Europäisches Patentamt

(19) European Patent Office *EP000763531B1*

Office européen des brevets (11) EP 0 763 531 B1
(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: C07D 277/32
of the grant of the patent:
22.03.2000 Bulletin 2000/12

(21) Application number: 96306214.6

(22) Date of filing: 28.08.1996

(54) Preparation of substituted thiazoles

Herstellung von substituierten Thiazolen
Préparation de substitués de thiazoles

(84) Designated Contracting States: • Heyes, Graham

AT BE CH DE DK ES FR GR IE IT LI LU NL PT SE Durham City DH1 4BW (GB)
• Grayson, James Ian
(30) Priority: 14.09.1995 GB 9518824 Western Hill, Durham City DH1 4RL (GB)
• Clarke, Russell
(43) Date of publication of application: Chester-le-Street, Co. Durham DH3 4BW (GB)
19.03.1997 Bulletin 1997/12
(74) Representative: Stuttard, Garry Philip et al
(73) Proprietors: Urquhart-Dykes & Lord
• Fine Organics Ltd. Tower House
Middlesbrough Cleveland TS2 1UB (GB) Merrion Way
• Agro-Kanesho Company Limited Leeds LS2 8PA (GB)
Minato-ku, Tokyo 107 (JP)
(56) References cited:
(72) Inventors: EP-A- 0 446 913 DE-A- 3 631 538
• Jackson, Arthur
Washington, Tyne & Wear NE38 7HY (GB) • J. PRAKT. CHEM. 1980, vol. 322, no. 4, pages
629-637, XP002022211 SCHULZE, K. ET AL.:
EP 0 763 531 B1

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
99(1) European Patent Convention).

Printed by Jouve, 75001 PARIS (FR)

 EP 0 763 531 B1

Description

[0001] The present invention is concerned with the preparation of thiazoles which are substituted in the 5 position,
namely those having a haloalkyl group in that position. The invention is particularly directed to the preparation of 2-halo-
5 5-(haloalkyl) thiazoles. It may be exemplified by reference to the preparation of 2-chloro-5-(chloromethyl) thiazole.
[0002] This latter compound is an important intermediate in the manufacture of agrochemical and pharmaceutical
products but there is no method available for its preparation which lends itself to the manufacture of the product on a
commercial scale. Such methods as are available entail disadvantages which would render them impractical or une-
conomical if attempts were made to adopt them commercially.
10 [0003] By way of example, German Patent Specification No. DE 3631538 describes a method of preparing 2-chloro-
5-(chloromethyl) thiazole by chlorination of allyl isothiocyanate. However the reaction requires the use of high temper-
atures and of a large excess of chlorine or other chlorinating agent. In addition, the desired product is produced with
a large number of other substances, from which the desired substituted thiazole is separable only with difficulty.
[0004] An alternative method for the preparation of 2-chloro-5-(chloromethyl) thiazole is described in European Pat-
15 ent Specification No. 0446913. According to that method, 2-chloroallyl isothiocyanate is chlorinated using chlorine or
another chlorinating agent and gives the desired substituted thiazole in a higher yield than is obtainable by the above-
described prior process, without the need for the large excess of chlorinating agent and the high temperatures which
together are characteristic of that process. However the allyl isothiocyanate which is the starting material for the im-
proved process is prepared from 2,3- dichloropropene, which latter compound is not readily available. Thus this alter-
20 native method, while showing some practical advantages over the first-mentioned method, is not suitable for the man-
ufacture of 2-chloro-5-(chloromethyl) thiazole on a significant scale.
[0005] It is therefore an object of the present invention to provide a process for the manufacture of 2-halo-5-(haloalkyl)
thiazoles, in particular 2-chloro-5-(chloromethyl) thiazole, by which some at least of the disadvantages of knpwn proc-
esses for this purpose are reduced or avoided.
25 [0006] The process according to the present invention comprises reacting an isothiocyanate compound of the general
formula

Hal.CH(R 1 ). CH=C(R 2 ).NCS,

30
wherein the symbol Hal represents a chlorine or bromine atom and the symbols R1 and R2 each represents a hydrogen
atom or an alkyl group containing from 1 to 3 carbon atoms, in solution with a chlorinating or brominating agent.
[0007] The product obtained by the process according to the present invention is a thiazole which has a haloalkyl
group in the 5 position and has the general formula
35

40

45
wherein the symbols Hal each represents a chlorine or bromine atom, which may be the same or different, and the
symbols R1 and R2 have the meaning given above. Thus where each symbol Hal represents a chlorine atom and where
each of the symbols R1 and R2 represents a hydrogen atom, the product obtained is 2-chloro-5-(chloromethyl) thiazole.
[0008] The isothiocyanate which is a starting material for the process according to the present invention may be
50 prepared by the method described by K. Schulze et al in Journal fuer Praktische Chemie, 1980, Vol. 322 at pages 629
to 637, wherein a compound of the general formula

Hal. CH(R 1 ). CH = C(R 2 ). Hal

55
wherein the symbols Hal, R1 and R2 have the meanings given above, is reacted with an alkali metal thiocyanate or
with ammonium thiocyanate. For example the starting material may be 3-chloroprop-1-enyl isothiocyanate and may
be prepared by reacting 1,3-dichloropropene with potassium thiocyanate in this way. 1,3-dichloropropene is a com-

2
 EP 0 763 531 B1

pound which is produced in large quantities as a fumigant and is a readily available and a much cheaper starting
material than 2,3-dichloropropene.
[0009] The halogenating agent used in the process according to the present invention may be any suitable chlorin-
ating or brominating agent. As chlorinating agent it is particularly preferred to use chlorine itself or sulphuryl chloride.
5 The reaction is preferably carried out at a temperature within the range from -40° C to +50°C, most preferably within
the range from -25° to 0°C.
[0010] The reaction is carried out in solution in a suitable solvent. The solvent should preferably be one which does
not react with the halogenating agent. For example, when the halogenating agent is a chlorinating agent, suitable
solvents include aliphatic or cycloaliphatic hydrocarbons such as hexane or cyclohexane, and chlorinated hydrocar-
10 bons, for example dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,2,3-trichloropropane,
1,1,2,2-tetrachloroethane and chlorobenzene.
[0011] When the isothiocyanate compound which is used as a starting material in the process according to the present
invention has been prepared by the method of K. Schulze et al from a di-halo compound as described above, the
solvent used in that method may be the same as that used in the subsequent conversion of the isothiocyanate com-
15 pound to the thiazole, in which case it is not necessary to separate the isothiocyanate compound before carrying out
the process of the invention.
[0012] The time required for the process of the present invention depends upon the temperature at which it is chosen
to carry out the reaction. In general a reaction time of from 1 to 24 hours is preferred.
[0013] The substituted thiazole prepared according to the invention may be separated from the reaction mixture by
20 any desired method, for example by distillation or crystallisation. As an alternative, the thiazole may be converted to
the form of a salt, for example the hydrochloride, and crystallised from the reaction mixture in that form and in high
purity. The salt obtained in this way may be used as such in any further reaction or may be converted to the free base,
for example by neutralisation with a base, or by vacuum distillation.
[0014] The substituted thiazole obtained by the present process may be further purified if desired, for example by
25 recrystallisation or by distillation.
[0015] The invention will now be further described with reference to the following Examples, which illustrate, by way
of example, the preparation of 2-chloro-5-(chloromethyl) thiazole or the corresponding hydrochloride salt by the process
according to the present invention.

30 Example 1.

[0016] 10g of 3-chloroprop-1-enyl isothiocyanate prepared by the method of K. Schulze et al described above were
dissolved in 70ml of dichloromethane and a total 15g of chlorine gas was bubbled into the solution over a period of 2
hours, while the temperature of the solution was maintained at between 10° and 20°C. At the end of this time, GC
35 analysis showed that the isothiocyanate had been consumed.
[0017] Removal of the solvent from the resulting reaction mixture, followed by vacuum distillation at 80°C under 2mm
Hg, yielded 6g of 2-chloro-5-(chloromethyl) thiazole, in the form of a pale yellow oil which solidified on cooling.

Example 2
40
[0018] To a solution of 45g of 3-chloroprop-1-enyl isothiocyanate in 90ml of 1,2-dichloroethane, 50.5g of sulphuryl
chloride was added over a period of 10 hours at a temperature of -10° C. The reaction mixture was allowed to warm
to 25°C overnight.
[0019] The solution was cooled to -15°C and the pale yellow solid was isolated by filtration and then washed with
45 hexane. The product was 38.2g of 2-chloro-5-(chloromethyl) thiazole hydrochloride, of melting point 59-61°C, being a
yield of 61.6%.

Example 3

50 [0020] To a solution of 57g of 3-chloroprop-1-enyl isothiocyanate in 100ml of dichloromethane, 75.0g of sulphuryl

chloride was added over a period of 10 hours at a temperature from -10° to 0°C. The reaction mixture was allowed to
warm to 25° C overnight and GC analysis showed that the isothiocyanate had been consumed.
[0021] Removal of the solvent from the reaction mixture, followed by vacuum distillation at 81 to 83° C and 2mm Hg,
yielded 30.8g of a fraction which contained 2-chloro-5-(chloromethyl) thiazole of 75% purity. A portion of this fraction,
55 which was in the form of an oil, was recrystallised from 2 volumes of hexane at -25°C and gave the pure thiazole in
the form of a white solid, of melting point 28-31° C.

3
 EP 0 763 531 B1

Example 4

[0022] To a solution of 50g of 3-chloroprop-1-enyl isothiocyanate in 100ml of dichloromethane, 54g of sulphuryl

chloride was added over 5 hours at between 0° and -10°C. The reaction mixture was allowed to warm to 25°C overnight.
5 A further 6g of sulphuryl chloride was added over 1.5 hours at between 0° and -10°C and then the reaction mixture
was allowed to stand overnight, to complete the reaction. The solution was cooled to -20°C and the resulting pale
yellow solid was isolated by filtration.
[0023] The separated product was 42.4g of 2-chloro-5-(chloromethyl) thiazole hydrochloride, formed from the thia-
zole itself and by-product hydrogen chloride formed in the reaction. The salt had a melting point of 58-62°C and a
10 purity, determined by GC, of 94%.
[0024] The mother liquors were evaporated and the residue was dissolved in 30ml of dichloromethane. On addition
of hydrogen chloride gas at -10°C to the solution, a further 2g of the thiazole hydrochloride salt was precipitated. The
precipitated salt was separated by filtration and had a melting point of 61-63°C.

15 Example 5.

[0025] A solution of 277.7g of 3-chloroprop-2-enyl thiocyanate in 1,1,2,2-tetrachloroethane (1600ml) was prepared

from 1-3-dichloropropene by the above-described method of K. Schulze et al. The solution was heated to 120°C and
held at this temperature for 5 hours. GC analysis showed complete conversion of this thiocyanate to 3-chloroprop-
20 1-enyl isothiocyanate.
[0026] The solution was filtered to remove insoluble by-products and then cooled to between 0° and -10°C. Sulphuryl
chloride (283g) was added to the solution at this temperature over a period of 10 to 12 hours and then the reaction
mixture was held at this temperature for a further 1 hour, after which time the reaction was complete.
[0027] The reaction mixture was fractionally distilled and gave a main fraction of 235g, containing 57% of 2-chloro-
25 5-(chloromethyl) thiazole and 36% of residual 1,1,2,2-tetrachloroethane. The crude distilled product was dissolved in
470ml hexane and cooled to -25° C to crystallise the thiazole. 93g of white crystalline 2-chloro-5-(chloromethyl) thiazole
of purity 98% and melting point 27-30°C was obtained. The overall yield based on 3-chloroprop-2-enyl thiocyanate
was 33%.

30 Example 6

[0028] To a solution of 45g of 3-chloroprop-1-enyl isothiocyanate in 90ml of 1,2-dichloroethane, 50.5g of sulphuryl

chloride was added over 10 hours at -10°C. The reaction mixture was allowed to warm to 25° C overnight, to complete
the reaction. The solution was cooled to -15°C and the product, a pale yellow solid, was isolated by filtration and
35 washed with hexane. 38.2g of 2-chloro-5-(chloromethyl) thiazole hydrochloride was thus obtained, having a melting
point of 59-61°C and being a yield of 61.6%.

Example 7

40 [0029] A solution of 240g of 3-chloroprop-2-enyl thiocyanate in 1400g of 1,1,2-trichloroethane was held at 110° C
for 18 hours. GC analysis showed complete conversion to the isothiocyanate. The solution was filtered to remove
insoluble by-products and then cooled to 0°C. 223g of sulphuryl chloride was added at this temperature over a period
of 10 hours and the reaction mixture was held at this temperature for a further 1 hour. The reaction mixture was frac-
tionally distilled and gave a main fraction containing 96.2g of 2-chloro-5-(chloromethyl) thiazole, being a yield of 32%
45 on the original thiocyanate.

Example 8

[0030] The reaction was carried out as in Example 7, except that the 1,1,2-trichloroethane solvent was replaced by
50 the same weight of chlorobenzene. After the chlorination with sulphuryl chloride, the chlorobenzene was removed by
evaporation under vacuum and the residue was dissolved in dichloromethane and saturated with gaseous hydrogen
chloride. A 23% yield of 2-chloro-5-(chloromethyl) thiazole hydrochloride was isolated as a pale yellow solid.

Example 9
55
[0031] A solution of 50g of 3-chloroprop-2-enyl thiocyanate in 300g of 1,2,3-trichloropropane was held at 150°C for
4 hours after which GC analysis showed complete conversion of the thiocyanate to isothiocyanate. The solution was
filtered to remove insoluble by-products and then cooled to -20° C. At this temperature, a solution of 60g of sulphuryl

4
 EP 0 763 531 B1

chloride in 180g of dichloromethane was added over a period of 8 hours and the reaction mixture was then warmed
to 25° C. Fractional distillation of the reaction mixture gave a main fraction containing 18.6g of 2-chloro-5-(chloromethyl)
thiazole of 85% purity, the remainder being 1,2,3-trichloropropane.

5 Example 10

[0032] A solution of 100g of 3-chloroprop-2-enyl thiocyanate in 600ml of 1,2-dichloroethane was heated to 110° C
in an autoclave and held at this temperature for 12 hours. The excess pressure was 1.0 bar. The solution was filtered
to remove insoluble by-products and the solvent was evaporated, giving a final volume of 300ml. To this solution 153g
10 of sulphuryl chloride was added at -20°C over 18 hours. The reaction mixture was allowed to warm to 20° C and was
then cooled to -20° C to crystallize the product hydrochloride. The 2-chloro-5-(chloromethyl) thiazole hydrochloride
was filtered off as a pale yellow solid and was washed with hexane. The weight of the hydrochloride thus obtained was
102.1g, being a yield of 66.6%.
[0033] As will be apparent from the foregoing Examples, in the case of 2-chloro-5-(chloromethyl) thiazole, the process
15 makes possible the production of the substituted thiazole in good yields by means of a reaction at acceptable temper-
atures starting from 1,3-dichloropropene, which as already mentioned is a compound which is produced in large quan-
tities as a fumigant and is therefore readily available.

20 Claims

1. A process for the preparation of a substituted thiazole of general formula

25

30

wherein the symbols Hal each represents a chlorine or bromine atom, which may be the same or different, and
35 the symbols R1 and R2 each represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms,
characterised in that it comprises reacting an isothiocyanate compound of the general formula

Hal.CH(R 1 ). CH=C(R 2 ).NCS

40
in solution with a chlorinating or brominating agent.

2. A process according to Claim 1, characterised in that both of the symbols R1 and R2 represent a hydrogen atom.

45 3. A process according to either of the preceding claims, characterised in that the symbol Hal represents a chlorine
atom.

4. A process according to any of the preceding claims, characterised in that the isothiocyanate compound has been
prepared by reacting a compound of the general formula
50

Hal.CH(R 1 ). CH=C(R 2 ).Hal

wherein the symbols Hal, R1 and R2 have the above meanings, with an alkali metal thiocyanate or with ammonium
55 thiocyanate.

5. A process according to Claim 4, characterised in that said preparation of the isothiocyanate compound is conducted
in the same solvent as is used for reacting the resulting isothiocyanate compound with a chlorinating or brominating

5
 EP 0 763 531 B1

agent.

6. A process according to any of the preceding claims, characterised in that the chlorinating agent is chlorine or
sulphuryl chloride.
5
7. A process according to any of the preceding claims, characterised in that the solvent is an aliphatic or cycloaliphatic
hydrocarbon or a chlorinated hydrocarbon.

8. A process according to Claim 7, characterised in that the solvent is hexane or cyclohexane.

10
9. A process according to Claim 7, characterised in that the solvent is dichloromethane, chloroform, 1,2-dichlo-
roethane, 1,1,2-trichloroethane, 1,2,3-trichloropropane, 1,1,2,2-tetrachloroethane or chlorobenzene.

10. A process according to any of Claims 1 to 5, characterised in that the solvent is 1,2-dichloroethane and the chlo-
15 rinating agent is sulphuryl chloride.

11. A process according to any of the preceding claims, characterised in that the reaction is carried out at a temperature
within the range from -40°C to +50°C.

20 12. A process according to Claim 11, characterised in that the temperature is within the range from -25°C to 0°C.

13. A process according to any of the preceding claims, characterised in that the substituted thiazole so prepared is
separated from the reaction mixture by distillation or crystallisation.

25 14. A process according to any of Claims 1 to 12, characterised in that the substituted thiazole so produced is converted
to a salt and separated in that form by crystallisation.

Patentansprüche
30
1. Verfahren zur Herstellung von substituiertem Thiazol mit der allgemeinen Formel

35

40

wobei die Symbole Hal jeweils ein Chlor- oder Bromatom darstellen, welche gleich oder voneinander verschieden
sein können, und die Symbole R1 und R2 jeweils ein Wasserstoffatom oder eine Alkylgruppe, die 1 bis 3 Kohlen-
45 stoffatome enthält, darstellen, dadurch gekennzeichnet, daß es ein Umsetzen einer Isothiozyanatverbindung mit
der allgemeinen Formel

Hal.CH(R 1 ). CH=C(R 2 ).NCS

50
in Lösung mit einem Chlorierungs- oder Bromierungsmittel umfaßt.

2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß sowohl das Symbol R1 als auch R2 ein Wasserstoff-
atom darstellen.
55
3. Verfahren gemäß einem der vorgehenden Ansprüche, dadurch gekennzeichnet, daß das Symbol Hal ein Chlor-
atom darstellt.

6
 EP 0 763 531 B1

4. Verfahren gemäß einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Isothiozyanatverbin-
dung durch Umsetzen einer Verbindung mit der allgemeinen Formel

Hal.CH(R 1 ). CH=C(R 2 ).Hal ,

5

wobei die Symbole Hal, R1 und R2 die obigen Bedeutungen haben, mit Alkalimetallthiozyanat oder mit Ammoni-
umthiozyanat hergestellt wurde.

10 5. Verfahren gemäß Anspruch 4, dadurch gekennzeichnet, daß die Herstellung der Isothiozyanatverbindung in dem
gleichen Lösungsmittel durchgeführt wird, wie es für das Umsetzen der resultierenden Isothiozyanatverbindung
mit einem Chlorierungs- oder Bromierungsmittel verwendet wird.

6. Verfahren gemäß einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß das Chlorierungsmittel
15 Chlor oder Sulfurylchlorid ist.

7. Verfahren gemäß einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß das Lösungsmittel ali-
phatischer oder cycloaliphatischer Kohlenwasserstoff oder chlorierter Kohlenwasserstoff ist.

20 8. Verfahren gemäß Anspruch 7, dadurch gekennzeichnet, daß das Lösungsmittel Hexan oder Cyclohexan ist.

9. Verfahren gemäß Anspruch 7, dadurch gekennzeichnet, daß das Lösungsmittel Dichlormethan, Chloroform,
1,2-Dichlorethan, 1,1,2-Trichlorethan, 1,2,3-Trichlorpropan, 1,1,2,2-Tetrachlorethan oder Chlorbenzol ist.

25 10. Verfahren gemäß einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß das Lösungsmittel 1,2-Dichlorethan
und das Chlorierungsmittel Sulfurylchlorid ist.

11. Verfahren gemäß einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Umsetzung bei einer
Temperatur im Bereich von -40°C bis +50°C durchgeführt wird.
30
12. Verfahren gemäß Anspruch 11, dadurch gekennzeichnet, daß die Temperatur im Bereich von -25°C bis 0°C liegt.

13. Verfahren gemäß einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß das so hergestellte sub-
stituierte Thiazol von der Reaktionsmischung mittels Destillation oder Kristallisation abgetrennt wird.
35
14. Verfahren gemäß einem der Ansprüche 1 bis 12, dadurch gekennzeichnet, daß das so hergestellte substituierte
Thiazol zu einem Salz umgewandelt und in dieser Form mittels Kristallisation abgetrennt wird.

40 Revendications

1. Procédé pour la préparation d'un thiazole substitué de formule générale

45

50

dans laquelle les symboles Hal représentent, chacun, un atome de chlore ou de brome, qui peuvent être identiques
55 ou différents, et les symboles R1 et R2 représentent, chacun, un atome d'hydrogène ou un groupe alkyle contenant
1 à 3 atomes de carbone, caractérisé en ce qu'il comprend la réaction d'un composé isothiocyanate de formule
générale

7
 EP 0 763 531 B1

Hal.CH(R 1 ). CH=C(R 2 ).NCS

en solution avec un agent de chloration ou de bromation.

5
2. Procédé selon la revendication 1, caractérisé en ce que les deux symboles R1 et R2 représentent un atome d'hy-
drogène.

3. Procédé selon l'une ou l'autre des revendications précédentes, caractérisé en ce que le symbole Hal représente
10 un atome de chlore.

4. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que le composé isothiocyanate
a été préparé en faisant réagir un composé de formule générale

15
Hal.CH(R 1 ).CH=C(R 2 ).Hal

dans laquelle les symboles Hal, R1 et R2 ont les significations indiquées ci-dessus, avec un thiocyanate de métal
alcalin ou avec un thiocyanate d'ammonium.
20
5. Procédé selon la revendication 4, caractérisé en ce que ladite préparation du composé isothiocyanate est mise
en oeuvre dans le même solvant que celui utilisé pour faire réagir l'isothiocyanate résultant avec un agent de
chloration ou de bromation.

25 6. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que l'agent de chloration est
le chlore ou le chlorure de sulfuryle.

7. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que le solvant est un hydro-
carbure aliphatique ou cycloaliphatique ou un hydrocarbure chloré.
30
8. Procédé selon la revendication 7, caractérisé en ce que le solvant est l'hexane ou le cyclohexane.

9. Procédé selon la revendication 7, caractérisé en ce que le solvant est le dichlorométhane, le chloroforme, le 1,2-di-
chloroéthane, le 1,1,2-trichloroéthane, le 1,2,3-trichloropropane, le 1,1,2,2,-tétrachloroéthane ou le chlorobenzè-
35 ne.

10. Procédé selon l'une quelconque des revendications 1 à 5, caractérisé en ce que le solvant est le 1,2-dichloroéthane
et l'agent de chloration est le chlorure de sulfuryle.

40 11. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que la réaction est mise en
oeuvre à une température dans la plage de -40 à +50°C.

12. Procédé selon la revendication 11, caractérisé en ce que la température est dans la plage de -25 à 0°C.

45 13. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que le thiazole substitué ainsi
préparé est séparé du mélange réactionnel par distillation ou cristallisation.

14. Procédé selon l'une quelconque des revendications 1 à 12, caractérisé en ce que le thiazole substitué ainsi préparé
est converti en sel et séparé sous cette forme par cristallisation.
50

55