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Dalfopristin

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Dalfopristin

Dalfopristin;Dalfopristin Mesylate;(3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(DiethylaMino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a-octahydro-14-hydroxy-4,12-diMethyl-3-(1-Methylethyl)-3H-21,18-nitrilo-1H,22H-pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetr

Preparation: J.C. Barriere et al., EP 191662; eidem, US 4668669 (1986, 1987 both to Rhone-Poulenc)

Rhone-Poulenc Sante …..LINK

  • Dalfopristin
  • Dalfopristina
  • Dalfopristina [INN-Spanish]
  • Dalfopristine
  • Dalfopristine [INN-French]
  • Dalfopristinum
  • Dalfopristinum [INN-Latin]
  • RP 54476
  • UNII-R9M4FJE48E

Usage
A Viiginiamycin M1 (V672810) derivative. A streptogramin antibiotic used to treat infections by staphylococci and by vancomycin-resistant Enterococcus faecium.
Usage
Dalfopristin is a semi-synthetic analogue of ostreogyrcin A (virginiamycin M, pristinamycin IIA, streptogramin A) formed by addition of diethylaminoethylthiol to the 2-pyrroline group of ostreogyrcin, followed by oxidation to the sulphone. The structural changes provide a more hydrophobic compound with a readily ionisable group for generating a salt. Dalfopristin is used commercially in synergistic combination with quinupristin (70:30). There is little published data on the synthesis, biological or antibiotic activity of dalfopristin alone, however the combination product is highly effective, including activity against antibiotic resistant strains.
Brief background information
Salt ATC Formula MM CAS
J01FG02 C 34 H 50 N 4 O 9 S 690.86 g / mol 112362-50-2

Application

  • antibiotic (used for bacteremia caused by the vancomycin-resistant Enterococcus faecium )

Dalfopristin
Dalfopristin.png
Systematic (IUPAC) name
(3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(diethylamino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a- octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-nitrilo-1H,22H-pyrrolo[2,1-c][1,8,4,19]-dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a603007
Legal status
Pharmacokinetic data
Half-life 1 hour
Identifiers
CAS number 112362-50-2 Yes
ATC code None
PubChem CID 6435782
DrugBank DB01764
Chemical data
Formula C34H50N4O9S 
Mol. mass 690.85 g/mol

Dalfopristin is a semi-synthetic streptogramin antibiotic analogue of ostreogyrcin A (virginiamycin M, pristinamycin IIA, streptogramin A).[1] The combination quinupristin/dalfopristin (marketed under the trade name Synercid) was brought to the market by Rhone-Poulenc Rorer Pharmaceuticals in 1999.[2] Synercid (weight-to-weight ratio of 30% quinupristin to 70% dalfopristin) is used to treatinfections by staphylococci and by vancomycin-resistant Enterococcus faecium.[3]

Synthesis

Through the addition of diethylaminoethylthiol to the 2-pyrroline group and oxidation of the sulfate of ostreogrycin A, a structurally more hydrophobic compound is formed. This hydrophobic compound contains a readily ionizable group that is available for salt formation.[1]

Large Scale Preparation

Dalfopristin is synthesized from pristinamycine IIa through achieving a stereoselective Michael-type addition of 2-diethylaminoethanethiol on the conjugated double bond of the dehydroproline ring [4] . The first method found was using sodium periodate associated with ruthenium dioxide to directly oxidize the sulfur derivative into a sulfone. However, using hydrogen peroxidewith sodium tungstate in a 2-phase medium produces an improved yield, and is therefore the method of choice for large scale production.

The production of the dalfopristin portion of quinupristin/dalfopristin is achieved through purifying cocrystallization of the quinupristin and dalfopristin from acetone solutions.[4]

Physical Characteristics (as mesylate salt)

Appearance White to yellow solid
Physical State Solid
Solubility Soluble in ethanol, methanol, DMSO, DMF, and water (0.072 mg/ml)
Storage -20°C
Boiling Point 940.5°C at 760 mmHg
Melting Point 150°C
Density 1.27 g/cm^3
Refractive Index n20D 1.58
pK Values pKa: 13.18 (Predicted), pKb: 8.97 (Predicted)

Antimicrobial Activity

Alone, both dalfopristin and quinupristin have modest in vitro bacteriostatic activity. However, 8-16 times higher in vitro bactericidal activity is seen against many gram-positive bacteria when the two streptogramins are combined [5] . While quinupristin/dalfopristin is effective against staphylococci and vancomycin-resistant Enterococcus faecium, in vitro studies have not demonstrated bactericidal activity against all strains and species of common gram-positive bacteria.

Mechanism of Action

Both dalfopristin and quinupristin bind to sites located on the 50S subunit of the ribosome. Initial dalfopristin binding results in a conformational change of the ribosome, allowing for increased binding by quinupristin.[5] A stable drug-ribosome complex is created when the two drugs are used together. This complex inhibits protein synthesis through prevention of peptide-chain formation and blocking the extrusion of newly formed peptide chains. In many cases, this leads to bacterial cell death.

Mechanism of Resistance

Streptogramin resistance is mediated through enzymatic drug inactivation, efflux or active transport of drug out of the cell, and most commonly, conformational alterations in ribosomal target binding sites.[5] Enzymatic drug inactivation may occur in staphylococcal and enterococcal species through production of dalfopristin-inactivating acetyltransferase or quinupristin-inactivating hydrolase. Efflux or active transport of the drug may occur in coagulase-negative staphylococci and Enterococcus faecium. Constitutive ribosome modification has been seen in staphylococci with resistance seen in quinupristin only.

While resistance to dalfopristin may be conferred via a single point of mutation, quinupristin/dalfopristin offers the benefit of requiring multiple points of mutation targeting both dalfopristin and quinupristin components to confer drug resistance.[5] Comparatively, only 2-5% of staphylococcal isolates collected in France show resistance to a related streptogramin, pristinamycin, in over 35 years of use.

Drug Interactions

Both dalfopristin and quinupristin are extensively hepatically metabolized, excreted from the feces, and serve as an inhibitor of cytochrome P450 (CYP) 3A4 enzyme pathway.[5]Caution should be taken with concommitent use with drugs metabolized by the CYP3A4 pathway. Concomitant use of quinupristin/dalfopristin with cyclosporine for 2–5 days has shown to result in a two-fold increase in cyclosporine levels.

No adverse effects have been seen in patients with hepatic impairment and no recommendations by the manufacturer have been made for dose reduction ofquinupristin/dalfopristin in this patient population.

Commercialization

While little information is available regarding the regulatory and commercialization history of Dalfopristin alone, Synercid (quinupristin/dalfopristin), made by Rhone-Poulenc Rorer Pharmaceuticals, was approved in 1999 as an IV injectable for the treatment of vancomycin resistant Enterococcus faecium and complicated skin and skin structure infections.[2]Dalfopristin can be purchased alone on the internet from various chemical manufacturers as a mesylate salt.

Synthesis pathway

Synthesis a)

US 4668669

OR

http://www.google.com/patents/EP0191662A1

    EXAMPLE 4

  • By proceeding in a similar manner to that described in subs. Ple 1, but starting from 5.5 g of (2-dimethylamino ethyl) thio-26 pristinaffycine II B, of 0.67 cm3 trifluoroacetic acid 1.8 g of meta-chloroperbenzoic acid and after purification by “flash” chromatography [eluent: chloroform-methanol (90:10 by volume)], collecting fractions of 30 cm3 and concentration to dryness fractions 23-40 under reduced pressure (2.7 kPa) at 30 ° C, 0.4 g of (2-dimethylamino ethyl) sulfinyl-26 pristinamycin II B (isomer A 2 70% 1 15% A isomer, isomer B 1 7%, isomer B 28%) as a yellow powder melting at 150 ° C.
  • NMR spectrum (isomer 2):

    • 1.77 (s,-CH 3 at 33)
    • 2.41 (s, – N (CH 3) 2)
    • 2.70 to 3.20 (mt,
      Figure imgb0032

      > CH 2-15 and H 4)

    • 3.82 (s,> CH 2 at 17)
    • 4.84 (m, – H 3 and H-27)
    • 5.52 (d,H13)
    • 6.19 (d, H-11)
    • 6.42 (m,> NH at 8)
    • 8.14 (s, – H 20)
  • The (2-dimethylamino ethyl) thio pristinamycin II B-26 can be prepared as follows:

    • By proceeding in a similar manner to that described in Example 3, but using 2.7 g of pristinamycin II A and 0.58 g of dimethylamino-ethanethiol and 2 after purification by “flash” chromatography [eluent: chloroform -methanol (90:10 by volume)] and concentration to dryness fractions 11-17 under reduced pressure (2.7 kPa) at 30 ° C, 1.1 g of (2-dimethylamino ethyl) thio-26 pristinamycin II B as a yellow powder melting at 100 ° C.
  • NMR spectrum:

    • 2.35 (s, 6H:-N (CH 3) 2)
    • 2.80 (m, 4H:-S-CH 2 CH 2 – <N)
    • 3 40 (ddd, 1H: – H 26)
    • 4.75 (d, 1 H, H-27)
    • 8.10 (s, 1 HH 20)

Trade Names

Country Trade name Manufacturer
Germany Sinertsid Aventis Pharma
United Kingdom – “- Aventis
Italy – “- Aventis
USA – “- Aventis
Ukraine No No

Formulations

  • injection of 180 mg / vial, 420 mg / vial

Links

  • US 4,668,669 (Rhône-Poulenc Sante; 26.5.1987; F-prior. 11.1.1985).
  • US 4,798,827 (Rhône-Poulenc Sante; 17.1.1989; F-prior. 22.5.1986).
  • GB 2206879 (Rhône-Poulenc Rorer; appl. 7/7/1987; GB -prior. 18/1/1989).

Chemical structure for DALFOPRISTIN

References

  1.  Dalfopristin (as mesylate) (CAS 112362-50-2)
  2.  http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/50747_Synercid.cfm
  3.  Allington DR, Rivey MP (2001). “Quinupristin/dalfopristin: a therapeutic review”. Clin Ther 23 (1): 24–44. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478.
  4.  Barriere, J.C.; Berthaud, N.; Beyer, D.; Dutka-Malen, S.; Paris, J.M.; Desnottes, J.F. (April 1998). “Recent Developments in Streptogramin Research”. Current Pharmaceutical Design 4 (2): 155–190. PMID 10197038. Retrieved 24 November 2013.
  5. Allington, Douglas R.; Rivey, Michael P. (January 2001). “Quinupristin/Dalfopristin: A Therapeutic Review”. Clinical Therapeutics 23 (1): 1–21. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478.

Dalfopristin

Title: Dalfopristin
CAS Registry Number: 112362-50-2
CAS Name: (26R,27S)-26-[[2-(Diethylamino)ethyl]sulfonyl]-26,27-dihydrovirginiamycin M1
Additional Names: 26-(2-diethylaminoethyl)sulfonylpristinamycin IIB
Manufacturers’ Codes: RP-54476
Molecular Formula: C34H50N4O9S
Molecular Weight: 690.85
Percent Composition: C 59.11%, H 7.29%, N 8.11%, O 20.84%, S 4.64%
Literature References: Semisynthetic polyunsaturated macrolactone type II streptogramin, q.v. Prepn: J.-C. Barriere et al., EP191662; eidem, US 4668669 (1986, 1987 both to Rhone-Poulenc). In vitro activity: H. C. Neu et al., J. Antimicrob. Chemother. 30,Suppl. A, 83 (1992). HPLC determn in plasma: A. Le Liboux et al., J. Chromatogr. B 708, 161 (1998)
Properties: White solid, mp ~150°.
Melting point: mp ~150°
Derivative Type: Mixture with quinupristin
CAS Registry Number: 126602-89-9
Manufacturers’ Codes: RP-59500
Trademarks: Synercid (Rh>e-Poulenc)
Literature References: Semisynthetic streptogramin comprised of two synergistic components in a defined 70:30 percent w/w mixture of dalfopristin and quinupristin, q.v., mesylate salts. HPLC determn for quality control: B. Vasselle et al., J. Pharm. Biomed. Anal. 19, 641 (1999). In vitro activity in comparison with pristinamycin, q.v.: A. Lozniewski et al., Pathol. Biol. 48, 463 (2000). Clinical trial in vancomycin resistant Enterococcus faecium (VREF) infection: R. C. Moellering et al., J. Antimicrob. Chemother. 44, 251 (1999); in skin infections: R. L. Nichols et al., ibid. 263. Review: B. Pavan, Curr. Opin. Invest. Drugs 1, 173-180 (2000).
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Antibiotics).
EP0252720A2 * Jul 7, 1987 Jan 13, 1988 MAY &amp; BAKER LIMITED Pristinamycin process
EP0298177A1 * Jul 7, 1987 Jan 11, 1989 Rhone-Poulenc Sante Process for preparing pristinamycine IIB derivatives
US4866172 * Apr 12, 1988 Sep 12, 1989 May & Baker Limited Pristinamycin process
WO1992001693A1 * Jul 15, 1991 Jan 17, 1992 Rhone Poulenc Rorer Sa Method for the preparation of sulphinyl pristinamycin ii¿b?
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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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