time reference 1.790.08 0.15 0.17 0.33 0.34 0.49 0.52 0.58 0.59 1.00 3.96 7.69 10.96 11.45 12.70 12.97 22.28 1. De Spiegeleer B, Vergote V, Pezeshki A, Peremans K, Burvenich C. Impurity profiling quality control testing of synthetic peptides using liquid chromatography-photodiode array-fluorescence and liquid chromatography-electrospray ionization-mass spectrometry: The obestatin case. Anal Biochem. 2008;376:229234. doi: 10.1016/j.ab.2008.02.014.[ 2. Nicolas EC, Scholz TH. Active drug substance impurity profiling – Part I. LC/UV diode array spectral matching. J Pharm Biomed Anal. 1998;16:813824. doi: 10.1016/S0731-7085(97)00131- 3Roy J. Pharmaceutical impurities – A mini review. AAPS PharmSciTech. 2002;3:article 6. doi: 10.1208/pt030206. ICH guidelines – International Conference on Harmonization, Q3A(R2) Impurities in new drug substances CPMP/ICH/2737/99. (October 2006) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC50000 2675.pdf [Accessed on 5 November 2010 at 11:06] 3. Authorized Lumefantrine USP Salmous Standard (Februari 2009) http://www.usp.org/pdf/EN/nonUSStandards/lumefantrine.pdf [Accessed on 24 October 2010 at 17:14] 4. Lumefantrine: Document QAS/06.186/FINAL (WHO Ph. Int. – July 2008) http://www.who.int/medicines/publications/pharmacopoeia/Lumef_monoFINALQAS06_186_July 08.pdf [Accessed on 24 October 2010 at 17:37] 5. Lee H. Pharmaceutical applications of liquid chromatography coupled with mass spectrometry (LC/MS) J Liq Chromatogr Relat Technol. 2005;28:11611202. doi: 10.1081/JLC-200053022.] 6. Cesar ID, Nogueira FHA, Pianetti GA. Simultaneous determination of artemether and lumefantrine in fixed dose combination tablets by HPLC with UV detection. J Pharm Biomed Anal. 2008;48:951954. doi: 10.1016/j.jpba.2008.05.022 7. Cesar ID, Nogueira FHA, Pianetti GA. Comparison of HPLC, UV spectrophotometry and potentiometric titration methods for the determination of lumefantrine in pharmaceutical products. J Pharm Biomed Anal. 2008;48:223226. doi: 10.1016/j.jpba.2008.05.006. 8. Patil KR, Rane VP, Sangshetti JN, Shinde DB. A Stability-Indicating LC Method for Lumefantrine. Chromatographia. 2009;69:375379. doi: 10.1365/s10337-008-0894-x. [Cross Ref] 9. Munjal V, Paliwal N, Chaursia BK, Varshney B, Ahmed T, Paliwal J. LC-tandem mass spectrometry method for quantification of lumefantrine in human plasma and its application to bioequivalence study. Chromatographia. 2010;71:505510. doi: 10.1365/s10337-009-1446-8. [Cross Ref] 10. ICH guidelines – International Conference on Harmonization, Q1A(R2) Stability testing of new drug substances and products CPMP/ICH/2736/99. (August 2003) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].
(19) (PDF) Process for high purity lumefantrine. Available from: https://www.researchgate.net/publication/221933417_Process_for_high_purity_lumefantrine [accessed Feb 06 2022].
PATENT
PAPER
Tropical Journal of Pharmaceutical Research October 2013; 12 (5): 791-798 ISSN: 1596-5996 (print); 1596-9827 (electronic) © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved. Available online at http://www.tjpr.org
CLIP
NMR
1H NMR
COSY
NOESY
HSQC
DEPT
13C NMR
DSC
CLIP
CLIP
Click to access DPC-2016-8-3-91-100.pdf
REFERENCES
[1] Ulrich Beutler, C Peter.; Fuenfschilling.; and Andreas, Steinkemper.; Novartis Pharma AG; Chemical and Analytical Development: CH-4002 Basel, Switzerland, Organic Process Research & Development 2007, 11, 341- 345.
[2] Boehm, M. Fuenfschilling.; Krieger, P. C.; Kuesters, E. M.; Struber, F.; Org. Process Res. DeV. 2007, 11, 336- 340.
[3] (a) Rao, D. R.; Kankan, R. N.; Phull, M. S.; Patent Application CN 1009-3724 20060424, 2005. (b) Deng, R.; Zhong, J.; Zhao, D.; Wang, J.; Yaoxue, X. 2000, 35 (1), 22. (c) Allmendinger, Th.; Wernsdorfer, W. H. PCT WO 99/67197.
[4] Perrumattam, J.; Shao, Ch.; Confer, W. L. Synthesis 1994, 1181.
[5] Fuenfschilling, P. C.; Hoehn P.; Mutz J.-P. Organic Process Res. Dev. 2007, 11, 13.
[6] Di Nunno, L.; Scilimati, A. Tetrahedron 1988, 44, 3639.
[7] Pharmacopeial Forum, Vol. 36(2) [Mar.-Apr. 2010]
Preparation of 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4-chlorobenzylidene)-9H-floren-4-yl] ethanol (Lumefantrine) 1.
To a stirred solution of NaOH (1.97 g 0.0492 mol) in methanol (100 ml) there was added 1-(2, 7- dichloro-9 H-fluren-4-yl)-2-(dibutyl amino) ethanol (10 g, 0.0246 mol) and para chloro benzaldehyde (5.24 g 0.0372). The suspension obtained was stirred at reflux temperature till the absence of starting material by TLC. After confirming the product formation reaction mixture was cooled to room temperature and further stirred at same temperature for overnight. The precipitated solids were filtered and washed with methanol and dried under vacuum at 50°C to get desired compound. (Purity by HPLC: 99%).
IR (cm-1): 3408, 3092, 2953, 2928, 2870, 2840, 1634, 1589, 1487, 1465, 1443, 1400, 1365, 1308, 1268, 1241, 1207, 1173, 1156, 1085, 1071, 1014, 980, 933, 874, 839, 815, 806, 770;
1H NMR (CDCl3, δ ppm): 7.75 (d, 1H, CH, J 1.5 Hz), 7.68 (d, 1H, CH, J 1.5 Hz), 7.60-7.63 (m, 1H, CH), 7.32-7.35 (dd, 1H, CH, J 1.7,8.3 Hz), 7.45-7.50 (m, 1H, CH), 5.35-5.39 (dd, 1H, CH, J 3.0,9.9 Hz), 2.41-2.74 (m, 1H, CH2Ha), 2.86-2.92 (m, 1H, CH2Hb), 2.41-2.74 (m, 4H, CH2), 1.25-1.56 (m, 8H, CH2), 0.97 (t, 1H, CH, J 7.2 Hz), 7.60-7.63 (m, 1H, CH), 7.45-7.50 (m, 4H, CH), 4.54 (broad, 1H, OH),
13C NMR (CDCl3, δ ppm): 138.2, 141.5, 120.6, 133.2, 126.3, 135.0, 135.0, 136.4, 123.9, 128.3, 132.8, 123.0, 139.8, 65.5, 60.0, 53.5, 29.1, 20.6, 14.0, 127.6, 134.7, 130.5, 129.1, 133.2;
MS: m/z: 528 [M+H]+ ; Analysis calcd. for C30H32Cl3NO: C, 68.12; H, 6.10; N, 2.65% Found: C, 68.38; H, 6.14; N, 2.63 %.
CLIP
One-dimensional 1H NMR spectrum of B) a lumefantrine standard,
A CLIP
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532012000100010&lng=en&nrm=iso
CLIP
A simple and precise method for quantitative analysis of lumefantrine …
https://www.ncbi.nlm.nih.gov › NCBI › Literature › PubMed Central (PMC)
by P Hamrapurkar – 2010 – Cited by 2 – Related articles
[2–4] Thus, today lumefantrine is a drug of choice in antimalarial treatment against P. …. The NMRspectra observed triplet at 0.943-0.989 (methyl protons of alkyl …
The spectroscopic techniques were used to confirm the identity of lumefantrine. The IR spectra, showed strong absorption band at 3404.67 cm-1 (OH), 2953.28 cm-1 (aliphatic and aromatic CH), 1757.31 cm-1 (-C=C-), 933 cm-1 (alkanes) and 696.37-373.22 cm-1 (Cl). Thus, IR spectra confirmed the presence of these functional groups in the structure of lumefantrine.
The mass spectrum showed a sharp molecular ion peak at 528.0 m/z in Q1 MS (m/z, parent ion) parameter at negative polarity confirming the molecular weight of lumefantrine.
The NMR spectra observed triplet at 0.943-0.989 (methyl protons of alkyl chain); a multiplet at 1.372-1.498 (methylene protons of alkyl chains); a multiplet at 2.449-2.909 (methylene protons of alkyl chain); broad singlet at 4.573 (OH proton); and multiplet at 7.314-7.733 (aromatic proton), thus confirming identity of lumefantrine.
IH NMR PREDICT
13C NMR PREDICT
References
- Jump up^ Toovey S, Jamieson A, Nettleton G (2003). “Successful co-artemether (artemether-lumefantrine) clearance of falciparum malaria in a patient with severe cholera in Mozambique”. Travel medicine and infectious disease. 1 (3): 177–9. doi:10.1016/j.tmaid.2003.09.002. PMID 17291911.
- Jump up^ White, Nicholas J.; van Vugt, Michele; Ezzet, Farkad (1999). “Clinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine”. Clinical Pharmacokinetics. 37 (2): 105–125. doi:10.2165/00003088-199937020-00002. ISSN 0312-5963.
- Jump up^ Cui, Liwang; Su, Xin-zhuan (2009). “Discovery, mechanisms of action and combination therapy of artemisinin”. Expert Review of Anti-infective Therapy. 7 (8): 999–1013. doi:10.1586/eri.09.68. PMC 2778258
. PMID 19803708. - Jump up^ http://aac.asm.org/content/56/5/2465.full
- Jump up^ Laman, M; Moore, BR; Benjamin, JM; Yadi, G; Bona, C; Warrel, J; Kattenberg, JH; Koleala, T; Manning, L; Kasian, B; Robinson, LJ; Sambale, N; Lorry, L; Karl, S; Davis, WA; Rosanas-Urgell, A; Mueller, I; Siba, PM; Betuela, I; Davis, TM (2014). “Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial”. PLoS Med. 11: e1001773. doi:10.1371/journal.pmed.1001773. PMC 4280121. PMID 25549086.
 |
|
| Clinical data | |
|---|---|
| AHFS/Drugs.com | International Drug Names |
| MedlinePlus | a609024 |
| Routes of administration |
Oral |
| ATC code | P01BF01 (WHO) (combination with artemether) |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | 82186-77-4  |
| PubChem (CID) | 6437380 |
| DrugBank | DB06708  |
| ChemSpider | 4941944 |
| UNII | F38R0JR742 |
| KEGG | D03821 |
| ChEBI | CHEBI:156095 |
| ChEMBL | CHEMBL38827 |
| Chemical and physical data | |
| Formula | C30H32Cl3NO |
| Molar mass | 528.939 g/mol |
| 3D model (Jmol) | Interactive image |
Title: Lumefantrine
CAS Registry Number: 82186-77-4
CAS Name: (9Z)-2,7-Dichloro-9-[(4-chlorophenyl)methylene]-a-[(dibutylamino)methyl]-9H-fluorene-4-methanol
Additional Names: 2-dibutylamino-1-[2,7-dichloro-9-(4-chlorobenzylidene)-9,11-fluoren-4-yl]ethanol; dl-benflumelol; benflumetol; BFL
Manufacturers’ Codes: CPG-56695
Molecular Formula: C30H32Cl3NO
Molecular Weight: 528.94
Percent Composition: C 68.12%, H 6.10%, Cl 20.11%, N 2.65%, O 3.02%
Literature References: Racemic aryl alcohol originally synthesized in the 1970’s by the Academy of Military Medical Sciences in Beijing, China. Inhibits hemozoin formation. Prepn: R. Deng et al., CN 1042535 (1990 to Acad. Military Med. Sci., Microbiol. & Epidemic Dis. Instit.); C.A. 114, 6046 (1991). LC determn in plasma: A. Annerberg et al., J. Chromatogr. B 822, 330 (2005). In vitro activity against Plasmodium falciparum: B. Pradines et al., Antimicrob. Agents Chemother. 43, 418 (1999).
Properties: Odorless, yellow powder. Poorly sol in water, oil, and most organic solvents. Sol in unsaturated fatty acids.
Derivative Type: Co-artemether
CAS Registry Number: 141204-94-6
Manufacturers’ Codes: CPG-56697
Trademarks: Coartem (Novartis); Riamet (Novartis)
Literature References: Fixed 6:1 mixture with artemether, q.v. Clinical pharmacokinetics and bioavailability: F. Ezzet et al., Br. J. Clin. Pharmacol. 46, 553 (1998). Clinical trial in children against P. falciparum malaria: C. Hatz et al., Trop. Med. Int. Health 3, 498 (1998); in adults: S. Looareesuwan et al., Am. J. Trop. Med. Hyg. 60, 238 (1999). Review of comparative clinical trials in malaria: A. A. Omari et al., Trop. Med. Int. Health 9, 192-199 (2004).
Therap-Cat: Antimalarial.
Keywords: Antimalarial.
///////////lumefantrine, lumefantrene, Antimalarial, CPG-56695, CPG 56695,
CCCCN(CCCC)CC(O)C1=C2C(=CC(Cl)=C1)\C(=C/C1=CC=C(Cl)C=C1)C1=C2C=CC(Cl)=C1
Designing Polymers for Amorphous Solid Dispersions — AAPS Blog
By: Laura I. Mosquera-Giraldo and Lynne S. Taylor Imagine spending billions of dollars in the discovery of a new drug, and then realizing that it is impractical to administer it orally because it cannot reach the systemic circulation and achieve a therapeutic effect. This is the case for many emerging drugs that are insoluble in water, […]
via Designing Polymers for Amorphous Solid Dispersions — AAPS Blog
Ranolazine Intermediate, An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers
http://pubs.acs.org/doi/suppl/10.1021/op300056k
Preparation of 1-(2-Methoxyphenoxy)-2,3-epoxypropane 4.
To a stirring solution of 2-methoxy phenol 2 (10 kg, 80.55 mol) and water (40 L) at about 30 °C was added sodium hydroxide (1.61 kg, 40.25 mol) and water (10 L). After stirring for 30−45 min, epichlorohydrin 3 (22.35 kg, 241.62 mol) was added and stirred for 10−12 h at 25−35 °C. Layers were separated, and water (40 L) was added to the organic layer (bottom layer) containing product. Sodium hydroxide solution (3.22 kg, 80.5 mol) and water (10 L) were added at 27 °C and stirred for 5−6 h at 27 °C.
The bottom product layer was separated and washed with sodium hydroxide solution (3.0 kg 75 mol) and water (30 L). Excess epichlorohydrin (3) was recovered by distillation of the product layer at below 90 °C under vacuum (650−700 mmHg) to give 13.65 kg (94%) of title compound with 98.3% purity by HPLC, 0.2% of 2- methoxy phenol 2, 0.1% of epichlorohydrin 3, 0.1% of chlorohydrin 11, 0.3% of dimer 12 and 0.3% of dihydroxy 13.
1 H NMR (400 MHz, CDCl3, δ) 6.8−7.0 (m, 4H), 4.3 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 3.8 (dd, J = 5.6 Hz, 5.3 Hz, 1H), 3.7 (s, 3H), 3.2−3.4 (m, 1H), 2.8 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 2.7 (dd, J = 5.6 Hz, 5.3 Hz, 1H);
IR (KBr, cm−1 ) 2935 (C−H, aliphatic), 1594 and 1509 (CC, aromatic), 1258 and 1231 (C−O−C, aralkyl ether), 1125 and 1025 (C−O−C, epoxide);
MS (m/z) 181 (M+ + H).
Compound Details
| Properties | |
| MWt | 180.2 |
| MF | C10H12O3 |
CAS 2210-74-4
| Glycidyl 2-methoxyphenyl ether | |
| Guaiacol glycidyl ether |
1H NMR PREDICT
13C NMR PREDICT
COSY PREDICT
CREDIT……….http://www.molbase.com/en/synthesis_2210-74-4-moldata-95563.html
DR REDDYS LABORATORIES
An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers
† Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45,46, and 54, Bachupally, Qutubullapur – 500073, Andhra Pradesh, India
‡ Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad – 500 072, Andhra Pradesh, India
Org. Process Res. Dev., 2012, 16 (10), pp 1660–1664
DOI: 10.1021/op300056k
Publication Date (Web): September 14, 2012
Copyright © 2012 American Chemical Society
*Telephone: +91 4044346000. Fax: +91 4044346285. E-mail: rakeshwarb@drreddys.com.
////////////////1-(2-Methoxyphenoxy)-2,3-epoxypropane, β-Adrenoblockers, ranolazine
COc2ccccc2OCC1CO1
OTHER COMPD
ADRAFINIL
ADRAFINIL
2-((diphenylmethyl)sulfinyl)-acetohydroxamicaci;2-((diphenylmethyl)sulfinyl)-n-hydroxy-acetamid;2-((diphenylmethyl)sulfinyl)-n-hydroxyacetamide;2-(benzhydrylsulfinyl)acetohydroxamicacid;ADRAFINIL;2-[(DIPHENYLMETHYL)SULFINYL]ACETOHYDROXAMIC ACID;CRL 40028;OLMIFON
- CAS 63547-13-7
- MF:C15H15NO3S
- MW:289.35
- EINECS:264-303-1
WATCH THIS POST AS DETAILS LIKE SYNTHESIS ARE UPDATED………….
Adrafinil is touted mainly for its stimulant properties and ability to provide alertness and wakefulness.
- Stay up late/stay awake during normal sleeping hours: Adrafinil may be helpful for night workers who need a kick-start adapting their body’s natural circadian rhythm of wakefulness in the daytime and sleepiness in the evening to their job needs. This can also make it helpful for periodic late-night study sessions. Adrafinil is best taken in the afternoon or evening for nighttime wakefulness.
- Boost energy, alertness, and focus during the day time: Adrafinil can also be used as an energy-boost during waking hours.
- CONTACT SKYPE CATHERINESSPC WICKR
Adrafinil (INN) (brand name Olmifon)[2] is a discontinued wakefulness-promoting agent (or eugeroic) that was formerly used inFrance to promote vigilance (alertness), attention, wakefulness, mood, and other parameters, particularly in the elderly.[3][4] It was also used off-label by individuals who wished to avoid fatigue, such as night workers or others who needed to stay awake and alert for long periods of time. Additionally, “adrafinil is known to a larger nonscientific audience, where it is considered to be a nootropic agent.”[3] Adrafinil is a prodrug; it is primarily metabolized in vivo to modafinil, resulting in very similar pharmacological effects.[3] Unlike modafinil, however, it takes time for the metabolite to accumulate to active levels in the bloodstream. Effects usually are apparent within 45–60 minutes when taken orally on an empty stomach. Adrafinil was marketed in France under the trade name Olmifon[2] until September 2011 when it was voluntarily discontinued.[4]
Pharmacology
Pharmacodynamics
Because α1-adrenergic receptor antagonists were found to block effects of adrafinil and modafinil in animals, “most investigators assume[d] that adrafinil and modafinil both serve as α1-adrenergic receptor agonists.”[3] However, adrafinil and modafinil have not been found to bind to the α1-adrenergic receptor and they lack peripheral sympathomimetic side effects associated with activation of this receptor;[5] hence, the evidence in support of this hypothesis is weak, and other mechanisms are probable.[3] Modafinil was subsequently screened at a variety of targets in 2009 and was found to act as a weak, atypical blocker of the dopamine transporter(and hence as a dopamine reuptake inhibitor), and this action may explain some or all of its pharmacological effects.[6][7][8] Relative to adrafinil, modafinil possesses greater specificity in its action, lacking or having a reduced incidence of many of the common side effects of the former (including stomach pain, skin irritation, anxiety, and elevated liver enzymes with prolonged use).[9][10][11] There is a case report of two patients that adrafinil may increase interest in sex.[3] A case report of adrafinil-induced orofacial dyskinesia exists.[12][13] Reports of this side effect also exist for modafinil.[12]
Pharmacokinetics
In addition to modafinil, adrafinil also produces modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056) as metabolites, which form from metabolic modification of modafinil.
History
Adrafinil was discovered in 1974 by two chemists working for the French pharmaceutical company Laboratoires Lafon who were screening compounds in search of analgesics.[14] Pharmacological studies of adrafinil instead revealed psychostimulant-like effects such as hyperactivity and wakefulness in animals.[14] The substance was first tested in humans, specifically for the treatment of narcolepsy, in 1977–1978.[14] Introduced by Lafon (now Cephalon), it reached the market in France in 1984,[4] and for the treatment of narcolepsy in 1985.[14][15] In 1976, two years after the discovery of adrafinil, modafinil, its active metabolite, was discovered.[14] Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market.[14] Modafinil was first approved in France in 1994, and then in the United States in 1998.[15] Lafon was acquired by Cephalon in 2001.[16] As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.[4]
Society and culture
Regulation
Athletic doping
Adrafinil and its active metabolite modafinil were added to the list of substances prohibited for athletic competition according to World Anti-Doping Agency in 2004.[17]
New Zealand
In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine due to risks of it being used as a party drug. At that time adrafinil was not scheduled in New Zealand.[18]
Research
In a clinical trial with clomipramine and placebo as active comparators, adrafinil showed efficacy in the treatment of depression.[3] In contrast to clomipramine however, adrafinil was well-tolerated, and showed greater improvement in psychomotor retardation in comparison.[3] As such, “further investigations of the antidepressive effects of adrafinil are warranted.”[3]
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SYNTHESIS
Adrafinil (CAS NO.63547-13-7) was discovered in the late 1970s by scientists working with the French pharmaceutical company Group Lafon. First offered in France in 1986 as an experimental treatment for narcolepsy, Lafon later developed modafinil, the primary metabolite of adrafinil. Modafinil possesses greater selective alpha-1 adrenergic activity than adrafinil without the side effects of stomach pain, skin irritations, feelings of tension, and increases in liver enzyme levels.
It is important to monitor the liver of an individual using adrafinil. It can cause liver damage in some instances.
The Adrafinil with CAS registry number of 63547-13-7 is also known as 2-[(Diphenylmethyl)sulfinyl]-N-hydroxyacetamide. The IUPAC name is 2-Benzhydrylsulfinyl-N-hydroxyacetamide. It belongs to product categories of Aromatics Compounds; Aromatics; Intermediates & Fine Chemicals; Pharmaceuticals; Sulfur & Selenium Compounds. This chemical is a light pink solid and its EINECS registry number is 264-303-1. In addition, the formula is C15H15NO3S and the molecular weight is 289.35. This chemical is harmful if swallowed.
Physical properties about Adrafinil are: (1)ACD/LogP: 1.596; (2)ACD/LogD (pH 5.5): 1.60; (3)ACD/LogD (pH 7.4): 1.53; (4)ACD/BCF (pH 5.5): 9.60; (5)ACD/BCF (pH 7.4): 8.34; (6)ACD/KOC (pH 5.5): 175.52; (7)ACD/KOC (pH 7.4): 152.63; (8)#H bond acceptors: 4; (9)#H bond donors: 2; (10)#Freely Rotating Bonds: 6; (11)Index of Refraction: 1.653; (12)Molar Refractivity: 78.858 cm3; (13)Molar Volume: 215.542 cm3; (14)Polarizability: 31.262 10-24cm3; (15)Surface Tension: 67.25 dyne/cm; (16)Density: 1.342 g/cm3
Preparation of Adrafinil: it is prepared by reaction of diphenyl methyl bromide with thiourea. This reaction needs reagent NaOH. After reacting with chloroacetic acid, hydrochloric acid amine and hydrogen peroxide, the product is obtained. The yield is about 73%.
Uses of Adrafinil: it is used as non-amphetamine-type psychostimulant and can wake up and raise awareness. For the elderly arousal disorder and depressive symptoms in symptomatic treatment.
Benzhydrylsulphinyl-acetohydroxamic Acid (Adrafinil)1
Diphenylmethanethiol
15.2 g (0.2 mol) of thiourea and 150 ml of demineralized water are introduced into a 500 ml three-neck flask equipped with a central mechanical stirrer, and with a dropping funnel and a condenser on the (respective) side-necks.The temperature of the reaction mixture is brought to 50°and 49.4g (0.2 mol) of bromodiphenyl- methane are added all at once whilst continuing the heating. After refluxing for about 5 minutes, the solution, which has become limpid, is cooled to 20°C and 200 ml of 2.5 N NaOH are then added dropwise whilst maintaining the said temperature. The temperature is then again kept at the reflex for 30 minutes after which, when the mixture has returned to ordinary temperature (15-25°C), the aqueous solution is acidified with 45 ml of concentrated hydrochloric acid. The supernatant oil is extracted with 250 ml of diethyl ether and the organic phase is washed with 4×80 ml of water and then dried over magnesium sulphate. 39 g of crude diphenylmethane-thiol are thus obtained. Yield 97.5%.
Benzhydryl-thioacetic acid
10 g (0.05 mol) of diphenylmethane-thiol and 2g (0.05 mol) of NaOH dissolved in 60 ml of demineralised water are introduced successively into a 250 ml flask equipped with a magnetic stirrer and a reflux condenser. The reactants are left in contact for 10 minutes whilst stirring, and a solution consisting of 7g (0.075 mol) of chloroacetic acid, 3g (0.075 mol) of NaOH pellets and 60 ml of demineralized water is then added all at once. The aqueous solution is gently warmed to about 50°C for 15 minutes, washed with 50 ml of ether, decanted and acidified with concentrated hydrochloric acid. after filtration, 10.2g of benzhydryl-thioacetic acid are thus obtained. Melting point 129-130°C. Yield 79%.
Ethyl benzhydryl-thioacetate
The following reaction mixture is heated under reflux for 7 hours: 10.2 g (0.0395 mol) of benzhydryl-thioacetic acid, 100 ml of anhydrous ethanol and 2 ml of sulphuric acid. When heating has been completed, the ethanol isevaporated in vacuo; the oily residue is taken up in 100 ml of ethyl ether and the organic solution is then washed with water, with an aqueous sodium carbonate solution and then with water until the wash waters have a neutral pH. After drying over sodium sulphate, the solvent is evaporated. 10.5g of ethyl benzhydryl- thioacetate are thus obtained. Yield 93%.
Benzhydryl-thioacetohydroxamic acid
The following three solutions are prepared:
- Ethyl Benzhydryl-thioacetate 10.8 g (0.0378 mol) in 40 ml methanol
- Hydroxylamine hydrochloride 5.25 g (0.0756 mol) in 40 ml methanol
- Potassium Hydroxide pellets 7.3 g (0.0134 mol) in 40 ml methanol
The solutions are heated, if necessary, until they become limpid, and when the temperatures have again fallen to below 40°C, the solution of potassium hydroxide in methanol is poured into the solution of hydroxylamine hydrochloride in alcohol. Finally, at a temperature of about 5° to 10°C, the solution of ethyl benzhydryl- thioacetate is added in its turn. After leaving the reactants in contact for 10 minutes, the sodium chloride is filtered off the limpid solution obtained is kept for about 15 hours at ordinary temperature. The methanol is then evaporated under reduced pressure, the residual oil is taken up in 100 ml of water and the aqueous solution is acidified with 3 N hydrochloric acid. The hydroxamic acid which has crystallized is filtered off, washed with water and then dried. 9.1 g of product are obtained. Yield = 87.5%. Melting point 118-120°C.
Adrafinil (CRL 40,028)
10.4g (0.038 mol) of benzhydryl-thioacetohydroxamic acid are oxidized at 40°C, over the course of 2 hours, by means of 3.8 ml (0.038 mol) of hydrogen peroxide of 110 volumes strength (33%), in 100 ml of acetic acid.
When the oxidation has ended, the acetic acid is evaporated under reduced pressure and the residual oil is taken up in 60 ml of ethyl acetate. The product which has crystallized is filtered off and then purified by recrystallisation from a 3:2 (by volume) mixture of ethyl acetate and isopropyl alcohol.
8g (73%) of Adrafinil, mp 159-160°C, are thus obtained. H2O Solubility
CLIP
Figure 2: GC/MS extracted ion chromatogram (a) and mass spectrum (b) of derivatized adrafinil in the electron ionization mode (monitoring the m/z 167, 165 and 152 ions; all the four peaks are derivatised adrafinil products).
Figure 4: LC/ESI-MS full scan chromatogram of adrafinil and its metabolites (a) (modafinil acid RT 3.8 min, adrafinil RT 4.0 min, modafinil RT 4.1 min), and LC/ESI-MS full scan mass spectra of modafinil acid (b), adrafinil (c), and (d) modafinil. (b, c and d showing the similar ions at m/z 167, 165, 152 together with the appropriate sodium and potassium adducts).
NMR
1H NMR PREDICT
13C NMR PREDICT
Patent
https://www.google.com/patents/US6180678 below
FIG. 1 shows the structure of adrafinil and its metabolites.
FIG. 2 shows the chemical synthesis of adrafinil.
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References
- Jump up^ Robertson P, Hellriegel ET (2003). “Clinical pharmacokinetic profile of modafinil”. Clin Pharmacokinet. 42 (2): 123–37. doi:10.2165/00003088-200342020-00002.PMID 12537513.
- ^ Jump up to:a b Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 20–. ISBN 978-3-88763-075-1.
- ^ Jump up to:a b c d e f g h i Milgram, Norton (1999). “Adrafinil: A Novel Vigilance Promoting Agent”.CNS Drug Reviews. 5 (3): 193–212. doi:10.1111/j.1527-3458.1999.tb00100.x. Retrieved2 October 2014.
- ^ Jump up to:a b c d AFSSAPS (2011). “Point d’information sur les dossiers discutés en commission d’AMM Séance du jeudi 1er décembre 2011 – Communiqué”.
- Jump up^ Simon P, Chermat R, Puech AJ (1983). “Pharmacological evidence of the stimulation of central alpha-adrenergic receptors”. Prog. Neuropsychopharmacol. Biol. Psychiatry. 7 (2-3): 183–6. doi:10.1016/0278-5846(83)90105-7. PMID 6310690.
- Jump up^ Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH (May 2009). “Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil”. The Journal of Pharmacology and Experimental Therapeutics. 329 (2): 738–46. doi:10.1124/jpet.108.146142.PMC 2672878. PMID 19197004.
- Jump up^ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (Feb 2015). “Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter”. Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026.
- Jump up^ Quisenberry AJ, Baker LE (Dec 2015). “Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats”. Psychopharmacology. 232 (24): 4411–9.doi:10.1007/s00213-015-4065-0. PMID 26374456.
- Jump up^ Ballas, Christos A; Deborah Kim; Claudia F Baldassano; Nicholas Hoeh (July 2002). “Modafinil: past, present and future”. Expert Review of Neurotherapeutics. 2 (4): 449–57.doi:10.1586/14737175.2.4.449. PMID 19810941.
- Jump up^ Alan F. Schatzberg; Charles B. Nemeroff (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 850–. ISBN 978-1-58562-309-9.
- Jump up^ Ballas, Christos A; Kim, Deborah; Baldassano, Claudia F; Hoeh, Nicholas (2002). “Modafinil: past, present and future”. Expert Review of Neurotherapeutics. 2 (4): 449–457.doi:10.1586/14737175.2.4.449. ISSN 1473-7175. PMID 19810941.
- ^ Jump up to:a b Jeffrey K Aronson (31 December 2012). Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Newnes. pp. 6–. ISBN 978-0-444-59503-4.
- Jump up^ Thobois S, Xie J, Mollion H, Benatru I, Broussolle E (2004). “Adrafinil-induced orofacial dyskinesia”. Mov. Disord. 19 (8): 965–6. doi:10.1002/mds.20154. PMID 15300665.
- ^ Jump up to:a b c d e f Antonio Guglietta (28 November 2014). Drug Treatment of Sleep Disorders. Springer. pp. 212–. ISBN 978-3-319-11514-6.
- ^ Jump up to:a b Jie Jack Li; Douglas S. Johnson (27 March 2013). Modern Drug Synthesis. John Wiley & Sons. pp. 2–. ISBN 978-1-118-70124-9.
- Jump up^ url=http://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=1366624
- Jump up^ World Anti-Doping Agency – 2007 Prohibited List
- Jump up^ MCC Minutes Out of Session Meeting. Medsafe.govt.nz (2013-05-23). Retrieved on 2013-12-18.
External links
- “SID 184744 – PubChem Substance Summary“. PubChem Project. National Center for Biotechnology Information. Retrieved 7 December 2005.
- “Adrafinil – Bank of Automated Data on Drugs“. Bank of Automated Data on Drugs. VIDAL. Archived from the original on 5 October 2008. Retrieved 4 October 2008.
- Milgram, Norton W.; Callahan, Heather; Siwak, Christina (September 1992). “Adrafinil: A Novel Vigilance Promoting Agent” (PDF). CNS Drug Reviews. 5 (3): 193–212.doi:10.1111/j.1527-3458.1999.tb00100.x.
- Thobois, S. P.; Xie, J.; Mollion, H.; Benatru, I.; Broussolle, E. (August 2004). “Adrafinil-induced orofacial dyskinesia”. Movement Disorders. 19 (8): 965–966.doi:10.1002/mds.20154. PMID 15300665.
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| Clinical data | |
|---|---|
| Trade names | Olmifon |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | Oral |
| ATC code | N06BX17 (WHO) |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | 80% |
| Metabolism | 75% (Liver) |
| Metabolites | Modafinil |
| Biological half-life | 1 hour (T1/2 is 12–15 hours for modafinil)[1] |
| Excretion | Kidney |
| Identifiers | |
|
Systematic (IUPAC) name: (±)-2-Benzhydrylsulfinylethanehydroxamic acid
|
|
| Synonyms | CRL-40028 |
| CAS Number | 63547-13-7 |
| PubChem (CID) | 3033226 |
| DrugBank | DB08925 |
| ChemSpider | 2297976 |
| UNII | BI81Z4542G |
| KEGG | D07348 |
| ChEMBL | CHEMBL93077 |
| Chemical and physical data | |
| Formula | C15H15NO3S |
| Molar mass | 289.351 g/mol |
| 3D model (Jmol) | Interactive image |
////////////ADRAFINIL
-
O=S(C(c1ccccc1)c2ccccc2)CC(=O)NO
Update……………..
Adrafinil
-
- Synonyms:CRL-40028
- ATC:N06BX17
- Use:α-adrenoceptor agonist (for symptomatic treatment of vigilance and depressive manifestations), stimulant
- Chemical name:2-[(diphenylmethyl)sulfinyl]-N-hydroxyacetamide
- Formula:C15H15NO3S
- MW:289.36 g/mol
- CAS-RN:63547-13-7
- EINECS:264-303-1
- LD50:>2048 mg/kg (M, i.p.); 1950 mg/kg (M, p.o.)
Substance Classes
Synthesis Path
Substances Referenced in Synthesis Path
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 91-01-0 | C13H12O | benzhydrol | Benzenemethanol, α-phenyl- |
| 63547-24-0 | C15H14O3S | (benzhydrylsulfinyl)acetic acid | Acetic acid, [(diphenylmethyl)sulfinyl]- |
| 63547-22-8 | C15H14O2S | (benzhydrylthio)acetic acid | Acetic acid, [(diphenylmethyl)thio]- |
| 79-11-8 | C2H3ClO2 | chloroacetic acid | Acetic acid, chloro- |
| 77-78-1 | C2H6O4S | dimethyl sulfate | Sulfuric acid, dimethyl ester |
| 4237-48-3 | C13H12S | diphenylmethanethiol | Benzenemethanethiol, α-phenyl- |
| 63547-22-8 | C15H14O2S | 2-(diphenylmethylthio)acetic acid | Acetic acid, [(diphenylmethyl)thio]- |
| 63547-44-4 | C15H15NO2S | 2-[(diphenylmethyl)thio]-N-hydroxyacetamide | Acetamide, 2-[(diphenylmethyl)thio]-N-hydroxy- |
| 7803-49-8 | H3NO | hydroxylamine | Hydroxylamine |
| 62-56-6 | CH4N2S | thiourea | Thiourea |
Trade Names
| Country | Trade Name | Vendor | Annotation |
|---|---|---|---|
| F | Olmifon | Cephalon |
Formulations
- cps. 300 mg
References
-
- DOS 2 642 511 (Lab. Lafon; appl. 22.9.1976; GB-prior. 2.10.1975).
- US 4 066 686 (Lab. Lafon; 3.1.1978; GB-prior. 2.10.1975).
- US 4 098 824 (Lab. Lafon; 4.7.1978; GB-prior. 2.10.1975).
Title: Adrafinil
CAS Registry Number: 63547-13-7
CAS Name: 2-[(Diphenylmethyl)sulfinyl]-N-hydroxyacetamide
Additional Names: 2-(benzhydrylsulfinyl)acetohydroxamic acid
Manufacturers’ Codes: CRL-40028
Trademarks: Olmifon (Lafon)
Molecular Formula: C15H15NO3S
Molecular Weight: 289.35
Percent Composition: C 62.26%, H 5.23%, N 4.84%, O 16.59%, S 11.08%
Literature References: a-Adrenergic agonist. Prepn, pharmacology: L. Lafon, BE 846880; US 4066686 (1977, 1978 both to Lafon). Mode of action: J. Duteil et al., Eur. J. Pharmacol. 59, 121 (1979); C. Rozé et al., Arch. Int. Pharmacodyn. Ther. 265, 119 (1983). Psychopharmacology in mice: F. A. Rambert et al., J. Pharmacol. 17, 37 (1986).
Properties: Crystals from ethyl acetate-isopropyl alcohol, mp 159-160°. Soly in water <1 g/l. LD50 in mice (mg/kg): <2048 i.p.; 1950 gastric admin (Lafon).
Melting point: mp 159-160°
Toxicity data: LD50 in mice (mg/kg): <2048 i.p.; 1950 gastric admin (Lafon)
Therap-Cat: Treatment of depression.
Keywords: a-Adrenergic Agonist; Antidepressant.
THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
+91 9323115463GLENMARK SCIENTIST , INDIA
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New Drug Approvals 13 lakh plus views
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Dr. Anthony Melvin Crasto
Principal Scientist, Glenmark Pharma      |
Generics: FDA´s New Guidance on Prior Approval Supplements
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FDA says that “this guidance is intended to assist applicants preparing to submit to FDA prior approval supplements (PASs) and amendments to PASs for abbreviated new drug applications (ANDAs)”.
Specifically, the guidance describes how the Generic Drug User Fee Amendments of 2012 (GDUFA) performance metric goals apply to:
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View original post 679 more words
Doxercalciferol, доксэркальциферол , دوكساركالسيفيرول , 度骨化醇
Doxercalciferol
- Molecular FormulaC28H44O2
- Average mass412.648
доксэркальциферол [Russian]
دوكساركالسيفيرول [Arabic]
度骨化醇 [Chinese]
1,3-Cyclohexanediol, 4-methylene-5-[(2E)-2-[(1R,3aS,7aR)-octahydro-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexen-1-yl]-4H-inden-4-ylidene]ethylidene]-, (1R,3S,5Z)-
54573-75-0
|
Title: Doxercalciferol CAS Registry Number: 54573-75-0 CAS Name: (1a,3b,5Z,7E,22E)-9,10-Secoergosta-5,7,10(19),22-tetraene-1,3-diol Additional Names: 1a-hydroxyvitamin D2; 1-hydroxyergocalciferol Trademarks: Hectorol (Bone Care) Molecular Formula: C28H44O2 Molecular Weight: 412.65 Percent Composition: C 81.50%, H 10.75%, O 7.75% Literature References: Synthetic vitamin D prohormone. Prepn: H.-Y. P. Lam et al., Science 186, 1038 (1974); eidem, Steroids30, 671 (1977); H. E. Paaren et al., J. Org. Chem. 45, 3253 (1980). Comparative activity and toxicity: G. Sjöden et al., Proc. Soc. Exp. Biol. Med. 178, 432 (1985). Metabolism to bioactive form: J. C. Knutson et al., Endocrinology 136, 4749 (1995). Pharmacology: J. W. Coburn et al., Nephrol. Dial. Transplant. 11, Suppl. 3, 153 (1996). Clinical trial for suppression of secondary hyperparathyroidism in hemodialysis: J. M. Frazao et al., ibid. 13, Suppl. 3, 68 (1998). Properties: Crystals, mp 138-140°. uv max (ethanol): 265 nm (e 18300). LD50 orally in rats: 3.5-6.5 mg/kg (Sjöden). Melting point: mp 138-140° Absorption maximum: uv max (ethanol): 265 nm (e 18300) Toxicity data: LD50 orally in rats: 3.5-6.5 mg/kg (Sjöden) Therap-Cat: Antihyperparathyroid. Keywords: Antihyperparathyroid. |
CLIP
Doxercalciferol (1α-hydroxyvitamin D2) is a commercially approved vitamin D derivative used to treat chronic kidney disease (CKD) patients whose kidneys cannot metabolically introduce a hydroxyl group at C1. A new process for the production of doxercalciferol from ergocalciferol was developed using a continuous photoisomerization of a known vitamin D intermediate as the key step, thus circumventing the limitations of batch photoisomerization processes. Doxercalciferol is produced in an overall yield of about 10% from ergocalciferol.
Doxercalciferol
1H NMR (CDCl3) δ 6.40 (d, 1H, J = 11.2), 6.04 (d, 1H, J = 11.2), 5.35 (s, 1H), 5.15–5.29 (m, 2H), 5.03 (s, 1H), 4.45 (dd, 1H, J = 7.3, 4.0), 4.21–4.31 (m, 1H), 2.81–2.90 (m, 1H), 2.62 (d, 1H, J = 13.3), 2.34 (dd, 1H, J = 13.3, 6.5), 1.83–2.11(m, 6H), 1.42–1.79 (m, 7H), 1.21–1.40 (m, 3H), 1.04 (d, 3H, J = 6.6), 0.94 (d, 3H, J = 6.8), 0.86 (t, 6H, J = 7.3), 0.58 (s, 3H) ppm.
Doxercalciferol (trade name Hectorol) is drug for secondary hyperparathyroidism and metabolic bone disease.[1] It is a synthetic analog of ergocalciferol (vitamin D2). It suppresses parathyroid synthesis and secretion.[2]
PATENT
CLIP
References
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| Names | |
|---|---|
| IUPAC name
(1S,3R,5Z,7E,22E)-9,10-Secoergosta-5,7,10,22-tetraene-1,3-diol |
|
| Other names
1-Hydroxyergocalciferol; 1-Hydroxyvitamin D2; 1α-Hydroxyergocalciferol; 1α-Hydroxyvitamin D2; Hectorol; TSA 840 |
|
| Identifiers | |
| 54573-75-0 |
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| 3D model (Jmol) | Interactive image |
| ChEMBL | ChEMBL1200810 |
| ChemSpider | 4444554 |
| DrugBank | DB06410 |
| ECHA InfoCard | 100.170.997 |
| 2790 | |
| PubChem | 5281107 |
| UNII | 3DIZ9LF5Y9 |
| Properties | |
| C28H44O2 | |
| Molar mass | 412.66 g·mol−1 |
| Pharmacology | |
| H05BX03 (WHO) | |
|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
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Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle “
| Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle <1220>” |
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When applying for a Certificate of Suitability (CEP) for an API, detailed information has to be provided regarding the synthesis stages, the starting material and the intermediates. In the event that the starting materials or the intermediates are already covered by a CEP, the EDQM has recently published a “Public Document” entitled “Use of a CEP to describe a material used in an application for another CEP”. The document contains regulations on how to reference the “CEP X” of a starting material or an intermediate in the application for the “CEP Y” of an API. The requirements for both scenarios are described as follows:
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New Drug Approvals