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SOFOSBUVIR HPLC

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Figure US20100298257A1-20101125-C00039

Figure US20100298257A1-20101125-C00042

SEE           http://www.google.co.in/patents/US20100298257

Example 28

  • Chemical Purity Determination by HPLC
  • Various HPLC conditions can be used to determine the chemical purity of the compounds disclosed herein. One such example is disclosed above in relation to the thermodynamic aqueous solubility studies. Another example is disclosed below.
  • HPLC Conditions:
    • LC: Waters Alliance 2695 Separations Module, Waters 2996 PDA detector and Waters Empower 2 Software (Version 6.00)
    • Column: Phenomenex Luna C18(2); 4.6×50 mm; 3 μm
    • Flow rate: 1.2 mL/min
    • Injection Volume: 10 μL
    • Mobile phase: Solvent A: 95% Water with 5% Methanol and 10 mM Ammonium Acetate; pH˜5.3
    • Gradient Solvent B: MeOH with 10 mM Ammonium Acetate hold at 0% B 3 min
      • 0-47% B 3-4 min
      • hold at 47% B 4-10 min
      • 47%-74% B 10-11 min
      • hold at 74% B 11-13.5 min
      • return to 0% B 13.5-13.6 min
      • hold at 0% B 13.6-15.5 min
  • Under these conditions, the purity of 4, RP-4, and SP-4 was determined to be ˜99.6, ˜99%, and ˜99.5%, respectively. It is noted that higher purities can be realized by optimizing the methods disclosed above.
  • Inspection of the XRPD diffractograms shows that the two crystalline single diastereoisomers gave clearly different XRPD patterns. Additionally, there was a clear difference in the melting point of the two crystalline diastereoisomers, with RP-4 having a considerably higher onset than SP-4 (136° C. vs. 94° C.).
  • Example 29Additional Separation Methods
  • The following SFC separation (conditions listed below) yielded adequate separation of a mixture of the diastereomers, RP-4 and SP-4.
  • Preparative Method: Analytical Method:
    Chiralpak AS-H (2 × 25 cm) SN# 07-8656 Chiralpak AS-H (25 ×
    0.46 cm)
    20% methanol/CO2 (100 bar) 20% methanol/CO2 (100 bar)
    50 ml/min, 220 nm. 3 ml/min, 220 nm.
    Conc.: 260 mg/30 ml methanol,
    inj vol.: 1.5 ml
  • The following SFC separation (conditions listed below) yielded adequate separation of a mixture of the diastereomers, RP-4 and SP-4.
  • Preparative Method: Analytical Method:
    Chiralpak IA(2 × 15 cm) 802091 Chiralpak IA(15 × 0.46 cm)
    30% isopropanol(0.1% DEA)/CO2, 40% methanol(DEA)/CO2, 100 bar
    100 bar
    60 mL/min, 220 nm. 3 mL/min, 220 nm.
    inj vol.: 2 mL, 20 mg/mL methanol
  • TABLE 16
    Summary of results from the batch characterization of RP-4, 4, and SP-4.
    Analysis RP-4 4 SP-4
    Proton NMR Single diastereoisomer 1:1 Mixture of Single diastereoisomer
    diastereoisomers
    XRPD Crystalline – different Amorphous Crystalline – different
    DSC from SP-4 Endotherm; 59° C. from RP-4
    Endotherm; melt – 136° C. Endotherm; melt – 94° C.
    TGA No wt loss, No wt loss, decomposition No wt loss,
    decomposition >240° C. >240° C. decomposition >240° C.
    IR See above See above See above
    Aq Solubility 1.58 6.11 5.65
    (mg · ml−1)
    HPLC Purity 96.9% 99.6% 99.5%
    40° C./75% RH No form change Deliquescence inside 1.5 h Deliquescence inside 4.5 h
    25° C./53% RH Deliquescence No form change
    GVS Non-hygroscopic up to 90% Non-hygroscopic up to 60%
    RH RH

 

 

    Example 27Thermodynamic Aqueous Solubility

  • Aqueous solubility was determined by suspending a sufficient amount of compound in water to give a maximum final concentration of ≧10 mg.ml−1 of the parent free-form of the compound. The suspension was equilibrated at 25° C. for 24 hours then the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg.ml−1 in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.
  • TABLE 14
    HPLC Method Parameters for Solubility Measurements
    Type of method: Reverse phase with gradient elution
    Column: Phenomenex Luna, C18 (2) 5 μm 50 × 4.6 mm
    Column Temperature 25
    (° C.):
    Standard Injections (μl): 1, 2, 3, 5, 7, 10
    Test Injections (μl): 1, 2, 3, 10, 20, 50
    Detection: 260, 80
    Wavelength,
    Bandwidth (nm):
    Flow Rate (ml · min−1): 2
    Phase A: 0.1% TFA in water
    Phase B: 0.085% TFA in acetonitrile
    Time (min) % Phase A % Phase B
    Timetable: 0.0 95 5
    1.0 80 20
    2.3 5 95
    3.3 5 95
    3.5 95 5
    4.4 95 5
  • [0306]
    Analysis was performed under the above-noted conditions on an Agilent HP1100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SR1.
  • TABLE 15
    Aqueous solubility result for RP-4, 4, and SP-4.
    pH of Unfiltered
    Sample ID mixture Solubility/mg · ml−1 Comments
    RP-4 7.12 1.58 Suspension
    4 7.03 6.11 Residual solid
    SP-4 6.88 5.65 Residual solid

 

 

 

Fig 1

FIG 1

Chemical structures of RBV, BOC, TVR, and VRT-127394. Shown are the chemical structures of the anti-HCV drugs RBV {1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide)} (A), BOC {(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S)-2(tertbutylcarbamoylamino)-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide} (B), TVR {(3S,3aS,6aR)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1, 2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide} (C), and VRT-127394 (R diastereoisomer of TVR) (D).

Blank plasma samples used for matrix effect (ME) assessment and for the preparation of calibration and control samples were obtained from citrated blood (1,850 × g, 10 min, +4°C, Beckman J6B centrifuge) collected from Vaquez disease patients on the occasion of their regular phlebotomy.

The blank plasma used for the preparation of the calibration and quality control (QC) samples was acidified with 10% FA (50 μl of 10% FA added to 950 μl of plasma). The acidification of plasma aims at preventing the conversion of TVR to its epimer VRT-127394 that occurs in vivo and in vitro. (Tibotec-Janssen, personal communication).

Equipment.The LC system used consisted of Rheos Allegro quaternary pumps equipped with an online degasser and an HTS PAL autosampler (CTC Analytics AG, Zwingen, Switzerland) controlled by Janeiro-CNS 1.1 software (Flux Instruments AG, Thermo Fischer Scientific Inc., Waltham, MA). Separations were done on a Hypercarb 3-μm column (2.1 mm ID by 100 mm; Thermo Fischer Scientific) placed in a column oven thermostat regulated at +80°C (HotDog 5090; ProLab GmbH, Reinach, Switzerland). The chromatographic system was coupled to a triple-stage quadrupole quantum mass spectrometer (Thermo Fischer Scientific) equipped with an electrospray ionization (ESI) Ion Max interface and operated with the Xcalibur software package (version 2.0; Thermo Fischer Scientific).

READ T……http://aac.asm.org/content/57/7/3147.full

READ

http://www.us.edu.pl/uniwersytet/jednostki/wydzialy/chemia/acta/ac14/zrodla/14_AC14.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291777/

 

 

UPDATE………….DEC2015
File:Sofosbuvir structure.svg

SOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)

Sofosbuvir synthesis routes currently used include the following two methods:



https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

Preparation Example 1 sofosbuvir implementation

Step (a):

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ8.25 & 7.94 (1: 1);

1 HNMR (CDCl 3 , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

13 C NMR (CDCl 3 , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

Step (b):

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ3.54ppm;

13 C NMR (CDCl 3 , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

MS (M + H): 530.1.

Preparation of compounds of formula 2 shown in Example 3-2

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

1 HNMR (CDCl 3 , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-18.16 / -18.26.

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(4) nucleophile as NaN 3 , phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN 3 (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N 3 ).

1 HNMR (CDCl 3 , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

31 PNMR- (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ2.04 / 2.19.

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

1 HNMR (CDCl 3 , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-2.71 / -2.93.

Preparation Example 3 sofosbuvir implementation

(1) X is SCN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

(2) X is N 3

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

(3) X is CN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

File:Sofosbuvir structure.svg


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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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