Chapter IX Some Physiologically Active compounds.pdf

CHAPTER IX

SOME PHYSIOLOGICALLY ACTIVE COMPOUNDS

IX,1. ASPIRIN (ACETYLSALICYLIC ACID)

Phenols, unlike amines, cannot be acetylated satisfactorily in aqueous

solution : acetylation proceeds readily with acetic anhydride in the presence

of a little concentrated sulphuric acid as catalyst. Salicylic acid (o-hydroxy-

benzoic acid) upon acetylation yields acetylsalicylic acid or aspirin :

PWQJ /v° COCH '

( Y

+ (CH 8 CO) 2 0

» [ I

+ CH 3 COOH

"vk

V COOH

Salicylic acid

Aspirin

Place 10 g. of dry salicylic acid and 15 g. (14 ml.) of acetic anhydride

in a small conical flask, add 5 drops of concentrated sulphuric acid, and

rotate the flask in order to secure thorough mixing. Warm on a water

bath to about 50-60°, stirring with the thermometer, for about 15 minutes.

Allow the mixture to cool and stir occasionally. Add 150 ml. of water,

stir well and filter at the pump. Recrystallise the crude acetylsalicylic

acid from a mixture of equal volumes of acetic acid and water.

The following is an alternative method of purifying the crude aspirin.

Dissolve the solid in about 30 ml. of hot alcohol and pour the solution

into about 75 ml. of warm water : if a solid separates at this point, warm

the mixture until solution is complete and then allow the clear solution

to cool slowly. Beautiful needle-like crystals will separate. The yield

is 13 g. The air-dried crude product may also be recrystallised from

benzene or from ether - light petroleum (b.p. 40-60°).

Acetylsalicylic acid decomposes when heated and does not possess a

true, clearly-defined m.p. Decomposition points ranging from 128° to

135° have been recorded ; a value of 129-133° is obtained on an electric

hot plate (Fig. //, 11, 1). Some decomposition may occur if the com-

pound is recrystallised from a solvent of high boiling point or if the boiling

period during recrystallisation is unduly prolonged.

IX,2. PHENACETIN

Phenacetin may be conveniently prepared in the laboratory from p-amino-

phenol. The latter is readily acetylated with acetic anhydride to give p-acetyl-

aminophenol; this is ethylated in the form of the sodio derivative to yield

acetyl p-phenetidine (phenacetin) :

NH 2

NHCOCH 3

NHCOCH,

(CH.CO).O

NaOC t H, solution;

C.H.I

p-Aminophenol

p-Aoetylaminophenol

Phenaoetin

096

/V O H

[IX,2)

PHYSIOLOGICALLY ACTIVE COMPOUNDS

997

Phenacetin may also be prepared by acetylation of the commercially available

p-phenetidine : *

C 2 H 5

p-Phenetidine

Phenacetin

Mefltod A

Suspend 11 g. of ^>-aminophenol in 30 ml. of water contained in a

250 ml. beaker or conical flask and add 12 ml. of acetic anhydride. Stir

(or shake) the mixture vigorously and warm on a water bath. The solid

dissolves. After 10 minutes, cool, filter the solid acetyl derivative at

the pump and wash with a little cold water. Recrystallise from hot

water (about 75 ml.) and dry upon filter paper in the air. The yield

of jp-acetylaminophenol, m.p. 169° (1), is 14 g.

Place 1*55 g. of clean sodium in a 2-50 ml. round-bottomed flask

equipped with a reflux condenser. Add 40 ml. of absolute alcohol (or

rectified spirit). If all the sodium has not disappeared after the vigorous

reaction has subsided, warm the flask on a water bath until solution is

complete. Cool the mixture and add 10 g. of p-acetylaminophenol.

Introduce 15 g. (8 ml.) of ethyl iodide slowly through the condenser and

reflux the mixture for 45-60 minutes. Pour 100 ml. of water through the

condenser at such a rate that the crystalline product does not separate ;

if crystals do separate, reflux the mixture until they dissolve. Then cool

the flask in an ice bath : collect the crude phenacetin with suction and

wash with a little cold water. Dissolve the crude product in 80 ml. of

rectified spirit; if the solution is coloured, add 2 g. of decolourising carbon

and filter. Treat the clear solution with 125 ml. of hot water and allow

to cool. Collect the pure phenacetin at the pump and dry in the air.

The yield is 9-5 g., m.p. 137°.

5A T hydrochloric acid (or 9 ml. of the concentrated acid) have been added;

stir the solution with about 5 g. of decolourising carbon for 5 minutes,

warm, and filter the solution with suction. Transfer the cold filtered solu-

tion of j?-phenetidine hydrochloride to a 700 ml. conical flask, add 13 g.

(12 ml.) of acetic anhydride and swirl the contents to dissolve the anhy-

dride. Immediately add a solution of 16 g. of crystallised sodium acetate

in 50 ml. of water and stir (or swirl) the contents of the flask vigorously.

Cool the reaction mixture in an ice bath, filter with suction and wash Vith

cold water. Recrystallise from hot water (with the addition of a little

decolourising carbon, if necessary), filter and dry. The yield of pure

phenacetin, m.p. 137°, is 12 g.

Notes.

(1) If the m.p. is unsatisfactory, dissolve the product in dilute alkali in the cold

and then reprecipitate it by the addition of acid to the neutralisation point. This

procedure will eliminate traces of the diacetate of £>-aminophenol which may be

* Prepared inter alia thus :

EttSO 4 ,

p-Nitrophenol

+ p-Nitrophenetole

Reduction

+ p-Phenetidine

MethodB

Dissolve 14 g. of ^-phenetidine (2) in 240 ml. of water to which 20 ml. of

998

PRACTICAL ORGANIC CHEMISTRY

[IX,

present; the acetyl group attached to nitrogen is not affected by cold dilute alkali,

but that attached to oxygen is readily hydrolysecl by the reagent.

(2) The p-phenetidine is usually coloured and the procedure given permits a

preliminary treatment with decolourising carbon, thus leading to an almost colour-

less phenacetin directly.

Acetylation of the amine may also be effected by boiling with 20 ml. of glacial

acetic acid and 14 ml. of acetic anhydride for 15-20 minutes, followed by decomposi-

tion of the excess of anhydride with water and, after boiling for 5 minutes, pouring

with stirring into about 75 ml. of water ; the product is appreciably coloured.

IX,3. ANTIPYRIN

When ethyl acetoacetate is warmed with an equivalent quantity of phenyl-

hydrazine, the compound (I), which is not a true hydrazone, is first formed;

this undergoes ring formation (II) with loss of ethyl alcohol upon further

heating. The product (II) is N or l-phenyl-3-methyl-5-pyrazolone.

CH 3 C(OH)=CHCOOC 2 H 5

_ H o CH 3 C=CHCOOC a H 5

(I)

H,NNHC 6 H 6

NHNHC 6 H 6

-C.H.OH

CH 3 C=CH\

\ C Q (H )

NH—NC f H 5

This substance may be conveniently methylated with dimethyl sulphate to

yield l-phenyl-2 : 3-dimethyl-5-pyrazolone or antipyrin (III) :

| \ C O <CH.),SO^ - \ C( ) (m )

NH—NC 6 H 6 ««*NaOHaq. CHg N N C 6 H 6

l-Phenyl-3-methyl-5-pyrazolone. Mix together 50 g. (49 ml.) of

redistilled ethyl acetoacetate (Section 111,151) and 40 g. (36-5 ml.) of

phenylhydrazine (CAUTION in handling) (Section IV,89) in a large

evaporating dish. Heat the mixture on a water bath in the fume cup-

board for 1 hour and stir from time to time with a glass rod. Allow the

heavy reddish syrup to cool somewhat, add about 100 ml. of ether and

stir the mixture vigorously. The syrup, which is insoluble in ether, will

solidify within 15 minutes. Filter the solid at the pump and wash it

thoroughly with ether to remove coloured impurities. Recrystallise it

from hot water or from a mixture of equal volumes of alcohol and water.

The yield of phenylmethylpyrazolone (colourless crystals, m.p. 127°) is

52 g.

l-Phenyl-2 : S-dimethyl^S-pyrazolone (antipyrin). In a 500 ml.

three-necked flask, equipped with a dropping funnel, a mercury-sealed

stirrer and a double surface condenser and set up in the fume cupboard,

place a solution of 10 g. of sodium hydroxide in a small volume of water

and also a solution of 43*5 g. of phenylmethylpyrazolone in 20 ml. of

methyl alcohol. Warm the mixture on a water bath and add 36 g.

(27 ml.) of dimethyl sulphate (CAUTION: toxic, see discussion prior to

CH 3 C=CH X

CH 3 C=CH\

—^

PHYSIOLOGICALLY ACTIVE COMPOUNDS

999

Section IV,49). Reflux the mixture for 1 hour and allow to cool, with

continuous stirring. Distil off the methyl alcohol. Add hot water to the

residue, filter from impurities, extract the antipyrine with benzene, and

evaporate the solvent. Recrystallise the crude product from benzene or

benzene - light petroleum or from hot water with the addition of a

little decolourising carbon. The yield of antipyrin (white crystalline solid,

m.p. 113°) is 35 g.

IX,4. BROMURAL (a-BROMO-/SO-VALERYLUREA)

iso- Valeric acid is converted by phosphorus and bromine into a-bromo-

wo-valeryl bromide ; the latter upon heating with urea gives bromural :

(CH 3 ) 2 CHCH 2 COOH

-^l

(CH a ) 2 CHCHBrCOBr

CO(XH,),

-> (CH 3 ) 2 CHCBrCONHCONH 2

Bromural

Equip a 1 litre bolt-head flask with dropping funnel and a double

surface reflux condenser * ; to the top of the latter attach a device (e.g.,

Fig. //, 8, 1, c) for the absorption of the hydrogen bromide evolved.

Place 100 g. (108 ml.) of dry iso-valeric acid (Section 111,80) and 12 g.

of purified red phosphorus (Section 11,50,5) in the flask. Add 255 g.

(82 ml.) of dry bromine (Section 11,49,5) slowly through the dropping

funnel at such a rate that little or no bromine is lost with the hydrogen

bromide evolved ; the addition occupies 2-3 hours. Warm the reaction

mixture on a water bath until the evolution of hydrogen bromide is

complete and the colour of the bromine has disappeared. Pour off the

liquid reaction product into a Claisen flask and distil under the reduced

pressure of a water pump. Collect the a-bromo-iso-valeryl bromide at

117-122°/25-30 mm. The yield is 150 g.

In a 500 ml. bolt-head flask provided with a thermometer (reaching

almost to the bottom) and a calcium chloride (or cotton wool) guard

wo-Valeric acid

a-Bromo-wo-valeryl bromide

tube, place 100 g. of a-bromo-iso-valer} 7 ! bromide and 50 g. of dry, finely-

divided urea. Start the reaction by warming the flask on a water bath ;

the temperature soon rises to about 80°. Maintain this temperature for

about 3 hours ; the mass will liquefy and then resolidify. Transfer the

sticky reaction product to a large beaker containing saturated sodium

bicarbonate solution, stir mechanically and add more saturated sodium

bicarbonate solution in small quantities until effervescence ceases. Filter

at the pump, suck as dry as possible and dry the crude bromural upon

filter paper in the air. Recrystallise the dry product from toluene.

Alternatively, recrystallise the moist product from hot water (ca. 700 nil.).

The yield of pure bromural, m.p. 154-155°, is 28 g.

* It is best to employ an apparatus with ground glass joints. Failing this, an old rubber

stopper or a cork covered with paraffin wax may be used.

1000

PRACTICAL ORGANIC CHEMISTRY

[IX,

IX,5. BENZOCAINE (ETHYL p-AMINOBENZOATE)

Benzocaine (or anaesthesine) is conveniently prepared from p-nitrobenzoic

acid by either of the following methods :

(i) p-Nitrobenzoic acid is first reduced with tin and hydrochloric acid to

p-aminobenzoic acid, and the latter is esterified with ethyl alcohol in the

presence of hydrogen chloride :

COOH

COOCJI f i

Sn, HQ

C.H.OH,

NH 2

(ii) ^-Nitrobenzoic acid is first converted into the ethyl ester and the latter

is reduced with hydrogen in the presence of Adams' platinum oxide catalyst:

COOH

COOC 2 H 5

O C.H.OH,

H,S0 4 , C.H.

N0 2 N0 2 NH,

Method 1. p-Aminobenzoic acid. Place 15 g. of p-nitrobenzoic

acid (Section IV, 154) in a 1 litre round-bottomed flask fitted with a

reflux condenser. Introduce 35 g. of powdered tin and 75 ml. of con-

centrated hydrochloric acid. Heat the mixture gently until the reaction

commences, and remove the flame. Shake the flask frequently and take

care that the insoluble acid adhering to the sides of the flask is transferred

to the reaction mixture : occasional gentle warming may be necessary.

After about 20 minutes, most of the tin will have reacted and a clear

solution remains. Allow to cool somewhat and decant the liquid into a

1 litre beaker ; wash the residual tin by decantation with 15 ml. of water,

and add the washings to the contents of the beaker. Add concentrated

ammonia solution (sp. gr. 0-88) until the solution is just alkaline to

litmus ; filter off the precipitate of hydrated tin oxide and wash well

with water. If the total volume of the combined filtrate and washings

exceeds 200 ml., evaporate in a large evaporating dish on a water bath

until the volume has been reduced to 175-200 ml. : filter off any solid

which separates. Acidify the liquid to litmus with glacial acetic acid

and evaporate on a water bath until crystals commence to separate;

cool in ice, filter the crystals at the pump and dry in the steam oven.

The yield of p-aminobenzoic acid, m.p. 192°, is 13 g.

Ethyl p-aminobenzoate (esterification of p-aminobenzoic acid). Place

80 ml. of absolute ethyl alcohol in a 250 ml. conical flask equipped with

a two-holed cork and wash-bottle tubes. Pass dry hydrogen chloride

(Section 11,48,7) through the alcohol until saturated—the increase in

weight is about 20 g.—and transfer the solution to a 250 ml. round-

bottomed flask. Introduce 12 g. of ^-aminobenzoic acid, fit a double

surface condenser to the flask, and reflux the mixture for 2 hours. Upon

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