FR2460926A1 - PREPARATION OF MINERAL ACIDS SALTS OF CYSTEAMINES - Google Patents

Abstract

PREPARATION OF HIGH PURITY CYSTEAMINE MINERAL ACID SALTS. IT CONSISTS OF HYDROLYZING BY A MINERAL ACID IN THE PRESENCE OF WATER, A THIAZOLIDINE DISUBSTITUTED IN -2, PREVIOUSLY OBTAINED BY REACTION OF A HYDROGENOSULFATE OF AMINO ALKYL WITH A COMPOUND CONTAINING AN ION SULFHYDRATE (-SUNEH) IN THE PRESENCE OF . THIS PROCESS ALLOWS VERY PURE PRODUCTS TO BE OBTAINED WITH GOOD PERFORMANCE, WITHOUT DANGER DURING HANDLING AND WITHOUT RISK OF POLLUTION OF THE SURROUNDING AIR, IN PARTICULAR BY SH.

Description

The present invention relates to a novel

  process for preparing mineral acid salts of cystea

  by hydrolysis of di-substituted thiazolidines in

position -2.

  The mineral acid salts of cysteamine (2-aminoethanethiol), of the following formula I, and those of

  its derivatives of general formula I ', are particularly

  interesting as radiation protection agents and as intermediates for the manufacture of medicines:

HX.NH2-CH2-CH2-SH (I)

and

R3 R5

HX.NH2 - I -C-SH (I ')

! 16

3 5 6

  In these formulas, R3 R4, R and R are hydrogen

  or lower alkyl and X is a mineral acid radical

  ral. To this day, cysteamine, for example,

  was prepared industrially by reaction of ethylene-

  imine with hydrogen sulphide, in accordance with the

  However, this process of the prior art has the same effect as that described in US Pat. No. 5,325,225.

  very serious drawback illustrated by the reaction scheme

III:

NH2-CH2-CH2

NH2-CH2-CH2-SH + NH ---> / S

NH2-CH2-CH2-

  (III) that is to say, that during this process, in addition to the formation reaction of cysteamine, there is a side reaction involving cysteamine and ethyleneimine, and leads to the formation of a

  secondary product: bis (2-aminethyl) sulfide.

  In order to prevent this undesirable side reaction from occurring, it is necessary, in accordance with the prior art, to

  give way with a strictly controlled procedure, that is

  to operate: a) in the presence of a large excess of sulfur

  hydrogen in the reaction system: b) with

  a large amount of solvent when

  sold in the diluted state; (c) and at an extreme temperature

  weak. Moreover, since there is production of a pro-

  secondary bis (2-aminoethyl) sulfide, the yield of cysteamine does not exceed 60-7C%, and as inevitably this sulphide contaminates cysteamine,

  final product is of low quality.

  Starting materials, ethyleneimine and hydrogen sulfide

  gene, are dangerous products; since the latter is a toxic gas with a very unpleasant odor, not only is there a risk during its handling, but

  can also cause air pollution around the

and aggravate it.

  The present invention makes it possible to avoid these

  advantages of the prior art and to obtain, on an industrial scale, in a hygienic and safe manner, with a good yield and a high degree of purity,

  mineral acid salts of cysteamine and its derivatives.

  The novel process for the preparation of these cysteamine salts, and its derivatives, consists in hydrolyzing, by a mineral acid, a disubstituted thiazolidine.

  in -2, obtained by reaction of a hydrogen sulfate

  minoalkyl with a compound containing a hydrogen sulfide ion

(-SH) in the presence of a ketone.

  According to the present invention, it is

  a compound of formula I '(wherein R3, R4, R5 and R are hydrogen or lower alkyl and X is a mineral acid radical) from a -2-disubstituted thiazolidine of the following formula IV: R3

R4 - C - NH R1

61 C (IV)

R6 _ C- S / R2

  R in which R1 and R2, similar or different, are

  each a linear or branched chain alkyl group

  preferably having 1 to 10 carbon atoms and most preferably 1 to 5 carbon, or a phenyl group, or together form a ring; R3, R4, R5 and R6 are

hydrogen or lower alkyl.

  This compound IV is hydrolysed by means of a mineral acid in the presence of water, as shown in Scheme V following t

R3 R3

R4-C-NH R1 R4-C-NH2 R

+ + HXH20 - HX + o = C

R6-C-S R2 R6-C-SH1R2

R À5

(V)

  This starting material does not exhibit the reactivi-

  of the thiol and primary amine groups, but its hydrolysis by the mineral acid releases a dialkylketone

  with a practically quantitative yield, in accordance

  Scheme V, i.e., its characteristic lies in its cyclic structure, represented in formula IV. Particularly suitable for hydrolysis are the following mineral acids: sulfuric, nitric, phosphoric, and the like, the preferred ones comprising

  halohydric acids such as hydrochloric acid, bromine

  hydric and the like. The amount of acid used is equivalent to or slightly greater than the amount necessary to react with the moles of 2,2-dialkyl thiazolidine involved. The procedure is preferably carried out with the elimination of the dialkyl ketone reaction system as it progresses. formation, so that the balance leans towards the desired products. When the dialkyl ketone form is removed by evaporation, distillation or the like, or is dissolved in the organic solvent by heating the system comprising the organic solvent.

  which is immiscible with water (eg benzene, chlorine

  form or the like), the reaction takes place with a

  increased. The temperature varies within a range of

  from room temperature to 100 C. After this

  thermal drolysis (lasting 2 to 3 hours), soil

  organic material is separated for reuse, the water is evaporated as much as possible and then

  the residue is cooled and dried to give, with a

  high dose, a mineral acid salt of cysteamine

high purity.

  As mentioned above, one of the aims of the invention is a new process for the preparation of thiazolidines disubstituted in the form of -2, used as raw materials for the preparation of these salts of

cystéamines.

  So far, 2,2-dimethyl thiazolidine was prepared

  by reaction of ethyleneimine with hydrogen sulphide

  gene in the presence of acetone, as shown in the diagram

  following (Ann Chem 566, 210 (1950)).

NH + 0 C CH3

> NH + 0 = CC + H2S

CH3 H

CH2 ---- N. \ CH3 -

C + H20

  However, according to this process of the prior art, it is also necessary to use ethyleneimine,

  and it is also inevitable to use sulfur sulfide

  as in the form of a free gas, exactly as it was the case for preparing cysteamine in the previously described prior art process. Consequently, since the prior art involves the use of these materials,

  dangerous, toxic and of high cost, it also

  the serious drawbacks described above: dangerous use, difficult adjustment of the reaction and risk of

air pollution.

  As a result, a new and very interesting process has been sought and found, in accordance with the invention, which involves as raw material instead of aziridine.

  (ethyleneimine), for the synthesis of the thiazolidines cor-

  corresponding to formula IV, an amino hydrogenosulphate

  alkyl. Aminoalkyl hydrogenosulphates, represented by the general formula VI: 3 R5

NH2 - 4- C --- OS03H (VI)

  R 4 R 6 wherein R 3, R 4, R 5 and R 6 are hydrogen or lower alkyl are prepared by reaction of 2-aminoalkanol with sulfuric acid; they are inexpensive and suitable as raw material because their use does not cause the disadvantages encountered in the mode

  which involves the use of aziridine.

  Therefore, the present invention includes a

  industrial production of thiazolidines disubsti-

  killed in -2, of formula IV, of high purity with a

  high level, by reaction of aminoaluminum hydrogenosulphate

  kyle of formula VI, with a compound containing an ulfhydrate ion (-SH), in the presence of a ketone of formula VII R1

\ C = 0 (VII)

  R2 / wherein R1 and R2 have the same definition as above. These hydrogen sulphates of formula VI can be easily prepared, with good yields, by

  a dehydration reaction of amino-2 alkanol

  merce, by means of sulfuric acid; they are safe, stable and cost-effective against aziridine. According to the invention, all the compounds of formula VI are suitable, but the preferred ones are those for which R3, R4, R5 and R6 are hydrogen or methyl group.

  With regard to the ketone of formula VIIp.

  especially those compounds in which R 1 and R 2 are straight or branched chain alkyl having 1 to 5 carbon atoms, or phenyl, or together form a ring. Among those which are more particularly suitable are: acetone, methyl ethyl ketone, methyl isobutyl acetone, cyclohexanone, and

  similar. As they are all obtained industrial-

  they are readily available. The amount of

  the ketone used is greater than that which is theoretically

  necessary. Excess ketone is recovered when

  the reaction is complete, and can be reused

  conde times. It is also possible to carry out a heterogeneous reaction

gene with water.

  In the present description, the term

  compounds having an SH ion (sulfhydrate),

  which can release this ion, for example, sulfhydrate, sulfide, polysulfide, sulfur and the like. These compounds can be used appropriately, separately

  or in combination, and it may even be possible to use

  Hydrogen sulfide. Are readily available

  for example their alkali metal salts such as sodium sulfhydrate or potassium sulfide. It is preferable that the amount of the compound containing the hydrogen sulfide ion, used in the reaction system, is equivalent, or preferably 1 to 2 times equivalent,

  to the theoretical amount related to the quantity of hydro-

  aminoalkyl genosulfate. Therefore, it is preferable

  than in the reaction system, the amount of

of metai

  volume / alkali is the amount of moles of hydrogen

aminoalkyl genosulfate.

  The reaction proceeds at a satisfactory speed

  at temperatures ranging from room temperature to

  at 150.degree. C., preferably between 50.degree. and 120.degree.

  reaction reactions are not critical, and can be operated properly under pressure, with agitation, or

  at reflux. The duration of the operation depends on the temperature

  reaction, the type of ketone used, and

  usually ranges from 1 to 10 hours.

  When the reaction is complete, the secondary products

  The sulfates and unreacted sulfur compounds are removed by filtration, the ketone phase, in which the desired product is dissolved, is separated from the aqueous phase, then distilled or sublime

  to obtain with a good yield a thiazolidine di-

  substituted in -2, of high purity.

  The following non-limiting examples constitute

  kill an illustration to better understand the invention.

EXAMPLE 1

  To a solution of 12 g of NaOH in 20 ml of water are added 42.4 g of 2-aminoethyl hydrogen sulphate, then 48 g of 70% pure sodium hydrogen sulfide and 200 ml of methyl ethyl ketone. This mixture is allowed to react to

  QC for 3 hours in an autoclave. When the

  action is completed, the mixture is allowed to cool.

  naked at room temperature, and the precipitate is separated

  by filtration. The filtrate is in turn separated into

  is aqueous and methyl ethyl ketone phase. The aqueous phase

  washed twice with methyl ethyl

  which is then joined to the methyl ethyl ketone phase. All the ketone phases thus obtained are concentrated and the residue is distilled under pressure.

  reduced to give 33.3 g of 2-methyl-2-ethyl-thiazolidine

  boiling at 72 ° C. under 10 mm Hg (84.7% yield). The values of the infra-red spectrum and the boiling point are identical to those of a reference sample.

EXAMPLE 2

  The procedure of Example 1 is repeated with 12 g

  of NaOH, 10 ml of water, 42.4 g of amino hydrogen sulphate,

  2 ethyl, 30 g of sodium sulfhydrate (purity 70%) and

  200 ml of one of the six kinds of ketone listed above

  sub, to obtain with good yields the thiazolines

  corresponding dines: acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methyl n-amyl ketone eVacetophenone. The results

the next board.

Temple-

Reaction reinforcement (oC)

BOARD

  Product obtained Dimethyl-2,2 thiazolidine are presented in Boiling point (C), 59.3 (under 14.5mmHg) Methyl ethyl ketone

Methyl iso-

  butyl ketone 110 Cyclohexanone 120 Methyl-n-amyl ketone Acetophenone 120

Methyl-2

thyl-2 thia-

zolidine

Methyl-2 iso-

butyl-2 thiazolidine

Spiro Cyclo

hexane-1: 2'-

thiazolidine] Methyl-2

amyl-2 thia-

  Zolidine 2-methyl-2-phenylthiazolidine 72.0 mmHg) 77.5 (6.5 mmHg) 94.0 (3.5 mmHg) 102.5 (4.5 mmHig) 127.0 (3mmHg) ) Type of acetone ketone

yield

  56.0 82.6 56.3 76.1 52; 4, 8 For each of the thiazolidines obtained, the

  infra-red spectrum and the boiling point, are identi-

  those of the reference standard.

EXAMPLE 3

  To a solution of 12 g of NaOH in 20 ml of water is added 42.4 g of 2-aminoethyl hydrogen sulphate, then 36 g of pure sodium sulphoxide-70%, 9.6 g of powder. of sulfur

  and 200 ml of methyl ethyl ketone. We let this material react

  lange for 3 hours at 90 C in an autoclave. When the reaction is complete, allow the mixture to cool

  obtained at room temperature, and the operating mode is repeated

  of Example 1 to obtain 35 g of methyl-2

  2-ethyl thiazolidine (89.1% yield).

EXAMPLE 4

  Allowed to react in an autoclave for 1 hour and

  at 85 ° C., a mixture comprising 42.4 g of hydrogenosulphonate

  2-aminoethyl ester, 25.2 g of 70% pure sodium hydrogen sulfate, 82.2 g of 92% pure sodium sulfide nonahydrate and 200 ml of methyl ethyl ketone. When the

  reaction is complete, the mixture is allowed to cool.

  action at room temperature, then repeat the mode

  The procedure of Example 1 gives 24.6 g of methyl

  2-ethyl-thiazolidine (yield 62.6%).

EXAMPLE 5

  Take a mixture identical to that of Example 4, and

  it is refluxed for 6 hours. When the reaction

  After completion, this reaction mixture is allowed to cool.

  at room temperature, then the procedure is as in Example 1, which gives 23.5 g of methyl-2

  2-ethylthiazolidine (yield 59.8%).

EXAMPLE 6

  A mixture comprising 42.4 g of 2-aminoethylhydosulphate, 82.2 g of sodium sulphide nonahydrate of 92% purity, 20 ml is reacted for 1 hour and a half in an autoclave at 105.degree. of water and 200 ml of methyl ethyl ketone. When the reaction is complete, it is allowed to cool to ambient temperature, and then the procedure is as in Example 1 to obtain 22.6 g of methyl-2.

  ethyl-2-yiazolidine (yield 57.5%).

EXAMPLE 7

  To a solution of 12 g of NaOH in 20 ml of water are successively added 42.4 g of 2-aminoethylhydosulphate, 2 g of sodiumhydrochloride (70% pure) and 200 ml of ethyl. ethyl ketone. This mixture is stirred for 6 days at room temperature and then filtered off.

  the precipitate thus formed. Then, we repeat the mode o-

  Example 1 to give 9.7 g of methyl-2

  2-ethylthiazolidine (yield 24.7%).

EXAMPLE 8

  19.8 g of KOH and 42.4 g of 2-aminoethyl hydrogen sulphate are dissolved in 108.2 g of a 25% solution of potassium sulphhydrate and 200 ml of potassium hydroxide are added thereto.

  acetone. The mixture thus obtained is reacted during

  3 hours in an autoclave at 75 C.

  following the procedure of Example 1, which gives

  15.4 g of 2,2-dimethyl thiazolidine (yield 43.8%).

EXAMPLE 9

  A mixture comprising 42.2 g of amino hydrogen sulphate

  No. 2-ethyl, 80.8 g of potassium sulphide, 43% pure, 1 ml of water and 200 ml of methyl isobutyl ketone, is reacted for 3 hours in an autoclave.

   C. Then the procedure of the example is repeated

  p 1 to obtain 13.9 g of 2-methyl-2-isobutyl thia-

zolidine (yield 29.1%).

EXAMPLE 10

  To a solution of 12 g of NaOH in 20 ml of water,

  46.6 g of 1-amino-propyl-2-hydrogenosulphate are added, followed by 32.4 g of sodium sulfhydrate (70% purity) and

  ml of methyl ethyl ketone. The reaction is allowed to

  The mixture thus obtained for 2 hours and a half at 90 ° C. in an autoclave When the reaction is complete, it is left

  the mixture is cooled to room temperature, then

  yield as in Example 1, to obtain 19.7 g of

  2-ethyl-2-ethyl-thiazolidine boiling at 67.8 C under 10

mm Hg (50% yield).

EXAMPLE 11

  50.8 g of 2-amino-2-methyl-2-hydrogenosulphate are added

  propyl, to a solution of 12 g of NaOH in 20 ml of water.

  Then the whole is added with 32.4 g of 70% pure sodium hydrogen sulfide and 200 ml of methyl ethyl ketone. The mixture thus obtained is allowed to react for 2 hours and a half at 90 ° C. in an autoclave. When the reaction is complete, this reaction mixture is allowed to cool to room temperature, and the precipitate formed is removed by filtration. The filtrate is separated in the aqueous phase and in the methyl ethyl ketone phase. The aqueous phase is washed 2 times with 30 ml of methyl ethyl ketone, and all the phases / ketones are combined before being concentrated to form crystals which are separated by filtration. The crystals obtained are sublimed under reduced pressure, under 6 mm of mercury,

  in an oil bath to give 14.3 g of trimethyl

  2,4,4 ethyl-2 thiazolidine, in the form of white crystals

(yield 32.8%).

EXAMPLE 12

  A solution of 24 g of NaOH in 40 ml of water, is

  with 10.2 g of hydrogen sulphide, with

  in an ice bath to facilitate its adsorption.

  tion. 42.4 g of amino-2-hydrogen sulphate are added

  ethyl and 200 ml of methyl ethyl ketone. We let

The mixture thus obtained is stirred for 3 hours at 900 ° C. in an autoclave. When the reaction is complete, this mixture is allowed to cool to room temperature. The procedure described in the example is then resumed.

  1, and 26.1 g of 2-methyl-2-ethyl-2-thiazole are obtained.

dine (yield 66.4%).

EXAMPLE 13

  To 58.6 g of dimethyl-2,2 thiazolidine obtained in the e-

  In Example 2, a solution of 53.7 g of 35% hydrochloric acid in the same amount of water is added dropwise with cooling in an ice bath. This mixture is heated; a release of acetone occurs at 560C; the heating is continued until the temperature of

  distillation reaches 99 C. This treatment, to be

  plet, requires about 2 hours and a half. The solution

  residual action is concentrated under pressure

  duit, almost to dryness. The residue obtained is

  100 ml of isopropyl alcohol, the mixture is

  cooled and filtered, and crystals are obtained

  white. These crystals are dried at 40.degree.

  then continue drying on pentoxide

  overnight, and 55.1 g of chlorine are obtained.

  cysteamine hydrate (97% yield), to a degree of

  retained 98.9%, with a melting point of 68.2 C.

EXAMPLE 14

  A mixture prepared by diluting 88.7 g of bromine

  at 47% in 1.3 times of water, is added dropwise to

  drop, with ice-cooling, to 58.6 g of 2,2-dimethyl thiazolidine. The mixture thus obtained is treated as described in Example 13, which gives 76.4 g of cysteamine hydrobromide (96.7% yield), with a purity of 98.75%, with a melting point of

41.5 C.

EXAMPLE 15

  The procedure is as in Example 13, but with the replacement of 2-dimethyl-2-thiazolidine with 65.6 g of methyl-2

  2-ethylthiazolidine and 54.8 g of chlorhydrin are obtained.

  cysteamine (96.5%), to a degree of

  retained 98.87%, and a / usion point of 68.30 C.

EXAMPLE 16

  1 80 g of 2-methyl-2-isobutylthiazolidine prepared as

  described in Example 2, a solution prepared by diluting 53.7 g of% hydrochloric acid in an equal amount of water is added dropwise with cooling in an ice bath. The resulting mixture is supplemented with 50 ml of benzene, and the whole is heated to

  reflux for 2 hours with stirring. The benzene phase

  that is separated, and is added to the aqueous phase 50 ml of benzene with stirring, to extract it. The benzene fractions are concentrated under reduced pressure, almost

  to dryness. The residue obtained is supplemented with 100 ml of

  cool isopropyl, then this mixture is cooled and filtered

  to give white crystals. These crystals are

  under reduced pressure at 40 ° C., then over phosphorus pentoxide overnight, and 55.9 g of

  cysteamine hydrochloride (98.4% yield) with a

  purity of 98.85% and a / usion point of 68.5 C.

EXAMPLE 17

  The procedure of Example 16 is repeated, but with

  dimeth-2,5-2,5-ethyl-2-thiazolidine as the starting material

  dine and trimethyl-2,4,4 ethyl / thiazolidine, respectively obtained in Example 10 and Example 11, in place of 2-methyl-2-isobutyl thiazolidine. We obtain

  the hydrochlorides of the corresponding cysteamine derivatives.

Claims (8)

  1. Process for the preparation of a mineral acid salt of a cysteamine of formula 3 R3 R5 HX. NH2 ---- C ---- C ---- SH 4 R   in which R 3, R 4, R 5 and R 6 are hydrogen or lower alkyl and X is a mineral acid radical, characterized in that a thiazolidine disubstituted in the presence of water is hydrolyzed with a mineral acid in the presence of water. - 2 of formula R4 R6 R3 H He ----. ---- NOT R1 - ... i _ Se / R2 R5   in which R1 and R2, similar or different, are each   either a linear or branched chain alkyl group, or a phenyl group, or together form a ring,   R3, R4, R5 and R6 having the same definition as above.   2. Method according to claim 1, characterized in   what R1 and R2, when they are alkyl groups,   have 1 to 10 carbon atoms, preferably 1 to 5.   3. Method according to one of claims 1 or 2,   characterized in that the mineral acid is a halogenoacetic acid   water, preferably hydrochloric acid or hydrobromide than.   4. Method according to one of claims 1 to 3,   in that it operates in an interval ranging from room temperature at 100C.   5. Method according to one of claims 1 to 4,   characterized in that the -2-disubstituted thiazolidine is prepared by reacting a 2-amino-alkylsulfate of formula R3 R5 NH2 ---- C ---- & ---- So3H 1 4 16 R R   in which R3, R4, R5 and R6 have the same definition as above, with a compound comprising a hydrogen sulfide ion (-SH), in the presence of a ketone of formula: R1 X C = O R2 /   R1 and R2 having the same definition as above.   6. Method according to claim 5, characterized in   R3, R4, R5 and R6 are hydrogen or methyl.   7. Process according to claim 5 or 6, characterized   in that the term "compound containing an -SH ion" is understood to mean a compound capable of releasing this ion, such as sulfur,   sulphide, sulphide or polysulphide, in particular sulfur   sodium hydrate or potassium sulphide.   8. Products obtained by the process according to one of the Claims 1 to 7