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Showing posts with label RUSSIA. Show all posts
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Sunday 26 July 2015

Voriconazole



ChemSpider 2D Image | Voriconazole | C16H14F3N5O.
 VORICONAZOLE


CAS  137234-62-9
(aR,bS)-a-(2,4-Difluorophenyl)-5-fluoro-b-methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimideethanol
 2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
Manufacturers' Codes: UK-109496
Trademarks: Vfend (Pfizer)
MF: C16H14F3N5O
MW: 349.31
Percent Composition: C 55.01%, H 4.04%, F 16.32%, N 20.05%, O 4.58%
Properties: mp 127°. [a]D25 -62° (c = 1 in methanol).
Melting point: mp 127°
Optical Rotation: [a]D25 -62° (c = 1 in methanol)
Therap-Cat: Antifungal (systemic)

1H NMR......... http://file.selleckchem.com/downloads/nmr/S144202-Voriconazole-HNMR-Selleck.pdf
1H NMR DMSO-d6, peak at 3.3 is HOD


m.p=134
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 
9.04 (1H), 
8.84 (1H), 
8.23 (1H), 
7.61 (1H), 
7.28 (1H), 
7.17 (1H), 
6.91 (1H), 
5.97 (1H), 
4.80 (1H), 
4.34 (1H), 
3.93 (1H), 
1.1 (3H).............US8263769



13 C NMR
DMSO-d6



 1H NMR PREDICT


 





 13C NMR PREDICT




COSY PREDICT


HMBC PREDICT






HPLC


Voriconazole, (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol having the structure of formula (I), is an antifungal drug used for preventing or treating fungal infection, e.g., human local fungal infection caused by candida, trichophyton, microspourum or epidemophyton; mucosal infection, by candida albicans (e.g., thrush and candidiasis); and whole body fungal infection, by aspergilus.

Voriconazole has two asymetric carbon atoms, and therefore, 4 stereoisomers, enantiomers of two diastereomeric pairs are involved in the preparation thereof which is generally conducted by a) separating an enantiomeric pair having (2R,3S) and (2S,3R) configurations; and then b) separating the (2R,3S)-stereoisomer using an optically active acid (e.g., R-(−)-10-camphosulfonic acid). The structural specificity and instability under a basic condition make the stereoselective synthesis of voriconazole difficult.
To date, only two methods for preparing voriconazole have been reported. One is based on a coupling reaction using an organic lithium salt, and the other, on Reformatsky-type coupling reaction.
For example, Korean Patent No. 1993-0011039 and European Patent No. 0,440,372 disclose a method shown in Reaction Scheme A for preparing the desired enantiomeric pair by a) adding an organic lithium derivative of 4-chloro-6-ethyl-5-fluoropyrimidine to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone at −70° C.˜−50° C. to obtain an enantiomer mixture; and b) separating the desired enantiomer by chromatography.

However, this coupling reaction using a strong base such as LDA or NaHMDS produces (2R,3S)/(2S,3R) and (2R,3R)/(2S,3S) diastereomers in a mole ratio of 1.1:1 without stereoselectivity, and the desired (2R,3S)/(2S,3R)-enantiomeric pair is isolated in a yield of only 12˜25%. Further, the lithium salt used in the reaction is difficult to be applied to mass production because of the required anhydrous condition at −78° C.
PCT Publication No. WO 2006/065726 discloses a method shown in Reaction Scheme B for preparing the desired enantiomeric pair by repeating the procedure of Reaction Scheme A except for using a different solvent.

However, despite the merit of this reaction which allows the separation of the desired enantiomeric pair by crystallization, it is hampered by the same problems associated with Reaction Scheme A and the yield of the desired enantiomeric pair is only 26%.
In order to solve the problems, as shown in Reaction Scheme C, Korean Patent Publication No. 1999-0036174 and U.S. Pat. No. 6,586,594 B1 disclose a method for preparing voriconazole by conducting Reformatsky-type reaction to enhance the stereoselectivity and yield, and then reductively removing the chlorine substituent in the presence of a palladium catalyst.

In this reaction, the (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pairs were formed in a mole ratio of 9:1, and the yield of the isolated voriconazole hydrochloride was as high as 65%. However, the pyrimidine derivative used as a starting material is difficult to remove when remains unreacted, which leads to the lowering of the product purity.
Further, the literature ([Organic Process Research & Development 2001, 5, 28-36], Pfizer Inc.) teaches that the chlorine substituent of the pyrimidine derivative adversely influences the coupling reaction pattern as shown in Reaction Scheme D and Table 1.


TABLE 1
Reformatsky-type reaction of compounds (VI, VII) and (IV)
Compound Compound Unreacted Debrominated Compound Compound
Pyrimidine (VIII) (%) (IX) (%) pyrimidine (%) pyrimidine (%) (X) (%) (XI) (%)
Compound 47.5 24.0 0.0 15 4.3 9.2
(VI)
Compound 5.3 4.6 8.5 28 0.0 51.6
(VII)
Example 1 of Korean Patent Publication No. 1999-0036174 (see Reaction Scheme C) shows that the (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pairs were obtained in a mole ratio of 10:1, but the product mixture contained unreacted compound of formula (IV) (7%) and unknown byproduct suspected to be the compound of formula (XI) (14%). Thus, the procedure of Reaction Scheme C gives an impure product mixture, the isolation of the desired product by recrystallization giving only a yield of 40˜45%.

 MORE..................


In the synthesis of Voriconazole, it is thought that two important steps are step i) of preparing the pyrimidine derivative as an intermediate for use in the subsequent coupling reaction with high yield and high purity, and step ii) of increasing stereoselectivity in carrying out the coupling reaction between the pyrimidine derivative and the ketone derivative to obtain the resultant tertiary alcohol with high purity and high yield.
First, the pyrimidine derivative has been prepared as depicted in the following Reaction Scheme 1 under reflux without any solvent according to Korean Patent No. 1993-0011039 and EP 0440372. It is reported that the yield of pyrimidine derivative is as low as 66%. However, the method of Reaction Scheme 1 is not suitable for mass production owing to its severe reaction condition and low yield.
In addition, Korean Patent No. 10-0269048 and EP 0871625 disclose that the pyrimidine derivative is prepared via the method of Reaction Scheme 1 in the presence of a solvent, and the yield of the target product is 90%. However, in this case, there are problems in that phosphoryl chloride used in an excessive amount is hardly removed and the resultant product has low purity.
Meanwhile, Korean Unexamined Patent Publication No. 10-2009-0014468 discloses a process for preparing substituted thiopyrimidine derivatives by introducing a thiol group to a pyrimidine derivative, as shown in the following Reaction Scheme 2, to increase the purity of the pyrimidine derivative.
However, the above process is not amenable to industrial mass production due to the increased number of steps as compared to Reaction Scheme 1, the use of expensive thiol derivatives, and the bad odor generated during the step using thiol. Next, Korean Patent No. 1993-0011039 and EP 0440372 disclose processes for carrying out a coupling reaction between pyrimidine derivatives and ketone derivatives. Herein, as shown in the following Reaction Scheme 3, LDA (lithium diisopropylamide), a strong base, or sodium bis(trimethylsilyl)amide is used to perform the coupling reaction.
However, the above methods are problematic in that they use highly explosive strong bases and require equipment capable of cryogenic reaction. Above all, the methods provide very low yield due to the low stereoselectivity and difficulty in separating isomers, and thus are not amenable to mass production.
To overcome the above-mentioned problems, Korean Patent No. 10-0269048 and EP 0871625 disclose a method by which the stereoselectivity is increased through the Reformatsky-type coupling reaction as depicted in the following Reaction Scheme 4, and enantiomeric pairs (2R,3S/2S,3R) are separated in the form of their hydrochloride salts via crystallization, thereby increasing the yield.
However, the method is problematic in that it results in a relatively low yield of 65% despite a high ratio of the enantiomeric pairs of 9:1 (2R,3S/2S,3R:2R,3R/2S,3S).
The method has another problem related to the removal of halo after the hydrochloride salts are treated with base.
EP 0069442 discloses a method for preparing 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone, one of the main intermediates of Voriconazole, according to the following Reaction Scheme 5.
However, the above method provides a low yield of 40%.






 








..............................

 Scheme E.

wherein,

 Example 7 Preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol(voriconazole)
10 g of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol (R)-camsylate obtained in Example 6 was added to a mixture of 50 ml of water and 50 ml of dichloromethane, and a 40% sodium hydroxide solution was slowly added thereto to adjust the pH to 11˜12. The organic layer was separated therefrom and dried over magnesium sulfate, and the organic solvent was removed under a reduced pressure. The resulting solution was crystallized with 18 ml of isopropanol, cooled to 0° C., stirred for 2 hours, and dried to obtain the white title compound (5.56 g, yield: 93%).
m.p=134
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.04 (1H), 8.84 (1H), 8.23 (1H), 7.61 (1H), 7.28 (1H), 7.17 (1H), 6.91 (1H), 5.97 (1H), 4.80 (1H), 4.34 (1H), 3.93 (1H), 1.1 (3H)
The optical purity of the compound obtained from HPLC analysis was >99.9%.
Comparative Example Preparation of (2R,3S)/(2S,3R)-(2R,3R)/(2S,3S)-3-(4-chloro-5-fluoropyrimidine-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol hydrochloride
5.29 g of zinc powder treated with 1N HCl and 0.26 g of lead powder were added to 33.5 ml of tetrahydrofuran and stirred, and 3.98 g of iodine dissolved in 10.6 ml of tetrahydrofuran was slowly added thereto for 10 min while heating to 45° C. The resulting mixture was cooled to 2° C., and a solution dissolving 3.53 g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone in 30 ml of tetrahydrofuran, 5 g of 6-(1-bromo-ethyl)-4-chloro-5-fluoropyrimidine and 0.32 g of iodine were slowly added thereto for 10 min. The obtained mixture was heated to 25° C. and reacted for 1 hour.
4.67 g of glacial acetic acid and 12 ml of water were added to the reaction solution, solid metal residue was filtered out, and tetrahydrofuran was removed under a reduced pressure.
The resulting residue was extracted twice with 66 ml of ethyl acetate, and the extract was successively washed with 4.67 g of disodium ethylenediaminetetraacetate dehydrate dissolved in 12 ml of water, and 30 ml of brine. The organic layer was concentrated to 40 ml volume, and 0.86 g of HCl dissolved in 4.3 ml of isopropanol was added thereto at 25° C.
The obtained crystal was filtrated, washed with 10 ml of ethyl acetate, and dried to obtain the title compound as a yellow crystal (2.81 g, yield: 42%).
m.p=126˜130° C.
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.84 (1H), 8.73 (1H), 7.93 (1H), 7.28 (1H), 7.20 (1H), 6.91 (1H), 4.82 (1H), 4.54 (1H), 3.93 (1H), 1.14 (3H)
The enantiomer ratio obtained from HPLC analysis of the reaction solution by using an internal standard material was 10:1, and 14.39% of unknown byproduct was formed. Further, the ratio of (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pair obtained from HPLC analysis of the crystallized hydrochloride was 94.4%:4.8%.


..................
http://www.google.co.in/patents/WO2009024214A1?cl=en


Example 18
(2R.3S)-2-(2.4-Difluorophenvn-3-(5-fluoropyrimidin-4-yl)-1 -d H-1.2.4-triazol-
1-yl)butan-2-ol (voriconazole), compound of Formula (\) To a solution of the racemic material as obtained in example 15 (1.28 g, 3.66 mmol) in acetone (29 ml) was added a solution of (1R)-10-camphorsulfonic acid (0.85 g, 3.66 mmol) in methanol (9.6 ml). The solvents were removed at reduced pressure, and the residue was dissolved in a mixture of acetone (10 ml) and methanol (2 ml). Crystals formed spontaneously after 3 h. Acetone (10 ml) was added, and the mixture was stirred overnight. The solid was isolated by filtration, washed with a small amount of acetone and dried. The solid was dissolved in a mixture of acetone (14 ml) and methanol (4 ml) at reflux. The solution was cooled to rt and stirred for 90 min. Isolation of the precipitate formed by filtration, washing with acetone and drying afforded 0.72 g of the acid addition salt. 0.70 g of the solid material was taken up in dichloromethane (10 ml) and water (10 ml), and the pH was adjusted to 11 by addition of aqueous sodium hydroxide (15% sol.). The layers were separated, and the aqueous layer was extracted with dichloromethane (5 ml). The combined organic layers were washed with water (3 x 10 ml) and brine, and dried (sodium sulfate). Concentration at reduced pressure afforded 0.36 g (28% yield, 56% of the available enantiomer) of voriconazole as a white crystalline solid. Purity, HPLC: 99.8% (RT=4.91 min). Mp. 122.6 0C (Lit. 134 0C). MS, m/z (% rel. int.): 224.0 (27), 350.1 (100), 391.0 (10). 1H NMR (600 MHz, DMSO-d6): δ 9.02 (1H, d, J 3.0 Hz)1 8.83 (1 H1 d, J 1.8 Hz), 8.21 (1 H1 s), 7.59 (1 H1 s), 7.24 (1H1 ddd, J 7.0 Hz, J 9.0 Hz, J 9.0 Hz), 7.16 (1H, ddd, J 2.4 Hz, J 9.0 Hz, J 11.8 Hz), 6.89 (1H, ddd, J 2.4 Hz, J 8.4 Hz, J 8.4 Hz), 5.95 (1 H, s), 4.77 (1 H, d, J 14.4 Hz), 4.31 (1H, d, J 14.4 Hz), 3.90 (1 H, q, J 7.0 Hz), 1.08 (3H1 d, J 7.0 Hz).
Example 19
(2R.3S)-2-(2.4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -d H-1.2.4-triazol-
1 -yl)butan-2-ol (voriconazole), compound of Formula (I) (2R,3S)-2-(2,4-Difluorophenyl)-3-[5-fluoropyrimidin-4-yl]-1-(1 H-1 ,2,4-triazol- 1-yl)butan-2- ol (R)-10-camphorsulfonate (656 g, 1.13 mol) was parted between dichloromethane (3 L) and water (3 L), and the pH of the aqueous phase was slowly adjusted to pH 12.3 with aqueous sodium hydroxide (40% w/v, 130 mL). The phases were separated, and the aqueous layer was extracted with dichloromethane (1 L). The combined organic layers were washed with water (3 x 1.5 L) and filtered. The solvent was changed to isopropanol (1.3 L) via gradual addition/evaporation at reduced pressure. After stirring for 3 h at 20 0C, the temperature was lowered to -5 0C. The mixture was stirred for another 1.5 h, and the product was isolated by suction filtration, washed with isopropanol (0.3 L) and dried at 20 0C and vacuum for 2.5 days. 285 g (72% yield) of the title compound was obtained as a white solid. Purity, HPLC: 99.8%. Optical purity, HPLC: >99.9%. 1H NMR (300 MHz, DMSO-d6): δ 9.05 (1H1 d, J 3.0 Hz), 8.86 (1H1 d, J 1.8 Hz), 8.24 (1H, s), 7.62 (1H, s), 7.24 (2H, m), 6.92 (1H, dt, J 2.1, 8.0 Hz), 5.99 (1H, s), 4.81 (1H1 d, J 14.1 Hz), 4.34 (1H1 d, J 14.4 Hz), 3.93 (1H, q, J 7.2 Hz), 1.11 (3H1 d, J 6.9 Hz). 13C NMR spectrum and IR spectrum for the isolated compound are attached.



 


......................
PAPER
J. Org. Chem.201378 (22), pp 11396–11403
DOI: 10.1021/jo4019528



..........................
Org. Proc. Res. Dev.20015 (1), pp 28–36
DOI: 10.1021/op0000879
(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1). ...............to provide the title compound as a white solid (7.6 g, 40% mass yield or 80% of available enantiomer), mp 134 °C
1H NMR (DMSO-d6) δ 1.1 (d, 3H), 3.93 (q, 1H), 4.34 (d, 1H), 4.80 (d, 1H), 5.97 (bs, 1H), 6.91 (ddd, 1H), 7.17 (ddd, 1H), 7.28 (ddd, 1H), 7.61 (s, 1H), 8.23 (s, 1H), 8.84 (s, 1H), 9.04 (s, 1H) ppm.




Cited PatentFiling datePublication dateApplicantTitle
US658659426 Jul 19961 Jul 2003Pfizer, Inc.Preparation of triazoles by organometallic addition to ketones and intermediates therefor
CN1488630A8 Oct 200214 Apr 2004张文更Method for preparing triazole antifungal agent
CN1814597A9 Dec 20059 Aug 2006北京丰德医药科技有限公司New method for preparing voriconazole
EP0440372A124 Jan 19917 Aug 1991Pfizer LimitedTriazole antifungal agents
GB2452049A

Title not available
WO1993007139A11 Oct 199215 Apr 1993Pfizer LtdTriazole antifungal agents
WO1997006160A126 Jul 199620 Feb 1997Michael ButtersPreparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A213 Dec 200522 Jun 2006Reddys Lab Ltd DrProcess for preparing voriconazole
WO2007013096A126 Jun 20061 Feb 2007Msn Lab LtdImproved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole)
WO2007132354A229 Jan 200722 Nov 2007Medichem SaProcess for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof
WO2009024214A1 *10 Jul 200826 Feb 2009Axellia Pharmaceuticals ApsProcess for the production of voriconazole
WO2009084029A22 Dec 20089 Jul 2009Venkatesh BhingolikarImproved process for the preparation of (2r,3s)-2-(2,4- difluqrophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol
US8575344 *1 Feb 20115 Nov 2013Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
US20130005973 *1 Feb 20113 Jan 2013Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
WO2011096697A2 *1 Feb 201111 Aug 2011Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
US8263769 *4 Aug 200811 Sep 2012Hanmi ScienceProcess for preparing voriconazole
US85753441 Feb 20115 Nov 2013Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
US20100190983 *4 Aug 200829 Jul 2010Hanmi Pharm, Co., Ltd.Process for preparing voriconazole

WO1997006160A1 *26 Jul 199620 Feb 1997Michael ButtersPreparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A2 *13 Dec 200522 Jun 2006Reddys Lab Ltd DrProcess for preparing voriconazole
EP0440372A1 *24 Jan 19917 Aug 1991Pfizer LimitedTriazole antifungal agents
Reference
1
Butters et al., "Process Development of Voriconazole: A Novel Broad-Spectrum Triazole Antifungal Agent," Organic Process Research & Development, 2001, vol. 5, pp. 28-36.

References:
Ergosterol biosynthesis inhibitor. Prepn: S. J. Ray, K. Richardson, EP 440372eidem, US 5278175 (1991, 1994 both to Pfizer); R. P. Dickinson et al.Bioorg. Med. Chem. Lett. 6, 2031 (1996).
Mechanism of action: H. Sanati et al.,Antimicrob. Agents Chemother. 41, 2492 (1997). In vitro antifungal spectrum: F. Marco et al., ibid. 42, 161 (1998).
HPLC determn in plasma: R. Gage, D. A. Stopher, J. Pharm. Biomed. Anal. 17, 1449 (1998).
Review of pharmacology and clinical development: P. E. Verweij et al., Curr. Opin. Anti-Infect. Invest. Drugs 1, 361-372 (1999); J. A. Sabo, S. M. Abdel-Rahman, Ann. Pharmacother. 34, 1032-1043 (2000).
Clinical pharmacokinetics: L. Purkins et al., Antimicrob. Agents Chemother. 46, 2546 (2002).
Clinical comparison with amphotericin B: T. J. Walsh et al., N. Engl. J. Med. 346, 225 (2002).


MOLFILE
COPY BLUE PORTION ONLY 
START
64684.mol
  ChemDraw07261512442D

 26 28  0  0  0  0  0  0  0  0999 V2000
    0.5118    1.1267    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.2030    0.7149    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.9179    0.3031    0.0000 H   0  0  0  0  0  0  0  0  0  0  0  0
   -0.6206    1.4298    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.2030    2.1447    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -0.6206    2.8595    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.4441    2.8595    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -1.8559    2.1447    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
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   -1.8559    0.7149    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    0.2088    0.0000    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5062   -0.4117    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.9236    0.4118    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.9236    1.2411    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.5928    1.7215    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.3354    2.5107    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.5118    2.5107    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.2545    1.7215    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.6205   -0.7149    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
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    0.6205   -2.1446    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.4440   -2.1446    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.8559   -2.8595    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    1.8559   -1.4297    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.4440   -0.7149    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.8559    0.0000    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
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M  END

END


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Aerial view of the spit (Strelka) of Vasilyevsky Island


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 सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE
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09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।



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