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LIDOCAINE

CAS Registry Number: 137-58-6 
CAS Name: 2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide 
Additional Names: 2-diethylamino-2¢,6¢-acetoxylidide; w-diethylamino-2,6-dimethylacetanilide; lignocaine 
Trademarks: Cuivasil (IDC); Lidoderm (Hind); LidoPosterine (Kade); Vagisil (Combe) 
Molecular Formula: C14H22N2O 
Molecular Weight: 234.34 
Percent Composition: C 71.75%, H 9.46%, N 11.95%, O 6.83% 
Literature References: Long-acting, membrane stabilizing agent against ventricular arrhythmia. Originally developed as a local anesthetic. Prepn: N. M. Löfgren, B. J. Lundqvist, US2441498 (1948 to Astra); A. D. H. Self, A. P. T. Easson, GB706409 (1954 to May & Baker); I. P. S. Hardie, E. S. Stern, GB758224 (1956 to J. F. Macfarlane & Co.); Zhuravlev, Nikolaev, Zh. Obshch. Khim.30, 1155 (1960). Toxicity studies: E. R. Smith, B. R. Duce, J. Pharmacol. Exp. Ther.179, 580 (1971); G. H. Kronberg et al.,J. Med. Chem.16, 739 (1973). Review of pharmacokinetics: N. L. Benowitz, W. Meister, Clin. Pharmacokinet.3, 177 (1978). Review of action as local anesthetic: Löfgren, Studies on Local Anesthetics: Xylocaine, A New Synthetic Drug (Hoeggstroms, Stockholm, 1948); Cooper, Pharm. J.171, 68 (1953). Reviews of anti-arrhythmic agents: J. L. Anderson et al.,Drugs15, 271 (1978); L. H. Opie, Lancet1, 861 (1980); E. Carmeliet, Ann. N.Y. Acad. Sci.427, 1 (1984). Comprehensive description: K. Groningsson et al.,Anal. Profiles Drug Subs.14, 207-243 (1985); M. F. Powell, ibid.15, 761-779 (1986). Review of use in treatment of postherpetic neuralgia: P. S. Davies, B. S. Galer, Drugs64, 937-947 (2004).Properties: Needles from benzene or alcohol, mp 68-69°. bp4 180-182°; bp2 159-160°. Insol in water. Sol in alcohol, ether, benzene, chloroform, oils. Partition coefficient (octanol/water, pH 7.4): 43. 
Melting point: mp 68-69° 
Boiling point: bp4 180-182°; bp2 159-160° 
Log P: Partition coefficient (octanol/water, pH 7.4): 43 
Derivative Type: Hydrochloride 
CAS Registry Number: 73-78-9; 6108-05-0 (monohydrate) 
Trademarks: Basicaina (Galenica); Batixim (So.Se.); Dynexan (Kreussler); Heweneural (Hevert); Licain (DeltaSelect); Lidesthesin (Ritsert); Lidofast (Angelini); Lidoject (Hexal); Lidrian (Baxter); Odontalg (Giovanardi); Sedagul (Wild); Xylocaine (AstraZeneca); Xylocard (AstraZeneca); Xylocitin (Jenapharm); Xyloneural (Strathmann) 
Molecular Formula: C14H22N2O.HCl 
Molecular Weight: 270.80 
Percent Composition: C 62.09%, H 8.56%, N 10.34%, O 5.91%, Cl 13.09% 
Properties: Crystals, mp 127-129°; monohydrate, mp 77-78°. Very sol in water, alcohol; sol in chloroform. Insol in ether. pH of 0.5% aq soln: 4.0-5.5. LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg). 
Melting point: mp 127-129°; mp 77-78° 
Toxicity data: LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg) 
Therap-Cat: Anesthetic (local); antiarrhythmic (class IB). 
Therap-Cat-Vet: Anesthetic (local). 
Keywords: Anesthetic (Local); Antiarrhythmic.

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CLIP

https://pubs.acs.org/doi/10.1021/ed076p1557

http://www.asianjournalofchemistry.co.in/User/ViewFreeArticle.aspx?ArticleID=19_7_12

PATENT

https://patents.google.com/patent/CN102070483B/en#:~:text=The%20method%20comprises%20the%20following,as%20solvent%20and%20carbonate%20isPreparation method of the present invention, it can be two-step approach, comprises the steps:1) 2,6-xylidine is dissolved in the acetone, adds carbonate then, the back that stirs drips chloroacetyl chloride, and 20~35 ℃ (room temperature) be stirring reaction 3h down; After-filtration is finished in reaction, and after filter cake was washed with water to filtrate and is neutrality, drying made intermediate chloracetyl-2, the 6-xylidine, and yield is about about 94%; 
2) intermediate that step 1) is made is dissolved in the acetone, adds carbonate then, and the back that stirs drips diethylamine, back flow reaction 8h; After-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, in the step 1) 2, the mol ratio of 6-xylidine, chloroacetyl chloride and carbonate is 1: 1.2~1.7: 1.3~2.0, is preferably 1: 1.5: 1.6. 
Step 2) intermediate chloracetyl-2 in, the mol ratio of 6-xylidine, diethylamine and carbonate is 1: 1.5~2.5: 1.2~2.0, is preferably 1: 2: 1.5.In addition, preparation method of the present invention owing to all be that solvent, carbonate are catalyzer with acetone in the two-step reaction, therefore can further optimize reaction process on the basis of two-step approach, namely the intermediate of Sheng Chenging needn’t pass through aftertreatment, prepares lignocaine by one kettle way.Described one kettle way comprises the steps: 2,6-xylidine is dissolved in the acetone, adds carbonate then, after stirring, drips chloroacetyl chloride, and 20~35 ℃ (room temperature) be reaction 3h down; After reaction is finished, without processing, directly drip diethylamine, back flow reaction 8h, after-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, described 2, the mol ratio of 6-xylidine, chloroacetyl chloride, diethylamine and carbonate is 1: 1.2~1.7: 1.5~2.5: 2.5~3.5, is preferably 1: 1.5: 2: 2.5. 
In addition, preparation method of the present invention adopts TLC monitoring reaction progress, and the developping agent of TLC is sherwood oil: ethyl acetate (V/V)=3: 1.The invention has the advantages that, the method synthesis technique for preparing lignocaine of the present invention is simple, do not need in the intermediate aftertreatment first pickling numerous and diverse step of alkali cleaning again, avoided unnecessary loss, therefore the yield of the intermediate that makes of the inventive method and lignocaine is all higher, and the lignocaine purity that makes is good, reaches more than 99%, has favorable industrial application prospect; In addition, the inventive method uses acetone to make solvent, and this solvent is nontoxic substantially non-stimulated, and can recycle, and is environmentally friendly. 
EmbodimentBelow further specify the present invention by specific embodiment, but be not used for limiting the scope of the invention. 
Embodiment 1 two-step approach prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 200g salt of wormwood again, and mechanical stirring evenly back drips 100mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 156g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 94%, fusing point is 145.0~147.0 ℃.2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 112g salt of wormwood, drips the 60g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 90g white powder, is lignocaine, yield is 95%, and fusing point is 67.0~68.0 ℃, and content is 99.05%. 
Embodiment 2 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 163g salt of wormwood again, and mechanical stirring evenly back drips 80mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 136g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 82%, fusing point is 145~146 ℃. 
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 90g salt of wormwood, drips the 45g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 84g white powder, is lignocaine, yield is 89%, and fusing point is 66~67 ℃, and content is 99.15%. 
Embodiment 3 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 250g salt of wormwood again, and mechanical stirring evenly back drips 113mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 150g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 90%, fusing point is 147~148 ℃. 
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 150g salt of wormwood, drips the 75g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 88g white powder, is lignocaine, yield is 93%, and fusing point is 68~69 ℃, and content is 98.75%. 
Embodiment 4 one kettle ways prepare lignocaineIn the 5000mL there-necked flask, add 305g 2, the 6-xylidine, make solvent with 2000mL acetone, add 700g salt of wormwood again, mechanical stirring evenly back slowly drips 230mL chloroacetyl chloride (1.5h drips off), room temperature (35 ℃) is stirring reaction 3h down, and TLC point plate (use sherwood oil: ethyl acetate (V/V)=3: 1 is made developping agent) demonstration reacts completely; Dropwise 5 50g diethylamine then, the back back flow reaction 8h that stirs, TLC monitoring (developping agent is the same) shows and reacts completely; The reaction solution suction filtration, filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, gets light yellow solid, uses sherwood oil recrystallization secondary then, makes 482g white lignocaine crystal, and total recovery is 82%, and fusing point is 68.0~69.0 ℃, and content is 99.75%. 
Comparative example 1 existing method prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineIn the 1000mL there-necked flask, with 102g 2, the 6-xylidine is dissolved in the 400mL glacial acetic acid, stirs slowly to add the 100mL chloroacetyl chloride down, is heated to 45 ℃, adds 200g solid sodium acetate (containing crystal water) then, reaction 2h; After reaction finished, ice bath was cooled to below 10 ℃, suction filtration, filter cake is washed with water to filtrate and is neutral, and drying is 1 hour under 100 ℃ of temperature, makes the 111g white powder, be intermediate chloracetyl-2,6-xylidine, yield are that 67% fusing point is 145.0~148.0 ℃. 
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL toluene, and the dissolving back drips 60g diethylamine, back flow reaction 3.5h fast; After reaction finished, ice bath was cooled to 5 ℃, suction filtration, filtrate is used the 3mol/L hcl as extraction agent, and the acid solution that extraction is obtained is cooled to 10 ℃ then, stirs slowly to add 6mol/L KOH solution down, be alkalescence (pH8~9) to solution, with pentane extraction, organic layer was after washing, Anhydrous potassium carbonate drying after ice bath was cooled to 20 ℃, vapor bath is steamed and is desolventized, make the 74g white powder, be lignocaine, yield is 78%, fusing point is 66.0~67.0 ℃, and content is 97.15%.Embodiment 1 compares with comparative example 1, its intermediate chloracetyl-2, and the yield of 6-xylidine obviously improves, and reaches 94%, and the total recovery of final product lignocaine also is significantly improved, and the content of lignocaine is brought up to about 99%.Embodiment 4 compares with comparative example 1, and the total recovery of lignocaine is significantly improved, and reach 82%, and content is brought up to more than 99%. 
Though above with a general description of the specific embodiments, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention. 
CLIPhttps://www.cerritos.edu/chemistry/chem_212/Documents/Lab/10_lidocaine.pdf

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Procedure: (1st week)A: Synthesis of 2,6-Dimethylaniline via Reduction of 2,6-Dimethylnitrobenzene 1. Dissolve1.0 g of 2,6-dimethylnitrobenzene in 10 mL of glacial acetic acid in a 50 mL Erlenmeyer flask. 2. In a 25 mL flask, dissolve 4.6 grams of SnCl2 · 2H2O in 8 mL of concentrated HCl, inside the fume hood. 3. Add the SnCl2 solution in one portion to the nitroxylene solution, magnetically swirl and mix, and let the mixture stand for 15 minutes. 4. Cool the mixture and collect the crystalline salt (dimethylaniline in the salt form: C6H5NH3 +Cl- ) in a Buchner funnel. 5. Transfer the moist crystals to an Erlenmeyer flask, add 5-10 mL of water, and make the solution strongly basic (to remove the acid and change C6H5NH3 +Clback intoC6H5NH2) by adding 30% KOH solution (12 to 17 mL required). 6. After cooling extract with three 10 mL portions of ether, rinse the ether extracts twice with 10 mL of water, and dry over K2CO3. 7. Evaporate the dried and filtered solution to an oil, transfer and rinse into a 50 mL Erlenmeyer flask, complete evaporation, weigh, and calculate the %yield of 2,6-dimethylaniline. 
B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield. 
B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield. 
D. Synthesis of the bisulfate salt of lidocaine 1. Dissolve the lidocaine in ether (10 mL per gram of lidocaine) and add 2 mL of 2.2 M sulfuric acid in ethanol per gram of lidocaine. 2. Stir and scratch with a glass rod to mix and induce crystallization. 3. Dilute the mixture with an equal volume of acetone to aid filtration and collect the salt in a small Buchner funnel. 4. Rinse the solid on the funnel with a few milliliters of acetone and air dry and weigh the product. 5. Calculate the % yield of this step. *** Overall % Yield The overall % YCLIPhttp://home.sandiego.edu/~khuong/chem302L/Handouts/Lidocaine_handout_Su07.pdfSynthetic Strategy Lidocaine will be prepared via a three-step linear synthesis starting from 2,6-dimethylnitrobenzene. The reduction of 2,6-dimethylnitrobenzene 1 with three equivalents of stannous chloride (SnCl2) yields the ammonium salt 2. It is very important that the reaction mixture is strongly acidic during this reaction because the reduction of nitrobenzene using different reducing reagents and conditions can afford a variety of functional groups: nitroso, hydroxylamine (zinc dust, pH 4), azoxy (sodium arsenite), azo (zinc, weakly basic), or hydrazo (zinc, strongly basic). In industrial settings, often iron or tin with hydrochloric acid is used instead of stannous chloride because iron and tin are cheaper, but the reduction takes much longer. In the workup portion of the reaction, the ammonium salt 2 is reacted with an aqueous potassium hydroxide solution, liberating the free 2,6-dimethylaniline 3 in an acid-base reaction.

str1

The reaction of 3 with the bifunctional α-chloroacetyl chloride leads to α-chloro-2,6-dimethylacetanilide 4. A slight excess of the acid chloride is used to ensure the complete conversion of the amine to the amide. The formation of the amide is a result of the significantly higher reactivity (~106 times) of the acyl chloride over the alkyl chloride. The addition of sodium acetate solution avoids the formation of HCl which would protonate unreacted 3 causing it to co-precipitate with the desired product 4.

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In the last step, diethylamine performs a nucleophilic substitution (SN2) on the remaining alkyl chloride. Diethylamine serves both as a nucleophile to form lidocaine 5, and as acid scavenger, leading to formation of NH2Et2 + Cl- in this reaction. Since diethylamine is not a very strong nucleophile, it is used in excess here to improve the yield and speed up the reaction. The unreacted amine is later removed by extraction with water. The aqueous extraction of lidocaine with acid separates the unreacted chloroanilide 4 and the lidocaine. After addition of a strong base like aqueous potassium hydroxide, crude lidocaine is obtained.

str1

Procedure Synthesis of 2,6-dimethylaniline (3) Dissolve 15 g of SnCl2•2H2O in 27 mL of concentrated hydrochloric acid. If necessary, heat the mixture gently. Add this solution in one portion to a solution of 3 mL of 2,6-dimethylnitrobenzene in 34 mL of glacial acetic acid. Swirl the resulting mixture and then allow it to stand for 15 minutes before placing the mixture in an ice bath. Collect the formed precipitate by vacuum filtration. Place the wet precipitate obtained above in a beaker and add 20 mL of water. Neutralize the acidic mixture by carefully adding an 8 M aqueous potassium hydroxide with continuous stirring until basic to litmus. Place the mixture in an ice bath. Upon cooling to room temperature, extract the mixture three times with diethyl ether. Combine the organic layers and wash them twice with water and once with brine. Dry the organic layer over anhydrous potassium carbonate. Decant away from the drying agent and evaporate the diethyl ether from a dry, preweighed flask using a rotary evaporator. The oily residue will be your crude product 3. Obtain and record the following information: 1. crude product description (co2. crude weight/percent yieldSynthesis of α-chloro-2,6-dimethylacetanilide (4) Dissolve 3 in 17 mL of glacial acetic acid. Add 1.1 equivalents (based on the moles of 3) of α-chloroacetyl chloride to this solution. Heat the solution to 40-50 o C for ten minutes to complete the reaction. Upon cooling, add a solution of ~3.3 g sodium acetate trihydrate in 67 mL water and then place the resulting mixture in an ice bath. Collect the precipitate by vacuum filtration. Rinse the filter cake with copious amounts of water in order to remove the acetic acid. It is important that the product be completely free of acetic acid after this step (why?). The pH of the individual water rinses can be checked with litmus paper to determine if the product is acid free. Allow for the product to air-dry on a watch glass until the next meeting. There is a reasonable chance that you will not obtain a precipitate as described above. If this is the case, you can try “seeding” using a small sample of authentic product from a classmate. If this does not work, check the TLC to be sure that you have formed product and devise an extractive workup that will separate the unreacted aniline 3 from the desired product 4. (Make sure you understand how to do this even if you obtain a precipitate in the first place). After the aqueous workup and following removal of solvent, you should obtain a solid. If not, check the TLC, using a sample of authentic product from a classmate as a standard. If the product appears relatively pure, you can continue even though the material is not a solid. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. mp (if a solid) 
4. TLC analysis 5. IR (check for presence of amide functional group) Synthesis of lidocaine; α-(N,N-diethylamino)-2,6-dimethylacetanilide (5). In a round bottom flask, dissolve α-chloro-2,6-dimethylacetanilide 4 in 17 mL of toluene. Before continuing, spot several (4 to 5) TLC plates in advance with this solution of 4. Provide three lanes and spot the 4 on the “SM” and “CO-SPOT” lanes. You will use these plates to monitor the progress of this reaction. Add three equivalents of diethylamine to the round bottom flask, and reflux the mixture vigorously until the reaction is complete. The amount of time required for complete reaction depends on many factors but it will likely take anywhere from more than a few minutes up to several hours. If the reaction is not complete when your lab period ends, you can stopper the reaction and reflux it for additional time at the next period. Usually a white precipitate forms during the reflux. Upon cooling, transfer the reaction mixture to a separatory funnel and extract the mixture three times with water. Next, extract the organic layer with two portions of 3 M hydrochloric acid. Cool the combined acidic aqueous extracts in an ice bath and then add 8 M aqueous potassium hydroxide slowly until the mixture is strongly basic again. The formation of a thin, dark yellow oily layer on top or a white solid is observed at this point. Place the mixture in an ice bath. Once the mixture is chilled, try to initiate the crystallization of the final product if no solid has formed at this point. Collect the obtained precipitate by filtration using a Büchner funnel. Wash it with twice with water and then press it as dry as possible. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. TLC analysis Recrystallize the crude product from hexanes. Regardless of the final physical state of your product (solid or oil), obtain and record the following: 1. pure product description (color, physical state, etc.) 2. pure product weight/percent yield 3. overall (three-step) percent yield (from starting material 1) 4. TLC analysis 5. melting point (if a solid) 6. IR 7. 1 H and 13C NMR spectra of lidocaine will be given to you. Turn in a sample of your final product. 

1H NMR

13C NMR

MS

IR KBR

Lidocaine is an antiarrhythmic medicine and also serves as a local anaesthetic drug. It is utilized in topical application to relieve pain, burning and itching sensation caused from skin inflammations. This drug is mainly used for minor surgeries. Figure 1 shows the 1H NMR spectrum of 200 mM lidocaine in CDCl3.

Proton NMR spectrum of 200 mM lidocaine in CDCl3.

Figure 1. Proton NMR spectrum of 200 mM lidocaine in CDCl3.

1H NMR Relaxation

Figures 2, 3 and 4 show the relaxation time measurements. It can be seen that the relaxation times are shortest for the CH2 protons and longest for the CH protons. The first data point amplitude increases with the number of protons for the related peak.

Proton T1 relaxation time measurement of 200 mM lidocaine in CDCl3.

Figure 2. Proton T1 relaxation time measurement of 200 mM lidocaine in CDCl3.

Proton T2 relaxation time measurement of 200 mM lidocaine in CDCl3.

Figure 3. Proton T2 relaxation time measurement of 200 mM lidocaine in CDCl3.

COSY spectrum of 200 mM lidocaine in CDCl3.

Figure 4. COSY spectrum of 200 mM lidocaine in CDCl3. The cross-peaks and corresponding exchanging protons are labeled by colour-coded arrows and ellipses.

2D COSY

Figure 4 shows the 2D COSY spectrum where two spin systems (6,7,8) to (10,11) can be clearly seen. For instance, the methyl groups at 10 and 11 positions bond to aromatic protons at 6 and 8 positions, while the methyl groups at 16 and 17 positions bond to the ethylene groups at 14 and 15 positions. No coupling occurs at positions (6,7,8) to (16,17) or (14,15).

2D Homonuclear J-Resolved Spectroscopy

The chemical shift in the 2D homonuclear j-resolved spectrum appears along the direct (f2) direction and the effects of coupling between protons appear along the indirect (f1) dimension. This enables the assignment of chemical shifts of multiplets and may help in measuring unresolved couplings. Also, a decoupled 1D proton spectrum is produced by the projection along the f1 dimension. The 2D homonuclear j-resolved spectrum of lidocaine, plus the 1D proton spectrum (blue line) are shown in Figure 5.

Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3

Figure 5. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3. The multiplet splitting frequencies for different couplings are colour- coded.

The projection which is vertical reveals how the multiplets disintegrate into a single peak, which makes the 1D spectrum more simplified. Peak multiplicities are produced by vertical traces from peaks in the 2D spectrum and help in determining the frequencies of proton-proton coupling. When coupling frequencies are compared between different peaks, information can be obtained regarding which peaks are bonded to each other. Also, Information regarding the coupling strength can be obtained from the size of the coupling frequencies. These couplings substantiate the results of the COSY experiment.

However, in this experiment, the effects of second order coupling appear in the f1 direction as additional peaks which are equidistant from the coupling partners detached from the zero frequency in the f1 dimension. These peaks provide proof of second order coupling partners, but are generally considered as artifacts. Figure 6 shows these coupling partners and additional peaks marked by colour-coded arrows and ellipses.

Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3 showing the extra peaks due to strong couplings.

Figure 6. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3 showing the extra peaks due to strong couplings.

1D 13C Spectra

Figure 7 shows the 13C NMR spectra of 1 M lidocaine in CDCl3. Since the 1D Carbon experiment is highly susceptible to the 13C nuclei in the specimen, it easily and clearly resolves 9 resonances. In this experiment, only carbons coupled to protons are seen.

Carbon spectra of 1 M lidocaine in CDCl3.

Figure 7. Carbon spectra of 1 M lidocaine in CDCl3.

Given the fact that the DEPT spectra do not display the peaks at 170 and 135ppm, they must be part of quaternary carbons. The DEPT-135 and the DEPT-45 experiments provide signals of CH3, CH2 and CH groups, while the DEPT-90 experiment provides only the signal of CH groups. However, in DEPT-135 the CH2 groups occur as negative peaks. It can thus be summed up that the peaks between 45 and 60ppm belong to ethylene groups; the peaks between 10 and 20ppm are part of the methyl groups; and the peaks between 125 and 130ppm belong to methyne groups. A similar study can be carried out on the C and CH peaks.

Heteronuclear Correlation

The Heteronuclear Correlation (HETCOR) experiment identifies the proton signal that appears along the indirect dimension and the carbon signal along the direct dimension. Figure 8 shows the HETCOR spectrum of 1 M lidocaine in CDCl3. in the 2D spectrum, the peaks reveal which proton is attached to which carbon. This experiment helps in resolving assignment uncertainty from the ID carbon spectra.

HETCOR spectrum of 1 M lidocaine in CDCl3.

Figure 8. HETCOR spectrum of 1 M lidocaine in CDCl3.

Heteronuclear Multiple Quantum Coherence

Heteronuclear Multiple Quantum Coherence (HMQC) is similar to the HETCOR experiment and is utilized to associate proton resonances to the carbons that are coupled directly to those protons. But in the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 9 shows the HMQC spectrum of 1 M lidocaine in CDCl3. In the 2D spectrum, the peaks show which proton is attached to which carbon. For conclusive peak assignment, a similar study with the HETCOR spectrum can be carried out.

HMQC spectrum of 1 M lidocaine in CDCl3.

Figure 9. HMQC spectrum of 1 M lidocaine in CDCl3.

Heteronuclear Multiple Bond Correlation

The Heteronuclear Multiple Bond Correlation (HMBC) experiment can be employed to achieve long-range correlations of proton and carbon via two or three bond couplings. Similar to the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 10 shows the HMBC spectrum of 1 M lidocaine in CDCl3.

HMBC spectrum of 1 M lidocaine in CDCl3, with some of the long-range couplings marked.

Figure 10. HMBC spectrum of 1 M lidocaine in CDCl3, with some of the long-range couplings marked.

The couplings amid the molecular positions appear analogous to the couplings seen in the COSY spectrum; however, the HMBC also displays couplings to quaternary carbons, which are not seen either in HMQC or COSY experiments. In addition, there is a correlation between protons and carbons. This is attributed to three-bond bonding from 14 and 15 and vice versa, as shown in light green in Figure 1.

SYN

Synthesis of lidocaine T. J. Reilly (1999). “The Preparation of Lidocaine”. J. Chem. Ed. 76 (11): 1557.

File:Synthesis of lidocaine.png

CLIP

The Present Synthesis Of Lidocaine Begins With 2,6-Dimethylnitrobenzene (1). This Compound Can Be Made From 1,3-Dimethylbenzene, Also Known As M-Xylene, Which Is More Difficult To Make. Luckily,

This problem has been solved!

See the answer

REFER TO THE SCHEME FOR THE SYNTHESIS OF LIDOCAINE SHOWN BELOW © NH, CI q NH2 avec NO2 SnCl2/ HCI CH3COOH KOH CH3COOH 2 3 1 2
  1. The present synthesis of lidocaine begins with 2,6-dimethylnitrobenzene (1). This compound can be made from 1,3-dimethylbenzene, also known as m-xylene, which is more difficult to make. Luckily, m-xylene is commercially available, so a synthesis of 1 from m-xylene is a practical alternative if one wants to begin the synthesis of lidocaine with m-xylene. Suppose you want to prepare 1 from m-xylene. Show with chemical equations the reagents that you would use, and the possible isomers that would result.

2. The practical transformation of 1 into 3 is carried out by the following scheme:

1 in glacial CH3COOH + SnCl2 in conc. HCI vacuum filtration 2 as a solid precipitate dissolve in aq. KOH to pH > 10 3+ impuri

Suppose you dissolve the solid precipitate of 2 in water, but forget to include the KOH in the second step above. What would happen after the extraction with ether? Give your answer in terms of what would be found in the ether layer, and in the aqueous layer.

3. Suppose you’re out of acetic acid (CH3COOH) and decide to use ethanol (CH3 CH2OH) as the solvent in the transformation of 3 into 4. Would this be a wise choice, and why?

NH, CI ZI Cl CH2COOH 3 4

4.The amide 4 has a nitrogen attached to the benzene ring, and a chlorine attached to a primary carbon. Yet, it doesn’t react with itself in a nucleophilic displacement. Why is the nitrogen in the amide not nucleophilic? Give your answer in terms of the resonance forms of amides in general:

H N. ? NH2

5. In the reaction below, what factors come into play to favor attack of the aniline 3 on the carbonyl carbon of the acid chloride (carbon 1 in red), rather than at the a-carbon (carbon 2 in red)?

H N. NH2 1 cl 2 cl 3 4

6. Before carrying out the transformation below, compound 4 and the glassware used must be oven-dried. What would happen if the reaction was attempted using wet 4?

H N. H N. N H Cl N toluene 4 5

7.In the reaction below, what factors come into play to favor attack of diethylamine on the a-carbon (carbon 1 in red), rather than on the amide C=O carbon (carbon 2 in red)?

ZI N IZ: IZ LO

8. In the reaction below, why does the amine nitrogen (#1 in red) undergo protonation with H2SO4 preferentially over the amide nitrogen (#2 in red)? In other words, why is nitrogen 1 basic, but nitrogen 2 is not?

H2SO4 HSO4 5

9.Lidocaine and other drugs containing amino groups are usually marketed as their hydrochloride or hydrogen sulfate salts, rather than as “free amines.” Provide two reasons why this practice makes sense.

10.Although lidocaine is marketed as its hydrochloride salt, it doesn’t exhibit the same level of physiological activity as the free amine. The free amine is more lipophilic and diffuses across a neuron cell membrane more rapidly than the ionic salt, resulting in a more rapid onset of anesthesia. Therefore, sodium bicarbonate (NaHCO3) is added to a solution of lidocaine prior to injection. How does the addition of sodium bicarbonate promote a faster anesthetic effect?

CLIP

CLIP

Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia.[7][8] When used for local anaesthesia or in nerve blocks, lidocaine typically begins working within several minutes and lasts for half an hour to three hours.[8][9] Lidocaine mixtures may also be applied directly to the skin or mucous membranes to numb the area.[8] It is often used mixed with a small amount of adrenaline (epinephrine) to prolong its local effects and to decrease bleeding.[8]

If injected intravenously, it may cause cerebral effects such as confusion, changes in vision, numbness, tingling, and vomiting.[7] It can cause low blood pressure and an irregular heart rate.[7] There are concerns that injecting it into a joint can cause problems with the cartilage.[8] It appears to be generally safe for use in pregnancy.[7] A lower dose may be required in those with liver problems.[7] It is generally safe to use in those allergic to tetracaine or benzocaine.[8] Lidocaine is an antiarrhythmic medication of the class Ib type.[7] This means it works by blocking sodium channels and thus decreasing the rate of contractions of the heart.[7] When injected near nerves, the nerves cannot conduct signals to or from the brain.[8]

Lidocaine was discovered in 1946 and went on sale in 1948.[10] It is on the World Health Organization’s List of Essential Medicines.[11] It is available as a generic medication.[8][12] In 2018, it was the 233rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.[13][14]

Medical uses

Local numbing agent

The efficacy profile of lidocaine as a local anaesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block, and surface anaesthesia. Longer-acting substances such as bupivacaine are sometimes given preference for spinal and epidural anaesthesias; lidocaine, though, has the advantage of a rapid onset of action. Adrenaline vasoconstricts arteries, reducing bleeding and also delaying the resorption of lidocaine, almost doubling the duration of anaesthesia.

Lidocaine is one of the most commonly used local anaesthetics in dentistry. It can be administered in multiple ways, most often as a nerve block or infiltration, depending on the type of treatment carried out and the area of the mouth worked on.[15]

For surface anaesthesia, several formulations can be used for endoscopies, before intubations, etc. Buffering the pH of lidocaine makes local numbing less painful.[16] Lidocaine drops can be used on the eyes for short ophthalmic procedures. There is tentative evidence for topical lidocaine for neuropathic pain and skin graft donor site pain.[17][18] As a local numbing agent, it is used for the treatment of premature ejaculation.[19]

An adhesive transdermal patch containing a 5% concentration of lidocaine in a hydrogel bandage, is approved by the US FDA for reducing nerve pain caused by shingles.[20] The transdermal patch is also used for pain from other causes, such as compressed nerves and persistent nerve pain after some surgeries.

Heart arrhythmia

Lidocaine is also the most important class-1b antiarrhythmic drug; it is used intravenously for the treatment of ventricular arrhythmias (for acute myocardial infarctiondigoxin poisoning, cardioversion, or cardiac catheterization) if amiodarone is not available or contraindicated. Lidocaine should be given for this indication after defibrillation, CPR, and vasopressors have been initiated. A routine preventive dose is no longer recommended after a myocardial infarction as the overall benefit is not convincing.[21]

Epilepsy

A 2013 review on treatment for neonatal seizures recommended intravenous lidocaine as a second-line treatment, if phenobarbital fails to stop seizures.[22]

Other

Intravenous lidocaine infusions are also used to treat chronic pain and acute surgical pain as an opiate sparing technique. The quality of evidence for this use is poor so it is difficult to compare it to placebo or an epidural.[23]

Inhaled lidocaine can be used as a cough suppressor acting peripherally to reduce the cough reflex. This application can be implemented as a safety and comfort measure for patients who have to be intubated, as it reduces the incidence of coughing and any tracheal damage it might cause when emerging from anaesthesia.[24]

Lidocaine, along with ethanolammonia, and acetic acid, may also help in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge.[25][26]

For gastritis, drinking a viscous lidocaine formulation may help with the pain.[27]

Adverse effects

Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, and allergic reactions only rarely occur.[28] Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. ADRs by system are:

  • CNS excitation: nervousness, agitation, anxiety, apprehension, tingling around the mouth (circumoral paraesthesia), headache, hyperesthesia, tremor, dizziness, pupillary changes, psychosis, euphoria, hallucinations, and seizures
  • CNS depression with increasingly heavier exposure: drowsiness, lethargy, slurred speech, hypoesthesia, confusion, disorientation, loss of consciousness, respiratory depression and apnoea.
  • Cardiovascular: hypotensionbradycardiaarrhythmias, flushing, venous insufficiency, increased defibrillator threshold, edema, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.[29]
  • Respiratory: bronchospasm, dyspnea, respiratory depression or arrest
  • Gastrointestinal: metallic taste, nausea, vomiting
  • Ears: tinnitus
  • Eyes: local burning, conjunctival hyperemia, corneal epithelial changes/ulceration, diplopia, visual changes (opacification)
  • Skin: itching, depigmentation, rash, urticaria, edema, angioedema, bruising, inflammation of the vein at the injection site, irritation of the skin when applied topically
  • Blood: methemoglobinemia
  • Allergy

ADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (≥3 mg/min). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotensionbradycardiaarrhythmiascardiac arrest, muscle twitching, seizurescoma, and/or respiratory depression.[29]

It is generally safe to use lidocaine with vasoconstrictor such as adrenaline, including in regions such as the nose, ears, fingers, and toes.[30] While concerns of tissue death if used in these areas have been raised, evidence does not support these concerns.[30]

Interactions

Any drugs that are also ligands of CYP3A4 and CYP1A2 can potentially increase serum levels and potential for toxicity or decrease serum levels and the efficacy, depending on whether they induce or inhibit the enzymes, respectively. Drugs that may increase the chance of methemoglobinemia should also be considered carefully. Dronedarone and liposomal morphine are both absolutely a contraindication, as they may increase the serum levels, but hundreds of other drugs require monitoring for interaction.[31]

Contraindications

Absolute contraindications for the use of lidocaine include:

Exercise caution in patients with any of these:

Overdosage

Overdoses of lidocaine may result from excessive administration by topical or parenteral routes, accidental oral ingestion of topical preparations by children (who are more susceptible to overdose), accidental intravenous (rather than subcutaneous, intrathecal, or paracervical) injection, or from prolonged use of subcutaneous infiltration anesthesia during cosmetic surgery.

Such overdoses have often led to severe toxicity or death in both children and adults. Lidocaine and its two major metabolites may be quantified in blood, plasma, or serum to confirm the diagnosis in potential poisoning victims or to assist forensic investigation in a case of fatal overdose.

Lidocaine is often given intravenously as an antiarrhythmic agent in critical cardiac-care situations.[37] Treatment with intravenous lipid emulsions (used for parenteral feeding) to reverse the effects of local anaesthetic toxicity is becoming more common.[38]

Postarthroscopic glenohumeral chondrolysis

Lidocaine in large amounts may be toxic to cartilage and intra-articular infusions can lead to postarthroscopic glenohumeral chondrolysis.[39]

Pharmacology

Mechanism of action

Lidocaine alters signal conduction in neurons by prolonging the inactivation of the fast voltage-gated Na+ channels in the neuronal cell membrane responsible for action potential propagation.[40] With sufficient blockage, the voltage-gated sodium channels will not open and an action potential will not be generated. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations also affect other types of neurons.

The same principle applies for this drug’s actions in the heart. Blocking sodium channels in the conduction system, as well as the muscle cells of the heart, raises the depolarization threshold, making the heart less likely to initiate or conduct early action potentials that may cause an arrhythmia.[41]

Pharmacokinetics

When used as an injectable it typically begins working within four minutes and lasts for half an hour to three hours.[8][9] Lidocaine is about 95% metabolized (dealkylated) in the liver mainly by CYP3A4 to the pharmacologically active metabolites monoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half-life than lidocaine, but also is a less potent sodium channel blocker.[42] The volume of distribution is 1.1 L/kg to 2.1 L/kg, but congestive heart failure can decrease it. About 60% to 80% circulates bound to the protein alpha1 acid glycoprotein. The oral bioavailability is 35% and the topical bioavailability is 3%.

The elimination half-life of lidocaine is biphasic and around 90 min to 120 min in most patients. This may be prolonged in patients with hepatic impairment (average 343 min) or congestive heart failure (average 136 min).[43] Lidocaine is excreted in the urine (90% as metabolites and 10% as unchanged drug).[44]

History

Lidocaine, the first amino amide–type local anesthetic, was first synthesized under the name ‘xylocaine’ by Swedish chemist Nils Löfgren in 1943.[45][46][47] His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself.[45] It was first marketed in 1949.

Society and culture

Dosage forms

Lidocaine, usually in the form of its hydrochloride salt, is available in various forms including many topical formulations and solutions for injection or infusion.[48] It is also available as a transdermal patch, which is applied directly to the skin.

  • Lidocaine hydrochloride 2% epinephrine 1:80,000 solution for injection in a cartridge
  • Lidocaine hydrochloride 1% solution for injection
  • Topical lidocaine spray
  • 2% viscous lidocaine

Names

Lidocaine is the International Nonproprietary Name (INN), British Approved Name (BAN), and Australian Approved Name (AAN),[49] while lignocaine is the former BAN[citation needed] and AAN. Both the old and new names will be displayed on the product label in Australia until at least 2023.[50]

Xylocaine is a brand name.

Recreational use

As of 2021, lidocaine is not listed by the World Anti-Doping Agency as a substance whose use is banned in sport.[51] It is used as an adjuvant, adulterant, and diluent to street drugs such as cocaine and heroin.[52] It is one of the three common ingredients in site enhancement oil used by bodybuilders.[53]

Adulterant in cocaine

Lidocaine is often added to cocaine as a diluent.[54][55] Cocaine and lidocaine both numb the gums when applied. This gives the user the impression of high-quality cocaine, when in actuality the user is receiving a diluted product.[56]

Compendial status

Veterinary use

It is a component of the veterinary drug Tributame along with embutramide and chloroquine used to carry out euthanasia on horses and dogs.[58][59]

References

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  2. ^ “Lidocaine”Dictionary.com UnabridgedRandom House.
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  4. ^ “Lidocaine Hydrochloride Injection BP 1% w/v – Summary of Product Characteristics (SmPC)”(emc). 29 June 2020. Retrieved 11 April 2021.
  5. ^ “Xylocaine MPF- lidocaine hydrochloride injection, solution Xylocaine- lidocaine hydrochloride injection, solution Xylocaine- lidocaine hydrochloride,epinephrine bitartrate injection, solution”DailyMed. Retrieved 11 April 2021.
  6. ^ “Ztlido- lidocaine patch”DailyMed. Retrieved 11 April 2021.
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  45. Jump up to:a b Löfgren N (1948). Studies on local anesthetics: Xylocaine: a new synthetic drug (Inaugural dissertation). Stockholm, Sweden: Ivar Heggstroms. OCLC 646046738.[page needed]
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External links

IUPAC name2-(diethylamino)-
N-(2,6-dimethylphenyl)acetamide
CAS Number137-58-6 as HCl: 73-78-9
PubChem CID3676as HCl: 6314
IUPHAR/BPS2623
DrugBankDB00281 as HCl: DBSALT001508
ChemSpider3548 as HCl: 6075
UNII98PI200987as HCl: EC2CNF7XFP
KEGGD00358 as HCl: D02086 
ChEBICHEBI:6456 as HCl: CHEBI:50512
ChEMBLChEMBL79 as HCl: ChEMBL541521
PDB ligandLQZ (PDBeRCSB PDB)
CompTox Dashboard (EPA)DTXSID1045166 
ECHA InfoCard100.004.821 
Chemical and physical data
FormulaC14H22N2O
Molar mass234.343 g·mol−1
3D model (JSmol)Interactive image
Melting point68 °C (154 °F)
showSMILES
showInChI

////////LIDOCAINE, lignocaine

wdt-17

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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