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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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Aseptic Manufacturing Operation: Chinese Company Zhuhai United Laboratories does not comply with EU GMP
While the focus of attention has been on Indian manufacturers during the last 2 years now also Chinese manufacturers are in the spot light. On 15 June 2015 the National Agency for Medicines and Medical Devices of Romania entered a GMP Non-Compliance Report for Zhuhai United Laboratories into EudraGMDP. Read more about the GMP deviations observed at Zhuhai United.
While the focus of attention has been on Indian manufacturers during the last 2 years now also Chinese manufacturers are again in the spot light. Just recently the EU found serious GMP deviations at an API manufacturer (Huzhou Sunflower Pharmaceuticals) and on 15 June 2015 the National Agency for Medicines and Medical Devices of Romania entered a GMP Non-Compliance Report for Zhuhai United Laboratories Co., LTD located at Sanzao Science &Technology Park, National Hi-Tech Zone, Zhuhai, Guangdong, 519040, China into EudraGMDP.
According to the report issued by the…
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Inna Ben-Anat, Global QbD Director of Teva Pharmaceuticals
Meet Inna Ben-Anat, Global QbD Director of Teva Pharmaceuticals. Inna is a key thought leader in Quality by Design for generics.
https://www.linkedin.com/pub/inna-ben-anat/6/47a/670
Ben-Anat, InnaASSOCIATE DIRECTOR, HEAD OF QDD STRATEGY | TEVA PHARMACEUTICALSAssociate Director, Head of QbD Strategy Chemical Engineer with a degree in Quality Assurance and Reliability (Technion-Israel Institute of Technology). QbD Strategy Leader at Teva (USA). Headed the implementation of a global QbD training programme. More than 12 years of pharmaceutical development experience.
Inna Ben-Anat is a Quality by Design (QbD) Strategy Leader in Teva Pharmaceuticals USA. In this role, Inna has implemented global QbD training program, and is supporting R&D teams in developing Quality by Design strategies, optimizing formulations and processes and assisting develop product specifications. Additionally, Inna supports Process Engineering group with process optimization during scale-up and supports Operations in identification and resolution of any technical issues. Inna has extensive expertise in process development, design…
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Determining Criticality-Process Parameters and Quality Attributes
Determining Criticality-Process Parameters and Quality Attributes Part I: Criticality as a Continuum
As the pharmaceutical industry tries to embrace the methodologies of quality by design (QbD) provided by the FDA’s process validation (PV) guidance (1) and International Conference on Harmonization (ICH) Q8/Q9/Q10 (2-4), many companies are challenged by the evolving concept of criticality as applied to quality attributes and process parameters. Historically, in biopharmaceutical development, criticality has been a frequently arbitrary categorization between important high-risk attributes or parameters and those that carry little or no risk. This binary designation was usually determined during early development for the purposes of regulatory filings, relying heavily on scientific judgment and limited laboratory studies.
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With the most recent ICH and FDA guidances…
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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
ML-236B, Mevastatin (compactin)
Mevastatin (compactin, ML-236B) is a hypolipidemic agent that belongs to the statins class.
It was isolated from the mold Penicillium citrinum by Akira Endo in the 1970s, and he identified it as a HMG-CoA reductase inhibitor,[1] i.e., a statin. Mevastatin might be considered the first statin drug;[2] clinical trials on mevastatin were performed in the late 1970s in Japan, but it was never marketed.[3] The first statin drug available to the general public was lovastatin.
In vitro, it has antiproliferative properties.[4]
A British group isolated the same compound from Penicillium brevicompactum, named it compactin, and published their results in 1976.[5] The British group mentions antifungal properties with no mention of HMG-CoA reductase inhibition.
High doses inhibit growth and proliferation of melanoma cells.[6]
| Systematic (IUPAC) name | |
|---|---|
| (1S,7R,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate | |
| Clinical data | |
| Identifiers | |
| 73573-88-3 |
|
| None | |
| PubChem | CID: 64715 |
| IUPHAR/BPS | 3031 |
| DrugBank | DB06693 |
| ChemSpider | 58262 |
| UNII | 1UQM1K0W9X |
| KEGG | C13963 |
| ChEBI | CHEBI:34848 |
| ChEMBL | CHEMBL54440 |
| Chemical data | |
| Formula | C23H34O5 |
| 390.513 g/mol | |
 |
|
Title: Mevastatin
CAS Registry Number: 73573-88-3
CAS Name: (2S)-2-Methylbutanoic acid (1S,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-7-methyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
Additional Names: 7-[1,2,6,7,8,8a-hexahydro-2-methyl-8-(methylbutyryloxy)naphthyl]-3-hydroxyheptan-5-olide; 2b-methyl-8a-(2-methyl-1-oxobutoxy)mevinic acid lactone; compactin; 6-demethylmevinolin
Manufacturers’ Codes: CS-500; ML-236 B
Molecular Formula: C23H34O5
Molecular Weight: 390.51
Percent Composition: C 70.74%, H 8.78%, O 20.49%
Literature References:
Fungal metabolite which is a potent inhibitor of HMG-CoA reductase, the rate controlling enzyme in cholesterol biosynthesis. Isoln from Penicillium citrinum: A. Endo et al., DE 2524355 corresp to US 3983140 (1975, 1976 to Sankyo).
Isoln from P. brevicompactum, crystal and molecular structure: A. G. Brown et al., J. Chem. Soc. Perkin Trans. 1 1976,1165.
Inhibition of HMG-CoA reductase activity: A. Endo et al., FEBS Lett. 72, 323 (1976); M. S. Brown et al., J. Biol. Chem. 253,1121 (1978).
Therapeutic effects in primary hypercholesterolemia: A. Yamamoto et al., Atherosclerosis 35, 259 (1980).
Total synthesis: N. Y. Wang et al., J. Am. Chem. Soc. 103, 6538 (1981); M. Hirama, M. Uei, ibid. 104, 4251 (1982); N. N. Girotra, N. L. Wendler, Tetrahedron Lett. 23, 5501 (1982); C.-T. Hsu et al., J. Am. Chem. Soc. 105, 593 (1983); P. A. Grieco et al., ibid. 1403; D. L. J. Clive et al., J. Am. Chem. Soc. 110, 6914 (1988). Review of syntheses: T. Rosen, C. H. Heathcock, Tetrahedron 42,4909-4951 (1986).
Review of mevastatin and related compounds: A. Endo, J. Med. Chem. 28, 401-405 (1985).
Properties: Crystals from aq ethanol, mp 152°. [a]D22 +283° (c = 0.48 in acetone). uv max: 230, 237, 246 nm (log e 4.28, 4.30, 4.11).
Melting point: mp 152°
Optical Rotation: [a]D22 +283° (c = 0.48 in acetone)
Absorption maximum: uv max: 230, 237, 246 nm (log e 4.28, 4.30, 4.11)
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References
- Endo, Akira; Kuroda M.; Tsujita Y. (December 1976). “ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium”. Journal of Antibiotics (Tokyo) 29 (12): 1346–8. doi:10.7164/antibiotics.29.1346. PMID 1010803.
- “The story of statins”.
- Endo, Akira (Oct 2004). “The origin of the statins”. Atheroscler Suppl. 5 (3): 125–30. doi:10.1016/j.atherosclerosissup.2004.08.033.PMID 15531285.
- Wachtershauser, A.; Akoglu, B; Stein, J (2001). “HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2”. Carcinogenesis 22 (7): 1061–7. doi:10.1093/carcin/22.7.1061. PMID 11408350.
- Brown, Allan G.; Smale, Terry C.; King, Trevor J.; Hasenkamp, Rainer; Thompson, Ronald H. (1976). “Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum.”. J. Chem. Soc., Perkin Trans. 1 (11): 1165–1170.doi:10.1039/P19760001165. PMID 945291.
- ^ Glynn, Sharon A; O’Sullivan, Dermot; Eustace, Alex J; Clynes, Martin; O’Donovan, Norma (2008). “The 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells”. BMC Cancer8: 9. doi:10.1186/1471-2407-8-9. PMC 2253545. PMID 18199328.
The present invention
http://www.google.com/patents/US6204032
is related to a new method for producing ML-236B, a precursor of pravastatin sodium, in particular to a method for producing ML-236B lactone form(I), free acid form (II), and sodium salt(III) shown in the following formulae by using a new microorganism isolated from soil. ML-236B is obtained from the culture broth of this microorganism and it is used as a substrate of pravastatin sodium which is a potent cholesterol-lowering agent used in treatment for hypercholesterolemia.
2. Description of the Prior Art
It has been known that heart disease such as myocardial infarction, arteriosclerosis have been caused mainly by hyperlipidemia, especially hypercholesterolemia. It was reported by U.S. Pat. No. 3,983,140 and UK. Patent No. 1,453,425 that a cholesterol-lowering compound called ML-236B produced by a fungus Penicillium sp. had been discovered. ML-236B is produced by soil microorganisms or chemical conversion. It was reported that Penicillium brevicompactin, Penicilmyces sp., Trichoderma longibraiatum, Trichoderma pseudokoningi, Hyphomyces chrisopomus and Penicillium citrium produced ML-236B(David et al., “Biotechnology of filamentous fungi”, p241; JP Publication No. Pyung 4-349034).
Particularly, Sankyo Pharmaceutical Company, Japan, had developed Penicillium citrium SANK 18767 by mutation of a strain Penicillium citrium NRRL-8082 which was reported in 1971. By continuing strain development for 14 years, they had obtained Penicillium citrium Thom SANK 13380. ML-236B productivity had risen from 1.75 mg/l to 42.5 mg/l.
However, the method above described required so much time about 14 years to develop a strain with high ML-236B productivity. It also needed a little long cultivation time, 14 days, and showed relatively low ML-236B productivity.
The invention will be described in more detail in the drawings.
FIG. 1 is the IR spectrum of ML-236B obtained from this invention;
and
FIG. 2 is the 13C-NMR spectrum of ML-236B obtained from this invention.
The physical properties such as appearance, melting point. molecular weight, elemental analysis, formular, UV spectrum, IR spectrum, solubility and specific rotation of ML-236B obtained from Example 2, 3 and Comparative Example are described in Table 1.
| TABLE 1 | ||
| COMPARATIVE | ||
| Article | EXAMPLE 2, 3 | EXAMPLE |
| Appearance | white crystal | white crystal |
| Melting point (° C.) | 150˜152 | 150˜152 |
| Molecular weight | calculated 390.2635 | experimental 390.2392 |
| experimental 390.2392 | ||
| Elemental | C 70.74, H 8.77, O 20.49 | C 70.74, O 20.49, H 8.77 |
| Analysis (%) | C 70.55 , H 8.69 | |
| calculated | C 70.85 , H 8.02 | |
| experimental | ||
| Formula | C23H34O5 | C23H34O5 |
| UV spectrum | 230, 237, 246 | 230, 237, 246 |
| (nm, MeOH) | ||
| IR spectrum | 3509, 2964, 2938, 2884, | 3509, 2964, 2938, 2884, |
| (cm−1, KBr ) | 1744, 1698, 1445, 1385, | 1744, 1699, 1445, 1385, |
| 1236, 1206, 1182, 1151, | 1236, 1206, 1182, 1150, | |
| 1077, 1056 | 1076, 1056 | |
| Solubility | methanol, chloroform, | methanol, chloroform, |
| soluble | ethanol, ethyl acetate | ethanol, ethyl acetate |
| insoluble | water | water |
| Specific rotation | +283n | +283n |
| [α]D | ||
13C NMR data of ML-236B are shown in Table 2 and FIG. 2.
| TABLE 2 | |||||
| The | δ c(ppm) | The | δ c(ppm) | ||
| number | EX- | COMPAR- | number | EX- | COMPAR- |
| of | AMPLE | ATIVE | of | AMPLE | ATIVE |
| carbon | 2,3 | EXAMPLE | carbon | 2,3 | EXAMPLE |
| C-1 | 171.50 | 170.67 | C-13 | 124.48 | 123.33 |
| C-2 | 39.31 | 38.44 | C-14 | 134.35 | 133.38 |
| C-3 | 63.18 | 62.12 | C-15 | 128.96 | 127.96 |
| C-4 | 36.88 | 35.84 | C-16 | 133.49 | 132.37 |
| C-5 | 77.22 | 76.26 | C-17 | 31.66 | 30.70 |
| C-6 | 33.75 | 32.82 | C-18 | 14.66 | 13.64 |
| C-7 | 24.83 | 23.78 | C-19 | — | — |
| C-8 | 37.66 | 36.67 | C-20 | 177.79 | 176.55 |
| C-9 | 38.31 | 37.40 | C-21 | 42.56 | 41.50 |
| C-10 | 68.45 | 67.51 | C-22 | 27.55 | 26.48 |
| C-11 | 27.06 | 26.30 | C-23 | 12.59 | 11.49 |
| C-12 | 21.74 | 20.74 | C-24 | 17.74 | 16.64 |
By using a new microorganism which was obtained from this invention, the productivity of pravastatin precursor was elevated highly and the pravastatin precursor could be prepared in a simple way in short time.
Therefore, the present invention could be used effectively in production of pravastatin precursor.
DR ANTHONY MELVIN CRASTO
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Pravastatin
Pravastatin (marketed as Pravachol or Selektine) is a member of the drug class of statins, used in combination with diet, exercise, and weight-loss for lowering cholesterol and preventing cardiovascular disease.
Medical uses
Pravastatin is primarily used for the treatment of dyslipidemia and the prevention of cardiovascular disease.[1] It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.[1]
The evidence for the use of pravastatin is generally weaker than for other statins. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT), failed to demonstrate a difference in all-cause mortality or nonfatal myocardial infarction/fatal coronary heart disease rates between patients receiving pravastatin 40mg daily (a common starting dose) and those receiving usual care.[2]
Mechanism of action
Pravastatin acts as a lipoprotein-lowering drug through two pathways. In the major pathway, pravastatin inhibits the function of hydroxymethylglutaryl-CoA (HMG-CoA) reductase. As a reversiblecompetitive inhibitor, pravastatin sterically hinders the action of HMG-CoA reductase by occupying the active site of the enzyme. Taking place primarily in the liver, this enzyme is responsible for the conversion of HMG-CoA to mevalonate in the rate-limiting step of the biosynthetic pathway for cholesterol. Pravastatin also inhibits the synthesis of very-low-density lipoproteins, which are the precursor to low-density lipoproteins (LDL). These reductions increase the number of cellular LDL receptors and, thus, LDL uptake increases, removing it from the bloodstream.[6] Overall, the result is a reduction in circulating cholesterol and LDL. A minor reduction in triglycerides and an increase in high-density lipoproteins (HDL) are common.
History
Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc..[7] It is presently being marketed outside Japan by thepharmaceutical companyBristol-Myers Squibb. In 2005, Pravachol was the 22nd highest-selling brand-name drug in the United States, with sales totaling $1.3 billion.[8]
The U.S. Food and Drug Administration approved generic pravastatin for sale in the United States for the first time on April 24, 2006. Generic pravastatin sodium tablets are manufactured byBiocon Ltd, India and TEVA Pharmaceuticals in Kfar Sava, Israel.[8]
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BIOCON LIMITED Patent: WO2005/19155 A1, 2005 ; Location in patent: Page/Page column 8 ;http://google.com/patents/WO2005019155A1?cl=en
The present invention relates to a novel process for the preparation of substantially pure l^^^^^δa-hexahydro-beta,delta/6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-/ (beta R, delta R, lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid, sodium salt.
BACKGROUND OF THE INVENTION
US 4,346,227 discloses l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid, sodium salt. The compound is also known by the synonyms 3-beta-Hydroxycompactin; Eptastatin and Pravastatin. The compound is used as cholestrerol lowering agent which inhibit the enzyme H G CoA reductase.
The step of conversion of l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid to its sodium salt is crilcial. The prior art methods convert the acid form into sodium salt form as final step to afford the sodium salt. The prior art methods for the preparation of sodium salt from the l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-t(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)-1-Naphthaleneheptanoic acid are disclosed herein as reference.
WO 98/45410 discloses preparation of 1,2,6,7,8,8a-hexahydro-beta,delta, 6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid sodium by feeding compactin sodium to the microorganism Streptomyces exfoliatus and recovering the hydroxylated compactin sodium (l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid sodium salt) by extraction, purification by semi preparative HPLC and crystallization.
The process involves use of HPLC, which is a tedious and expensive technique and cannot be scaled up beyond a limit.
WO 00/46175 discloses a process for preparation of
l/2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-1-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid sodium salt from lactone by hydrolyzing with sodium hydroxide.
Also amine salts can be transformed to sodium salt by treating with sodium hydroxide and/or sodium alkoxide.
When amine salts are employed, it involves an extra step i.e., the preparation of the amine salt.
US 2003/0050502 discloses a process for preparation of sodium salt of a statin by contacting a solution of hydroxy acid of the statin with sodium-2-ethylhexanoate and recovering the corresponding sodium salt.
The process involves use of expensive reagent sodium-2-ethyl hexanoate.
The prior art methods suffer from one or more disadvantages like use of expensive reagents, need of special equipment to carry out the operation or increased number of steps for the preparation of sodium salt of l,2,6,7,8,8a-hexahydro-beta,delta/6-trihydroxy-2-methyl-8-[(2S)-2-me hyl-l-oxobutoxy]-, (beta R,delta
R/lS^δS/δS/δaR)- 1-Naphthaleneheptanoic acid.
The present invention relates to a process, which overcomes all the disadvantages of the prior art and results in substantially pure product in high yields.
Example 1
To a solution of 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-δ-(2-methyl-butyryloxy)-l,2,6,7,δ,δa-hexahydro-naphthalen-l-yl]-heptanoic acid ( 70 g, 0.165 mol) in ethyl acetate (500 ml), solid sodium carbonate (δ.76 g, 0.0δ25 mol) was added and stirred for 2 hours. l,2/6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)-1-Naphthaleneheptanoic acid sodium salt was precipitated. The reaction mixture was filtered and cake was washed with ethyl acetate to get free flowing crystals of l,2,6,7,δ,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)- 1-Naphthaleneheptanoic acid sodium (FORMULA I). Yield: 65 g, δδ% Example 2
To a solution of 3,5~Dihydroxy-7-[6-hydroxy-2-methyl-δ-(2-methyl-butyryloxy)-l,2,6,7,δ,δa-hexahydro-naphthalen-l-yl]-heptanoic acid (10 Kg, 23.6 mol) in isobutyl acetate (60 L), solid sodium carbonate (1.25 Kg, 11.8 moi) was added and stirred for 3 hoursl,2,6,7,8,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)-1-Naphthaleneheptanoic acid sodium salt was precipitated. The reaction mixture was filtered and cake was washed with isobutyl acetate to get free flowing crystals of l,2,6,7,δ,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)- 1-Naphthaleneheptanoic acid sodium (FORMULA I). Yield: 9 Kg, δ5%
Example 3
To a solution of 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-δ-(2-methyl-butyryloxy)-l,2,6,7,δ,δa-hexahydro-naphthalen-l-yl]-heptanoic acid (100. Kg, 236 mol) in butyl acetate (600 L), solid sodium carbonate (12.5 Kg, 118 mol) was added and stirred for 3 hours. l,2,6,7,8,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)-1-Naphthaleneheptanoic acid sodium salt was precipitated. The reaction mixture was filtered and cake was washed with butyl acetate to get free flowing crystals of l,2,6,7,δ,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)- 1-Naphthaleneheptanoic acid sodium (FORMULA I). Yield: 95 Kg, 90%
FORMULA I
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US2005/113446 A1, ; Page/Page column 6 ;
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http://www.google.com/patents/EP0975738A1?cl=en
Description of the Drawings
The invention will be described in more detail in the drawings. Fig. 1 is the IR spectrum of pravastatin sodium Fig. 2 is the13C-NMR spectrum of pravastatin sodium Fig. 3 is the H-NMR spectrum of pravastatin sodium
EXPERIMENTAL EXAMPLE
The physical properties of pravastatin sodium obtained from Example 1 and Comparative Example are described in Table 3.
Table 3
IR spectrum, “C-NMR spectrum, H-NMR spectrum of pravastatin sodium obtained from this invention are represented in Fig. 1, Fig. 2 and Fig. 3, respectively. By using a new microorganism Streptomyces exfoliatus YJ-118 isolated from this invention, ML-236B concentration in culture broth could be raised to 0.5% (w/v) and pravastatin sodium productivity was increased up to 600—1,340 mg/ / much higher than that of other microorganisms (60 mg/ / ) .
EXAMPLE 1
To 125 ml Erlenmeyer flask containing 20 ml seed culture medium(I) that comprises glucose 1%, yeast extract 0.2%, skim milk 0.2%, casein hydrolyte (N-Z amine) 0.5%, pH 7.0. 0.02% (w/v) ML-236B was added and Streptomyces exfoliatus YJ-118 isolated from manufacturing Example was inoculated. The cultivation was done at 27° C., 200 rpm, for 2 days on a rotary shaker. 20 ml of seed culture above was inoculated in 2 l Erlenmeyer flask containing 400 ml production medium(II) that comprises glucose 1.0%, yeast extract 1.0%, polypeptone 0.5%. K2HPO4 0.1%, MgSO4.7H2O 0.05%, NaCl 0.01˜0.1%, pH 7.2 and the flask was cultured at 27° C., 150 rpm. One day after cultivation, 0.05% (w/v) ML-236B (formula II-a) was added every day till the final concentration of ML-236B in culture broth became 0.2% (w/v). The cultivation was continued at 27° C., 150 rpm for 6 days and 0.3% glucose was fed once every two days 2 times in total. After then, the culture broth was adjusted to pH 9.0 and stirred for 3 hr. After centrifugation cell mass was removed and the supernatant was applied to a column of HP-20 500 ml. After washed with water, pravastatin sodium was eluted with 25% acetone solution. Pravastatin sodium fraction was concentrated in vacuo and the residue was applied to semi preparative HPLC(Kromasil C18 resin). Pravastatin sodium was eluted with 35% acetonitrile solution and was obtained as white crystal 1,254 mg (627 mg/l),
References
- “Prevachol”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- No Authors Listed (2002). “Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)”. JAMA288 (23): 2998–3007. doi:10.1001/jama.288.23.2998. PMID12479764.
- Pfeffer MA, Keech A, Sacks FM, et al. “Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.” Circulation 2002;105:2341-2346
- Williams, Eni. “Pravachol Side Effects Center”. RxList. Retrieved 1 December 2012.
- “Pravastatin”. LactMed. U.S. National Library of Medicine. Retrieved 1 December 2012.
- Vaughan, C. J., and A. M. Gotto, Jr. 2004. Update on statins: 2003. Circulation 110: 886–892.
- Yoshino G, Kazumi T, Kasama T, et al. (1986). “Effect of CS-514, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on lipoprotein and apolipoprotein in plasma of hypercholesterolemic diabetics”. Diabetes Res. Clin. Pract.2 (3): 179–81. doi:10.1016/S0168-8227(86)80020-1. PMID3091343.
- “FDA Approves First Generic Pravastatin”. Retrieved 2008-01-20.
| WO2001044144A2 * | Dec 14, 2000 | Jun 21, 2001 | M Lakshmi Kumar | Process for the preparation of sodium salts of statins |
| US20020082295 * | Oct 5, 2001 | Jun 27, 2002 | Vilmos Keri | Pravastatin sodium substantially free of pravastatin lactone and epi-pravastatin, and compositions containing same |
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 