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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole


Abstract Image

Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O-alkylation, oxidation, and N-alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16

Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole

Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and ChemistryChinese Academy of SciencesSouth Beijing Road 40−1, Urumqi, Xinjiang 830011, P. R. China
University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
§CAS Key Laboratory for Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences555 Zuchongzhi Road, Shanghai 201203, P. R. China
Topharman Shanghai Co., Ltd.Building 1, No. 388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201209, P. R. China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00438
*Tel: +86-0991-3835679. Fax: +86-0991-3835679. E-mail: haji@ms.xjb.ac.cn., *Tel: +86-21-20231000-2407. Fax: +86-21-20231000-2407. E-mail: shenjingshan@simm.ac.cn.
ESI-MS: m/z = 434.22 [M + H].
1H NMR (500 MHz, DMSO-d6) δ (ppm): 11.61 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 9.4 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.84–6.78 (m, 2H), 6.30 (d, J = 9.4 Hz, 1H), 4.05 (t, J = 6.4 Hz, 2H), 3.06 (brs, 4H), 2.61 (brs, 4H), 2.43 (t, J = 7.1 Hz, 2H), 1.86–1.75 (m, 2H), 1.69–1.57 (m, 2H).
13C NMR (125 MHz, DMSO-d6) δ (ppm): 162.35, 160.55, 148.36, 140.76, 140.49, 140.12, 133.47, 129.34, 125.92, 125.19, 121.99, 118.57, 116.73, 113.36, 112.11, 110.96, 98.68, 67.71, 57.47, 53.08, 51.83, 26.66, 22.81.
/////////////Brexpiprazole
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ブレキサノロン , Brexanolone, Allopregnanolone


Allopregnanolone.png

ChemSpider 2D Image | Allopregnanolone | C21H34O2

Image result for Brexanolone

Brexanolone

318.501 g/mol, C21H34O2

CAS: 516-54-1

ブレキサノロン

MFCD00003677
Pregnan-20-one, 3-hydroxy-, (3α,5α)-
Pregnan-20-one, 3-hydroxy-, (3α,5α)- [ACD/Index Name]
S39XZ5QV8Y
TU4383000
UNII:S39XZ5QV8Y
(1S,2S,7S,11S,14S,15S,5R,10R)-14-acetyl-5-hydroxy-2,15-dimethyltetracyclo[8.7.0.0<2,7>.0<11,15>]heptadecane
(+)-3a-Hydroxy-5a-pregnan-20-one
(+)-3α-Hydroxy-5α-pregnan-20-one
(3α,5α)-3-Hydroxypregnan-20-one [ACD/IUPAC Name]
10446
3211363 [Beilstein]
3a-Hydroxy-5a-pregnan-20-one

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD. 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633919.htm?utm_campaign=031919_PR_FDA%20approves%20new%20drug%20for%20post-partum%20depression&utm_medium=email&utm_source=Eloqua

March 19, 2019

Release

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD.

“Postpartum depression is a serious condition that, when severe, can be life-threatening. Women may experience thoughts about harming themselves or harming their child. Postpartum depression can also interfere with the maternal-infant bond. This approval marks the first time a drug has been specifically approved to treat postpartum depression, providing an important new treatment option,” said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Because of concerns about serious risks, including excessive sedation or sudden loss of consciousness during administration, Zulresso has been approved with a Risk Evaluation and Mitigation Strategy (REMS) and is only available to patients through a restricted distribution program at certified health care facilities where the health care provider can carefully monitor the patient.”

PPD is a major depressive episode that occurs following childbirth, although symptoms can start during pregnancy. As with other forms of depression, it is characterized by sadness and/or loss of interest in activities that one used to enjoy and a decreased ability to feel pleasure (anhedonia) and may present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, or suicidal ideation.

Zulresso will be available only through a restricted program called the Zulresso REMS Program that requires the drug be administered by a health care provider in a certified health care facility. The REMS requires that patients be enrolled in the program prior to administration of the drug. Zulresso is administered as a continuous IV infusion over a total of 60 hours (2.5 days). Because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring (monitors oxygen levels in the blood). While receiving the infusion, patients must be accompanied during interactions with their child(ren). The need for these steps is addressed in a Boxed Warning in the drug’s prescribing information. Patients will be counseled on the risks of Zulresso treatment and instructed that they must be monitored for these effects at a health care facility for the entire 60 hours of infusion. Patients should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away.

The efficacy of Zulresso was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of Zulresso or placebo and were then followed for four weeks. One study included patients with severe PPD and the other included patients with moderate PPD. The primary measure in the study was the mean change from baseline in depressive symptoms as measured by a depression rating scale. In both placebo controlled studies, Zulresso demonstrated superiority to placebo in improvement of depressive symptoms at the end of the first infusion. The improvement in depression was also observed at the end of the 30-day follow-up period.

The most common adverse reactions reported by patients treated with Zulresso in clinical trials include sleepiness, dry mouth, loss of consciousness and flushing. Health care providers should consider changing the therapeutic regimen, including discontinuing Zulresso in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors.

The FDA granted this application Priority Review and Breakthrough Therapydesignation.

Approval of Zulresso was granted to Sage Therapeutics, Inc.

Allopregnanolone, also known as 5α-pregnan-3α-ol-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP), as well as brexanolone (USAN),[1] is an endogenous inhibitory pregnane neurosteroid[2] which has been approved by the FDA as a treatment for post-partum depression. It is synthesized from progesterone, and is a potent positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.[2] Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolyticsedative, and anticonvulsant activity.[2][3][4] Endogenously produced allopregnanolone exerts a pivotal neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.[5] The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD).[2]

Biochemistry

Biosynthesis

The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.[2] Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[6]

Biological activity

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[2] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunitsexhibit the greatest potentiation.[7] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear.[8][9] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[10] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[11] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDAAMPAkainate, and glycine receptors.[12]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).[12] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.[13] In addition, allopregnanolone has recently been found to be an agonist of the newly discovered membrane progesterone receptors (mPR), including mPRδmPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[14][15] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[14][16] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[12][17]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[18] including α1 subtypes Cav1.2 and Cav1.3.[19] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.[19] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[19] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[20] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.[20]

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressantanxiolyticstress-reducingrewarding,[21] prosocial,[22] antiaggressive,[23]prosexual,[22] sedativepro-sleep,[24] cognitivememory-impairmentanalgesic,[25] anestheticanticonvulsantneuroprotective, and neurogenic effects.[2] Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of moodanxietypremenstrual syndromecatamenial epilepsy, and various other neuropsychiatric conditions.[26][27][28]

Increased levels of allopregnanolone can produce paradoxical effects, including negative moodanxietyirritability, and aggression.[29][30][31] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.[29][30] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[26][31] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[32]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[33][34]

Chemistry

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is very closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone(5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one).

Derivatives

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione).

Research

Allopregnanolone and the other endogenous inhibitory neurosteroids have short terminal half-lives and poor oral bioavailability, and for these reason, have not been pursued for clinical use as oral therapies, although development as a parenteral therapy for multiple indications has been carried out. However, synthetic analogs with improved pharmacokineticprofiles have been synthesized and are being investigated as potential oral therapeutic agents.

In other studies of compounds related to allopregnanolone, exogenous progesterone, such as oral micronized progesterone (OMP), elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[35] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.[35] As a result, there has been some interest in using OMP to treat catamenial epilepsy,[36] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to OMP, oral pregnenolonehas also been found to act as a prodrug of allopregnanolone,[37][38][39] though also of pregnenolone sulfate.[40]

Allopregnanolone has been under development by Sage Therapeutics as an intravenously administered drug for the treatment of super-refractory status epilepticuspostpartum depression, and essential tremor.[41] As of 19 March 2019 the FDA has approved allopregnanolone for postpartum depression.

References

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  24. ^ Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). “Steroid hormones and sleep regulation”Mini Rev Med Chem12 (11): 1040–8. doi:10.2174/138955712802762167PMID 23092405.
  25. ^ Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). “Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain”. Prog. Neurobiol113: 70–8. doi:10.1016/j.pneurobio.2013.07.004PMID 23948490.
  26. Jump up to:a b Bäckström T, Andersson A, Andreé L, et al. (December 2003). “Pathogenesis in menstrual cycle-linked CNS disorders”. Ann. N. Y. Acad. Sci1007: 42–53. doi:10.1196/annals.1286.005PMID 14993039.
  27. ^ Guille C, Spencer S, Cavus I, Epperson CN (July 2008). “The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment”Epilepsy Behav13 (1): 12–24. doi:10.1016/j.yebeh.2008.02.004PMC 4112568PMID 18346939.
  28. ^ Finocchi C, Ferrari M (May 2011). “Female reproductive steroids and neuronal excitability”. Neurol. Sci. 32 Suppl 1: S31–5. doi:10.1007/s10072-011-0532-5PMID 21533709.
  29. Jump up to:a b Bäckström T, Haage D, Löfgren M, et al. (September 2011). “Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons”. Neuroscience191: 46–54. doi:10.1016/j.neuroscience.2011.03.061PMID 21600269.
  30. Jump up to:a b Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (September 2009). “Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators”. Psychoneuroendocrinology34 (8): 1121–32. doi:10.1016/j.psyneuen.2009.02.003PMID 19272715.
  31. Jump up to:a b Bäckström T, Bixo M, Johansson M, et al. (February 2014). “Allopregnanolone and mood disorders”. Prog. Neurobiol113: 88–94. doi:10.1016/j.pneurobio.2013.07.005PMID 23978486.
  32. ^ Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (August 2006). “Allopregnanolone concentration and mood–a bimodal association in postmenopausal women treated with oral progesterone”. Psychopharmacology187 (2): 209–21. doi:10.1007/s00213-006-0417-0PMID 16724185.
  33. ^ Mellor DJ, Diesch TJ, Gunn AJ, Bennet L (2005). “The importance of ‘awareness’ for understanding fetal pain”. Brain Res. Brain Res. Rev49 (3): 455–71. doi:10.1016/j.brainresrev.2005.01.006PMID 16269314.
  34. ^ Lagercrantz H, Changeux JP (2009). “The emergence of human consciousness: from fetal to neonatal life”Pediatr. Res65 (3): 255–60. doi:10.1203/PDR.0b013e3181973b0dPMID 19092726[…] the fetus is sedated by the low oxygen tension of the fetal blood and the neurosteroid anesthetics pregnanolone and the sleep-inducing prostaglandin D2 provided by the placenta (36).
  35. Jump up to:a b Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T (June 2006). “Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone”. Maturitas54 (3): 238–44. doi:10.1016/j.maturitas.2005.11.005PMID 16406399.
  36. ^ Orrin Devinsky; Steven Schachter; Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6.
  37. ^ Saudan C, Desmarchelier A, Sottas PE, Mangin P, Saugy M (2005). “Urinary marker of oral pregnenolone administration”. Steroids70 (3): 179–83. doi:10.1016/j.steroids.2004.12.007PMID 15763596.
  38. ^ Piper T, Schlug C, Mareck U, Schänzer W (2011). “Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration”. Drug Test Anal3(5): 283–90. doi:10.1002/dta.281PMID 21538944.
  39. ^ Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I (2013). “Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits”Biol. Psychiatry73 (11): 1045–53. doi:10.1016/j.biopsych.2012.12.008PMC 3648625PMID 23348009.
  40. ^ Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, Mattern C, Farr SA (2010). “Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration”Eur. J. Pharmacol641 (2–3): 128–34. doi:10.1016/j.ejphar.2010.05.033PMC 3008321PMID 20570588.
  41. ^ “Brexanolone – Sage Therapeutics”. AdisInsight.

Further reading

Allopregnanolone
Skeletal formula of allopregnanolone
Ball-and-stick model of the allopregnanolone molecule
Names
IUPAC name

1-(3-Hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone
Other names

ALLO; Allo; ALLOP; AlloP; Brexanolone; 5α-Pregnan-3α-ol-20-one; 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP; Zulresso
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
Properties
C21H34O2
Molar mass 318.501 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////Brexanolone, Priority Review, Breakthrough Therapy designation, Zulresso, Sage Therapeutics Inc, FDA 2019, ブレキサノロン , Brexanolone, Allopregnanolone

CC(=O)C1CCC2C1(CCC3C2CCC4C3(CCC(C4)O)C)C

Prabotulinumtoxin A, プラボツリナムトキシンA


>Botulinum Toxin Type A Sequence
MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN
PPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGG
STIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGY
GSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPN
RVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKA
KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV
LNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFT
GLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEE
ITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNG
KKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEA
AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG
AVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAK
VNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKA
MININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDK
VNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINI
GSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNN
EYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTIT
NNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELN
EKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPR
GSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQA
GVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAK
LVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL

Prabotulinumtoxin A

プラボツリナムトキシンA;

Db00083

Formula
C6760H10447N1743O2010S32
CAS
93384-43-1
Mol weight
149320.8333

AGN 191622 / ANT-1207 / ANT-1401 / ANT-1403 / NT 201

        • APPROVED , FDA 2019, Jeuveau, 2019/2/1

Image result for Prabotulinumtoxina

  • Purified botulinum toxin from Clostridium botulinum, purified from culture via dialysis and acid precipitation.
  • Originator Daewoong Pharmaceutical
  • Developer Daewoong Pharmaceutical; Evolus
  • Class Analgesics; Antidepressants; Antimigraines; Antispasmodics; Bacterial proteins; Bacterial toxins; Botulinum toxins; Eye disorder therapies; Muscle relaxants; Skin disorder therapies; Urologics
  • Mechanism of Action Acetylcholine inhibitors; Glutamate antagonists; Membrane transport protein modulators; Neuromuscular blocking agents
  • Marketed Glabellar lines
  • Phase III Muscle spasticity
  • Phase II/III Blepharospasm; Facial wrinkles
  • 27 Feb 2019 Evolus plans to launch prabotulinumtoxin A for Glabellar lines in USA (IM)
  • 01 Feb 2019 Registered for Glabellar lines in USA (IM)
  • 26 Nov 2018 Daewoong Pharmaceutical expects to launch prabotulinumtoxin A for Glabellar lines in eight Middle Eastern countries, including UAE and Kuwait in 2018 (Parenteral)
  • AbobotulinumtoxinA
  • Botulinum A neurotoxin
  • Botulinum toxin A
  • Botulinum toxin type A
  • BTX-A
  • Evabotulinumtoxina
  • IncobotulinumtoxinA
  • OnabotulinumtoxinA
  • Prabotulinumtoxin A
  • Toxina botulínica A
  • Toxine botulinique A

For the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. Also for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents and for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above. Also used cosmetically to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) as well as for the treatment of excessive underarm sweating.

Botulinum toxin (BTX) is a neurotoxic protein produced by the bacterium Clostridium botulinum and related species.[1] It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction and thus causes flaccid paralysis.[2]Infection with the bacterium causes the disease botulism. The toxin is also used commercially in medicine, cosmetics and research.

Botulinum is the most acutely lethal toxin known, with an estimated human median lethal dose (LD50) of 1.3–2.1 ng/kg intravenously or intramuscularly and 10–13 ng/kg when inhaled.[3][clarification needed]

There are eight types of botulinum toxin, named type A–H. Types A and B are capable of causing disease in humans, and are also used commercially and medically.[4] Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals.[5] Type H is considered the deadliest substance in the world – an injection of only 2 ng can cause death to an adult.[6] Botulinum toxin types A and B are used in medicine to treat various muscle spasms and diseases characterized by overactive muscle. Commercial forms are marketed under the brand names Botox and Dysport, among others.[7][8]

Medical uses

Botulinum toxin is used to treat a number of problems.

Muscle spasticity

Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including post-stroke spasticity, post-spinal cord injury spasticity, spasms of the head and neck,[9] eyelid,[10] vagina,[11] limbs, jaw, and vocal cords.[12] Similarly, botulinum toxin is used to relax clenching of muscles, including those of the oesophagus,[13] jaw,[14]lower urinary tract and bladder,[15] or clenching of the anus which can exacerbate anal fissure.[16] It may also be used for improper eye alignment.[17] Botulinum toxin appears to be effective for refractory overactive bladder.[18]

Other muscle disorders

Strabismus is caused by imbalances in the actions of muscles that rotate the eyes, and can sometimes be relieved by weakening a muscle that pulls too strongly, or pulls against one that has been weakened by disease or trauma. Muscles weakened by toxin injection recover from paralysis after several months, so it might seem that injection would then need to be repeated. However, muscles adapt to the lengths at which they are chronically held,[19] so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect. If there is good binocular vision, the brain mechanism of motor fusion, which aligns the eyes on a target visible to both, can stabilize the corrected alignment.

In January 2014, botulinum toxin was approved by UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for treatment of restricted ankle motion due to lower limb spasticity associated with stroke in adults.[20]

On July 29, 2016, Food and Drug Administration (FDA), of the United States of America approved abobotulinumtoxinA for injection for the treatment of lower limb spasticity in pediatric patients two years of age and older.[21] AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity. In the United States of America, the FDA approves the text of the labels of prescription medicines. The FDA approves which medical conditions the drug manufacturer may sell the drug for. However, those approved by the FDA to prescribe these drugs may freely prescribe them for any condition they wish, called off-label use. Botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia.[22]

Excessive Sweating

Khalaf Bushara and David Park were the first to demonstrate a nonmuscular use of BTX-A while treating patients with hemifacial spasm in England in 1993, showing that botulinum toxin injections inhibit sweating, and so are useful in treating hyperhidrosis (excessive sweating).[23] BTX-A has since been approved for the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating of unknown cause), which cannot be managed by topical agents.[12][24]

Migraine

In 2010, the FDA approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache.[25]

Cosmetics

Botulinum toxin injected in human face

In cosmetic applications, botulinum toxin is considered safe and effective for reduction of facial wrinkles, especially in the uppermost third of the face.[26] Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin.[26] Smoothing of wrinkles is usually visible three days after treatment and is maximally visible two weeks following injection.[26] The treated muscles gradually regain function, and generally return to their former appearance three to four months after treatment.[26] Muscles can be treated repeatedly to maintain the smoothed appearance.[26]

Other

Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating,[24] neuropathic pain,[27] and some allergysymptoms.[12] In addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain.[28]

Side effects

While botulinum toxin is generally considered safe in a clinical setting, there can be serious side effects from its use. Most commonly, botulinum toxin can be injected into the wrong muscle group or spread from the injection site, causing paralysis of unintended muscles.

Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and trouble swallowing. Side effects are not limited to direct paralysis however, and can also include headaches, flu-like symptoms, and allergic reactions.[29] Just as cosmetic treatments only last a number of months, paralysis side-effects can have the same durations.[citation needed] At least in some cases, these effects are reported to dissipate in the weeks after treatment.[citation needed] Bruising at the site of injection is not a side effect of the toxin but rather of the mode of administration, and is reported as preventable if the clinician applies pressure to the injection site; when it occurs, it is reported in specific cases to last 7–11 days.[citation needed] When injecting the masseter muscle of the jaw, loss of muscle function can result in a loss or reduction of power to chew solid foods.[29]

Side effects from therapeutic use can be much more varied depending on the location of injection and the dose of toxin injected. In general, side effects from therapeutic use can be more serious than those that arise during cosmetic use. These can arise from paralysis of critical muscle groups and can include arrhythmiaheart attack, and in some cases seizures, respiratory arrest, and death.[29] Additionally, side effects which are common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes.[29]

In response to the occurrence of these side effects, in 2008 the U.S. Food and Drug Administration notified the public of the potential dangers of the botulinum toxin as a therapeutic. Namely, they warned that the toxin can spread to areas distant from the site of injection and paralyze unintended muscle groups, especially when used for treating muscle spasticity in children treated for cerebral palsy.[30] In 2009, the FDA announced that boxed warnings would be added to available botulinum toxin products, warning of their ability to spread from the injection site.[31] Additionally, the FDA announced name changes to several botulinum toxin products, meant to emphasize that the products are not interchangeable and require different doses for proper use. Botox and Botox Cosmetic were renamed onabotulinumtoxinA, Myobloc was renamed rimabotulinumtoxinB, and Dysport name renamed abobotulinumtoxinA.[31] In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each.[32] A similar warning was issued by Health Canada in 2009, warning that botulinum toxin products can spread to other parts of the body.[33]

Role in disease

Botulinum toxin produced by Clostridium botulinum is the cause of botulism.[10] Humans most commonly ingest the toxin from eating improperly-canned foods in which C. botulinumhas grown. However, the toxin can also be introduced through an infected wound. In infants, the bacteria can sometimes grow in the intestines and produce botulinum toxin within the intestine and can cause a condition known as floppy baby syndrome.[34] In all cases, the toxin can then spread, blocking nerves and muscle function. In severe cases, the toxin can block nerves controlling the respiratory system or heart, resulting in death.[1] Botulism can be difficult to diagnose, as it may appear similar to diseases such as Guillain–Barré syndromemyasthenia gravis, and stroke. Other tests, such as brain scan and spinal fluid examination, may help to rule out other causes. If the symptoms of botulism are diagnosed early, various treatments can be administered. In an effort to remove contaminated food which remains in the gut, enemas or induced vomiting may be used.[35] For wound infections, infected material may be removed surgically.[35] Botulinum antitoxin is available and may be used to prevent the worsening of symptoms, though it will not reverse existing nerve damage. In severe cases, mechanical respiration may be used to support patients suffering from respiratory failure.[35] The nerve damage heals over time, generally over weeks to months.[5] With proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced.[35]

Two preparations of botulinum antitoxins are available for treatment of botulism. Trivalent (A,B,E) botulinum antitoxin is derived from equine sources using whole antibodies. The second antitoxin is Heptavalent (A,B,C,D,E,F,G) botulinum antitoxin, which is derived from equine antibodies which have been altered to make them less immunogenic. This antitoxin is effective against all known strains of botulism.

Mechanism of action

Target molecules of botulinum neurotoxin (abbreviated BoNT) and tetanus neurotoxin (TeNT), toxins acting inside the axon terminal.[36]

Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to nerves which use the neurotransmitter acetylcholine. Once bound to the nerve terminal, the neuron takes up the toxin into a vesicle by receptor-mediated endocytosis.[37] As the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin which triggers it to push across the vesicle membrane and into the cell cytoplasm.[1] Once inside the cytoplasm, the toxin cleaves SNARE proteins, meaning that the acetylcholine vesicles can’t bind to the intracellular cell membrane,[37] preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to paralysis.[1]

The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases.[12] The active form consists of a two-chain protein composed of a 100-kDa heavy chain polypeptide joined via disulfide bond to a 50-kDa light chain polypeptide.[38] The heavy chain contains domains with several functions: it has the domain responsible for binding specifically to presynaptic nerve terminals, as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies.[1][38] The light chain is a zinc metalloprotease and is the active part of the toxin. It is translocated into the host cell cytoplasm where it cleaves the host protein SNAP-25, a member of the SNARE protein family which is responsible for fusion. The cleaved SNAP-25 is unable to mediate fusion of vesicles with the host cell membrane, thus preventing the release of the neurotransmitteracetylcholine from axon endings.[1] This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell.[1]

The seven toxin types (A-G) have different tertiary structures and sequence differences.[38][39] While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members.[36] The A, B, and E serotypes cause human botulism, with the activities of types A and B enduring longest in vivo (from several weeks to months).[38]

History

In 1820, Justinus Kerner, a small-town German medical officer and romantic poet, gave the first complete description of clinical botulism based on extensive clinical observations of so-called “sausage poisoning”.[40] Following experiments on animals and on himself, he concluded that the toxin acts by interrupting signal transmission in the somatic and autonomic motor systems, without affecting sensory signals or mental functions. He observed that the toxin develops under anaerobic conditions, and can be lethal in minute doses.[41] His prescience in suggesting that the toxin might be used therapeutically earned him recognition as the pioneer of modern botulinum toxin therapy.[42]

In 1895 (seventy-five years later), Émile van Ermengem, professor of bacteriology and a student of Robert Koch, correctly described Clostridium botulinum as the bacterial source of the toxin. Thirty-four attendees at a funeral were poisoned by eating partially salted ham, an extract of which was found to cause botulism-like paralysis in laboratory animals. Van Ermengem isolated and grew the bacterium, and described its toxin,[43] which was later purified by P Tessmer Snipe and Hermann Sommer.[44]

Food canning

Over the next three decades, 1895-1925, as food canning was approaching a billion-dollar-a-year industry, botulism was becoming a public health hazard. Karl Friedrich Meyer, a prodigiously productive Swiss-American veterinary scientist created a center at the Hooper Foundation in San Francisco, where he developed techniques for growing the organism and extracting the toxin, and conversely, for preventing organism growth and toxin production, and inactivating the toxin by heating. The California canning industry was thereby preserved.

World War II

With the outbreak of World War II, weaponization of botulinum toxin was investigated at Fort Detrick in Maryland. Carl Lamanna and James Duff[45] developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Army’s Chemical Corps was disbanded, Schantz moved to the Food Research Institute in Wisconsin, where he manufactured toxin for experimental use and generously provided it to the academic community.

The mechanism of botulinum toxin action – blocking the release from nerve endings of the neurotransmitter acetylcholine – was elucidated in the mid-1900s,[46] and remains an important research topic. Nearly all toxin treatments are based on this effect in various body tissues.

Strabismus

Ophthalmologists specializing in eye muscle disorders (strabismus) had developed the method of EMG-guided injection (using the electromyogram, the electrical signal from an activated muscle, to guide injection) of local anesthetics as a diagnostic technique for evaluating an individual muscle’s contribution to an eye movement.[47] Because strabismus surgery frequently needed repeating, a search was undertaken for non-surgical, injection treatments using various anesthetics, alcohols, enzymes, enzyme blockers, and snake neurotoxins. Finally, inspired by Daniel Drachman’s work with chicks at Johns Hopkins,[48] Alan B. Scott and colleagues injected botulinum toxin into monkey extraocular muscles.[49]The result was remarkable: a few picograms induced paralysis that was confined to the target muscle, long in duration, and without side-effects.

After working out techniques for freeze-drying, buffering with albumin, and assuring sterility, potency, and safety, Scott applied to the FDA for investigational drug use, and began manufacturing botulinum type A neurotoxin in his San Francisco lab. He injected the first strabismus patients in 1977, reported its clinical utility in 1980,[50] and had soon trained hundreds of ophthalmologists in EMG-guided injection of the drug he named Oculinum (“eye aligner”).

In 1986, Oculinum Inc, Scott’s micromanufacturer and distributor of botulinum toxin, was unable to obtain product liability insurance, and could no longer supply the drug. As supplies became exhausted, patients who had come to rely on periodic injections became desperate. For 4 months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections.[51]

Based on data from thousands of patients collected by 240 investigators, Allergan received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus and blepharospasm, using the trademark Botox.[52] This was under the 1983 US Orphan Drug Act.[53]

Cosmetics

Richard Clark, a plastic surgeon from Sacramento (CA), was the first to document a cosmetic use for botulinum toxin.[54] He treated forehead asymmetry caused by left sided forehead nerve paralysis that occurred during a cosmetic facelift. Since the injured nerve could possibly regenerate by 24 months, a two-year waiting period was necessary before definitive surgical treatment could be done. Clark realized that botulinum toxin, which had been previously used only for cross eyed babies and facial tics, could also be injected to smooth the wrinkles of the right forehead to match her paralyzed left. He received FDA approval for this cosmetic application of the toxin and successfully treated the person and published the case study in 1989.[54]

Marrying ophthalmology to dermatology, Jean and Alistair Carruthers observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines (“frown lines” between the eyebrows), thereby initiating the highly-popular cosmetic use of the toxin.[55] Brin, and a group at Columbia University under Monte Keen made similar reports.[56] In 2002, following clinical trials, the FDA approved Botox Cosmetic, botulinum A toxin to temporarily improve the appearance of moderate-to-severe glabellar lines.[57] The FDA approved a fully in vitro assay for use in the stability and potency testing of Botox in response to increasing public concern that LD50testing was required for each batch sold in the market.[58][59]

Chronic pain

William J. Binder reported in 2000 that patients who had cosmetic injections around the face reported relief from chronic headache.[60] This was initially thought to be an indirect effect of reduced muscle tension, but it is now known that the toxin inhibits release of peripheral nociceptive neurotransmitters, suppressing the central pain processing systems responsible for migraine headache.[61][62]

Society and culture

Economics

As of 2013, botulinum toxin injections are the most common cosmetic operation, with 6.3 million procedures in the United States, according to the American Society of Plastic Surgeons. Qualifications for Botox injectors vary by county, state and country. Botox cosmetic providers include dermatologists, plastic surgeons, aesthetic spa physicians, dentists, nurse practitioners, nurses and physician assistants.

The global market for botulinum toxin products, driven by their cosmetic applications, is forecast to reach $2.9 billion by 2018. The facial aesthetics market, of which they are a component, is forecast to reach $4.7 billion ($2 billion in the U.S.) in the same timeframe.[63]

Bioterrorism

Botulinum toxin has been recognized as a potential agent for use in bioterrorism.[64] It can be absorbed through the eyes, mucous membranes, respiratory tract, or non-intact skin.[65]

The effects of botulinum toxin are different from those of nerve agents involved insofar in that botulism symptoms develop relatively slowly (over several days), while nerve agent effects are generally much more rapid and can be instantaneous.[citation needed] Evidence suggests that nerve exposure (simulated by injection of atropine and pralidoxime) will increase mortality by enhancing botulinum toxin’s mechanism of toxicity.[citation needed]

With regard to detection, current protocols using NBC detection equipment (such as M-8 paper or the ICAM) will not indicate a “positive” when samples containing botulinum toxin are tested.[citation needed] To confirm a diagnosis of botulinum toxin poisoning, therapeutically or to provide evidence in death investigations, botulinum toxin may be quantitated by immunoassay of human biological fluids; serum levels of 12–24 mouse LD50 units per milliliter have been detected in poisoned patients.[66]

The Japanese doomsday cult Aum Shinrikyo produced botulinum toxin and spread it as an aerosol in downtown Tokyo during the 1990s, but the attacks caused no fatalities.[67]

During the early 1980s, the German and French newspapers reported that the police had raided a Baader-Meinhof gang safe house in Paris and had found a makeshift laboratory that contained flasks full of Clostridium botulinum, which makes botulinum toxin. Their reports were later found to be incorrect; no such lab was ever found.[68]

Brand names

Botulinum toxin A is marketed under the brand names Botox and Xeomin. Botulinum toxin B is marketed under the brand name Myobloc.

In the United States, botulinum toxin products are manufactured by a variety of companies, for both therapeutic and cosmetic use. A U.S. supplier reported in its company materials in 2011 that it could “supply the world’s requirements for 25 indications approved by Government agencies around the world” with less than one gram of raw botulinum toxin.[69]Myobloc or Neurobloc, a botulinum toxin type B product, is produced by Solstice Neurosciences, a subsidiary of US WorldMeds. AbobotulinumtoxinA), a therapeutic formulation of the type A toxin manufactured by Galderma in the United Kingdom, is licensed for the treatment of focal dystonias and certain cosmetic uses in the U.S. and other countries.[32]

Besides the three primary U.S. manufacturers, there are numerous other botulinum toxin producers. Xeomin, manufactured in Germany by Merz, is also available for both therapeutic and cosmetic use in the U.S.[70] Lanzhou Institute of Biological Products in China manufactures a BTX-A product; as of 2014 it was the only BTX-A approved in China.[70] BTX-A is also sold as Lantox and Prosigne on the global market.[71] Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea in 2009;[72]

Toxin production

Botulism toxins are produced by bacteria of the genus Clostridium, namely Clostridium botulinumC. butyricum, C. baratii and C. argentinense,[73] which are widely distributed, including in soil and dust. As well, the bacteria can be found inside homes on floors, carpet, and countertops even after cleaning.[citation needed] Some food products such as honey can contain amounts of the bacteria.[citation needed]

Food-borne botulism results, indirectly, from ingestion of food contaminated with Clostridium spores, where exposure to an anaerobic environment allows the spores to germinate, after which the bacteria can multiply and produce toxin.[citation needed] Critically, it is ingestion of toxin rather than spores or vegetative bacteria that causes botulism.[citation needed]Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening, and so is preventable.[citation needed] Infant botulism cases arise chiefly as a result of environmental exposure and are therefore more difficult to prevent.[citation needed] Infant botulism arising from consumption of honey can be prevented by eliminating honey from diets of children less than 12 months old.[74]

Organism and toxin susceptibilities

Proper refrigeration at temperatures below 3 °C (38 °F) retards the growth of Clostridium botulinum. The organism is also susceptible to high salt, high oxygen, and low pH levels.[5]The toxin itself is rapidly destroyed by heat, such as in thorough cooking.[75] The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.[76]

The botulinum toxin is denatured and thus deactivated at temperatures greater than 80 °C (176 °F).[77] As a zinc metalloprotease (see below), the toxin’s activity is also susceptible, post-exposure, to inhibition by protease inhibitors, e.g., zinc-coordinating hydroxamates.[38][78]

Research

Blepharospasm and strabismus

University-based ophthalmologists in the USA and Canada further refined the use of botulinum toxin as a therapeutic agent. By 1985, a scientific protocol of injection sites and dosage had been empirically determined for treatment of blepharospasm and strabismus.[79] Side effects in treatment of this condition were deemed to be rare, mild and treatable.[80]The beneficial effects of the injection lasted only 4–6 months. Thus, blepharospasm patients required re-injection two or three times a year.

In 1986, Scott’s micromanufacturer and distributor of Botox was no longer able to supply the drug because of an inability to obtain product liability insurance. Patients became desperate, as supplies of Botox were gradually consumed, forcing him to abandon patients who would have been due for their next injection. For a period of four months, American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved.[51]

In December 1989, Botox was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.[52]

Botox has not been approved for any pediatric use.[32] It has, however, been used off-label by physicians for several conditions. including spastic conditions in pediatric patients with cerebral palsy, a therapeutic course that has resulted in patient deaths.[32] In the case of treatment of infantile esotropia in patients younger than 12 years of age, several studies have yielded differing results.[22][better source needed]

Cosmetic

The cosmetic effect of BTX-A on wrinkles was originally documented by a plastic surgeon from Sacramento, California, Richard Clark, and published in the journal Plastic and Reconstructive Surgery in 1989.[54] Canadian husband and wife ophthalmologist and dermatologist physicians, JD and JA Carruthers, were the first to publish a study on BTX-A for the treatment of glabellar frown lines in 1992.[55] Similar effects had reportedly been observed by a number of independent groups (Brin, and the Columbia University group under Monte Keen.[56]) After formal trials, on April 12, 2002, the FDA announced regulatory approval of botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines).[57] Subsequently, cosmetic use of botulinum toxin type A has become widespread.[81] The results of Botox Cosmetic can last up to four months and may vary with each patient.[82] The US Food and Drug Administration approved an alternative product-safety testing method in response to increasing public concern that LD50 testing was required for each batch sold in the market.[58][59]

BTX-A has also been used in the treatment of gummy smiles,[83][84] the material is injected into the hyperactive muscles of upper lip, which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of gingiva.[85] Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose; the levator labii superioris (LLS), the levator labii superioris alaeque nasi muscle (LLSAN), and the zygomaticus minor (ZMi).[86][87]

Upper motor neuron syndrome

BTX-A is now a common treatment for muscles affected by the upper motor neuron syndrome (UMNS), such as cerebral palsy, for muscles with an impaired ability to effectively lengthen. Muscles affected by UMNS frequently are limited by weakness, loss of reciprocal inhibition, decreased movement control and hypertonicity (including spasticity). In January 2014, Botulinum toxin was approved by UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults.[20] Joint motion may be restricted by severe muscle imbalance related to the syndrome, when some muscles are markedly hypertonic, and lack effective active lengthening. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, so improved ability to move and exercise.

Sweating

Khalaf Bushara and David Park were the first to demonstrate a nonmuscular use of BTX-A while treating patients with hemifacial spasm in England in 1993, showing that botulinum toxin injections inhibit sweating, and so are useful in treating hyperhidrosis (excessive sweating).[23] BTX-A has since been approved for the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating of unknown cause), which cannot be managed by topical agents.[12][24]

Cervical dystonia

BTX-A is commonly used to treat cervical dystonia, but it can become ineffective after a time. Botulinum toxin type B (BTX-B) received FDA approval for treatment of cervical dystonia on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.[70]

Chronic migraine

Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic migraines on October 15, 2010. The toxin is injected into the head and neck to treat these chronic headaches. Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for migraine sufferers undergoing the Botox treatment.[88][89]

Since then, several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for patients with chronic migraine[90] who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), “detoxification” of patients with coexisting chronic daily headache due to medication overuse, and no current history of other preventive headache medications.[91]

Depression

A few small trials have found benefits in people with depression.[92][93]

Premature ejaculation

The drug is under development for the treatment of premature ejaculation.[93]

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  78. ^ Capková K, Salzameda NT, Janda KD (October 2009). “Investigations into small molecule non-peptidic inhibitors of the botulinum neurotoxins”Toxicon54 (5): 575–82. doi:10.1016/j.toxicon.2009.03.016PMC 2730986PMID 19327377.
  79. ^ Flanders M, Tischler A, Wise J, Williams F, Beneish R, Auger N (June 1987). “Injection of type A botulinum toxin into extraocular muscles for correction of strabismus”. Canadian Journal of Ophthalmology22 (4): 212–17. PMID 3607594.
  80. ^ “Botulinum toxin therapy of eye muscle disorders. Safety and effectiveness. American Academy of Ophthalmology”. Ophthalmology. Suppl: 37–41. September 1989. doi:10.1016/s0161-6420(89)32989-7PMID 2779991.
  81. ^ Giesler M (2012). “How Doppelgänger Brand Images Influence the Market Creation Process: Longitudinal Insights from the Rise of Botox Cosmetic”. Journal of Marketing76(6): 55–68. doi:10.1509/jm.10.0406.
  82. ^ “BOTOX Cosmetic (onabotulinumtoxinA) Product Information”Allergan. January 22, 2014.
  83. ^ Nayyar P, Kumar P, Nayyar PV, Singh A (December 2014). “BOTOX: Broadening the Horizon of Dentistry”Journal of Clinical and Diagnostic Research : JCDR8 (12): ZE25–9. doi:10.7860/JCDR/2014/11624.5341PMC 4316364PMID 25654058.
  84. ^ Al-Fouzan AF, Mokeem LS, Al-Saqat RT, Alfalah MA, Alharbi MA, Al-Samary AE (June 2017). “Botulinum Toxin for the Treatment of Gummv Smile”. The Journal of Contemporary Dental Practice18 (6): 474–478. doi:10.5005/jp-journals-10024-2068PMID 28621277.
  85. ^ Hwang WS, Hur MS, Hu KS, Song WC, Koh KS, Baik HS, Kim ST, Kim HJ, Lee KJ (January 2009). “Surface anatomy of the lip elevator muscles for the treatment of gummy smile using botulinum toxin”. The Angle Orthodontist79 (1): 70–7. doi:10.2319/091407-437.1PMID 19123705.
  86. ^ Gracco A, Tracey S (May 2010). “Botox and the gummy smile”. Progress in Orthodontics11 (1): 76–82. doi:10.1016/j.pio.2010.04.004PMID 20529632.
  87. ^ Mazzuco R, Hexsel D (December 2010). “Gummy smile and botulinum toxin: a new approach based on the gingival exposure area”. Journal of the American Academy of Dermatology63 (6): 1042–51. doi:10.1016/j.jaad.2010.02.053PMID 21093661.
  88. ^ Walsh S (October 15, 2010). “FDA approves Botox to treat chronic migraine”FDA Press Releases. Retrieved October 15, 2010.
  89. ^ Watkins T (October 15, 2010). “FDA approves Botox as migraine preventative”CNN (US).
  90. ^ Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, Diener HC, Brin MF (June 2010). “OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program”. Headache50 (6): 921–36. doi:10.1111/j.1526-4610.2010.01678.xPMID 20487038.
  91. ^ Ashkenazi A (March 2010). “Botulinum toxin type a for chronic migraine”. Current Neurology and Neuroscience Reports10 (2): 140–46. doi:10.1007/s11910-010-0087-5PMID 20425239.
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  93. Jump up to:a b http://adisinsight.springer.com/drugs/800008810

External links

Botulinum toxin A
Cartoon representation of Botulinum toxin. PDB entry 3BTA
Clinical data
Routes of
administration
IM (approved), SC, intradermal, into glands
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
ECHA InfoCard 100.088.372 Edit this at Wikidata
Chemical and physical data
Formula C6760H10447N1743O2010S32
Molar mass 149 kg/mol (149,321g/mol) g·mol−1
 ☒☑ (what is this?)  (verify)
Bontoxilysin
Identifiers
EC number 3.4.24.69
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDBstructures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO QuickGO

////////////Prabotulinumtoxin A, プラボツリナムトキシンA ,APPROVED , FDA 2019, Jeuveau, AGN 191622,  ANT-1207ANT-1401ANT-1403NT 201

Triclabendazole, トリクラベンダゾール


68786-66-3.png

Triclabendazole.svg

Triclabendazole

トリクラベンダゾール

CGA-89317

Formula
C14H9Cl3N2OS
CAS
68786-66-3
Mol weight
359.6581

Anthelmintic

5-Chloro-6-(2,3-dichlorophenoxy)-2-methylthio-1H-benzimidazole
68786-66-3 [RN]
DD6747000
Fasinex [Trade name]
MFCD00864519 [MDL number]

APPROVED, Egat, FDA 2019, 02/13/2019

Triclabendazole, sold under the brand name Egaten among others, is a medication used to treat liver flukes, specifically fascioliasisand paragonimiasis.[1] It is very effective for both conditions.[1] Treatment in hospital may be required.[1] It is taken by mouth with typically one or two doses being required.[1]

Side effects are generally few, but can include abdominal pain and headaches.[1] Biliary colic may occur due to dying worms.[2] While no harms have been found with use during pregnancy, triclabendazole has not been well studied in this population.[2] It is a member of the benzimidazole family of medications for worms.[1]

Triclabendazole was approved for medical use in the United States in 2019.[3] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] For human use it can also be obtained from the World Health Organization.[2] It is also used in other animals.[5]

Chemistry

It is a member of the benzimidazole family of anthelmintics. The benzimidazole drugs share a common molecular structure, triclabendazole being the exception in having a chlorinated benzene ring but no carbamate group. Benzimidazoles such as triclabendazole are generally accepted to bind to beta-tubulin therefore preventing the polymerization of microtubules.

History

Since late 1990s, triclabendazole became available as a generic drug, as patents expired in many countries. Many products were developed then. Among them, Trivantel 15, a 15% triclabendazole suspension, was launched by Agrovet Market Animal Health in the early 2000s. In 2009, the first triclabendazole injectable solution (combined with ivermectin) was developed and launched, also by Agrovet Market Animal Health. The product, Fasiject Plus, a triclabendazole 36% and ivermectin 0.6% solution, is designed to treat infections by Fasciola hepatica (both immature and adult liver flukes), roundworms and ectoparasites, as well.

Fasinex is a brandname for veterinary use while Egaten is a brandname for human use.

Patent

https://patents.google.com/patent/WO2012070068A2

Triclabendazole, chemically known as 5-chloro-6-(2,3-dichlorophenoxy)-2- (methylthio)-lH-benzimidazole represented by formula I,

Figure imgf000002_0001

is a halogenated benzimidazole compound that possesses high activity against immature and adult stages of the liver fluke, Faciola hepatica. The intensive use of Triclabendazole in endemic areas of facioliasis has resulted in the development of liver flukes resistant to this compound.

US 4, 197,307 discloses the process for the preparation of Triclabendazole, wherein 4- chloro-5-(2,3-dichlorophenoxy)-l,2-benzenediamine is reacted with carbondisulfide to give cyclic benzimidazole thione, which is further subjected to alkylation reaction with dimethyl sulfate to give Triclabendazole.

Chinese patent 10155523 ldescribes a process for the preparation of Triclabendazole by hydrolysing N-(4,5-dichloro-2-nitrophenyl)acetamide of formula VII to 4,5- dichloro-2-nitroaniline of formula VIII and condensing it with 2,3-dichlorophenol of formula VI in presence of a phase transfer catalyst to obtain 4-chloro-5(2,3- dichlorophenoxy)-2-nitroaniline of formula IV, which is further reduced in presence of Iron to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l ,2-diamine of formula III. The obtained diamine of formula III is cyclised in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)- lH-benzimidazole-2-thiol of formula II. The compound of formula II is methylated using dimethyl sulphate to obtain Triclabendazole of formula I. The process disclosed in this patent is illustrated in scheme 1 below:

Scheme 1

Figure imgf000003_0001

6-chloro-5-(2,3-dichlorophenoxy)-1H-benzimidazole-2-t ioi 4-chloro-5-(2,3-dichlorop enoxy)benzene-1 ,2-diamine

Figure imgf000003_0002

6-chloro-5-(2,3-dichlorophenoxy)-2-(methylthio)-1H-benzimidazole

I

However, the above prior art process is not preferred at a commercial scale because the hydrolysis of N-(4,5-dichloro-2-nitrophenyl)acetamide of formula VII is carried out before condensation with 2,3-dichlorophenol of formula VI, which is labile to formation of impurities and moreover the condensation is carried out in the presence of a phase transfer catalyst. Further, Iron is used as a catalyst for reduction which is riot environment friendly and involves tedious work-up. The final compound Triclabendazole is directly obtained by the methylating the compound of formula II using dimethylsulfate. The purity of thus obtained Triclabendazole is not high. Thus it is highly desirable to develop a process which overcomes most of the prior art drawbacks. The present inventors have developed a process for the preparation of Thiabendazole, which is environment friendly, technologically safe, simple and cost effective

Scheme 2

Figure imgf000005_0001
Figure imgf000005_0002

+ NH4CI + H20

Example 1: Preparation of 5-chIoro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH- benzimidazole (I)

(a) Preparation of 4-chloro-5(2,3-dichlorophenoxy)-2-nitroaniline;

2, 3-dichIorophenol (1 kg) in DMF (1.5 L), 2-nitro 4,5-dichloroacetanilide (1.52 kg), and potassium carbonate were heated into the flask for 12 hrs while maintaining the temperature at 90°C under vacuum and after that cooled to room temperature. Methanol (2 L), 48% caustic lye (0.3 kg) in 300 mL water were added to it and heated to 50°C for 4 hrs. Further water (4 L) was added, stirred, filtered and washed with water and with methanol.

Weight= 2 kg.

(b) Preparation of 4-chloro-5(2,3-dichlorophenoxy)-l,2-phenylenediamine;

Raney nickel (10.8 g) was added into a reaction mixture containing 4-chIoro- 5(2,3-dichlorophenoxy)-2-nitroaniline (900 g), methanol (3.4 L) at RT, caustic lye (2.72 g). Nitrogen was flushed into and charged with hydrogen. The reaction mixture was heated slowly to 100°C for 12 hrs, cooled to RT and filtered.

Weight: 819 g (c) Preparation of 6-chloro-5(2,,3-dichlorophenoxy)-lH- benzimidazole-2- thiol:

In the mixture of 4-chloro-5(2,3-dichlorophenoxy)-l ,2-phenylenediamine in methanol (800 g) and caustic lye (245 mL), carbondisulfide (259 g) was added slowly and the reaction mass was refluxed for 6 hrs. After completion of the reaction water (2.5 L) and acetic acid was added over a period of 2hrs at 60°C. Water was added (2.5 litre) again and heated to 90°C for 2hrs, filtered and washed with hot water to obtain the title compound.

Weight: 863 g.

(d) Preparation of 6-chloro-5(2.3-dichlorophenoxy)-2-(metylthio)-lH- benzimidazole:

6-chloro-5(2,3-dichlorophenoxy)-l H- benzimidazole-2-thiol(400kg) was added to methanol (700 L) and heated to 40°C. Dimethyl sulphate was added slowly at 40°C to it. The reaction mass was heated to 60-65°C and maintain for 6hrs. After completion of the reaction the reaction mass was cooled to 15°C, centrifuged the material and washed with 75 L of methanol to obtain wet cake of Triclabendazole methanesulfonate (520-560 kg).

Triclabendazole methanesulfonate (200 g) and methanol (1.2 L) was refluxed, cooled and charcoal was added and refluxed again for 1 hr. The reaction mass was filtered and concentrated hydrochloric acid was added. The precipitate was cooled to RT, stirred for 1 hr, filtered and Triclabendazole hydrochloride was isolated (250 g wet) .

The water was added to the above Triclabendazole hydrochloride and ammonia was charged and stired for 2-3 hrs. The reaction mass was filtered, washed with water and dried to obtain Triclabendazole.

Weight: 156 g.

Example 2:Preparation of 6-chloro-5(2,3-dichlorophenoxy)-2-(metylthio)-lH- benzimidazole In a RBF methanol (200 mL), 6-chloro-5(2,3-dichlorophenoxy)-lH- benzimidazole-2-thiol ((200 g) and dimethylsulfate (40 g) were heated to 60 ± 2°C and water (100 mL) was added and stirred for half an hr. Sodium carbonate solution (25 g Na2CC>3 in 200 mL water) was added slowly and temperature was raised to 60 °C and stirred for VA hr. After completion of reaction, the reaction mixture was cooled to 60°C, filtered, washed with water further washed with toluene and dried.

To the above wet crude 6-chloro-5(2,3-dichlorophenoxy)-2-(metylthio)-lH- benzimidazole, toluene (500 mL) was charged and water was removed azeotropically using Dean Stark apparatus. The mixture was heated to 100-1 12°C and 5 g charcoal was added, stirred for half an hr at 100-105°C. The reaction mixture was filtered through hyflow bed and washed with fresh toluene. The mother liquor was cooled to 70°C and isopropanol (7 mL) was added, cooled to room temperature to precipitate, filtered and washed with fresh toluene, dried at 75°C for 4 hrs to obtain pure Triclabendazole.

Yield of Triclabendazole is 85 gm. (81.7%).

Example 3: Purification of Triclabendazole:

The wet cake of Triclabendazole was heated to 90-100°C in toluene (1.92 litre). Water was removed azeotropically. The solution/mixture was cooled charcoal was added, refluxed and filtered. Again the obtained material was heated to 90-100°C, 180 ml of IPA was added, cooled to RT, filtered and dried for 24 hrs at 90-100°C.

Wt: 132 g (1st crop) and \2±\ g (2nd crop)

PATENT

https://patents.google.com/patent/CN103360323A/en

Figure CN103360323AD00041

Example 1: Preparation of the present invention, the step of azole trichlorobenzene as follows:

[0020] The first step, 4-chloro-5- (2,3-dichlorophenoxy) -2-nitroaniline, i.e. a compound of formula III in the reaction:

[0021] 1,2,3-trichlorobenzene was added in the reaction kettle 43.5kg, 40kg of 50% aqueous potassium hydroxide solution, was heated at reflux for 7 hours, xylene was added 150L, 4,5- dichloro-2-nitro 41.4kg of aniline and a catalyst TBAB5kg, reacted for 8 hours, the reaction temperature is controlled at 125 ° C, slowly cooled to room temperature under stirring, to precipitate a large number of brown crystals, was filtered, washed with chilled xylene crystals paint IOkg, drained, washed with water to of drying to give 4-chloro-5- (2,3-dichlorophenoxy) -2_ nitroaniline 54kg, yield: 81%, melting point: 145 ° C~150 ° C, the substance pattern shown in Figure 1; wherein the compound is 1,2,3-trichlorobenzene of formula I in the reaction; 4,5-dichloro-2-nitroaniline reaction of a compound of formula II;

[0022] The second step, 5-chloro _6_ (2, 3_-dichlorophenoxy) _2_ mercapto – benzimidazole was prepared, i.e. a compound of formula V in the reaction:

[0023] obtained in the first step chlorine _5_ 4_ (2, 3_-dichlorophenoxy) _2_ nitroaniline 54kg Dad added to the reaction, and then added at a concentration of 80% ethanol 540L, was heated until dissolution was added Raney nickel catalyst 5kg, was heated to a boil, a solution prepared by the dropwise addition of hydrazine hydrate and 30L 12kg ethanol solution dropwise 4 ~ 6 hours, the yellow solution was gradually faded, TLC detection reaction end, Raney nickel catalyst was removed by filtration, dried the filter cake was washed several times with ethanol, containing 4-chloro-5- (2,3-dichlorophenoxy) 1,2_ phenylenediamine filtrate was used directly in the next step, the filtrate was added potassium hydroxide 11kg after stirring until the whole solution was slowly added 18kg of carbon disulfide in the range of 25 V~30 ° C, after the addition was stirred at room temperature for 2 hours and then heated to reflux for 10 hours, add decolorizing charcoal 2.5kg, refluxing was continued for I h, cooled to 30 ° C or below, filtered, the filter cake was washed with ethanol, the filtrate after recovery of ethanol by distillation, the residue was diluted IOOkg added water, adjusted to pH 2 to 3 with 5% aqueous hydrochloric acid, filtered, washed well with water to nearly neutral, and drying, to give an off-white solid, 5-chloro-6- (2,3-dichlorophenoxy) -2-mercapto – benzimidazole- 47.5kg, melting point 290. . ~300 ° C, 85% yield; the pattern shown in Figure 2, wherein _5_ chloro-4- (2,3-dichlorophenoxy) -2_ nitroaniline compound of formula III in the reaction ; 4-chloro-5- (2,3-dichlorophenoxy) I, 2- phenylenediamine compound of formula IV in the reaction; 5-chloro-6- (2,3-dichlorophenoxy) -2-mercapto – benzimidazole compound of the formula V in the reaction;

Preparation [0024] The third step, triclabendazole, i.e., the reaction of the compound of formula VI:

[0025] The first gas _ ■ 5- obtained in step -6_ (2,3- _ ■ gas phenoxy) _2- mercapto – benzo taste Jie sit 47.5kg, oxygen potassium 8.5kg, a concentration of 80% 285kg of methanol, added to the reaction kettle was cooled to ice bath 5~10 ° C, was added dropwise dimethyl sulfate 19kg, 3 hours dropwise, stirring continued for 3 hours to obtain a reaction solution containing triclabendazole, the conditions of room temperature under added dropwise to the reaction solution containing triclabendazole in dilute sulfuric acid to adjust the pH 8-9, 50kg of purified water was added dropwise, dropwise 2 hours, stirring was continued for 2 hours at the same temperature, as a large amount of white solid precipitated a thick paste; 80kg of deionized water was added, stirred sufficiently dispersing the paste solids, filtered off with suction, washed to neutrality with 80kg purified water immersion, drying centrifuge, drying, to give a crude product triclabendazole 42kg, close was 81.5% with a purity of 95%, recrystallized from ethanol to give the desired product triclabendazole 39kg, yield 92.8%, content 99.5%, of which 5-chloro-6- (2,3-dichloro phenoxy) _2_ mercapto – benzimidazole compound of the formula V in the reaction; triclabendazole a compound of formula VI in the reaction.

PATENTS

Publication numberPriority datePublication dateAssigneeTitle
US2529887A *1949-05-191950-11-14Du PontProcess for the preparation of anisole
US3538108A *1967-08-171970-11-03Merck & Co IncWater – soluble 2 – substituted benzimidazole methanesulfonic acid salts
US4197307A *1977-04-121980-04-08Ciba-Geigy Corporation2-Alkylthio-, 2-alkylsulphinyl- and 2-alkylsulfonyl-6-phenylbenzimidazoles as anthelmintic agents
Family To Family Citations
US4492708A *1982-09-271985-01-08Eli Lilly And CompanyAntiviral benzimidazoles
CN101555231B *2009-05-042011-03-23扬州天和药业有限公司Method for preparing triclabendazole

Non-Patent

Title
HERNANDEZ-LUIS ET AL.: ‘Synthesis and biological activity of 2-trifluoromethyl)-1 H-benzimidazole derivatives against some protozoa and Trichinella spiralis’ EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol. 45, 07 April 2010, pages 3135 – 3141, XP027050440 *
SORIA-ARTECHE ET AL.: ‘Studies on the Selective S-oxidation of Albendazole, Fenbendazole, Triclabendazole, and Other Benzimidazole Sulfides’ J.MED.CHEM.SOC. vol. 49, no. 4, 2005, pages 353 – 358, XP055116213 *
TOWNSEND ET AL.: ‘The Synthesis and Chemistry of Certain Anthelmintic Benzimidazoles’ PARASITOLOGY TODAY vol. 6, no. 4, 1990, pages 107 – 112, XP055116216 *
ZHOU ET AL.: ‘Separation and characterization of synthetic impurites of triclabendazole by reversed -phase high performance liquid chromatography/electrospray ionization mass spectrometry’ JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS vol. 37, 2005, pages 97 – 107, XP027718678 *
BRIAN IDDON等: “2H-Benzimidazoles (Isobenzimidazoles). Part 7.” A New Route to Triclabendazole [5-Chloro-6- (2,3-dichlorophenoxy)-2-methylthio-l Hbenzimidazole] and Congeneric Benzimidazoles”, 《J. CHEM. SOC. PERKIN TRANS. 1》 *

Publication numberPriority datePublication dateAssigneeTitle

CN103319416A *2013-06-242013-09-25常州佳灵药业有限公司Novel veterinary drug triclabendazole sulfoxide and preparation method thereof
CN103319417A *2013-06-242013-09-25常州佳灵药业有限公司Method for preparing triclabendazole sulfoxide
CN103360323A *2013-06-242013-10-23常州佳灵药业有限公司Preparation method of triclabendazole
CN104230815A *2013-06-072014-12-24连云港市亚晖医药化工有限公司Preparation method of triclabendazole
Family To Family Citations
CN105218375A *2015-10-312016-01-06丁玉琴Synthesis method of 2-methyl-4-nitrobenzoic acid

References

  1. Jump up to:a b c d e f WHO Model Formulary 2008 (PDF). World Health Organization. 2009. pp. 94, 96. ISBN 9789241547659Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  2. Jump up to:a b c Wolfe, M. Michael; Lowe, Robert C. (2014). “Benzimidazoles”. Pocket Guide to GastrointestinaI Drugs. John Wiley & Sons. p. PT173. ISBN 9781118481554Archived from the original on 2016-12-20.
  3. ^ “Egaten (triclabendazole)” (PDF)FDA. Retrieved 18 February 2019.
  4. ^ “WHO Model List of Essential Medicines (19th List)” (PDF)World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  5. ^ “Triclabendazole – Drugs.com”http://www.drugs.comArchived from the original on 20 December 2016. Retrieved 10 December 2016.

Further reading

Triclabendazole
Triclabendazole.svg
Clinical data
Trade names Fasinex, Egaten, others
AHFS/Drugs.com International Drug Names
Routes of
administration
by mouth
ATC code
Pharmacokinetic data
Metabolism Oxidation to sulfone and sulfoxide metabolites
Elimination half-life 22–24 hs
Excretion Feces (>95%), urine (2%), milk (<1%)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.127.414 Edit this at Wikidata
Chemical and physical data
Formula C14H9Cl3N2OS
Molar mass 359.658 g·mol−1
3D model (JSmol)

////////////Triclabendazole, トリクラベンダゾール  , Egat, CGA-89317 , CGA 89317 ,Anthelmintic, fda 2019

Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis


Abstract Image

A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladium-catalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity.

Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis

 API R&D Laboratory, CMC R&D DivisionShionogi and Co., Ltd.1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan
 Production Technology Department, Manufacturing DivisionShionogi and Co., Ltd.1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan
§ Shionogi Pharmaceutical Research CenterShionogi and Co., Ltd.1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00409
Publication Date (Web): March 1, 2019
Copyright © 2019 American Chemical Society
This article is part of the Japanese Society for Process Chemistry special issue.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00409

///////Dolutegravir

Cenobamate


img

Cenobamate
CAS: 913088-80-9
Chemical Formula: C10H10ClN5O2
Molecular Weight: 267.67

Related CAS #: 913088-80-9   913087-59-9

Synonym: YKP-3089; YKP3089; YKP3089; Cenobamate

IUPAC/Chemical Name: (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate

  • 2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, carbamate (ester), (αR)- (9CI)
  • (1R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate
  • Carbamic acid (R)-(+)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl ester
  • 2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, 2-carbamate, (αR)-

Cenobamate, also known as YKP-3089, is a novel new antiepileptic drug candidate. Cenobamate showed broad-spectrum anticonvulsant activity. Cenobamate entered into clinical trials and was discontinued in 2015.

PATENT

WO 2006112685

SK HOLDINGS CO., LTD. [KR/KR]; 99 Seorin-dong Jongro-ku Seoul 110-110, KR

CHOI, Yong-Moon; US
KIM, Choon-Gil; KR
KANG, Young-Sun; KR
YI, Han-Ju; KR
LEE, Hyun-Seok; KR
KU, Bon-Chul; KR
LEE, Eun-Ho; KR
IM, Dae-Joong; KR
SHIN, Yu-Jin; KR

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006112685

Patent

US 20100323410

PATENT

WO 2011046380

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=9CF54FB903EC3DFB7B3237259E6419EB.wapp2?docId=WO2011046380&recNum=36&office=&queryString=&prevFilter=%26fq%3DOF%3AIL%26fq%3DICF_M%3A%22C07D%22&sortOption=Relevance&maxRec=1345

As disclosed in U. S. Patent Application Publication No. 2006/0258718 A1, carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl esters (hereinafter referred to as “the carbamate compounds”) with anticonvulsant activity are useful in the treatment of disorders of the central nervous system, especially including anxiety, depression, convulsion, epilepsy, migraines, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorders, neuropathic pain, strokes, cognitive impairment, neurodegeneration, strokes and muscle spasms.
Depending on the position of N in the tetrazole moiety thereof, the carbamate compounds are divided into two positional isomers: tetrazole-1-yl (hereinafter referred to as “1N tetrazole”) and treatzole-2-yl (hereinafter referred to as “2N tetrazole”). The introduction of tetrazole for the preparation of the carbamate compounds results in a 1:1 mixture of the two positional isomers which are required to be individually isolated for pharmaceutical use.
Having chirality, the carbamate compounds must be in high optical purity as well as chemical purity as they are used as medications.
In this regard, U. S. Patent Application Publication No. 2006/0258718 A1 uses the pure enantiomer (R)-aryl-oxirane as a starting material which is converted into an alcohol intermediate through a ring-opening reaction by tetrazole in the presence of a suitable base in a solvent, followed by introducing a carbamoyl group into the alcohol intermediate. For isolation and purification of the 1N and 2N positional isomers thus produced, column chromatography is set after the formation of an alcohol intermediate or carbamate.
For use in the preparation, (R)-2-aryl-oxirane may be synthesized from an optically active material, such as substituted (R)-mandelic acid derivative, via various routes or obtained by asymmetric reduction-ring formation reaction of α-halo arylketone or by separation of racemic 2-aryl-oxirane mixture into its individual enantiomers. As such, (R)-2-aryl-oxirane is an expensive compound.
In addition, the ring-opening reaction of (R)-2-aryl-oxirane with tetrazole is performed at relatively high temperatures because of the low nucleophilicity of the tetrazole. However, the ring opening reaction includes highly likely risk of a runaway reaction because tetrazoles start to spontaneously degrade at 110 ~ 120℃.
In terms of a selection of reaction, as there are two reaction sites in each (R)-2-aryl-oxirane and tetrazole, the ring-opening reaction therebetween affords the substitution of 1N- or 2N-tetrazole at the benzyl or terminal position, resulting in a mixture of a total of 4 positional isomers. Therefore, individual positional isomers are low in production yield and difficult to isolate and purify.
Preparation Example 1: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one
To a suspension of 2-bromo-2′-chloroacetophenone (228.3 g, 0.978 mol) and potassium carbonate (161.6 g, 1.170 mol) in acetonitrile (2000 mL) was added a 35 w/w% 1H-tetrazole dimethylformamide solution (215.1 g, 1.080 mol) at room temperature. These reactants were stirred for 2 h at 45℃ and distilled under reduced pressure to remove about 1500 mL of the solvent. The concentrate was diluted in ethyl acetate (2000 mL) and washed with 10% brine (3 x 2000 mL). The organic layer thus separated was distilled under reduced pressure to afford 216.4 g of an oily solid residue. To a solution of the solid residue in ethyl acetate (432 mL) was slowly added heptane (600 mL). The precipitate thus formed was filtered at room temperature and washed to yield 90.1 g (0.405 mol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (hereinafter referred to as 1N ketone ).
1H-NMR(CDCl 3) 8.87(s, 1H), d7.77(d, 1H), d7.39-7.62(m, 3H), d5.98(s, 2H)
Preparation Example 2: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one
After the filtration of Preparation Example 1, the filtrate was concentrated and dissolved in isopropanol (100 mL), and to which heptane (400 mL) was then added to complete the crystallization. Filtering and washing at 5℃ afforded 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (hereinafter referred to as “2N ketone”) as a solid. 94.7 g (0.425 mol).
1H-NMR(CDCl 3) d8.62(s, 1H), d7.72(d, 1H), d7.35-7.55(m, 3H), d6.17(s, 2H)
PREPARATION EXAMPLE 3: Preparation of Alcohol Compound of (R)-Configuration by enantioselective enzymatic reduction via various oxidoreductases
The following four solutions were prepared as follows:
Enzyme Solution 1
Competent Escherichia coli StarBL21(De3) cells (Invitrogen) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25 ℃ and 220 rpm, the cells were harvested and frozen at -20 ℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.
Enzyme Solution 2
RB791 cells ( E.coli genetic stock, Yale, USA) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25℃ and 220 rpm, the cells were harvested and frozen at -20℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.
Enzyme Solution 3
Enzyme solutions 3 was prepared in the same manner as described in Enzyme solution 1 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 3 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1 was used.
Enzyme Solution 4
Enzyme solutions 4 was prepared in the same manner as described for enzyme solution 2 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 4 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2 was used.
Different oxidoreductases contained in each enzyme solutions 1 to 4 were examined as follows for the conversion of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (1N ketone) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (2N ketone) to the corresponding 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (hereinafter, referred to as 1N alcohol ) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (hereinafter, referred to as “2N alcohol”), respectively.
Reaction batch A
160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)
100 ㎕ NADPH (40 mg/ml)
40 ㎕ 2-propanol
50 ㎕ enzyme solution 1
2 mg 1N ketone or 2N ketone
Reaction batch B
160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)
100 ㎕ NADPH (40 mg/ml)
40 ㎕ 2-propanol
50 ㎕ enzyme solution 2
2 mg 1N ketone or 2N ketone
Reaction batch C
350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)
0,05 mg NADP
50 ㎕ enzyme solution 3
10 mg 1N ketone or 2N ketone
250 ㎕ 4-methyl-2-pentanol
50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor
Reaction batch D
350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8
0,05 mg NADP
50 ㎕ enzyme solution 4
10 mg 1N ketone or 2N ketone
250 ㎕ 4-methyl-2-pentanol
50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor
After 24h of incubating each reaction batch A, B, C and D, 1 mL of acetonitrile was added to each reaction batch which was centrifuged and transferred into a HPLC analysis vessel for enantiomeric excess and conversion. Conversion and ee-value of products are listed in Table 1 below calculated using the following equations:
Conversion Rate (%) = [(Area of Product)/(Area of Reactant + Area of Product)]x100
ee-value(%) = [(Area of R-Configuration – Area of S-Configuration)/(Area of R-Configuration + Area of S-Configuration)] x 100
Table 1 [Table 1] 
PREPARATION EXAMPLE 4: Enzymatic reduction via oxidoreductase SEQ NO: 2
For the conversion of 1N/2N ketone to R-1N/R-2N alcohol, 30㎕ of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 300㎕ of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 100mg of a mixture of 1N ketone and 2N ketone (1N:2N=14%:86%), 0.04mg NADP and 300㎕ 2-butanol. The reaction mixture was incubated at room temperature under constant thorough mixing. After 48 hours, more than 98% of the ketones were reduced to an alcohol mixture of the following composition(R-2N alcohol 80%; S-2N alcohol 0%; R-1N alcohol 20%, S-1N alcohol 0%; 1N ketone 0%; 2N ketone 0%).
After general work up and recrystallization with ethyl acetate/hexane, optically pure alcohols were obtained as below:
(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (1N alcohol
1H-NMR(CDCl 3) d8.74(s, 1H), d7.21-7.63(m, 4H), d5.57(m, 1H), d4.90(d, 1H), d4.50(d, 1H), d3.18(d, 1H);
(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (2N alcohol)
1H-NMR(CDCl 3) d8.55(s, 1H), d7.28-7.66(m, 4H), d5.73(d, 1H), d4.98(d, 1H), d4.83(d, 1H), d3.38(br, 1H).
Preparation of Carbamate
Preparation Example 5: Preparation of Carbamic Acid (R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl)ethyl ester
50ml of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 250ml of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 50g (225mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one(2N ketone), 4mg NAD, 300 ml of 2-propanol and 150mL of butyl acetate. The reaction mixture was stirred at room temperature. After 48 hours more than 98% of 2N ketone was reduced to corresponding (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol) with >99%ee values. To this resulting mixture, 500mL of ethyl acetate was added. After being separated, the organic layer thus formed was washed with 10% brine (3 x 500mL). The organic layer thus formed was dried over magnesium sulfate and filtered and the filtrate was distilled under reduced pressure to give 50.4g (224 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol, optical purity 99.9%) as an oily residue. To this resulting crude product, 450mL of tetrahydrofuran was added. After cooling to -15℃, 38g (267mmol) of chlorosulfonyl isocyanate was slowly added and stirred at -10℃ for 2 h. The slow addition of water induced termination of the reaction. The resulting solution was concentrated under reduced pressure until about 300 mL of the solvent was removed. The concentrate was diluted with 600mL of ethyl acetate and washed with 10% brine (3 x 500 mL). The organic layer was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (90 mL) to which heptane (180 mL) was slowly added, leading to the completion of crystallization. The precipitate thus obtained was filtered and washed to afford 51.8 g (194 mmol) of carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester (optical purity 99.9%).
1H-NMR(Acetone-d 6) d8.74(s, 1H), d7.38-7.54(m, 4H), d6.59(m, 1H), d6.16(Br, 2H), d4.90(d, 1H), d5.09(m, 2H)
As described hitherto, carbamate compounds with high optical and chemical purity can be produced with an economical benefit in accordance with the present invention.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
AMINO ACID SEQUENCES
SEQ ID NO 1: Oryctolagus cuniculus from rabbit DSMZ 22167
SEQ ID NO 2: Candida magnoliae DSMZ 22052 protein sequence carbonyl reductase
SEQ ID NO 3: Candida vaccinii CBS7318 protein sequence carbonyl reductase
SEQ ID NO 4: Candida magnoliae CBS6396 protein sequence carbonyl reductase
NUCLEIC ACID SEQUENCES
SEQ ID NO 5: Oryctolagus cuniculus from rabbit DSMZ 22167
SEQ ID NO 6: Candida magnoliae DSMZ 22052 nucleic acid sequence carbonyl reductase
SEQ ID NO 7: Candida vaccinii CBS7318 nucleic acid sequence carbonyl reductase
SEQ ID NO 8: Candida magnoliae CBS6396 nucleic acid sequence carbonyl reductase

Clip

Our team enjoyed celebrating the news of FDA acceptance of our new drug application (NDA) for investigational antiepileptic drug, cenobamate. A special thank you to everyone on our team who worked tirelessly to make this milestone possible!
SK life science announces FDA acceptance of NDA submission for cenobamate, an investigational antiepileptic drug PDUFA date set for November 21, 2019 Fair Lawn, New Jersey, February 4, 2019 – SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals Co., Ltd., an innovative biopharmaceutical company focused on developing and bringing to market treatments for central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has accepted the filing of its New Drug Application (NDA) for cenobamate. Cenobamate, an investigational antiepileptic drug for the potential treatment of partial-onset seizures in adult patients, is the first molecule discovered and developed from inception through to the submission of an NDA without partnering or out-licensing from a Korean pharmaceutical company.
SK life science plans to commercialize cenobamate independently. The NDA submission is based on data from pivotal trials that evaluated the efficacy and safety of cenobamate. Results from the clinical trial program, which enrolled more than 1,900 patients, have been presented at medical conferences including the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) Annual Meetings. “The FDA’s acceptance of our NDA filing is a critical step toward our goal of introducing a new treatment option for people with uncontrolled epilepsy,” said Marc Kamin, M.D., chief medical officer at SK life science. “We look forward to working with the FDA during their review of our data on cenobamate.” Despite the availability and introduction of many new AEDs, overall treatment outcomes for people with epilepsy have not improved in 20 years
1 and the CDC states that nearly 60 percent of people with epilepsy are still experiencing seizures, showcasing a great unmet need for patients and their families. 2 Additionally, while some patients may experience a reduction in seizure frequency with current treatments, they continue to live with seizures.
2 The impact of continued seizures can be debilitating and life-altering and the complications of epilepsy can include depression and anxiety, cognitive impairment and SUDEP (sudden unexpected death in epilepsy).
3 About Epilepsy Epilepsy is a common neurological disorder characterized by seizures.
4 There are approximately 3.4 million people in the U.S. living with epilepsy, and approximately 65 million worldwide.
5 The majority of people with epilepsy (60%) have partial-onset seizures, which are located in just one part of the brain.
6 People with epilepsy are also at risk for accidents and other health complications including falling, drowning, car accidents, depression and anxiety and SUDEP. 3
About Cenobamate Cenobamate (YKP3089) was discovered by SK Biopharmaceuticaals and SK life science and is being investigated for the potential treatment of partial-onset seizures in adult patients. Cenobamate’s mechanism of action is not fully understood, but it is believed to work through two separate mechanisms: enhancing inhibitory currents through positive modulation of GABA-A receptors and decreasing excitatory currents by inhibiting the persistent sodium current. Global trials for adults with partial-onset seizures are ongoing to evaluate cenobamate safety.
Additional clinical trials are investigating cenobamate safety and efficacy in other seizure types. The U.S. Food and Drug Administration (FDA) accepted the filing of the New Drug Application for cenobamate for the potential treatment of partial-onset seizures in adults in February 2019. Cenobamate is not approved by the FDA or any other regulatory authorities. Safety and efficacy have not been established. About SK life science SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals, Co., Ltd., is focused on developing and commercializing treatments for disorders of the central nervous system (CNS).
Both are a part of the global conglomerate SK Group, the second largest company in Korea. SK life science is located in Fair Lawn, New Jersey. We have a pipeline of eight compounds in development for the treatment of CNS disorders including epilepsy, sleep disorder and attention deficit hyperactivity disorder, among others. The first product the company is planning to commercialize independently is cenobamate (YKP3089), an investigational compound for the potential treatment of partial-onset seizures in adult patients, currently in a Phase 3 global clinical trial.
For more information, visit SK life science’s website at http://www.SKLifeScienceInc.com.
For more information, visit SK Biopharmaceuticals’ website at http://www.skbp.com/eng. —-
1. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. https://www.ncbi.nlm.nih.gov/pubmed/29279892 Published online December 26, 2017.
2. Center for Disease Control and Prevention. Active Epilepsy and Seizure Control in Adults — United States, 2013 and 2015. https://www.cdc.gov/mmwr/volumes/67/wr/mm6715a1.htm?s_cid=mm6715a1 Accessed December 27, 2018.
3. Epilepsy Foundation. Staying Safe. https://www.epilepsy.com/learn/seizure-first-aid-and-safety/staying-safe Accessed November 20, 2018.
4. Epilepsy Foundation. What Is Epilepsy? https://www.epilepsy.com/learn/about-epilepsy-basics/what-epilepsy Accessed November 20, 2018.
5. Epilepsy Foundation. Facts about Seizures and Epilepsy. https://www.epilepsy.com/learn/about-epilepsybasics/facts-about-seizures-and-epilepsy Accessed November 20, 2018.
6. National Institute of Neurological Disorders and Stroke. The Epilepsies and Seizures: Hope through Research. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Epilepsies-andSeizures-Hope-Through#3109_9 Accessed November 20, 2018.

REFERENCES

1: Mula M. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2013
Mar;18(1):87-95. doi: 10.1517/14728214.2013.750294. Epub 2012 Nov 26. Review.
PubMed PMID: 23176519.

2: Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress
report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT
IX). Epilepsy Res. 2009 Jan;83(1):1-43. doi: 10.1016/j.eplepsyres.2008.09.005.
Epub 2008 Nov 12. PubMed PMID: 19008076.

/////////////YKP-3089, YKP3089, YKP3089, Cenobamate

NC(O[C@H](C1=CC=CC=C1Cl)CN2N=CN=N2)=O

Rovafovir Etalafenamide


2D chemical structure of 912809-27-9

Rovafovir etalafenamide

GS-9131

UNII-U8S0IC8DY7

 ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate

L-Alanine, N-((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydro-2-furanyl)oxy)methyl)phenoxyphosphinyl)-, ethyl ester
CAS: 912809-27-9
Chemical Formula: C21H24FN6O6P
Molecular Weight: 506.43

  • Originator Gilead Sciences
  • Class Antiretrovirals; Purine nucleosides; Small molecules
  • Mechanism of Action Nucleoside reverse transcriptase inhibitors
  • Phase II HIV-1 infections
  • 03 Apr 2018 Phase-II clinical trials in HIV-1 infections (Treatment-experienced) in Uganda (PO) (NCT03472326)
  • 21 Mar 2018 Gilead Sciences plans a phase II study for HIV-1 infections in March 2018 (NCT03472326)
  • 26 Mar 2009 Preclinical pharmacokinetics data in HIV-1 infections presented at the 237th American Chemical Society National Meeting (237th-ACS-2009)

Rovafovir Etalafenamide, also known as GS-9131, is an anti-HIV Nucleoside Phosphonate prodrug.

POSTER

http://www.croiconference.org/sites/default/files/posters-2017/436_White.pdf

Patent

WO 2006110157

WO 2008103949

WO 2010005986

PATENT

WO 2012159047

 

PATENT

WO-2019027920

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019027920&tab=PCTDESCRIPTION&maxRec=1000

As discussed in U.S. Pat. Nos. 7,871,991, 9,381,206, 8,951,986, and 8,658,617, ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate is a reverse transcriptase inhibitor that blocks the replication of HIV viruses, in vivo and in vitro, and has limited undesirable side effects when administered to human beings. This compound has a favorable in vitro resistance profile with activity against Nucleoside RT Inhibitor (NRTI)-Resistance Mutations, such as Ml 84V, K65R, L74V, and one or more (e.g., 1, 2, 3, or 4) TAMs (thymidine analogue mutations). It has the following formula (see, e.g., U.S. Pat. No. 7,871,991), which is referred to as Formula I:

[0004] Ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate is difficult to isolate, purify, store for an extended period, and formulate as a pharmaceutical composition.

[0005] The compound of formula la was previously identified as the most chemically stable form of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-

yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate. See, e.g. , U.S. Pat. Nos. 8,658,617,

8,951,986, and 9,381,206. However, a total degradation increase of 2.6% was observed when the compound of formula (la) was stored at 25 °C/60% RH over 6 months. Therefore, the compound of formula la requires refrigeration for long-term storage.

[0006] Accordingly, there is a need for stable forms of the compound of Formula I with suitable chemical and physical stability for the formulation, therapeutic use, manufacturing, and storage of the compound. New forms, moreover, can provide better stability for the active pharmaceutical substance in a pharmaceutical formulation.

PAPER

Bioorganic & Medicinal Chemistry (2010), 18(10), 3606-3617.

https://www.sciencedirect.com/science/article/pii/S0968089610002452?via%3Dihub

Image result for Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

Image result for Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

PAPER

 RSC Drug Discovery Series (2011), 4(Accounts in Drug Discovery), 215-237.

PAPER

https://aac.asm.org/content/52/2/648

Image result for GS-9131

REFERENCES

1: Rai MA, Pannek S, Fichtenbaum CJ. Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opin Emerg Drugs. 2018 May 10:1-9. doi: 10.1080/14728214.2018.1474202. [Epub ahead of print] PubMed PMID: 29737220.

2: Mackman RL. Anti-HIV Nucleoside Phosphonate GS-9148 and Its Prodrug GS-9131: Scale Up of a 2′-F Modified Cyclic Nucleoside Phosphonate and Synthesis of Selected Amidate Prodrugs. Curr Protoc Nucleic Acid Chem. 2014 Mar 26;56:14.10.1-21. doi: 10.1002/0471142700.nc1410s56. Review. PubMed PMID: 25606977.

3: De Clercq E. The clinical potential of the acyclic (and cyclic) nucleoside phosphonates: the magic of the phosphonate bond. Biochem Pharmacol. 2011 Jul 15;82(2):99-109. doi: 10.1016/j.bcp.2011.03.027. Epub 2011 Apr 8. Review. PubMed PMID: 21501598.

4: Mackman RL, Ray AS, Hui HC, Zhang L, Birkus G, Boojamra CG, Desai MC, Douglas JL, Gao Y, Grant D, Laflamme G, Lin KY, Markevitch DY, Mishra R, McDermott M, Pakdaman R, Petrakovsky OV, Vela JE, Cihlar T. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg Med Chem. 2010 May 15;18(10):3606-17. doi: 10.1016/j.bmc.2010.03.041. Epub 2010 Mar 27. PubMed PMID: 20409721.

5: Cihlar T, Laflamme G, Fisher R, Carey AC, Vela JE, Mackman R, Ray AS. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother. 2009 Jan;53(1):150-6. doi: 10.1128/AAC.01183-08. Epub 2008 Nov 10. PubMed PMID: 19001108; PubMed Central PMCID: PMC2612154.

6: Cihlar T, Ray AS, Boojamra CG, Zhang L, Hui H, Laflamme G, Vela JE, Grant D, Chen J, Myrick F, White KL, Gao Y, Lin KY, Douglas JL, Parkin NT, Carey A, Pakdaman R, Mackman RL. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob Agents Chemother. 2008 Feb;52(2):655-65. Epub 2007 Dec 3. PubMed PMID: 18056282; PubMed Central PMCID: PMC2224772.

7: Ray AS, Vela JE, Boojamra CG, Zhang L, Hui H, Callebaut C, Stray K, Lin KY, Gao Y, Mackman RL, Cihlar T. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent. Antimicrob Agents Chemother. 2008 Feb;52(2):648-54. Epub 2007 Dec 3. PubMed PMID: 18056281; PubMed Central PMCID: PMC2224749.

8: Birkus G, Wang R, Liu X, Kutty N, MacArthur H, Cihlar T, Gibbs C, Swaminathan S, Lee W, McDermott M. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother. 2007 Feb;51(2):543-50. Epub 2006 Dec 4. PubMed PMID: 17145787; PubMed Central PMCID: PMC1797775.

//////////////Rovafovir etalafenamide, GS-9131, PHASE 2

C[C@@H](C(OCC)=O)N[P@@](OC1=CC=CC=C1)(CO[C@H]2O[C@@H](N3C=NC4=C(N)N=CN=C34)C(F)=C2)=O

OLACAFTOR, VX 440


Image result for VX 440

NHOUNZMCSIHKHJ-FQEVSTJZSA-N.png

OLACAFTOR, VX 440

CAS 1897384-89-2

Molecular Formula: C29H34FN3O4S
Molecular Weight: 539.666 g/mol

CFTR corrector; UNII-RZ7027HK8F; RZ7027HK8F;

Target-based Actions, CFTR modulator

Indications, Cystic fibrosis

CS-0044588

UNII-RZ7027HK8F

RZ7027HK8F

Olacaftor (VX-440, VX440) is a next-generation CFTR corrector, shows the potential to enhance the amount of CFTR protein at the cell’s surface and for treatment of cystic fibrosis..

  • Originator Vertex Pharmaceuticals
  • Class Pyridines; Pyrrolidines
  • Mechanism of Action Cystic fibrosis transmembrane conductance regulator stimulants
  • Phase II Cystic fibrosis
  • 01 Jun 2018 Chemical structure information added
  • 01 Aug 2017 Vertex Pharmaceuticals completes a phase II trial in Cystic fibrosis (In adolescents, In adults, In the elderly, Combination therapy) in USA, Australia, Austria, Belgium, Canada, Denmark, Germany, Italy, Spain, Netherlands and United Kingdom (PO) (NCT02951182) (EudraCT2016-000454-36)
  • 18 Jul 2017 Efficacy and events data from a phase II trial in Cystic fibrosis released by Vertex Pharmaceuticals

PATENT

WO2016057572

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B67642F2D5C265D1AF3AC60194173694.wapp1nB?docId=WO2016057572&recNum=6&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A01N%22&sortOption=Pub+Date+Desc&maxRec=22922

PATENT

US9782408

PATENT

WO-2019028228

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019028228&tab=PCTDESCRIPTION&maxRec=1000

Processes for preparing (S)-2,2,4-trimethylpyrrolidine and its salts, particularly hydrochloride comprising the reaction of 2,2,6,6-tetramethyl-piperidin-4-one with chloroform and a base (sodium hydroxide), followed by reaction with an acid (hydrochloric acid), hydrogenation, reduction and salt synthesis is claimed. Also claimed is a process for the preparation of an intermediate of (S)-2,2,4-trimethylpyrrolidine hydrochloride. The compound is useful as an intermediate for the synthesis of CFTR modulators, useful for treating cystic fibrosis.
(5)-2,2,4-trimethylpyrrolidine free base and salt forms thereof, (R)-2,2,4-trimethylpyrrolidine free base and salt forms thereof, (,S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, and 5,5-dimethyl-3-methylenepyrrolidin-2-one are useful molecules that can be used in the synthesis of pharmaceutically active molecules, such as modulators of CFTR activity, for example those disclosed in PCT Publication Nos. WO 2016/057572, WO 2018/064632, and WO 2018/107100, including the following molecules, which are being investigated in clinical trials for the treatment of cystic fibrosis:

[0003] There remains, however, a need for more efficient, convenient, and/or economical processes for the preparation of these molecules.

[0004] Disclosed herein are processes for preparing 5,5-dimethyl-3-methylenepyrrolidin-2-one, (,S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, (,S)-2,2,4-trimethylpyrrolidine, and (R)-2,2,4-trimethylpyrrolidine, and their salt forms:


trimethylpyrrolidine-2-one)); ((R)-3,5,5-trimethylpyrrolidine-2-one));

((,S)-2,2,4-trimethylpyrrolidine) ;and 

Scheme 1. Synthesis of (S)-2,2,4-trimethylpyrrolidine

(2) (3) (4S) (1 S)

Scheme 2. Synthesis of (R)-2,2,4-trimethylpyrrolidine

(2) (3) (4R) (1 R)

Scheme 3. Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

3 C

EXAMPLES

Example 1. Reaction (a) and (b): Synthesis of 5,5-dimethyl-3-methylenepyrrolidin- 2-one

(2) (3) C (3)

Example 1A:

[0055] 2,2,6,6-tetramethylpiperidin-4-one (50.00 g, 305.983 mmol, 1.000 equiv), tributylmethylammonium chloride (2.89 g, 3.0 mL, 9.179 mmol, 0.030 equiv), chloroform (63.92 g, 43.2 mL, 535.470 mmol, 1.750 equiv), and DCM (dichloromethane) (100.0 mL, 2.00 vol) were charged to a 1000 mL three-neck round bottom flask equipped with an overhead stirrer. The reaction mixture was stirred at 300 rpm, and 50 wt% NaOH (195.81 g, 133.2 mL, 2,447.863 mmol, 8.000 equiv) was added dropwise (via addition funnel) over 1.5 h while maintaining the temperature below 25 °C with intermittent ice/acetone bath. The reaction mixture was stirred at 500 rpm for 18 h, and monitored by GC (3% unreacted piperidinone after 18 h). The suspension was diluted with DCM (100.0 mL, 2.00 vol) and H2O (300.0 mL, 6.00 vol), and the phases were separated. The aqueous phase was extracted with DCM (100.0 mL, 2.00 vol). The organic phases were combined and 3 M hydrochloric acid (16.73 g, 153.0 mL, 458.974 mmol, 1.500 equiv) was added. The mixture was stirred at 500 rpm for 2 h. The conversion was complete after approximately 1 h. The aqueous phase was saturated with NaCl, H2O (100.0 mL, 2.00 vol) was added to help reduce the emulsion, and the phases were separated. The aqueous phase was extracted with DCM (100.0 mL, 2.00 vol) twice. H2O (100.0 mL, 2.00 vol) was added to help with emulsion separation. The organic phases were combined, dried (MgS04), and

concentrated to afford 32.6 g (85%) of crude Compound (3) as a pale orange clumpy solid. The crude was recrystallized from hot (90°C) iPrOAc (isopropyl acetate) (71.7 mL, 2.2 vol. of crude), cooled to 80 °C, and -50 mg of crystalline Compound (3) was added for seeding. Crystallization started at 77 °C, the mixture was slowly cooled to ambient temperature, and aged for 2 h. The solid was collected by filtration, washed with 50/50 iPrOAc/heptane (20.0 mL, 0.40 vol) twice, and dried overnight in the vacuum oven at 40 °C to afford the desired product (23.70 g, 189.345 mmol, 62% yield) as a white sand colored crystalline solid. ¾ MR (400 MHz, CDCh, 7.26 ppm) δ 7.33 (bs, 1H), 5.96-5.95 (m, 1H), 5.31-5.30 (m, 1H), 2.6 (t, J= 2.5 Hz, 2H), 1.29 (s, 6H).

Synthesis IB:

[0056] i. Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidin-4-one (257.4 kg, 1658.0 mol, 1.00 eq.), tri-butyl methyl ammonium chloride (14.86 kg, 63.0 mol, 0.038 eq.), chloroform (346.5 kg, 2901.5 mol, 1.75 eq.) and DCM (683.3 kg) were added to a 500 L enamel reactor. The reaction was stirred at 85 rpm and cooled to 15~17°C. The solution of 50wt% sodium hydroxide (1061.4 kg, 13264.0 mol, 8.00 eq.) was added dropwise over 40 h while maintaining the temperature between 15~25°C. The reaction mixture was stirred and monitored by GC.

ii. The suspension was diluted with DCM (683.3 kg) and water (1544.4 kg). The organic phase was separated. The aqueous phase was extracted with DCM (683.3 kg). The organic phases were combined, cooled to 10°C and then 3 M hydrochloric acid (867.8 kg, 2559.0 mol, 1.5 eq.) was added. The mixture was stirred at 10-15 °C for 2 h. The organic phase was separated. The aqueous phase was extracted with DCM (683.3 kg x 2). The organic phases were combined, dried over Na2S04 (145.0 kg) for 6 h. The solid was filtered off and washed with DCM (120.0 kg). The filtrate was stirred with active charcoal (55 kg) for 6 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure (30~40°C, -O. lMPa). Then isopropyl acetate (338 kg) was added and the mixture was heated to 87-91°C, stirred for 1 h. Then the solution was cooled to 15 °C in 18 h and stirred for 1 h at 15 °C. The solid was collected by filtration, washed with 50% isopropyl acetate/hexane (80.0 kg x 2) and dried overnight in the vacuum oven at 50 °C to afford 5,5-dimethyl-3-methylenepyrrolidin-2-one as an off white solid, 55% yield.

Example 2. Reaction (c): Synthesis of (S)-3,5,5-trimethyl-pyrrolidin-2-one from 5,5-dimethyl-3-methylenepyrrolidin-2-one

(3) (4S)

Example 2A: Use of Rh Catalyst

[0057] Step 1 : Preparation of Rh Catalyst Formation: In a 3 L Schlenk flask, 1.0 L of tetrahydrofuran (THF) was degassed with an argon stream. Mandyphos Ligand SL-M004-1 (1.89 g) and [Rh(nbd)Cl]2 (98%, 0.35 g) (chloronorbornadiene rhodium(I) dimer) were added. The resulting orange catalyst solution was stirred for 30 min at room temperature to form a catalyst solution.

[0058] Step 2: A 50 L stainless steel autoclave was charged with 5,5-dimethyl-3-methylenepyrrolidin-2-one (6.0 kg, Compound (3)) and THF (29 L). The autoclave was

sealed and the resulting suspension was flushed with nitrogen (3 cycles at 10 bar), and then released of pressure. Next the catalyst solution from Step 1 was added. The autoclave was flushed with nitrogen without stirring (3 cycles at 5 bar) and hydrogen (3 cycles at 5 bar). The pressure was set to 5 bar and a 50 L reservoir was connected. After 1.5 h with stirring at 1000 rpm and no hydrogen uptake the reactor was flushed again with nitrogen (3 cycles at 10 bar) with stirring and additional catalyst solution was added. The autoclave was again flushed to hydrogen with the above described procedure (3 x 5 bar N2, 3 x 5 bar H2) and adjusted to 5 bar. After 2 h, the pressure was released, the autoclave was flushed with nitrogen (3 cycles at 5 bar) and the product solution was discharged into a 60 L inline barrel. The autoclave was charged again with THF (5 L) and stirred with 1200 rpm for 5 min. The wash solution was added to the reaction mixture.

[0059] Step 3 : The combined solutions were transferred into a 60 L reactor. The inline barrel was washed with 1 L THF which was also added into the reactor. 20 L THF were removed by evaporation at 170 mbar and 40°C. 15 L heptane were added. The distillation was continued and the removed solvent was continuously replaced by heptane until the THF content in the residue was 1% w/w (determined by NMR). The reaction mixture was heated to 89°C (turbid solution) and slowly cooled down again (ramp: 14°C/h). Several heating and cooling cycles around 55 to 65°C were made. The off-white suspension was transferred to a stirred pressure filter and filtered (ECTFE-pad, d = 414 mm, 60 my, Filtration time = 5 min). 10 L of the mother liquor was transferred back into the reactor to wash the crystals from the reactor walls and the obtained slurry was also added to the filter. The collected solid was washed with 2 x 2.5 1 heptane, discharged and let dry on the rotovap at 40°C and 4 mbar to obtain the product, (S)-3,5,5-trimethyl-pyrrolidin-2-one; 5.48 Kg (91%), 98.0% ee.

Synthesis 2B: Use of Ru Catalyst

[0060] The reaction was performed in a similar manner as described above in Example 2A except the use of a Ru catalyst instead of a Rh catalyst.

[0061] Compound (3) (300 g) was dissolved in THF (2640 g, 10 Vol) in a vessel. In a separate vessel, a solution of [RuCl(p-cymene){(R)-segphos}]Cl (0.439g, 0.0002 eq) in THF (660 g, 2.5 Vol) was prepared. The solutions were premixed in situ and passed

through a Plug-flow reactor (PFR). The flow rate for the Compound (3) solution was at 1.555 mL/min and the Ru catalyst solution was at 0.287 mL/min. Residence time in the PFR was 4 hours at 30 °C, with hydrogen pressure of 4.5 MPa. After completion of reaction, the TFIF solvent was distilled off to give a crude residue. Heptane (1026 g, 5 vol) was added and the resulting mixture was heated to 90 °C. The mixture was seeded with 0.001 eq. of Compound 4S seeds. The mixture was cooled to -15 °C at 20 °C/h. After cooling, heptane (410 g, 2 vol) was added and the solid product was recovered by filtration. The resulting product was dried in a vacuum oven at 35 °C to give (S)-3,5,5-trimethyl-pyrrolidin-2-one (281.77 g, 98.2 % ee, 92 % yield).

Example 2C: Analytical Measurements

[0062] Analytical chiral HPLC method for the determination of the conversion, chemoselectivity and enantiomeric excess of the products form Example 2A and 2B was made under the following conditions: Instrument: Agilent Chemstation 1100; Column: Phenomenex Lux 5u Cellulose— 2, 4.6 mm x 250 mm x 5 um, LHS6247; Solvent:

Heptane/iPrOH (90: 10); Flow: 1.0 ml/min; Detection: UV (210 nm); Temperature: 25°C; Sample concentration: 30 μΐ of reaction solution evaporated, dissolved in 1 mL;

heptane/iPrOH (80/20); Injection volume: 10.0 
Run time 20 min; Retention times: 5,5–dimethyl-3-methylenepyrrolidin-2-one: 13.8 min, (,S)-3,5,5-trimethyl-pynOlidin-2-one: 10.6 min, and (R)-3,5,5-trimethyl-pyrrolidin-2-one: 12.4 min.

Example 3: Alternate Synthesis of (S)-3,5,5-trimethyl-pyrrolidin-2-one from 5,5-dimethyl-3-methylenepyrrolidin-2-one

Ru(Me-allyl)2(C0D)2BF4

1 eq HBF4 Et20

5 bar H2 at 45°C

[0063] Mandyphos (0.00479 mmol, 0.12 eq) was weighed into a GC vial. In a separate vial, Ru(Me-allyl)2(COD) (16.87 mg, 0.0528 mmol) was weighed and dissolved in DCM (1328 \iL). In another vial HBF4 Et20 (6.6 μΐ,) and BF3 Et20 (2.0 μΐ,) were dissolved in DCM (240 μΐ.). To the GC vial containing the ligand was added, under a flow of argon, the Ru(Me-allyl)2(COD) solution (100 μΐ,; 0.00399 mmol, O. leq) and the HBF4 Et20 / BF3 -Et20 solution (20 μΐ^ 1 eq HBF4 Et20 and catalytic BF3 Et20). The resulting mixtures were stirred under a flow of argon for 30 minutes. 5,5-dimethyl-3-methylenepyrrolidin-2-one (5 mg, 0.0399 mmol) in EtOH (1 mL) was added. The vials were placed in the hydrogenation apparatus. The apparatus was flushed with H2 (3 χ) and charged with 5 bar H2. After standing for 45 minutes, the apparatus was placed in an oil bath at temperature of 45°C. The reaction mixtures were stirred overnight under H2. 200 μΙ_, of the reaction mixture was diluted with MeOH (800 μΐ.) and analyzed for conversion and ee. 1H MR (400 MHz, Chloroform-d) δ 6.39 (s, 1H), 2.62 (ddq, J = 9.9, 8.6, 7.1 Hz, 1H), 2.17 (ddd, J = 12.4, 8.6, 0.8 Hz, 1H), 1.56 (dd, J = 12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H).

IPC analytical method for Asymmetric Hydrogenation

(3) (4S) (4R)

Example 4. Synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride from (S)-3,5,5-trimethyl-pyrrolidin-2-one

(4S) (1S)HCI

Example 4A:

[0064] Anhydrous THF (100 ml) was charged to a dry 750 ml reactor and the jacket temperature was set to 50° C. Once the vessel contents were at 50° C, LiAlH4pellets (10 g, 263 mmol, 1.34 eq.) were added. The mixture was stirred for 10 minutes, then a solution of (4S) (25 g, 197 mmol) in anhydrous THF (100 ml) was added dropwise over 45 minutes, maintaining the temperature between 50-60° C. Once the addition was complete the jacket temperature was increased to 68° C and the reaction was stirred for 18.5 hrs. The reaction mixture was cooled to 30° C then saturated sodium sulfate solution (20.9 ml) was added dropwise over 30 minutes, keeping the temperature below 40° C. Vigorous evolution of hydrogen was observed and the reaction mixture thickened but remained mixable. The mixture thinned towards the end of the addition. The mixture was cooled to 20° C, diluted with iPrOAc (100 ml) and stirred for an additional 10 minutes. The suspension was then drained and collected through the lower outlet valve, washing through with additional iPrOAc (50 ml). The collected suspension was filtered through a Celite pad on a sintered glass funnel under suction and washed with iPrOAc (2×50 ml).

[0065] The filtrate was transferred back to the cleaned reactor and cooled to 0° C under nitrogen. 4M HCI in dioxane (49.1 ml, 197 mmol, leq.) was then added dropwise over 15 minutes, maintaining the temperature below 20°C. A white precipitate formed. The reactor was then reconfigured for distillation, the jacket temperature was increased to 100 °C, and distillation of solvent was carried out. Additional z-PrOAc (100 mL) was added during concentration, after >100 mL distillate had been collected. Distillation was continued until -250 mL total distillate was collected, then a Dean-Stark trap was attached and reflux continued for 1 hour. No water was observed to collect. The reaction mixture was cooled to 20 °C and filtered under suction under nitrogen. The filtered solid was washed with i-PrOAc (100 mL), dried under suction in nitrogen, then transferred to a glass dish and dried in a vacuum oven at 40 °C with a nitrogen bleed. Compound (1S)»HC1 was obtained as a white solid (24.2g, 82%).

Synthesis 4B:

[0066] To a glass lined 120 L reactor was charged LiAlH4 pellets (2.5 kg 66 mol, 1.2 equiv.) and dry THF (60 L) and warmed to 30 °C. To the resulting suspension was charged (¾)-3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over 2 hours while maintaining the reaction temperature at 30 to 40 °C. After complete addition, the reaction temperature was increased to 60 – 63 °C and maintained overnight. The reaction mixture was cooled to 22 °C and sampled to check for completion, then cautiously quenched with the addition of EtOAc (1.0 L, 10 moles, 0.16 eq) followed by a mixture of THF (3.4 L) and water (2.5 kg, 2.0 eq) then followed by a mixture of water (1.75 kg) with 50 % aqueous sodium hydroxide (750 g, 2 eq water with 1.4 eq sodium hydroxide relative to aluminum), followed by 7.5 L water (6 eq “Fieser” quench). After the addition was completed, the reaction mixture was cooled to room temperature, and the solid was removed by filtration and washed with THF (3 x 25 L). The filtrate and washings were combined and treated with 5.0 L (58 moles) of aqueous 37% HC1 (1.05 equiv.) while maintaining the temperature below 30°C. The resultant solution was concentrated by vacuum distillation to a slurry in two equal part lots on the 20 L Buchi evaporator.

Isopropanol (8 L) was charged and the solution reconcentrated to near dryness by vacuum distillation. Isopropanol (4 L) was added and the product slurried by warming to about 50 °C. Distillation from Isopropanol continued until water content by KF is < 0.1 %. Methyl tertbutyl ether (6 L) was added and the slurry cooled to 2-5 °C. The product was collected by filtration and rinsed with 12 L methyl tert-butyl ether and pulled dry with a strong nitrogen flow and further dried in a vacuum oven (55 °C/300 torr/N2 bleed) to afford (S)-2,2,4-trimethylpyrrolidine»HCl ((1S HC1) as a white, crystalline solid (6.21 kg, 75% yield). ¾ NMR (400 MHz, DMSO-^6) δ 9.34 (s, 2H), 3.33 (dd, J= 11.4, 8.4 Hz, 1H), 2.75 (dd, J= 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, 7= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, 7= 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, 7= 6.6 Hz, , 3H).

Synthesis 4C:

[0067] With efficient mechanical stirring, a suspension of LiAlH4 pellets (100 g 2.65 mol; 1.35 eq.) in THF (1 L; 4 vol. eq.) warmed at a temperature from 20 °C – 36 °C (heat of mixing). A solution of (¾)-3,5,5-trimethylpyrrolidin-2-one (250 g; 1.97 mol) in THF (1 L; 4 vol. eq.) was added to the suspension over 30 min. while allowing the reaction temperature to rise to -60 °C. The reaction temperature was increased to near reflux (-68 °C) and maintained for about 16 h. The reaction mixture was cooled to below 40 °C and cautiously quenched with drop-wise addition of a saturated aqueous solution of Na2S04 (209 mL) over 2 h. After the addition was completed, the reaction mixture was cooled to ambient temperature, diluted with /-PrOAc (1 L), and mixed thoroughly. The solid was removed by filtration (Celite pad) and washed with /-PrOAc (2 x 500 mL). With external cooling and N2 blanket, the filtrate and washings were combined and treated with drop-wise addition of anhydrous 4 M HC1 in dioxane (492 mL; 2.95 mol; 1 equiv.) while maintaining the temperature below 20 °C. After the addition was completed (20 min), the resultant suspension was concentrated by heating at reflux (74 – 85 °C) and removing the distillate. The suspension was backfilled with /-PrOAc (1 L) during concentration. After about 2.5 L of distillate was collected, a Dean-Stark trap was attached and any residual water was azeotropically removed. The suspension was cooled to below 30 °C when the solid was collected by filtration under a N2 blanket. The solid is dried under N2 suction and further dried in a vacuum oven (55 °C/300 torr/N2 bleed) to afford 261 g (89% yield) of (S 2,2,4-trimethylpyrrolidine»HCl ((1S HC1) as a white, crystalline solid. ¾ NMR (400 MHz, DMSO-^6) δ 9.34 (s, 2H), 3.33 (dd, J = 11 A, 8.4 Hz, 1H), 2.75 (dd, J= 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, J= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, J = 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J= 6.6 Hz, 3H). ¾ MR (400 MHz, CDCh) δ 9.55 (d, J= 44.9 Hz, 2H), 3.52 (ddt, J= 12.1, 8.7, 4.3 Hz, 1H), 2.94 (dq, J= 11.9, 5.9 Hz, 1H), 2.70 – 2.51 (m, 1H), 2.02 (dd, J= 13.0, 7.5 Hz, 1H), 1.62 (s, 3H), 1.58 – 1.47 (m, 4H), 1.15 (d, J= 6.7 Hz, 3H).

Synthesis 4D:

[0068] A 1L four-neck round bottom flask was degassed three times. A 2M solution of LiAlHun THF (100 mL) was charged via cannula transfer. (¾)-3,5,5-trimethylpyrrolidin-2-one (19.0 g) in THF (150 mL) was added dropwise via an addition funnel over 1.5 hours at 50-60 °C, washing in with THF (19 mL). Upon completion of the addition, the reaction was stirred at 60 °C for 8 hours and allowed to cool to room temperature overnight. GC analysis showed <1% starting material remained. Deionized water (7.6 mL) was added slowly to the reaction flask at 10-15 °C, followed by 15% potassium hydroxide (7.6 mL). Isopropyl acetate (76 mL) was added, the mixture was stirred for 15 minutes and filtered, washing through with isopropyl acetate (76 mL). The filtrate was charged to a clean and dry 500 mL four neck round bottom flask and cooled to 0-5 °C. 36% Hydrochloric acid (15.1 g, 1.0 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (190 mL), was carried out to leave a residual volume of -85 mL. Karl Fischer analysis = 0.11% w/w H2O. MTBE (methyl tertiary butyl ether) (19 mL) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (25 mL) and drying under vacuum at 40-45 °C to give crude (,S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (17.4 g, 78% yield). GC purity = 99.5%. Water content = 0.20% w/w. Chiral GC gave an ee of 99.0% (S). Ruthenium content = 0.004 ppm. Lithium content = 0.07 ppm. A portion of the dried crude ,S)-2,2,4-trimethylpyrrolidine hydrochloride (14.3g) was charged to a clean and dry 250 mL four-neck round bottom flask with isopropanol (14.3 mL) and the mixture held at 80-85 °C (reflux) for 1 hour to give a clear solution. The solution was allowed to cool to 50 °C (solids precipitated on cooling) then MTBE (43 mL) was added and the suspension held at 50-55 °C (reflux) for 3 hours. The solids were filtered off at 10 °C, washing with MTBE (14 mL) and dried under vacuum at 40 °C to give recrystallised (S)- 2.2.4- trimethylpyrrolidine hydrochloride ((1S)»HC1) as a white crystallised solid (13.5 g, 94% yield on recrystallisation, 73% yield). GC purity = 99.9%. Water content = 0.11% w/w. 99.6% ee (Chiral GC) (S). Ruthenium content = 0.001 ppm. Lithium content = 0.02 ppm.

Synthesis 4E:

[0069] A reactor was charged with lithium aluminum hydride (LAH) (1.20 equiv.) and 2-MeTHF (2-methyltetrahydrofuran) (4.0 vol), and heated to internal temperature of 60 °C while stirring to disperse the LAH. A solution of (¾)-3,5,5-trimethylpyrrolidin-2-one (1.0 equiv) in 2-MeTHF (6.0 vol) was prepared and stirred at 25 °C to fully dissolve the (S)- 3.5.5- trimethylpyrrolidin-2-one. The (¾)-3,5,5-trimethylpyrrolidin-2-one solution was added slowly to the reactor while keeping the off-gassing manageable, followed by rinsing the addition funnel with 2-MeTHF (1.0 vol) and adding it to the reactor. The reaction was stirred at an internal temperature of 60 ± 5 °C for no longer than 6 h. The internal temperature was set to 5 ± 5 °C and the agitation rate was increased. A solution of water (1.35 equiv.) in 2-MeTHF (4.0v) was prepared and added slowly to the reactor while the internal temperature was maintained at or below 25 °C. Additional water (1.35 equiv.) was charged slowly to the reactor while the internal temperature was maintained at or below 25 °C. Potassium hydroxide (0.16 equiv.) in water (0.40 vol) was added to the reactor over no less than 20 min while the temperature was maintained at or below 25 °C. The resulting solids were removed by filtration, and the reactor and cake were washed with 2-MeTHF (2 x 2.5 vol). The filtrate was transferred back to a jacketed vessel, agitated, and the temperature was adjusted to 15 ± 5 °C. Concentrated aqueous HC1 (35-37%, 1.05 equiv.) was added slowly to the filtrate while maintaining the temperature at or below 25 °C and was stirred no less than 30 min. Vacuum was applied and the solution was distilled down to a total of 4.0 volumes while maintaining the internal temperature at or below 55 °C, then 2-MeTHF (6.00 vol) was added to the vessel. The distillation was repeated until Karl Fischer analysis (KF) < 0.20% w/w H2O. Isopropanol was added (3.00 vol), and the temperature was adjusted to 70 °C (65 – 75 °C) to achieve a homogenous solution, and stirred for no less than 30 minutes at 70 °C. The solution was cooled to 50 °C (47 – 53 °C) over 1 hour and stirred for no less than 1 h, while the temperature was maintained at 50°C (47 – 53 °C). The resulting slurry was cooled to -10 °C (-15 to -5°C) linearly over no less than 12 h. The slurry was stirred at -10 °C for no less than 2 h. The solids were isolated via filtration or centrifugation and were washed with a solution of 2-MeTHF (2.25 vol) and IPA (isopropanol) (0.75 vol). The solids were dried under vacuum at 45 ± 5 °C for not less than 6 h to yield (,S)-2,2,4-trimethylpyrrolidine hydrochloride ((1S)»HC1).

Example 5: Phase Transfer Catalyst (PTC) Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0070] Various PTCs were tested as described below:

[0071] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq.), PTC (0.05 eq.), and chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added dropwise over 2 min. The reaction mixture was stirred until completion as assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic

phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion and assessed by

HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. The reaction results are summarized in the following table:

Example 6: Solvent Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0072] Various solvents and amounts were tested as described below:

[0073] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”)), tetrabutylammonium hydroxide (0.12 g, 0.153 mmol, 0.050 eq), chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.), and solvent (2v or 4v, as shown below) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion and assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. Reaction results are summarized in the following table:

Example 7: Base Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0074] In this experiment, various concentrations of NaOH were tested as described below:

[0075] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”), tetrabutylammonium hydroxide (0.12 g, 0.153 mmol, 0.050 eq), and chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath, and a solution of an amount wt% sodium hydroxide as shown in the Table below in water (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion and assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase is extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL,

2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC.

Reaction results are summarized in the following table:

Example 8: Phase Transfer Catalyst (PTC) Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0076] Various amounts of PTCs were tested as described below:

Tetrabutylammonium hydroxide (0.01 eq.), TBAB (0.01 eq.), Tributylmethylammonium chloride (0.01 eq.), Tetrabutylammonium hydroxide (0.02 eq.), TBAB (0.02 eq.), Tributylmethylammonium chloride (0.02 eq.), Tetrabutylammonium hydroxide (0.03 eq.), TBAB (0.03 eq.), Tributylmethylammonium chloride (0.03 eq.).

[0077] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”)), PTC (0.12 g, 0.153 mmol, 0.050 eq), and chloroform (1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath, and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion, assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H20 (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. The reaction results are summarized in the following table:

Reactions Conditions Result

8D Tetrabutylammonium hydroxide Almost complete

(0.02 eq.) overnight (2% starting

material), 82% solution yield

8E TBAB (0.02 eq.) Almost complete

overnight (2% starting material), 71% solution yield

8F Tributylmethylammonium chloride Incomplete overnight (4%

(0.02 eq.) starting material), 72%

solution yield

8G Tetrabutylammonium hydroxide Almost complete

(0.03 eq.) overnight (3% starting

material), 76% solution yield

8H TBAB (0.03 eq.) Almost complete

overnight (3% starting material), 76% solution yield

81 Tributylmethylammonium chloride Almost complete

(0.03 eq.) overnight (2% starting

material), 78% solution yield

Example 9. Preparation of 2,2,6,6-tetramethylpiperidin-4-one hydrochloride

2,2,6,6-tetramethylpiperidin-4-one 2,2,6,6-tetramethylpiperidin-4-one hydrochloride

[0078] 2,2,6,6-tetramethyl-4-piperidinone (30 g, 193.2 mmol, 1.0 eq) was charged to a 500 mL nitrogen purged three necked round bottomed flask equipped with condenser. IPA (300 mL, 10 vol) was added to the flask and the mixture heated to 60 °C until dissolved.

[0079] To the solution at 60 °C was added 5-6 M HC1 in IPA (40 mL, 214.7 mmol, 1.1 eq) over 10 min and the resulting suspension stirred at 60 °C for 30 min then allowed to cool to ambient temperature. The suspension was stirred at ambient temperature overnight, then filtered under vacuum and washed with IPA (3 x 60 mL, 3 x 2 vol). The cream colored solid was dried on the filter under vacuum for 10 min.

[0080] The wet cake was charged to a 1 L nitrogen purged three necked round bottomed flask equipped with condenser. IPA (450 mL, 15 vol) was added to the flask and the suspension heated to 80 °C until dissolved. The mixture was allowed to cool slowly to ambient temperature over 3 h and the resulting suspension stirred overnight at ambient temperature.

[0081] The suspension was filtered under vacuum, washed with IPA (60 mL, 2 vol) and dried on the filter under vacuum for 30 min. The resulting product was dried in a vacuum oven at 40 °C over the weekend to give a white crystalline solid, 21.4 g, 64% yield.

Example 10. Synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride from (S)-3,5,5-trimethyl-pyrrolidin-2-one

[0082] Each reactor was charged with (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF, H2, and the catalyst shown in the below table. The reactor was heated to 200 C and pressurized to 60 bar, and allowed to react for 12 hours. GC analysis showed that (S)-2,2,4-trimethylpyrrolidine was produced in the columns denoted by “+.”

[0083] A 2.5% solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 2% Pt-0.5%>Sn/SiO2catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 130 °C under 80 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%>

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (74.8%> yield, 96.1% ee).

Alternate synthesis

[0084] A 2.5%) solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 4% Pt-2%>Sn/Ti02catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 200 °C under 50 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (88.5% yield, 29.6%> ee).

Alternate synthesis

[0085] A 2.5% solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 2% Pt-0.5%>Sn/TiO2 catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 150 °C under 50 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%>

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H20. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (90.9% yield, 98.0%> ee).

Alternate synthesis

[0086] A 2.5%) solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.03 mL/min into a packed bed reactor prepacked with 2% Pt-8%>Sn/Ti02catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 40 mL/min. The reaction was carried out at 180 °C under 55 bar pressure with a residence time of 6 min. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36% Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (,S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (90.4%> yield, 96.8%> ee).

Patent

WO 2019010092

PATENT

US 20160095858

https://patents.google.com/patent/US20160095858A1/en

Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.

In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000 disease causing mutations in the CF gene have been identified (http://cftr2.org). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as F508del. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.

The deletion of residue 508 in F508del prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of F508del in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.

Accordingly, there is a need for novel treatments of CFTR mediated diseases.

////////////////OLACAFTOR, VX 440, Phase II,  Cystic fibrosis, CS-0044588UNII-RZ7027HK8FRZ7027HK8F

CC1CC(N(C1)C2=C(C=CC(=N2)C3=CC(=CC(=C3)F)OCC(C)C)C(=O)NS(=O)(=O)C4=CC=CC=C4)(C)C

Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban


Abstract Image

Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban

Process Technology Research Laboratories (PTRL)Daiichi Sankyo Co., Ltd.1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan
Plant Management DepartmentDaiichi Sankyo Chemical Pharma Co., Ltd.477 Takada, Odawara-shi, Kanagawa 250-0216, Japan
§Global Supply Chain – Technology FunctionDaiichi Sankyo, Inc.211 Mt. Airy Road, Basking Ridge, New Jersey 07920, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00413
This article is part of the Japanese Society for Process Chemistry special issue

We report the development of a novel synthetic method to access a key intermediate in the synthesis of edoxaban. The main features of the new synthetic method are an improvement in the approach for the synthesis of a key chiral bromolactone, application of an interesting cyclization reaction utilizing neighboring group participation to construct a differentially protected 1,2-cis-diamine, and implementation of plug-flow reactor technology to enable the reaction of an unstable intermediate on multihundred kilogram scale. The overall yield for the preparation of edoxaban was significantly increased by implementing these changes and led to a more efficient and environmentally friendly manufacturing process.

//////////

Viloxazine, ヴィロキサジン;


Viloxazine structure.svg

ChemSpider 2D Image | Viloxazine | C13H19NO3

Viloxazine

  • Molecular FormulaC13H19NO3
  • Average mass237.295 Da
2-[(2-Ethoxyphenoxy)methyl]morpholine
256-281-7 [EINECS]
3489
46817-91-8 free [RN], Hcl 35604-67-2
5I5Y2789ZF
Emovit [Wiki]
Morpholine, 2-((2-ethoxyphenoxy)methyl)-
Morpholine, 2-[(2-ethoxyphenoxy)methyl]-
UNII:5I5Y2789ZF
Viloxazine hydrochloride.png
Viloxazine hydrochloride OQW30I1332 35604-67-2

Polymorph

FORM A , B US226136693US2011032013

Viloxazine (trade names VivalanEmovitVivarint and Vicilan) is a morpholine derivative and is a selective norepinephrine reuptake inhibitor (NRI). It was used as an antidepressant in some European countries, and produced a stimulant effect that is similar to the amphetamines, except without any signs of dependence. It was discovered and brought to market in 1976 by Imperial Chemical Industries and was withdrawn from the market in the early 2000s for business reasons.

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Clip

https://www.sciencedirect.com/science/article/pii/S0040402015302659

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Patent

US 20180265482

https://patentscope.wipo.int/search/en/detail.jsf?docId=US226136693&tab=PCTDESCRIPTION&maxRec=1000

 Viloxazine ((R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine]) is a bicyclic morpholine derivative, assigned CAS No. 46817-91-8 (CAS No. 35604-67-2 for the HCl salt). It is characterized by the formula C 1319NO 3, with a molecular mass of 237.295 g/mol. Viloxazine has two stereoisomers, (S)-(−)- and (R)-(+)-isomer, which have the following chemical structures:
      Viloxazine is known to have several desirable pharmacologic uses, including treatment of depression, nocturnal enuresis, narcolepsy, sleep disorders, and alcoholism, among others. In vivo, viloxazine acts as a selective norepinephrine reuptake inhibitor (“NRI”).
      Between the two stereoisomers, the (S)-(−)-isomer is known to be five times as pharmacologically active as the (R)-(+)-isomer. See, e.g., “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds” (Journal of Medicinal Chemistry, Jan. 9, 1976, 19(8); 1074) in which it is disclosed that optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine were prepared and absolute configurations assigned. The synthesis of optical isomers of viloxazine analogs of known configuration was accomplished by resolution of the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomers.
      Some unsatisfactory methods of synthesizing viloxazine are known in the art. For example, as disclosed in U.S. Pat. No. 3,714,161, viloxazine is prepared by reacting ethoxyphenol with epichlorohydrin to afford the epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane. This epoxide intermediate is then treated with benzylamine followed with chloroacetyl chloride. The resulting morpholinone is then reduced by lithium aluminum hydride and then by Pd/C-catalyzed hydrogenation to yield viloxazine free base.
      Yet another unsatisfactory synthesis of viloxazine is disclosed in U.S. Pat. No. 3,712,890, which describes a process to prepare viloxazine HCl, wherein the epoxide intermediate, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, is reacted with 2-aminoethyl hydrogen sulfate in ethanol in the presence of sodium hydroxide to form viloxazine free base. The product is extracted with diethyl ether from the aqueous solution obtained by evaporating the solvent in the reaction mixture then adding water to the residue. The ethereal extract is dried over a drying agent and the solvent is removed. Viloxazine HCl salt is finally obtained by dissolving the previous residue in isopropanol, concentrated aqueous HCl, and ethyl acetate followed by filtration.
      The foregoing methods of synthesizing viloxazine suffer from a number of deficiencies, such as low reaction yield and unacceptably large amount of impurities in the resulting product. Effective elimination or removal of impurities, especially those impurities possessing genotoxicity or other toxicities, is critical to render safe pharmaceutical products. For example, certain reagents traditionally utilized in viloxazine HCl preparation, such as epichlorohydrin and 2-aminoethyl hydrogen sulfate, present a special problem due to their toxicity. There is a need for effective methods to remove or limit harmful impurities down to a level that is appropriate and safe according to contemporary sound medical standards and judgment. Accordingly, a continuing and unmet need exists for new and improved methods of manufacturing viloxazine and its various salts to yield adequate quantities of pharmacologically desirable API with predictable and reliable control of impurities.
     Polymorph control is also an important aspect of producing APIs and their associated salts that are used in pharmaceutical products. However, no polymorphs of viloxazine HCl have previously been disclosed. A need therefore exists for new polymorphic forms of viloxazine that have improved pharmacological properties.

PATENT

WO 2011130194

US2011032013

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011130194&recNum=110&docAn=US2011032013&queryString=(%20pheno*%20or%20isopropoxy*%20or%20oxiran*%20or%20bisoprolol*%20)%20and%20(%20C07C213*%20or%20C07C217*%20or%20C07C209*%20or%20C07C41*%20or%20C07D263*%20)&maxRec=2245

For the sake of convenience and without putting any limitations thereof, the methods of manufacture of viloxazine have been separated into several steps, each step being disclosed herein in a multiplicity of non-limiting embodiments. These steps comprise Step 1, during which 2-ethoxyphenol and epichlorhydrin are reacted to produce l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1); Step 2, during which l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1) is converted into viloxazine base which is further converted into viloxazine salt, and Step 3, during which viloxazine salt is purified/recrystallized, and various polymorphic forms of viloxazine salt are prepared.

The above-mentioned steps will be considered below in more details.

[0031] The process of the Step 1 may be advantageously carried out in the presence of a phase-transfer catalyst to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane. Alternatively, the process may make use of a Finkelstein catalyst described in more details below. Additionally, the reaction may take place without the use of the catalyst.

 FIG. 1, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with Step I of an exemplary synthesis of viloxazine:

STEP I:

Epoxide 1

In one embodiment of the Step 1, the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (epoxide 1) can be effected by the use of a phase transfer catalyst in the presence of a solid or liquid base with a solution of a corresponding phenol and epichlorohydrin in one or more solvents (Fig. 1). The phase transfer catalyst can be selected from ammonium salts, such as benzyltriethylammonium salts, benzyltrimethylammonium salts, and tetrabutylammonium salts, phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The solid or liquid base can be a carbonate such as alkali carbonate, NaOH, KOH, LiOH, LiOH/LiCl, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, or other appropriate base. The solvents used in the solution of a corresponding phenol and epichlorohydrin include but are not limited to ethers such as methyl t-butyl ether, ketones, non-substituted or substituted aromatic solvents (xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, DMF, dioxanes, non-substituted and substituted pyridines, acetonitrile, pyrrolidones, nitromethane , or other appropriate solvent. Additional catalyst, such as, for example, Finkelstein catalyst, can also be used in the process of this embodiment. This reaction preferably takes place at an elevated temperature. In one variation of the embodiment, the temperature is above 50°C. In another variation, epichlorohydrin, potassium carbonate, and a phase transfer catalyst are mixed with a solution of 2-ethoxyphenol in a solvent at an elevated temperature, such as 50 – 60°C. After the reaction is complete, the reaction mixture can be washed with water, followed by work-up procedures known in the art. Variations of this embodiment of the invention are further disclosed in Examples 1-8.

[0033] In one variation of the above embodiment of the Step 1 , Epoxide 1 is prepared by reacting 2-ethoxyphenol and epichlorohydrin in a solvent in the presence of two different catalysts, and a base in a solid state. The first catalyst is a phase transfer catalyst as described above; the second catalyst is a Finkelstein reaction catalyst. Without putting any limitation

hereon, metal iodide and metal bromide salts, such as potassium iodide, may be used as an example of a Finkelstein catalyst. The phase transfer catalyst and a solvent may be selected from any phase transfer catalysts and solvents known in the art. Potassium carbonate may be used as a non-limiting example of a solid base. Using the solid base in a powdered form may be highly beneficial due to the greatly enhanced interface and limiting the side reactions. This variation of the embodiment is further illustrated by Example 9. In another variation of the embodiment, liquid base such as triethylamine can be used to replace the solid base.

[0034] In a different embodiment of Step 1 , 2-ethoxyphenol and epichlorohydrin are reacted in a solvent-free system that comprises a solid or liquid base, a phase transfer catalyst as listed above and a Finkelstein catalyst.

[0035] FIG. 2, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with the Step I of another exemplary synthesis of viloxazine ( biphasic):

STEP I (alternative embodiment):

In this embodiment of Step 1, illustrated in Fig. 2, Epoxide 1 can be prepared by reacting epichlorohydrin with 2-ethoxyphenol in the presence of a catalytic amount of a phase transfer catalyst without the use of solvents at elevated temperatures in a two-stage process to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane with very few side products. This embodiment of the invention is further illustrated by a non-limiting Example 12. The phase transfer catalyst for this embodiment can be selected from ammonium salts such as benzyltriethylammonium salts, benzyltrimethylammonium salts, tetrabutylammonium salts, etc; phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The first stage of the process of this embodiment may take place without a solvent in a presence of a large excess of epichlorohydrin. This stage is followed by a de-chlorination stage, before or after

removal of excess epichlorohydrin, using a base and a solvent. The reaction produces l-(2-ethoxyphenoxy)-2,3-epoxypropane in high yield. Example of the bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di-or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine etc.), DMAP. In one variation of this embodiment of Step 1, the phase transfer catalyst may be used only at the de-chlorination stage of the process. The de-chlorination stage can be carried out in a biphasic system or in a single phase system. For a biphasic system, it can be an organic-aqueous liquid biphasic system, or a liquid-solid biphasic system. Solvents that are useful for the process include but are not limited to non-substituted and substituted aromatic solvents (e.g. toluene, benzene, chlorobenzene, dimethylbenzene, xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, dioxanes, DMF, DMSO, non-substituted and substituted pyridines, ketones, pyrrolidones, ethers, acetonitrile, nitromethane. As mentioned above, this process takes place at the elevated temperature. In one variation of the embodiment, the temperature is above 60°C. In another variation, 2-ethoxyphenol and epichlorohydrin are heated to 60 – 90°C for a period of time in the presence of phase transfer catalyst. Excess of epichlorohydrin is removed and the residue is dissolved in a solvent such as toluene or benzene treated with an aqueous base solution, such as NaOH, KOH, LiOH, LiOH/LiCl. In yet another variation of the embodiment, the residue after epichlorohydrin removal can be dissolved in one or more of the said solvent and treated with a base (solid or liquid but not an aqueous solution) and optionally a second phase transfer catalyst, optionally at elevated temperatures.

[0036] In yet another embodiment of Step 1 , Epoxide 1 can also be prepared by using a catalyst for a so-called Finkelstein reaction in the presence of a Finkelstein catalyst but without the need to use a phase transfer catalyst. Finkelstein catalysts useful herein include metal iodide salts and metal bromide salts, among others. In one variation of this embodiment, 2-ethoxyphenol and epichlorohydrin are dissolved in a polar aprotic solvent such as DMF, and a catalytic amount of an iodide such as potassium iodide and a base, as solid or liquid, are used. Preferably, the base is used as a solid, such as potassium carbonate powder. This embodiment is further illustrated by the Example 11.

[0037] In the alternative embodiment of Step 1 , Epoxide 1 can also be prepared by a different method that comprises reacting epichlorohydrin and the corresponding phenol in the presence of a base at a temperature lower than the ambient temperature, especially when a base solution is used, and without the use of a phase transfer catalyst. This embodiment is illustrated by the Example 10.

[0038] A very high, almost quantitative, yield of 1 -(2-ethoxyphenoxy)-2,3-epoxypropane can be obtained through realizing the above-described embodiments of Step 1 , with less impurities generated in Epoxide 1.

[0039] Epoxide 1 , produced in Step 1 as described above, is used to prepare viloxazine base (viloxazine), which is further converted into viloxazine salt through the processes of Step 2.

[0040] FIG. 3, depicted below, schematically illustrates the preparation of viloxazine

(“Step Ila”) and the preparation of viloxazine hydrochloride (“Step lib”), as well as their purification (“Step III”) in accordance with another example embodiment hereof:

STEP Ila:

Hydrogen Sulfate

STEP lib:

Step III:

Conversion

Viloxazine free base ► Viloxazine salt

Wash/ raction

Recrystallization

Purified viloxazine salt

In the embodiment of Step 2, illustrated in Fig. 3, the preparation of viloxazine base is achieved by reacting the Epoxide 1 intermediate prepared in Step 1 and aminoethyl hydrogen sulfate in presence of a large excess of a base as illustrated by the Examples 5-7 and 14. The base may be present as a solid or in a solution. Preferably, the molar ratio of the base to Epoxide 1 is more than 10. More preferably the ratio is more than 12. Even more preferably, the ratio is between 15 and 40. It was unexpectedly discovered that the use of a higher ratio of a base results in a faster reaction, less impurities, and lower reaction temperature.

[0041] Further advantages may be offered by a specific variation of this embodiment, wherein the base is added to the reaction mixture in several separate steps. For example, a third of the base is added to the reaction mixture, and the mixture is stirred for a period of time. Then the rest of the base is added followed by additional stirring. Alternatively, half of the base is added initially followed by the second half after some period of time, or the base is added in three different parts separated by periods of time. The bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, and combinations thereof. . In one embodiment of the invention, the base is KOH. In another embodiment, the base is NaOH. In a further embodiment, the base is K2C03 powder. In yet further embodiment, the base is triethylamine. This embodiment is illustrated further by

Examples 13,15 and 16.

[0042] In another exemplary embodiment of Step 2, viloxazine is produced by cyclization of novel intermediate compound “Diol 1 ,” which is made from Epoxide 1 and N-benzyl-aminoethanol. This method allows one to drastically reduce the use of potentially toxic materials in the manufacturing process, completely eliminating some of them such as aminoethyl hydrogen sulfate. The first stage of the reaction results in the formation of an intermediate of Formula 3 (Diol 1), which is a new, previously unidentified compound.

[0043] Formula 3

Diol 1

FIG. 4, depicted below, schematically illustrates the preparation of viloxazine and its salts via “Diol 1” in accordance with another exemplary embodiment hereof (Bn = benzyl, Et = ethyl):

Viloxazine HCI

As illustrated in Fig. 4, Diol 1 is turned into N-benzyl viloxazine by cyclization. Removal of the benzyl protective group yields viloxazine base. Similarly, FIG. 5, depicted below, schematically illustrates the cyclization of Diol 1, as well as some side-reactions thereof.

Uses

Viloxazine hydrochloride was used in some European countries for the treatment of clinical depression.[4][5]

Side effects

Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipationvertigoorthostatic hypotensionedema of the lower extremities, dysarthriatremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminasesseizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy,[6]) and increased libido.[7]

Drug interactions

Viloxazine increased plasma levels of phenytoin by an average of 37%.[8] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,[9] sometimes resulting in accidental overdose of theophylline.[10]

Mechanism of action

Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.[11] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.[11]

It was also found to up-regulate GABAB receptors in the frontal cortex of rats.[12]

Chemical properties

It is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.[13]

History

Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.[14]:610[15]:9 The drug was first marketed in 1976.[16] It was never approved by the FDA,[5] but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984.[17] It was withdrawn from markets worldwide in 2002 for business reasons.[14][18]

As of 2015, Supernus Pharmaceuticals was developing formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.[19][20]

Research

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[21][22] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[23]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM[24] without really improving daytime somnolence.[25]

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.[18]

Viloxazine has also been studied for the treatment of alcoholism, with some success.[26]

While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.[27]

It is also under investigation as a treatment for attention deficit hyperactivity disorder.[28]

REFERNCES

  1. ^ Bouchard JM, Strub N, Nil R (October 1997). “Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial”. Journal of Affective Disorders46 (1): 51–8. doi:10.1016/S0165-0327(97)00078-5PMID 9387086.
  2. ^ Case DE, Reeves PR (February 1975). “The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans”. Xenobiotica5 (2): 113–29. doi:10.3109/00498257509056097PMID 1154799.
  3. ^ “SID 180462– PubChem Substance Summary”. Retrieved 5 November 2005.
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  5. Jump up to:a b Dahmen, MM, Lincoln, J, and Preskorn, S. NARI Antidepressants, pp 816-822 in Encyclopedia of Psychopharmacology, Ed. Ian P. Stolerman. Springer-Verlag Berlin Heidelberg, 2010. ISBN 9783540687061
  6. ^ Edwards JG, Glen-Bott M (September 1984). “Does viloxazine have epileptogenic properties?”Journal of Neurology, Neurosurgery, and Psychiatry47 (9): 960–4. doi:10.1136/jnnp.47.9.960PMC 1027998PMID 6434699.
  7. ^ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). “Antidepressants and sexual stimulation: the correlation” [Antidepressants and sexual stimulation: the correlation]. L’Encéphale (in French). 24 (3): 180–4. PMID 9696909.
  8. ^ Pisani F, Fazio A, Artesi C, et al. (February 1992). “Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction”Journal of Neurology, Neurosurgery, and Psychiatry55 (2): 126–7. doi:10.1136/jnnp.55.2.126PMC 488975PMID 1538217.
  9. ^ Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). “A study of the interaction of viloxazine with theophylline”. Therapeutic Drug Monitoring11 (5): 520–2. doi:10.1097/00007691-198909000-00005PMID 2815226.
  10. ^ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). “Theophylline intoxication following viloxazine induced decrease in clearance”. European Journal of Clinical Pharmacology30 (3): 351–3. doi:10.1007/BF00541543PMID 3732375.
  11. Jump up to:a b Lippman W, Pugsley TA (August 1976). “Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities”. Canadian Journal of Physiology and Pharmacology54 (4): 494–509. doi:10.1139/y76-069PMID 974878.
  12. ^ Lloyd KG, Thuret F, Pilc A (October 1985). “Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock”The Journal of Pharmacology and Experimental Therapeutics235 (1): 191–9. PMID 2995646.
  13. ^ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). “Behavioral and radioreceptor analysis of viloxazine stereoisomers” [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biulleten’ Eksperimental’noĭ Biologii i Meditsiny (in Russian). 97 (5): 576–8. PMID 6326891.
  14. Jump up to:a b Williams DA. Antidepressants. Chapter 18 in Foye’s Principles of Medicinal Chemistry, Eds. Lemke TL and Williams DA. Lippincott Williams & Wilkins, 2012. ISBN 9781609133450
  15. ^ Wermuth, CG. Analogs as a Means of Discovering New Drugs. Chapter 1 in Analogue-based Drug Discovery. Eds.IUPAC, Fischer, J., and Ganellin CR. John Wiley & Sons, 2006. ISBN 9783527607495
  16. ^ Olivier B, Soudijn W, van Wijngaarden I. Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors. Prog Drug Res. 2000;54:59-119. PMID 10857386
  17. ^ FDA. Orphan Drug Designations and Approvals: Viloxazine Page accessed August 1, 2-15
  18. Jump up to:a b Vignatelli L, D’Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003724. Review. PMID 18254030
  19. ^ Bloomberg Supernus profile Page accessed August 1, 2015
  20. ^ Supernus. Psychiatry portfolio Page accessed August 1, 2015
  21. ^ Attenburrow AA, Stanley TV, Holland RP (January 1984). “Nocturnal enuresis: a study”. The Practitioner228 (1387): 99–102. PMID 6364124.
  22. ^ ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). “Viloxazine versus imipramine in the treatment of enuresis”. The Turkish Journal of Pediatrics29 (4): 227–30. PMID 3332732.
  23. ^ Libert MH (1990). “The use of viloxazine in the treatment of primary enuresis” [The use of viloxazine in the treatment of primary enuresis]. Acta Urologica Belgica (in French). 58 (1): 117–22. PMID 2371930.
  24. ^ Guilleminault C, Mancuso J, Salva MA, et al. (1986). “Viloxazine hydrochloride in narcolepsy: a preliminary report”. Sleep9 (1 Pt 2): 275–9. PMID 3704453.
  25. ^ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). “Narcolepsy”Journal of Clinical Neurophysiology7 (1): 93–118. doi:10.1097/00004691-199001000-00008PMC 2254143PMID 1968069.
  26. ^ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). “Alcoholism and depression: a placebo controlled study with viloxazine”. International Journal of Clinical Pharmacology Research10 (5): 293–8. PMID 2079386.
  27. ^ León CA, Vigoya J, Conde S, Campo G, Castrillón E, León A (March 1994). “Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia” [Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia]. Acta Psiquiátrica Y Psicológica de América Latina (in Spanish). 40 (1): 41–9. PMID 8053353.
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Viloxazine
Viloxazine structure.svg
Viloxazine molecule spacefill.png
Clinical data
Routes of
administration
By mouthintravenous infusion[1]
ATC code
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
Elimination half-life 2–5 hours
Excretion Renal[2]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.051.148 Edit this at Wikidata
Chemical and physical data
Formula C13H19NO3
Molar mass 237.295 g/mol g·mol−1
3D model (JSmol)
Chirality Racemic mixture

/////////////////Viloxazine, ヴィロキサジン , Emovit, VivalanEmovitVivarint, Vicilan

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