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Practical Process Research and development; Development..Optimizing the Reaction by Minimizing Impurities
2000, Pages 165–184
Chapter 8 – Optimizing the Reaction by Minimizing Impurities
- Process Solutions L.L.C., Nicasio, California
The goals of process optimization change with the successful development of a project from early process research through scale-up into dedicated manufacturing. This general order of optimization may differ according to the nature of the process being considered; for instance, a process generating an inordinate amount of waste may be optimized to decrease waste before scaling up to the pilot plant. The initial goal of all process research and development is to maximize the amount of product generated under the reaction conditions. This is done by driving the reaction to completion, that is, by consuming any starting material that is charged in limiting amounts and by generating product with a minimal amount of by-products. Once the in-process yield has been optimized, the maximum yield of isolated product is expected. Rapid optimization is possible by judiciously changing solvents, reagents, catalysts, and ligands; investigations in this area allow the chemist considerable room for creativity and simplifying a process. Such changes may generate different impurities in the isolated intermediates, and it may be necessary to examine the tolerance of subsequent processes for the new impurities.
-
Chapter 8 – Optimizing the Reaction by Minimizing Impurities
-
Neal G. Anderson, PhD
For the past 17 years Neal has consulted to the pharmaceutical and fine chemical industries on chemical process research and development. He has presented short courses internationally on process R&D for “small molecules” to over 1400 participants from more than 160 companies. Keys to efficient scale-up are anticipating and then avoiding diffiulcties. Prior to consulting he worked at Bristol-Myers Squibb for 17 years. During that time, he had extensive hands-on experience with chemical process R&D in the lab, pilot plant, and manufacturing sites, including 12 manufacturing start-ups and process development for four major drugs. He is the author of Practical Process Research & Development(Academic Press; 2nd edition 2012).
Education & Training
- 1977-1979, post-doctoral studies, McNeil Laboratories
- 1977, Ph.D., Medicinal Chemistry, University of Michigan
- 1972, B.Sc., Honors Biology, University of Illinois
I consult to the pharmaceutical and fine chemical industries on developing and trouble-shooting processes to efficiently prepare drug substances and intermediates on large scale. Anticipating and avoiding problems are key for effective and efficient scale-up. For 17 years I have been consulting and presenting short courses internationally on process chemistry R & D for “small molecules” (over 1400 participants from more than 160 companies). Prior to consulting I worked at Bristol-Myers Squibb for 17 years. During that time I had extensive hands-on experience with chemical process development in the lab, pilot plant, and manufacturing sites, including 12 manufacturing start-ups and process development for four major drugs and many new drug candidates. I wrote Practical Process Research & Development (Academic Press, 2000; 2nd edition 2012).
Practical Process Research & Development describes the development of chemical processes for the pharmaceutical and fine chemicals industries. It provides a comprehensive, step-by-step approach to process R & D, and it is designed for those who want insights into generating rugged, practical, cost-effective processes. Guidelines for industrial process R & D are rarely taught in academia, although this book has been used as a textbook. It is primarily used by those in industry.
The second edition updates the first edition and includes topics not covered in the first edition
, such as genotoxins, biocatalysis, green solvents, predicting effective solvent combinations, and process validation. Almost 85% of the references cited were published after the first edition was published, and virtually all examples in the Figures are new. Trevor Laird kindly wrote a forward for this edition.
The second edition has been translated into Japanese and graced with a handsome cover. Noriaki Murase was the translation supervisor, and the translators were Shohei Imachi, Koreaki Imura, Dai Tatsuta, Taro Tsukude, Toyoharu Numata, Yujiro Furuya, Akira Manaka, and Noriaki Murase. Sayaka Nukatsuka was the editor. I am very grateful to these people for their hard work to translate my book.
I am grateful to Barry Sharpless and Jerry Moniot for writing forwards to the first edition I am also grateful to the following people for their translations of the first edition of my book. Noriaki Murase, Yoshinori Murata, Toyoharu Numata, Mio Sakai, and Tatsuo Ueki translated Practical Process Research & Development into Japanese. Kwang-Hyun Ahn, Yeung-Ho Park, and Sung-Kwan Hwang translated Practical Process Research & Development into Korean. Zhinong Gao and Wenhao Hu translated Practical Process Research & Development into Chinese.
free look- Evaluate the existing synthesis and identify steps, or sequences in the route that may pose a problem for large scale synthesis
- Propose alternatives to any problematic steps or sequences and then implement these alternatives bases upon laboratory experimentation using Ph.D. level chemists with process research expertise
- Ensure the synthesis is suitable for the immediate needs of the project, which maybe for only a few kilograms of API
- Ensure the synthesis is suitable for long term, large scale manufacturing
- Optimize reagent charges, operating temperatures, concentrations, work-up conditions and volumes, and solvent use in general
- Identify which steps can be combined to result in a “through process” and implement the through process
- Optimize purification schemes by identifying key crystalline intermediates and remove chromatographies from the synthesis
- Optimize recrystallization parameters to ensure consistently high purity with similar impurity profiles from batch to batch, with low mother liquor losses
- Institute appropriate analytical controls for in-process assays, end of reaction specifications, and acceptable intermediate or API purity
- The process research team works closely with the analytical team to integrate the chemistry and analytical controls into the process at an early stage of the development cycle. The process research is then documented into a JACS style development report that outlines the chemistry and synthetic approaches that were tried as part of the synthetic development effort. This development report also includes a detailed experimental with supporting analytical data for the successful chemistry that results from our effort.The experimental that is part of these development reports is much more detailed than any journal publication. When coupled with our analytical and cGMP capabilities, the process research we provide is an essential groundwork for any compound that is just advancing from nomination at the discovery phase into clinical trial development. The process we develop provides the foundation of the ultimate manufacturing process, and should not need any changes (at a later date), to the synthetic strategy or bond forming steps used to prepare the API.
Critical Assessment of Pharmaceutical Processes, A Rationale for Changing the Synthetic Route
Critical Assessment of Pharmaceutical Processes
A Rationale for Changing the Synthetic Route
Table of Contents
- 1. Introduction
- 2. Criteria for Process Assessment
-
- 2.1. Safety Issues2.1.1. Potential Safety Issues and Their Significance
- 2.1.2. Prediction and Assessment of Safety Issues
- 2.1.3. Options To Manage Safety Issues
- 2.1.4. Designing a Safer New Route
-
- 2.2. Environmental Issues
- 2.2.1. Potential Environmental Issues and Their Significance
- 2.2.2. Prediction and Assessment of Environmental Issues
- 2.2.3. Options To Manage Environmental Issues
- 2.2.4. Designing a New “Greener” Route
-
- 2.3. Legal Issues
- 2.3.1. Potential Legal Issues and Their Significance
- 2.3.2. Prediction and Assessment of Legal Issues Associated with Regulated Substances
- 2.3.3. Prediction and Assessment of Legal Issues Associated with Patent Infringement
- 2.3.4. Options To Manage Patent Issues
- 2.3.5. Designing a New Route with Freedom To Operate
-
- 2.4. Economic Issues
- 2.4.1. Potential Economic Issues and Their Significance
- 2.4.2. Prediction and Assessment of Economic Issues
- 2.4.3. Options To Manage Economic Issues
- 2.4.4. Designing a Cost-Effective New Route
-
- 2.5. Control Issues
- 2.5.1. Potential Control Issues and Their Significance
- 2.5.2. Prediction and Assessment of Control Issues
- 2.5.3. Options To Manage Control Issues
- 2.5.4. Designing a New Route with Adequate Control Measures
-
- 2.6. Throughput Issues
- 2.6.1. Potential Throughput Issues and Their Significance
- 2.6.2. Prediction and Assessment of Throughput Issues
- 2.6.3. Options To Manage Throughput Issues
- 2.6.4. Designing a New Route with High Throughput
- 3. Interrelationships between Process Issues
- 4. Conclusions
- 5. Acknowledgments
- 6. References
Pemirolast
Pemirolast (INN) is a mast cell stabilizer used as an anti-allergic drug therapy. It is marketed under the tradenames Alegysal and Alamast.
9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido-[1, 2-a]-pyrimidin-4-one
It has also been studied for the treatment of asthma.
https://www.google.com/patents/US9006431
Pemirolast is an orally-active anti-allergic drug which is used in the treatment of conditions such as asthma, allergic rhinitis and conjunctivitis. See, for example, U.S. Pat. No. 4,122,274, European Patent Applications EP 316 174 and EP 1 285 921, Yanagihara et al, Japanese Journal of Pharmacology, 51, 93 (1989) and Drugs of Today, 28, 29 (1992). The drug is presently marketed in e.g. Japan as the potassium salt under the trademark ALEGYSAL™.
Commercial pemirolast potassium has the disadvantage that it is known to give rise to sharp plasma concentration peaks in humans (see, for example, Kinbara et al, “Plasma Level and Urinary Excretion of TBX in Humans”, Japanese Pharmacology & Therapeutics, 18(3) (1990), and “Antiallergic agent—ALEGYSAL tablet 5 mg—ALEGYSAL tablet 10 mg—ALEGYSAL dry syrup”, Pharmaceutical Interview Form (IF), Revised in October 2007 (7th version), Standard Commodity Classification No.: 87449). The latter document also reports that the potassium salt of pemirolast is hygroscopic, which is believed to give rise to chemical instability, and possesses a bitter taste.
U.S. Pat. No. 4,122,274 describes a process for the production of salts of pemirolast, including potassium salts and (at Example 14) a sodium salt. As described herein, this technique produces a sodium salt that is physically unstable. Sodium salts of pemirolast are also mentioned (but a synthesis thereof not described) in international patent applications WO 2008/074975 and WO 2008/075028.
COMPARATIVE EXAMPLE 5Recrystallisation of Pemirolast Sodium According to the Method of U.S. Pat. No. 4,122,274
In U.S. Pat. No. 4,122,274, it is stated that the crude title product (pemirolast sodium) was recrystallised from water:ethanol to give pure title product. It is not clear from this level of detail what the ratio of water:ethanol employed was, so several experiments were performed with a view to reproducing the prior art technique.
- (i) Crude sodium salt of pemirolast (480 mg; from Example 4, method (I) above) was recrystallised from water and ethanol (95%) in a 1:1 ratio. The Na salt of pemirolast (480 mg, 1.92 mmol) was dissolved in H2O (8 mL) at 70° C. and EtOH 95% (8 mL) was added. The clear solution was allowed to reach room temperature and the solid material formed was filtered off, washed with a small amount of ethanol and dried in vacuum to give 316 mg of pure sodium salt.
- (ii) Crude sodium salt of pemirolast (500 mg; from Example 4, method (II) above) was dissolved in water (4.9 mL) at 70° C. Thereafter EtOH 95% (ca. 4.0 mL) was added at 70° C. until a solid started to form. Another 0.1 mL of water was added to get everything into solution. The solid material formed upon cooling was collected by filtration and dried under vacuum to give 348 mg of pure sodium salt.
- (iii) Crude sodium salt of pemirolast (300 mg; from Example 4, method (II) above) was recrystallised from water:ethanol (1:1 ratio; 10 mL) at 70° C. The solid material formed upon cooling was collected by filtration and dried under vacuum to give 174 mg of pure sodium salt.
- (iv) Crude sodium salt of pemirolast (300 mg; from Example 4, method (II) above) was recrystallised from water:ethanol (9:1 ratio, 4 mL) at 70° C. The solid material formed upon cooling was collected by filtration and dried under vacuum to give 219 mg of pure sodium salt.
All four samples of pure pemirolast sodium salt had the same physico-chemical properties (Raman spectra and NMR):
1H NMR (D2O) δ: 8.86-8.80 (m, 1H, CH), 8.57 (s, 1H, CH), 7.68-7.59 (m, 1H, CH), 7.22-7.13 (m, 1H, CH), 2.39 (s, 3H, CH3).
The PXRD pattern (measured in respect of Example 5(i) above) is shown in FIG. 3. It was concluded from this that this form of the sodium salt is an amorphous material mixed with a crystalline fraction.
The Raman spectrum was recorded directly after recrystallisation. All samples were then stored under ambient conditions on a shelf in a fume hood. About a month later, a Raman spectrum was recorded, which was significantly different to that recorded earlier. This is shown in FIG. 4, where the lower spectrum accords to the earlier measurement and the upper spectrum accords to the later measurement. In the light of these results, it was concluded that the prior art amorphous form of pemirolast sodium is physically unstable.
The amorphous material was also prepared by drying of the form obtained in accordance with Example 11 below at 40° C. and reduced pressure for 40 hours to yield 12 g of a pale yellow cotton-like amorphous solid.
………………………..
http://www.lookchem.com/Chempedia/Chemical-Technology/Organic-Chemical-Technology/18815.html
1) Firstly, 2-Amino-3-methylpyridine (I) is condensed with ethoxymethylenemalonodinitrile (II) to afford the monocyclic intermediate (III), which is in tautomeric equilibrium with the pyridopyrimidine derivative (IV). Next, the reaction of (IV) with aluminum azide (AlCl3.NaN3) in refluxing THF yields 4-imino-9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidine (V). Finally, this compound is first hydrolyzed with 1N HCl and then treated with KOH.
2) Compound (IV) can be converted to the final product by a one-pot reaction: (VI) is treated first with NaN3 in refluxing acetic acid, then hydrolyzed with HCl and finally treated with KOH.
………….
EXAMPLE 1
A suspension of 9-methyl-3-(1 H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one (68.5 g; 0.3 mols) in methanol (420 ml) and water (210 ml) heated at 50° C. is added with a 40% N-methylamine aqueous solution (30 ml, 0.35 mols) to pH=10. The solution is heated at 68-70° C., and acidified with formic acid (21 ml) to pH=3. After completion of the addition the mixture is kept at 68-70° C. for about 15 minutes and then cooled to 20-25° C. The precipitate is filtered, washed with methanol and dried under vacuum at 40° C. to give 9-methyl-3-(1 H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one with >99.8% HPLC purity (63 g, 92% yield).
EXAMPLE 2
9-Methyl-3-(1 H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one (63 g, 0.28 mols) is suspended in methanol (1000 ml). The resulting suspension is kept at 45° C. and slowly added with a 45% potassium hydroxide aqueous solution to pH 9-9.5. The suspension is stirred at 45° C. for about 15 minutes and then cooled to 20° C. The precipitate is filtered, washed with methanol and dried under vacuum at 80° C., to obtain Pemirolast Potassium (71.9 g; 0.27 mols, 96% yield) with HPLC purity >99.8%. 1H NMR(D2O, TMS) d (ppm): 2.02 (s, 3H); 6.83 (t, 1H); 7.22 (d, 1H); 8.18 (s, 1H); 8.47 (d, 1H).
References
- Tinkelman DG, Berkowitz RB (February 1991). “A pilot study of pemirolast in patients with seasonal allergic rhinitis”. Ann Allergy 66 (2): 162–5. PMID 1994787.
- Kawashima T, Iwamoto I, Nakagawa N, Tomioka H, Yoshida S (1994). “Inhibitory effect of pemirolast, a novel antiallergic drug, on leukotriene C4 and granule protein release from human eosinophils”. Int. Arch. Allergy Immunol. 103 (4): 405–9. doi:10.1159/000236662. PMID 8130655.
- Abelson MB, Berdy GJ, Mundorf T, Amdahl LD, Graves AL (October 2002). “Pemirolast potassium 0.1% ophthalmic solution is an effective treatment for allergic conjunctivitis: a pooled analysis of two prospective, randomized, double-masked, placebo-controlled, phase III studies”. J Ocul Pharmacol Ther 18 (5): 475–88. doi:10.1089/10807680260362759. PMID 12419098.
- Kemp JP, Bernstein IL, Bierman CW et al. (June 1992). “Pemirolast, a new oral nonbronchodilator drug for chronic asthma”. Ann Allergy 68 (6): 488–91. PMID 1610024.
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one
|
|
| Clinical data | |
| Trade names | Alamast |
| AHFS/Drugs.com | monograph |
| Pregnancy category |
|
| Legal status |
|
| Routes of administration |
Oral, ophthalmic |
| Identifiers | |
| CAS Registry Number | 69372-19-6  |
| ATC code | None |
| PubChem | CID: 57697 |
| IUPHAR/BPS | 7329 |
| DrugBank | DB00885  |
| ChemSpider | 51990 |
| UNII | 2C09NV773M |
| KEGG | D07476 |
| ChEMBL | CHEMBL1201198 |
| Chemical data | |
| Formula | C10H8N6O |
| Molecular mass | 228.21 g/mol |
| US4122274 * | May 25, 1977 | Oct 24, 1978 | Bristol-Myers Company | 3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones |
| EP0316174A1 | Nov 10, 1988 | May 17, 1989 | Tokyo Tanabe Company Limited | Aqueous preparation of 9-methyl-3-(1H-tetrazol-5-yl)-4H-Pyrido[1,2-a]pyrimidin-4-one potassium salt |
| EP1285921A1 | Jun 25, 2002 | Feb 26, 2003 | Dinamite Dipharma S.p.A. | A process for the preparation of high purity pemirolast |
| JPH0374385A | Title not available | |||
| WO2008074975A1 | Nov 16, 2007 | Jun 26, 2008 | Cardoz Ab | New combination for use in the treatment of inflammatory disorders |
| WO2008075028A1 | Dec 18, 2007 | Jun 26, 2008 | Cardoz Ab | New combination for use in the treatment of inflammatory disorders |
| US4122274 | May 25, 1977 | Oct 24, 1978 | Bristol-Myers Company | 3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones | |
| US5254688 * | Jun 19, 1991 | Oct 19, 1993 | Wako Pure Chemical Industries, Ltd. | Process for producing pyrido[1,2-a]pyrimidine derivative | |
| DE243821C | Title not available | ||||
| EP0462834A1 | Jun 20, 1991 | Dec 27, 1991 | Wako Pure Chemical Industries, Ltd | Process for producing pyrido [1,2-a]pyrimidine derivative | |
| WO1993025557A1 | Jun 7, 1993 | Dec 23, 1993 | Smithkline Beecham Plc | Process for the preparation of clavulanic acid |
Pemirolast Potassium (BMY 26517) cas100299-08-9is a histamine H1 antagonist and mast cell stabilizer that acts as an antiallergic agent.
Target: Histamine H1 Receptor
Pemirolast potassium (BMY 26517) is a new oral, nonbronchodilator antiallergy medication that is being evaluated for the therapy of asthma [1]. Pemirolast potassium (BMY 26517) inhibits chemical mediator release from tissue mast cells and is also shown to inhibit the release of peptides including substance P, Pemirolast potassium (BMY 26517) reduces kaolin intake by inhibition of substance P release in rats [2]. Pemirolast potently attenuates paclitaxel hypersensitivity reactions through inhibition of the release of sensory neuropeptides in rats [3]. Pemirolast potassium is used for the treatment of allergic conjunctivitis and prophylaxis for pulmonary hypersensitivity reactions to drugs such as paclitaxel [4].
Molecular formula: C10H7KN6O
Molecular Weight: 266.30
External links
- Mitsubishi Tanabe Pharma Corporation (2007). “ALEGYSAL (English)” (PDF). Retrieved 2008-09-02.
- “DailyMed Announcements”. U.S. National Library of Medicine. 2005. Retrieved 2008-09-02.
Necessity of Establishing Chemical Integrity of Polymorphs of Drug Substance Using a Combination of NMR, HPLC, Elemental Analysis, and Solid-State Characterization Techniques: Case Studies
Necessity of Establishing Chemical Integrity of Polymorphs of Drug Substance Using a Combination of NMR, HPLC, Elemental Analysis, and Solid-State Characterization Techniques: Case Studies
Moexipril
RS-10085-197
SPM-925
RS-10085 (free base)
Pharmacology
Moexipril is available as a prodrug moexipril hydrochloride, and is metabolized in the liver to form the pharmacologically active compound moexiprilat. Formation of moexiprilat is caused by hydrolysis of an ethyl ester group.[5] Moexipril is incompletely absorbed after oral administration, and its bioavailability is low.[6] The long pharmacokinetic half-life and persistent ACE inhibition of moexipril allows once-daily administration.[7]
Moexipril is highly lipophilic,[2] and is in the same hydrophobic range as quinapril, benazepril, and ramipril.[7] Lipophilic ACE inhibitors are able to penetrate membranes more readily, thus tissue ACE may be a target in addition to plasma ACE. A significant reduction in tissue ACE (lung, myocardium, aorta, and kidney) activity has been shown after moexipril use.[8]
It has additional PDE4-inhibiting effects.[9]
Side effects
Moexipril is generally well tolerated in elderly patients with hypertension.[10] Hypotension, dizziness, increased cough, diarrhea, flu syndrome, fatigue, and flushing have been found to affect less than 6% of patients who were prescribed moexipril.[3][10]
Mechanism of action
As an ACE inhibitor, moexipril causes a decrease in ACE. This blocks the conversion of angiotensin I to angiotensin II. Blockage of angiotensin II limits hypertension within the vasculature. Additionally, moexipril has been found to possess cardioprotective properties. Rats given moexipril one week prior to induction of myocardial infarction, displayed decreased infarct size.[11] The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition and bradykininproliferation.[8][12] Increased levels of bradykinin stimulate in the production of prostaglandin E2[13] and nitric oxide,[12] which cause vasodilation and continue to exert antiproliferative effects.[8] Inhibition of angiotensin II by moexipril decreases remodeling effects on the cardiovascular system. Indirectly, angiotensin II stimulates of the production of endothelin 1 and 3 (ET1, ET3)[14] and the transforming growth factor beta-1 (TGF-β1),[15] all of which have tissue proliferative effects that are blocked by the actions of moexipril. The antiproliferative effects of moexipril have also been demonstrated by in vitro studies where moexipril inhibits the estrogen-stimulated growth of neonatal cardiac fibroblasts in rats.[12] Other ACE inhibitors have also been found to produce these actions, as well.
WO 2014202659
http://www.google.com/patents/WO2014202659A1?cl=en
US4344949
http://www.google.co.in/patents/US4344949
References
- Hochadel, Maryanne, ed. (2006). The AARP Guide to Pills. Sterling Publishing Company. p. 640. ISBN 978-1-4027-1740-6. Retrieved2009-10-09.
- Belal, F.F, K.M. Metwaly, and S.M. Amer. “Development of Membrane Electrodes for the Specific Determination of Moexipril Hydrochloride in Dosage Forms and Biological Fluids.” Portugaliae Electrochimica Acta. 27.4 (2009): 463-475.
- Rodgers, Katie, Michael C Vinson, and Marvin W Davis. “Breakthroughs: New drug approvals of 1995 — part 1.” Advanstar Communications, Inc. 140.3 (1996): 84.
- Dart, Richard C. (2004). Medical toxicology. Lippincott Williams & Wilkins. p. 647. ISBN 978-0-7817-2845-4. Retrieved 2009-10-09.
- Kalasz, H, G. Petroianu, K. Tekes, I. Klebovich, K. Ludanyi, et al. “Metabolism of moexipril to moexiprilat: determination of in vitro metabolism using HPLC-ES-MS.” Medicinal Chemistry. 3 (2007): 101-106.
- Jump up^ Chrysant, George S, PK Nguyen. “Moexipril and left ventricular hypertrophy.” Vascular Health Risk Management. 3.1 (2007): 23-30.
- Cawello W, H. Boekens, J. Waitzinger, et al. “Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE-inhibition.” Int J Clin Pharmacol Ther. 40 (2002): 9-17.
- ^ Jump up to:a b c Chrysant, SG. “Vascular remodeling: the role of angiotensin-converting enzyme inhibitors.” American Heart Journal. 135.2 (1998): 21-30.
- Jump up^ Cameron, RT; Coleman, RG; Day, JP; Yalla, KC; Houslay, MD; Adams, DR; Shoichet, BK; Baillie, GS (May 2013). “Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)”. Biochemical Pharmacology 85 (9): 1297–1305. doi:10.1016/j.bcp.2013.02.026. PMC 3625111. PMID 23473803.
- White, WB, and M Stimpel. “Long-term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension.” Journal of human hypertension. 9.11 (1995): 879-884.
- Rosendorff, C. “The Renin-Angiotensin System and Vascular Hypertrophy.” Journal of the American College of Cardiology. 28 (1996): 803-812.
- Hartman, J.C. “The role of bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors.” The Annals of Thoracic Surgery. 60.3 (1995): 789-792.
- Jaiswal, N, DI Diz, MC Chappell, MC Khosia, CM Ferrario. “Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Characterization of receptors.” Hypertension. 19.2 (1992): 49-55.
- Phillips, PA. “Interaction between endothelin and angiotensin II.” Clinical and Experimental Pharmacology and Physiology. 26.7. (1999): 517-518.
- Youn, TJ, HS Kim, BH Oh. “Ventricular remodeling and transforming growth factor-beta 1 mRNA expression after nontransmural myocardial infarction in rats: effects of angiotensin converting enzyme inhibition and angiotensin II type 1 receptor blockade.” Basic research in cardiology. 94.4 (1999): 246-253.
////////////
| Systematic (IUPAC) name | |
|---|---|
|
(3S)-2-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
|
|
| Clinical data | |
| Trade names | Univasc |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a695018 |
| Pregnancy category |
|
| Legal status |
|
| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Bioavailability | 13-22% |
| Protein binding | 90% |
| Metabolism | Hepatic (active metabolite, moexiprilat) |
| Biological half-life | 1 hour; 2-9 hours (active metabolite) |
| Excretion | 50% (faeces), 13% (urine) |
| Identifiers | |
| CAS Registry Number | 103775-10-6 |
| ATC code | C09AA13 |
| PubChem | CID: 91270 |
| IUPHAR/BPS | 6571 |
| DrugBank | DB00691 |
| ChemSpider | 82418 |
| UNII | WT87C52TJZ |
| KEGG | D08225 |
| ChEMBL | CHEMBL1165 |
| Chemical data | |
| Formula | C27H34N2O7 |
| Molecular mass | 498.568 g/mol |
9-(5-oxotetrahydrofuran-2-yl)nonanoic acid methyl ester
9-(5-Oxotetrahydrofuran-2-yl)nonanoic acid methyl ester |
 |
| Name | 9-(5-Oxotetrahydrofuran-2-yl)nonanoic acid methyl ester | ||
| Synonyms | |||
| Name in Chemical Abstracts | 2-Furannonanoic acid, tetrahydro-5-oxo-, methyl ester | ||
| CAS No | 22623-86-5 | ||
| Molecular formula | C14H24O4 | ||
| Molecular mass | 256.35 | ||
| SMILES code | O=C1OC(CC1)CCCCCCCCC(=O)OC | ||
1H NMR
| 1H-NMR: 9-(5-Oxotetrahydrofuran-2-yl)nonanoic acid methyl ester | |||
| 500 MHz, CDCl3 | |||
| delta [ppm] | mult. | atoms | assignment |
| 1.24-1.45 | m | 10 H | 4-H, 5-H, 6-H, 7-H, 8-H |
| 1.57 | m | 2 H | 3-H |
| 1.70 | m | 1 H | 9-H |
| 1.82 | m | 1 H | 9-H |
| 2.27 | t | 2 H | 2-H |
| 2.30 | m | 2 H | 3-H (ring) |
| 2.50 | m | 2 H | 4-H (ring) |
| 3.67 | s | 3 H | O-CH3 |
| 4.48 | m | 1 H | 2-H (ring) |
13C NMR
| 13C-NMR: 9-(5-Oxotetrahydrofuran-2-yl)nonanoic acid methyl ester | |||
| 125.7 MHz, CDCl3 | |||
| delta [ppm] | assignment | ||
| 24.9 | C3 | ||
| 25.2 | C9 | ||
| 28.0-29.2 | C4, C5, C6, C7, C8, C3 (ring) | ||
| 34.0 | C2 | ||
| 35.5 | C4 (ring) | ||
| 51.4 | O-CH3 | ||
| 81.0 | C2 (ring) | ||
| 174.2 | C1 (O-C(=O)-) | ||
| 177.2 | C5 (O-C(=O)-, ring) | ||
| 76.5-77.5 | CDCl3 | ||
IR |
| IR: 9-(5-Oxotetrahydrofuran-2-yl)nonanoic acid methyl ester | |||
| [Film, T%, cm-1] | |||
| [cm-1] | assignment | ||
| 2931, 2856 | aliph. C-H valence | ||
| 1776 | C=O valence, lactone | ||
| 1737 | C=O valence, ester | ||
| Cu |
     |
|
Synthesis of 9-(5-oxotetrahydrofuran-2-yl)nonanoic acid methyl ester |
| Reaction type: | addition to alkenes, radical reaction, ring closure reaction |
| Substance classes: | alkene, halogencarboxylic acid ester, lactone |
| Techniques: | working with cover gas, stirring with magnetic stir bar, heating under reflux, evaporating with rotary evaporator, filtering, recrystallizing, heating with oil bath |
| Degree of difficulty: | Easy |
Operating scheme
Instructions
http://www.oc-praktikum.de/nop/en/instructions/pdf/4005_en.pdf
Instruction (batch scale 100 mmol)
Equipment 250 mL two-neck flask, protective gas supply, reflux condenser, heatable magnetic stirrer, magnetic stir bar, rotary evaporator, Buechner funnel, suction flask, desiccator, oil bath Substances undecenoic acid methyl ester (bp 248 °C) 19.8 g (22.3 mL, 100 mmol) iodoacetic acid ethyl ester (bp 73-74 °C/ 21 hPa) 27.8 g (15.4 mL, 130 mmol) copper powder (finely powdered, >230 mesh ASTM) 30.5 g (480 mmol) tert-butyl methyl ether (bp 55 °C) 130 mL petroleum ether (bp 60-80 °C) 300 mL Reaction In a 250 mL two-neck flask with magnetic stir bar and a reflux condenser connected with a protective gas piping 19.8 g (22.3 mL, 100 mmol) undecenoic acid methyl ester and 27.8 g (15.4 mL, 130 mmol) iodoacetic acid ethyl ester are mixed with 30.5 g (480 mmol) copper powder under a protective gas atmosphere. Afterwards the reaction mixture is stirred at 130 °C oil bath temperature under protective gas for 4 hours. (Reaction monitoring see Analytics.)
Work up The reaction mixture is cooled down to room temperature, 30 mL tert-butyl methyl ether are added, the mixture is stirred for 5 minutes and filtered off. The copper powder on the filter is washed four times with 25 mL tert-butyl methyl ether each. Filtrates and wash solutions are combined, the solvent is evaporated at the rotary evaporator. A yellow oil remains as crude product. Crude yield: 25.4 g.
The crude product is dissolved in 300 mL petroleum ether under reflux. The solution is allowed to cool down to room temperature, then it is stored in the refrigerator over night for complete crystallization. The crystalline product is sucked off over a Buechner funnel and dried in the vacuum desiccator. The mother liquor is stored again in the refrigerator for a check of complete crystallization. Yield: 19.5 g (76.1 mmol, 76%); white solid, mp 34 °C Comments In order to achieve a quantitative reaction within 4 hours, a fivefold excess of copper is used.
Waste management Recycling The copper powder can be used three times.
Waste disposal Waste Disposal evaporated tert-butyl methyl ether (might contain iodoethane) organic solvents, containing halogen mother liquor from recrystallization organic solvents, containing halogen copper powder solid waste, free from mercury, containing heavy metals
Time 6-7 hours
Break After heating and before recrystallizing
Degree of difficulty Easy
Analytics Reaction monitoring with TLC Sample preparation: Using a Pasteur pipette, two drops of the reaction mixture are taken and diluted with 0.5 mL diethyl ether. TLC-conditions: adsorbant: TLC-aluminium foil (silica gel 60) eluent: petroleum ether (60/80) : acetic acid ethyl ester = 7 : 3 visualisation: The TLC-aluminium foil is dipped in 2 N H2SO4 and then dried with a hot air dryer. Reaction monitoring with GC Sample preparation: Using a Pasteur pipette, one drop of the reaction mixture is taken and diluted with 10 mL dichloromethane. From this solution, 0.2 µL are injected. 10 mg from the solid product are dissolved in 10 mL dichloromethane. From this solution, 0.2 µL are injected. GC-conditions: column: DB-1, 28 m, internal diameter 0.32 mm, film 0.25 µm inlet: on-column-injection carrier gas: hydrogen (40 cm/s) oven: 90 °C (5 min), 10 °C/min to 240 °C (40 min) detector: FID, 270 °C Percent concentration was calculated from peak areas.
Chromatogram |
| GC: crude product | |
| column | DB-1, L=28 m, d=0.32 mm, film=0.25 µm |
| inlet | on column injection, 0.2 µL |
| carrier gas | H2, 40 cm/s |
| oven | 90°C (5 min), 10°C/min –> 240°C (40 min) |
| detector | FID, 270°C |
| integration | percent concentration calculated from relative peak area |
| GC: pure product | |
| column | DB-1, L=28 m, d=0.32 mm, film=0.25 µm |
| inlet | on column injection, 0.2 µL |
| carrier gas | H2, 40 cm/s |
| oven | 90°C (5 min), 10°C/min –> 240°C (40 min) |
| detector | FID, 270°C |
| integration | percent concentration calculated from relative peak area |
Substances required |
| Batch scale: | 0.01 mol | 0.1 mol | 10-Undecenoic acid methyl ester |
| Educts | Amount | Risk | Safety | ||||||
|---|---|---|---|---|---|---|---|---|---|
| 10-Undecenoic acid methyl ester |
|
19.8 g | H- EUH- | P- | |||||
| Iodoacetic acid ethyl ester |
|
27.8 g | H300 H314 EUH- | P264 P280 P305 + 351 + 338 P310 | |||||
| Reagents | Amount | Risk | Safety | ||||||
| Copper powder |
|
30.5 g | H400 EUH- | P273 | |||||
| Solvents | Amount | Risk | Safety | ||||||
| tert-Butyl methyl ether |
|
130 mL | H225 H315 | P210 | |||||
| Petroleum ether (60-80) |
|
300 mL | H225 H304 H315 H336 H411 EUH- | P210 P261 P273 P301 + 310 P331 | |||||
| Others | Amount | Risk | Safety | ||||||
| Sulfuric acid 2N |
|
H314 H290 EUH- | P280 P301 + 330 + 331 P305 + 351 + 338 P309 + 310 | ||||||
| Solvents for analysis | Amount | Risk | Safety | ||||||
| Petroleum ether (60-80) |
|
H225 H304 H315 H336 H411 EUH- | P210 P261 P273 P301 + 310 P331 | ||||||
| Acetic acid ethyl ester |
|
H225 H319 H336 EUH066 | P210 P261 P305 + 351 + 338 | ||||||
| Dichloromethane |
|
H351 H315 H319 H335 H336 H373 | P261 P281 P305 + 351 + 338 |
Substances produced |
| Batch scale: | 0.01 mol | 0.1 mol | 10-Undecenoic acid methyl ester |
| Products | Amount | Risk | Safety | |
|---|---|---|---|---|
| 9-(5-Oxotetrahydrofuran-2-yl)nonanoic acid methyl ester |
Equipment |
| Batch scale: | 0.01 mol | 0.1 mol | 10-Undecenoic acid methyl ester |
 |
two-necked flask 250 mL |  |
protective gas piping | |
 |
reflux condenser |  |
heatable magnetic stirrer with magnetic stir bar | |
 |
rotary evaporator |  |
suction filter | |
 |
suction flask |  |
exsiccator with drying agent | |
 |
oil bath |
Simple evaluation indices |
| Batch scale: | 0.01 mol | 0.1 mol | 10-Undecenoic acid methyl ester |
| Atom economy | 53.9 | % | |
| Yield | 76 | % | |
| Target product mass | 19.5 | g | |
| Sum of input masses | 370 | g | |
| Mass efficiency | 53 | mg/g | |
| Mass index | 19 | g input / g product | |
| E factor | 18 | g waste / g product |
………………
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Alternative solvents can make preparative liquid chromatography greener
DOI: 10.1039/C5GC00887E, Paper
Alternative solvents can make preparative liquid chromatography greener
E-mail: lvy33@163.com
Alternative solvents can make preparative liquid chromatography greener
To make preparative Reversed-Phase High Performance Liquid Chromatography (RP-pHPLC) greener, alternative solvents were considered among others in terms of toxicity, cost, safety, workability, chromatographic selectivity and elution strength. The less toxic solvents ethanol, acetone and ethyl acetate were proposed as possible greener replacements for methanol, acetonitrile and tetrahydrofuran (THF).
For testing their feasibility, five ginkgo terpene trilactones were used as model analytes. The best “traditional” eluent, i.e., methanol–THF–water (2
:1:7) was used as the benchmark. A generic two-step chromatographic optimization procedure by UHPLC consisting of (1) a simplex design using the Snyder solvent triangle and (2) HPLC modelling software was used.
In the first step, two ternary mixtures were found (acetone–ethyl acetate–water (20.25:3.75:76) and ethanol–ethyl acetate–water (9.5:7.5:83)), which already gave better results than the benchmark. The second step in which the influence of the gradient time, temperature and ratio of the two best ternary isocratic solvents was studied, led to an optimal 10.5 min gradient and a minimum resolution of 5.76.
In the final step, scale-up from 2.1 to 22 mm i.d. pHPLC columns proceeded successfully. When 0.5 g of the sample was injected, baseline separation was maintained. Chromatographic and absolute purities for products exceeded 99.5% and 95% respectively. This example shows that using less toxic and cheaper solvents for pHPLC can go hand in hand with higher productivity and less waste.
SEE
http://www.rsc.org/suppdata/c5/gc/c5gc00887e/c5gc00887e1.pdf
New Drug Approvals 