Sicurezza amara - il bitrex
(2012-04-29, 13:51)quimico Ha scritto: Non vedo l'ora di leggerla allora.
L'idrossido di etruschio è difficile da trovare... Servono Etruschi freschi *Si guarda intorno*
Mi scuso per la sigla... Alcole etilico è la giusta dizione :-P

No, dai...era solo una battuta. EtOH è più di una sigla. :-D


Devo correggermi: il cloruro lo devo prima sintetizzare, però ho l'alcol benzilico. asd
*** Cercar di far bene e non di far molto. (A. L. Lavoisier) ***
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Ah ecco, allora siamo messi allo stesso punto Doc, anche a me manca solo C6H5CH2Cl, solo che il tipo non mi sta simpatico e temo un po' per la sua sintesi asd
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Ah, ma a questo si può facilmente ovviare: la Sigma lo vende!
*** Cercar di far bene e non di far molto. (A. L. Lavoisier) ***
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Va beh PhCH2Cl si fa facile dal PhCH2OH.
Ricordo solo a chi volesse usare tale agente alchilante (anche se è un arile) di starci attento.
Penso Max che tu riesca a procurartelo facile dalla SA. Comprane 50mL se ti spaventa averlo in giro. Io ce l'ho quasi sempre sotto cappa in laboratorio, a parte quando non serve e lo metto nell'armadio reagenti.
Son curioso di vedere la sintesi o perché no le sintesi.
Io penso di non aver problemi a procurarmi in laboratorio il necessario... Vedremo quando e se riuscirò a fare tale sintesi. Mi piacerebbe molto.

Tornando alla lidocaina. Una delle possibili sintesi è la seguente:

[Immagine: 800px-Synthesis_of_lidocaine.png]

Si scioglie nell'opportuno volume di acido acetico glaciale la 2,6-dimetilanilina (1 equiv), si raffredda a 10 °C, si gocciola lentamente il cloroacetile cloruro (1.1 equiv) sotto agitazione e si aggiunge sodio acetato (in soluzione acquosa al 50%). L'agitazione è mantenuta vigorosa per 30 minuti circa. Precipitano dei cristalli (il prodotto), si filtra e si lava con acqua con attenzione. Si lascia asciugare all'aria. Il prodotto è sufficientemente puro per esser usato in altre reazioni. Resa: 70-80% della teorica.
Il passaggio successivo è abbastanza semplice. Si scioglie il prodotto ottenuto in precedenza (1 equiv) in toluene (la ricetta iniziale proponeva il benzene ma eviterei per ovvi motivi), si aggiunge la dietilamina (2.5-3 equiv) e si scalda a riflusso per 4-5 ore. Si filtra il dietilamino cloridrato. La soluzione in toluene è lavata con HCl 3N (x 2volte, la prima volta con un volume di 2x mL, la seconda volta con un volume di x mL). Agli estratti acidi combinati, si aggiunge NaOH soluzione acquosa al 30% finché non precipita più solido. Il precipitato, che spesso è un olio, è ripreso in etere etilico. La soluzione eterea è trattata con potassio carbonato, si filtra e si evapora l'etere. Il grezzo viene purificato tramite distillazione frazionata.
b.p. 180-182 °C a 4mmHg; 159-160 °C a 2 mmHg
m.p. 68-69 °C


Se a qualcuno va, vi pongo la seguente domanda. Sapreste sintetizzare il Bitrex a partire da MeOC(=O)CH2OH? Potete usare composti con qualsiasi reagente inorganico, e qualsiasi composto organico con otto o meno atomi di carbonio.
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Rusty, ohilà
La sintesi del Bitrex è sempre stata un piccolo sogno nel cassetto. 
Si potrebbe pure fare. Partendo dalla lidocaina è facile. Invece se si deve preparare anche quest'ultima la cosa rimane fattibile, ma è un lavoro lungo e laborioso.

Vi riporto un patent che descrive la sua preparazione e quella delle sostanze ad esso correlate:
http://www.google.com/patents/EP1824814A2?cl=en

Per comodità metto qui la parte sperimentale:

EXAMPLE 1 
Preparation of N-{2-rr2.6-dimethvbhenylVaminol-2-oxoethyli-N.N- diethyl-benzenemethanaminium hydroxide (denatonium hydroxide) 
250 gram (1.07 mol) of 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (Lignocaine) was added to 600 ml of water at 30-35 °C. It was then slowly heated to 70-90 °C, followed by the addition of 175.4 gram (1.39 mol) benzyl chloride at 70-90 °C. The temperature was maintained at 70-90 °C for 20-24 hours while monitoring the reaction by thin layer chromatography for every 4 hours, until the remaining unreacted Lignocaine was less than 10 %. The reaction mass was then cooled to 35-40 °C. The aqueous reaction solution was extracted with 100 ml of toluene (twice) at 35-40 °C. Approximately 920 gram of aqueous denatonium chloride solution was obtained. The assay was 50.7 % as measured by titrimetry.
50% sodium hydroxide solution (129.3 gram sodium hydroxide in 129.3 ml water) was added hereto, i.e. 1.25 mol sodium hydroxide against 1 mol denatonium chloride, at 25-30 °C over a period of 3.0 hrs. The solid denatonium hydroxide was filtered and washed with 400 ml demineralised water and finally with 50 ml acetone.
After drying the residual product weighed 255 gram (Assay 98.75 % by titrimetry, melting range 151 - 155 °C, off-white crystals; LOD < 1 %; chloride content 0.01 %, ash content 0.10 %). The overall yield was 69.0 % based on lignocaine. 


EXAMPLE 2
Preparation of N-{2-rf2.6-dimethylphenyl)-aminol-2-oxoethyl|-N.N- diethyl-benzenemethanaminium hydroxide (denatonium hydroxide) from N- chloroacetyl-2,6-dimethylaniline
1000 gram (5.06 mol) of N-chloroacetyl-2,6-dimethylaniline was added to 3250 ml water at 30 - 35 °C. 280 gram of sodium carbonate and 550 gram (7.52 mol) of diethylamine was added hereto at 30-35 °C and the mixture was stirred for 2 hrs. It was then slowly heated to 60-62 °C and stirred for another 2 hrs at the same temperature. The temperature was raised to 70-90 °C and the mixture was stirred for 8 hrs at the same temperature. Then slowly 834 gram (6.59 mol) of benzyl chloride was added at 70 - 90 °C. The temperature was maintained for 20-24 hrs at 70-90 °C while monitoring the reaction by thin layer chromatography for every 4 hrs, until the unreacted lignocaine was less than 10%. The reaction mass was cooled to 35 - 40 °C. The aqueous reaction solution was extracted with 250 ml of toluene [twice] at 35 - 40 °C and the two layers separated. The upper layer was the toluene layer and the lower layer was the aqueous layer containing the denatonium chloride. About 3000 gram of an aqueous denatonium chloride solution was obtained, with a yield of 73.4 % denatonium chloride, as measured by titrimetry.
50 % sodium hydroxide solution (612 gram sodium hydroxide in 612 ml water) was added to the prepared denatonium chloride solution at 25-30 °C over a period of 3.0 hrs, i.e. 1.25 mol sodium hydroxide against 1 mol denatonium chloride. The isolated solid denatonium hydroxide was filtered and washed with 3000 ml of water, and finally washed with 500 ml of acetone.
After drying the product weighed 1225 gram. (Assay 99 % by titrimetry; melting range 152-156 °C, off-white crystals; LOD < 1 %; chloride content 0.01 %, ash content 0.10 %). The overall yield was 70.7 % based on N-chloroacetyl-2,6-dimethylaniline.


EXAMPLE 3 
Preparation of preparation of pure quaternary salts from pure quaternary hydroxide
100 gram (0.29 mol) of denatonium hydroxide was added to 150 ml of acetone at 30- 35 °C. A solution of 38.91 gram (0.319 mol) of benzoic acid in 150 ml of acetone was added at 30-35 °C, i.e. 1.1 mol benzoic acid against 1 mol denatonium hydroxide, and the thus obtained mixture was stirred for 30 min. at this temperature and 2.0 hrs at 30- 35 °C. Then the reaction mass was cooled to 18-22 °C and stirred for another 30 minutes, the solid filtered and subsequently washed with 25 ml acetone. 105 gram of denatonium benzoate was obtained on drying, yield was 80.52%. The quality met the USP specifications.

EXAMPLE 4 
Preparation of fatty derivative salts from pure quaternary hydroxide (denatonium palmitate)
50 grams (0.1462 mol) of denatonium hydroxide was dissolved in 50 ml of methanol at 30-45 °C. A solution of 37.5 gram (0.1462 mol i.e. 1 mol palmitic acid against 1 mol denatonium hydroxide) of palmitic acid in 150 ml of methanol was added at 30-45 °C, and the thus obtained mixture was stirred for 1 - 2 hours at 45-60 °C temperature. The solvent was then distilled off up to semi solid to solid mass. 84 grams of denatonium palmitate (with a quantitative yield) was obtained as off white solid, which is hygroscopic in nature. (Assay = 99.41%, S' Ash = 0.15%).

EXAMPLE 5 
Preparation of fatty derivative salts from pure quaternary hydroxide (denatonium linolate)
50 grams (0.1462 mol) of denatonium hydroxide was dissolved in 50 ml of methanol at 30-45 °C. A solution of 41 gram (0.1462 mol i.e. 1 mole linoleic acid against 1 mol denatonium hydroxide) of linoleic acid in 50 ml of methanol was added at 30-45 °C, and the thus obtained mixture was stirred for 1 - 2 hours at 45-60 °C temperature. The solvent was then distilled off up to thick brownish semi solid mass. 90 grams of denatonium lino late was obtained with a quantitative yield. (Assay = 100%, S' Ash = 0.09%).

EXAMPLE 6 
Preparation of fatty derivative salts from pure quaternary hydroxide (denatonium linolenate)
50 grams (0.1462 mol) of denatonium hydroxide was dissolved in 50 ml of methanol at 30-45 °C. A solution of 40.7 gram (0.1462 mol i.e. 1 mole linolenic acid against 1 mol denatonium hydroxide) of linolenic acid in 50 ml of methanol was added at 30-45 °C, and the thus obtained mixture was stirred for 1 - 2 hours at 45- 60 °C temperature. The solvent was then distilled off up to thick brownish semi solid mass. 93 grams of denatonium linolenate was obtained with a quantitative yield. (Assay = 99.11%, S' Ash = 0.09%). 

EXAMPLE 7 
Preparation of fatty derivative salts from pure quaternary hydroxide (denatonium eruciate)
50 grams (0.1462 mol) of denatonium hydroxide was dissolved in 50 ml of methanol at 30-45 °C. A solution of 54.5 gram (0.1462 mol i.e. 1 mole erucic acid against 1 mol denatonium hydroxide) of erucic acid (with 90.7 % assay) in 50 ml of methanol was added at 30-45 °C, and the thus obtained mixture was stirred for 1 - 2 hours at 45-60 °C temperature. The solvent was then distilled off up to yellow thick semi solid mass. 101 grams of denatonium eruciate was obtained with a quantitative yield. (Assay = 99.09%, S' Ash = 0.08%).


Qui ci sono un paio di articoli sulla sintesi della lidocaina:
1) http://bama.ua.edu/~kshaughn/ch338/hando...ocaine.pdf
2) http://www.chem.umass.edu/people/mcdanie...ocaine.pdf
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