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Showing posts with label MUMBAI FOOD. Show all posts
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Monday 22 June 2015

Pravastatin Sodium


Pravastatin.svg
Pravastatin Sodium
Pravastatin Sodium
CAS : 81131-70-6
(bR,dR,1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-Hexahydro-b,d,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-1-oxobutoxy]-1-naphthaleneheptanoic acid monosodium salt
sodium (+)-(3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methylbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoate; eptastatin sodium; 3b-hydroxycompactin sodium salt
CS-514; SQ-31000, Elisor (BMS); Lipostat (BMS); Liprevil (Schwarz); Mevalotin (Sankyo); Oliprevin (BMS); Pravachol (BMS); Pravaselect (Menarini); Pravasin (BMS); Selectin (BMS); Selipran (BMS); Vasten (Specia)
Molecular Formula: C23H35NaO7
Molecular Weight: 446.51
C 61.87%, H 7.90%, Na 5.15%, O 25.08%
Antilipemic; HMG CoA Reductase Inhibitors;
Properties: Odorless, white to off-white, fine or crystalline powder. uv max (methanol): 230, 237, 245 nm. Sol in methanol, water; slightly sol in isopropanol. Practically insol in acetone, acetonitrile, chloroform, ether.
Absorption maximum: uv max (methanol): 230, 237, 245 nm
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]
…………………………..
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
…………………………
US2005/113446 A1, ; Page/Page column 6 ;
……………………………
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
Figure imgf000015_0001
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

  1. “Prevachol”The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  2. 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.288.23.2998PMID12479764.
  3.  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
  4. Williams, Eni. “Pravachol Side Effects Center”. RxList. Retrieved 1 December 2012.
  5. “Pravastatin”LactMed. U.S. National Library of Medicine. Retrieved 1 December 2012.
  6. Vaughan, C. J., and A. M. Gotto, Jr. 2004. Update on statins: 2003. Circulation 110: 886–892.
  7. 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)80020-1PMID3091343.
  8. “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
HMG-CoA reductase inhibitor; bioactive metabolite of mevastatin, q.v. Prepn by microbial hydroxylation: A. Terahara, M. Tanaka, DE 3122499eidem, US 4346227 (1981, 1982 both to Sankyo);
N. Serizawa et al., J. Antibiot. 36, 604 (1983).
Structure elucidation: H. Haruyama et al., Chem. Pharm. Bull. 34, 1459 (1986).
HPLC determn in biological fluids: S. Baueret al.J. Chromatogr. B 818, 257 (2005).
Effect on serum lipid concentration: N. Nakaya et al., Atherosclerosis 61, 125 (1986);
on hepatic metabolism of cholesterol: E. Reihnér et al., N. Engl. J. Med. 323, 224 (1990).
Clinical comparison with probucol, q.v.: G. Yoshino et al., Lancet 2, 740 (1986).
Clinical reduction of risk of major cardiovascular events in patients with coronary heart disease: LIPID Study Group, N. Engl. J. Med. 339, 1349 (1998).
Clinical effect on risk of stroke: H. D. White et al., ibid. 343, 317 (2000).
Derivative Type: Lactone
Molecular Formula: C23H34O6
Molecular Weight: 406.51
Percent Composition: C 67.96%, H 8.43%, O 23.61%
Properties: Colorless plate crystals, mp 138-142°. [a]D22 +194.0° (c = 0.51 in methanol). uv max (methanol): 230, 237, 245 nm.
Melting point: mp 138-142°
Optical Rotation: [a]D22 +194.0° (c = 0.51 in methanol)
Absorption maximum: uv max (methanol): 230, 237, 245 nm

 

 

 

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Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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