GB2054573A - Salts of cysteamine - Google Patents
Salts of cysteamine Download PDFInfo
- Publication number
- GB2054573A GB2054573A GB8021313A GB8021313A GB2054573A GB 2054573 A GB2054573 A GB 2054573A GB 8021313 A GB8021313 A GB 8021313A GB 8021313 A GB8021313 A GB 8021313A GB 2054573 A GB2054573 A GB 2054573A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- cysteamine
- mineral acid
- reaction
- thiazolidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical class NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 150000003839 salts Chemical class 0.000 title claims abstract description 15
- 229960003151 mercaptamine Drugs 0.000 title claims description 18
- -1 2,2-disubstituted thiazolidines Chemical class 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 21
- 239000011707 mineral Substances 0.000 claims abstract description 21
- 150000002576 ketones Chemical class 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000007858 starting material Substances 0.000 abstract description 13
- 150000003548 thiazolidines Chemical class 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000203 mixture Substances 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000012071 phase Substances 0.000 description 12
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 11
- WSYUEVRAMDSJKL-UHFFFAOYSA-N ethanolamine-o-sulfate Chemical compound NCCOS(O)(=O)=O WSYUEVRAMDSJKL-UHFFFAOYSA-N 0.000 description 10
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 9
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- AGSHBVNPPGEAMB-UHFFFAOYSA-N 2-ethyl-2-methyl-1,3-thiazolidine Chemical compound CCC1(C)NCCS1 AGSHBVNPPGEAMB-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- SNPQRYOQWLOTFA-UHFFFAOYSA-N 2,2-dimethyl-1,3-thiazolidine Chemical compound CC1(C)NCCS1 SNPQRYOQWLOTFA-UHFFFAOYSA-N 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 3
- QCWJLAHDNKXFIQ-UHFFFAOYSA-N 2-methyl-2-(2-methylpropyl)-1,3-thiazolidine Chemical compound CC(C)CC1(C)NCCS1 QCWJLAHDNKXFIQ-UHFFFAOYSA-N 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 3
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- GRNCRQXGFPYLMR-UHFFFAOYSA-N 2-ethyl-2,4,4-trimethyl-1,3-thiazolidine Chemical compound CCC1(C)NC(C)(C)CS1 GRNCRQXGFPYLMR-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RGXZRDJYNDJZBY-UHFFFAOYSA-N (2-azaniumyl-2-methylpropyl) sulfate Chemical compound CC(C)(N)COS(O)(=O)=O RGXZRDJYNDJZBY-UHFFFAOYSA-N 0.000 description 1
- ZWVMLYRJXORSEP-LURJTMIESA-N (2s)-hexane-1,2,6-triol Chemical compound OCCCC[C@H](O)CO ZWVMLYRJXORSEP-LURJTMIESA-N 0.000 description 1
- FUJGHFAISHTYGC-UHFFFAOYSA-N 1-azaniumylpropan-2-yl sulfate Chemical compound NCC(C)OS(O)(=O)=O FUJGHFAISHTYGC-UHFFFAOYSA-N 0.000 description 1
- KJAFQTSTEUABJQ-UHFFFAOYSA-N 2-ethyl-2,5-dimethyl-1,3-thiazolidine Chemical compound CCC1(C)NCC(C)S1 KJAFQTSTEUABJQ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000003915 air pollution Methods 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-M hydrosulfide Chemical compound [SH-] RWSOTUBLDIXVET-UHFFFAOYSA-M 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920001021 polysulfide Polymers 0.000 description 1
- ZOCLAPYLSUCOGI-UHFFFAOYSA-M potassium hydrosulfide Chemical compound [SH-].[K+] ZOCLAPYLSUCOGI-UHFFFAOYSA-M 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009283 thermal hydrolysis Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
Mineral acid salts of cysteamine compounds are prepared by hydrolysing 2,2-disubstituted thiazolidines with mineral acid in the presence of water. The thiazolidines may be prepared by reacting aminoalkyl hydrogensulphate with a compound having hydrosulphide ion, in the presence of ketone. Thus, these salts can be prepared without the use of toxic starting materials.
Description
SPECIFICATION
Process for preparing mineral acid salts of cysteamines
This invention relates to a method of preparing mineral acid salts of cysteamines.
The mineral acid salts of cysteamine (namely 2-aminoethanethiol) and cysteamine derivatives, having the following formulae (I) and (I') respectively, are particuiarly useful as radiation protecting agents and intermediates for medical drugs.
HX.NH2-CH2-CH2-SH (I) and
wherein:
R3, R4, R5 and R6 are hydrogen or lower alkyl;
X is the acid radical.
With respect to the preparation of cysteamine(s) and derivatives thereof, hitherto, cysteamine, for example, has been industriaily prepared by the reaction of ethyleneimine and hydrogen sulphide, in accordance with the following scheme (all):
However, the prior method above described has extremely serious drawback as illustrated by the following scheme (Ill):
That is to say, according to the prior method, as is obvious from the scheme Ill, a side reaction occurs between cysteamine and ethyleneimine resulting in bis-2-aminoethyl sulphide as a by-product.To prevent this undesired side reaction, the prior method has required strict process controls, the example, as follows:
(a) the presence of a great excess of hydrogen sulphide in the reaction system;
(b) the use of large amounts of solvent so that the reactants are very dilute; and
(c) the carrying out of the reaction at extremely low temperature.
In addition, since bis-2-aminoethylsulphide is produced as a by-product, the cysteamine yield is reduced to only about 60-70%. As it is inevitable that the by-product of bis-2-aminoethylsulphide is present as contaminant in the final product of cysteamine, only low purity cysteamine is obtained.
An object of this invention is to obviate or mitigate the aforesaid disadvantages.
In accordance with the present invention there is provided a process for preparing a mineral acid salt of cysteamine of the formula:
wherein:
R3, R4, R5 and R6 are hydrogen or lower alkyl; and
X is a mineral acid radical, comprising hydrolysing a 2,2-disubstituted thiazolidine of the formula:
wherein:
R, and R2, which may be the same of different, are each straight or branched chain alkyl groups of from one to ten carbon atoms or phenyl groups, or R, is joined with R2 to form a ring; and
R3, R4, R5 and R6 are as defined above, with mineral acid in the presence of water.
The present inventors have researched a wide range of potential starting materials other than hydrogen sulphide, which is dangerous and difficult to handle, and ethyleneimine, which has the disadvantages described above.
Thus, in the present invention mineral acid salts of cysteamine having the formula (I') (wherein R3, R4, R5 and Re are hydrogen or lower alkyl; and X is acid radical) are produced from 2,2-disubstituted thiazolidine of the formula (IV) as starting material.
wherein:
R1 and R2, which may be the same or different, are each a straight or branched chain alkyl group, of from one to ten carbon atoms and preferably one to five carbon atoms, or a phenyl group, or R, is joined with R2 to form a ring; R3, R4, R5 and Re are hydrogen or C, to C,O alkyl groups. This compound is hydrolysed with mineral acid in the presence of water as illustrated by the following scheme (V):
This starting material does not have the reactivities of the thiol and primary amine groups, but it is hydrolysed with mineral acid to release dialkylketone in almost quantitative yield, as illustrated by the scheme (V).It is characterised by its cyclic structure of formula (IV). Among the mineral acids for hydrolysis, acids such as sulphuric acid, nitric acid and phosphoric acid may be suitably used. The preferred acids include, for example, hydrohalic acids such as hydrochloric acid and hydrobromic acid.
The mineral acid is preferably employed in an amount which is equivalent or slightly greater than the amount required to react completely with the amount of 2,2-dialkylthiazolidine employed.
The process is preferably conducted with continuous removal of the formed dialkylketone out of the reaction system in order that the equilibrium lies to the side of the products. When the dialkylketone formed is driven off by evaporation, distillation etc., or is dissolved in the organic solvent by warming the system with the water-immiscible organic solvent (e.g. benzene, chloroform, etc), the reaction proceeds with an increased yield. The reaction temperature may be varied within the range of from room temperature to 1 00 C. After such thermal hydrolysis (for 2 to 3 hours), the organic solvent, if used, may be then separated, as much as possible of the water is driven off by evaporation, and then the residue is cooled and dried to obtain the mineral acid salt of cysteamine in high yield and high purity.
Hitherto, 2,2-dimethyl thiazolidine has been prepared by the reaction of ethyleneimine on hydrogen sulphide in the presence of acetone, as illustrated by the following scheme (Ann.
Chem. 566 210(1950)):
However, according to the prior method, it is also necessary to use ethyleneimine and it is also inevitable that hydrogen sulphide in the form of free gas be used just as for preparing cysteamine according to the prior method described above. Since the prior method requires these high-priced, poisonous and dangerous starting materials, it has the same serious drawbacks as mentioned above.
The invention thus provides an advantageous method for producing mineral acid salts of cysteamine and cysteamine compounds, in good yield and high purity, which does not exhibit the disadvantages of the conventional process described above.
The invention is an industrial mass production process of mineral acid salt of cysteamine and derivative thereof in a safe and hygienic manner without using hydrogen sulphide as in the prior art method. Since hydrogen sulphide is a poisonous and offensive smelling gas, it not only involves a risk when handling it but also it is a source of offensive smells and air pollution.
Therefore, in this technical field, the method without using hydrogen sulphide is advantageous.
Another advantage of the present invention is that it is an advantageous and safety process for preparing 2,2-disubstituted thiazolidines, which is used as the starting material for said salts, without using harmful and high-priced starting materials such as ethyleneimine and hydrogen sulphide.
The key to this method of preparation resides in the discovery that, instead of aziridine, aminoalkyl hydrogensulphate can be used as a starting material for the synthesis of thiazolidine corresponding to the formula (IV).
Aminoalkyl hydrogensulphates, represented by the following general formula (Vl).
wherein:
R3, R4, R5 and Re are hydrogen or lower alkyl, are prepared by reacting 2-amino alkylalcohol with sulphuric acid, and they are low in price and suitable for the starting material of the present process which does not exhibit the disadvantages of the conventional process wherein aziridine has been used as the starting material.
Thus, the present invention also provides an industrial method of producing 2,2-disubstituted thiazolidines of the formula (IV) in good yield and high purity by reacting the starting material, namely aminoalkyl hydrogensulphate of the formula (VI), with a compound containing hydrosulphide ion (SH) in the presence of ketone having the following formula (VII)
wherein:
R1 and R2 are as defined above.
Aminoalkyl hydrogensulphates, which have the formula (Vl) and are used as the starting material, may be easily prepared in good yield by the dehydration reaction of 2-aminoalkylalcohol (obtained commercially) with sulphuric acid, and are safer, more stable and lower-priced than aziridine. According to the present invention, all of the compounds of the formula (VI) are suitably used, and the preferred esters include, for example, the compounds wherein R3, R4, R5, and Re are hydrogen atoms or methyl groups.
With respect to ketone of the formula (VII), any of the compounds corresponding to the formula may be used, and the preferred ketones include, for example, the compounds wherein
R1 and R2 are straight or branched chain alkyl of 1 to 5 carbons or phenyl, or R1 is joined with
R2 to form a ring. Ketones which are particularly suitable are: acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone. All of these are readily available commercially. The ketone is preferably employed in an amount which is greater than the amount required theoretically. The excess of the ketone may be recovered after the completion of reaction and then may be further employed in the reaction for the second time. A heterogeneous reaction may be also conducted with water.
The compounds having hydrosulphide ion (-SH) as used throughout of this specification refer to those which can release the hydrosulphide ion, for example, hydrosulphide, sulphide, polysulphide and sulphur. Such compound may be suitably used separately or in combination therewith and even hydrogen sulphide may be used when desired. The following compounds are illustrative: alkali metal salts such as sodium hydrosulphide and potassium sulphide, all of which are readily available. It is preferable that the hydrosulphide ion-containing compound is used in the reaction system in such amount as equivalent or more, preferably from one to twofold equivalents, of hydrosulphide ion (-SH) based on the amount of aminoalkyl hydrogensulphate.Therefore, it is preferable that, in the reaction system the alkali metal atom is present in a molar amount twice as much as the aminoalkyl hydrogensulphate.
The reaction proceeds at a satisfactory rate at temperatures of from room temperature to 1 50 C, preferably from 50 to 1 20 C. The reaction conditions are not critical and the reaction may be suitably carried out under pressure, with stirring or at reflux. The process duration is determined by the reaction temperature and the nature of the ketone and generally it varies within the range of from one to ten hours. After completion of reaction, the by-product of sulphates and unreacted sulphur-compounds may be filtered off and the ketone phase wherein the desired product is dissolved separated from the water phase, followed by the distillation or sublimation, yielding 2,2-disubstituted thiazolidines in good yield and high purity.
The following examples further illustrate the invention:
EXAMPLE 1
To a solution of 1 2.0g of sodium hydroxide in 20 ml of water, 42.4g of 2-aminoethyl hydrogensulfate is added, followed by the addition of 48.0g of sodium hydrosulfide (the content thereof being 70%) and 200 ml of methyl ethyl ketone. The mixture is allowed to react at a temperature of 90 C for 3 hours in an autoclave.
After completion of the reaction, the reaction mixture is allowed to cool to room temperature, and the precipitate is filtered off. The filtrate is separated into methyl ethyl ketone phase and water phase. The water phase is washed two times with 30 ml of methyl ethyl ketone and then combined with said methyl ethyl ketone phase. Thus combined methyl ethyl ketone phases are concentrated. The residue is distilled under reduced pressure to yield 33.3g of 2-methyl-2-ethyl thiazolidine having a boiling point of 72.0 C (at 10 mm. Hg) (yield 84.7%). 1. R. and b. p.
thereof are identical with those of reference standard.
EXAMPLE 2
Using 1 2.0g of sodium hydroxide, 10 ml of water, 42.4g of 2-aminoethyl hydrogensulfate, 30.0g of sodium hydrosulfide (70% pure) and 200 ml of one of the six kinds of ketones set forth in the following, the procedure of Example 1 is respectively repeated to yield respectively corresponding thiazolidines in good yield: acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methyl n-amy ketone and acetophenone.
The results are shown in the following Table.
Reaction Boiling
Kind of ketone temperature Product point Yield ('C) ('C) (%)
Acetone 75 2,2-Dimethyl 59.3 56.0
thiazolidine (at 14.5mmHg) Methyl ethyl 90 2-Methyl-2- 72.0 82.6 ketone ethyl thiazo- (at 1 OmmHg) lidine
Methyl iso- 110 2-Methyl-2- 77.5 56.3 butyl ketone isobutyl (at 6.5mmHg) thiazolidine
Cyclohexanone 120 Spiro cyclo 94.0 76.1
hexane-1,2'- (at 3.5mmHg) thiazolidine
Methyl-n-amyl 120 2-Methyl-2- 102.5 52.4 ketone amyl-thiazo- (at 4.5mmHg) lidine
Acetophenone 120 2-Methyl-2- 127.0 50.8
phenyl- (at 3mmHg)
thiazolidine
With respect to each thiazolidine, I. R. and b. p. thereof are respectively identical those of reference standard.
EXAMPLE 3
To a solution of 1 2.0g of sodium hydroxide in 20 ml of water, 42.4g of 2-aminoethyl hydrogensulfate is added, followed by the addition of 36.0g of sodium hydrosulfide (70% pure), 9.6g of sulfur powder and 200 ml of methyl ethyl ketone. The mixture is allowed to react for 3 hours at a temperature of 90"C in an autoclave.
After completion of the reaction, the reaction mixture is allowed to cool to room temperature, and the procedure described in Example 1 is repeated to yield 35.0g of 2-methyl-2-ethyl thiazolidine (yield 89.1%).
EXAMPLE 4
A mixture, which comprises 42.4g of 2-aminoethyl hydrogensulfate, 25.2g of sodium hydrosulfide (70% pure), 82.2g of sodium sulfide nonahydrate (92% pure) and 200 ml of methyl ethyl ketone, is allowed to react for 1.5 hours at 85"C in an autoclave.
After completion of the reaction, the reaction mixture is allowed to cool to room temperature, thereafter the procedure described in Example 1 is repeated to yield 24.6g of 2-methyl-2-ethyl thiazolidine (yield 62.6%).
EXAMPLE 5
A mixture comprising 42.4g of 2-aminoethyl hydrogensulfate, 25.2g of sodium hydrosulfide (the content thereof being 70%), 82.2g of sodium sulfide nonahydrate (the content thereof being 92%) and 200 ml of methyl ethyl ketone is refluxed for a period of 6 hours.
After completion of the reaction, the reaction mixture is cooled to room temperature, and then the operation is conducted under the same conditions as those of Example 1, yielding 23.5g of 2-methyl-2-ethyl thiazolidine (yield 59.8%).
EXAMPLE 6
A mixture comprising 42.49 of 2-aminoethyl hydrogensulfate, 82.2g of sodium sulfide nonahydrate (92% pure), 20 ml of water and 200 ml of methyl ethyl ketone is allowed to react for 1.5 hours at 105"C in an autoclave.
After completion of the reaction, the reaction mixture is allowed to cool to room temperature, and thereafter 22.6g of 2-methyl-2-ethyl thiazolidine is produced in the same manner as in
Example 1 (yield 57.5%).
EXAMPLE 7
To a solution of 12.0g of sodium hydroxide in 20 ml of water, 42.49 of 2-aminoethyl hydrogensulfate, 25.29 of sodium hydrosulfide (70% purity) and 200 ml of methyl ethyl ketone are successively added. The mixture is stirred for 6 days at room temperature and then thus formed precipitate is filtered off. And thereafter the procedure described in Example 1 is repeated to give 9.7g of 2-methyl-2-ethyl thiazolidine (yield 24.7%).
EXAMPLE 8
19.89 of potassium hydroxide and 42.49 of 2-aminoethyl hydrogensulfate are dissolved in 108.2g of a 25% solution of potassium hydrosulfide, and 200 ml of acetone is further added thereto. Thus obtained mixture is reacted for a period of 3 hours at a temperature of 75"C in an autoclave.
The procedure described in Example 1 is repeated to yield 1 5.4g of 2, 2-dimethylthiazolidine (yield 43.8%).
EXAMPLE 9
A mixture comprising 42.4g of 2-aminoethyl hydrogensulfate, 80.8g of potassium sulfide (43% purity), 20 ml of water and 200 ml of methyl isobutyl ketone is allowed to react for 3 hours at 110"C in an autoclave.
Thereafter, the procedure described in Example 1 is repeated, yielding 1 3.9g of 2-methyl-2isobutyl thiazolidine (yield 29.1%).
EXAMPLE 10
To a solution of 1 2.0g of sodium hydroxide in 20 ml of water, 46.6g of 1-amino-2-propyl hydrogensulfate is added, followed by the addition of 32.4g of sodium hydrosulfide (70% purity) and 200 ml of methyl ethyl ketone. Thus formed mixture is allowed to react for 2.5 hours at 90"C in an autoclave.
After the end of reaction, the reaction mixture is allowed to cool to room temperature, and then the procedure described in Example 1 is repeated to yield 19.79 of 2, 5-dimethyi-2-ethyl thiazolidine having a boiling point of 67.8"C at 10 mm. Hg (yield 50.0%).
EXAMPLE 11
50.8g of 2-amino-2-methyl-1 -propyl hydrogensulfate is added to a solution of 12.09 of sodium hydroxide in 20 ml of water. And then 32.4g of sodium hydrosulfide (70% purity) and 200 ml of methyl ethyl ketone are further added thereto. Thus obtained mixture is allowed to react for 2.5 hours at 90"C in an autoclave.
After the end of reaction, the reaction mixture is allowed to cool to room temperature to form precipitate which is removed off by filtration. Thus obtained filtrate is separated into methyl ethyl ketone phase and water phase. The water phase is washed two times with 30 ml of methyl ethyl ketone and all of these methyl ethyl ketone phases are combined therewith. The mixture is concentrated to form a crystal which is filtered. Thus obtained crystal is sublimed under reduced pressure, at 6 mm. Hg, in an oil bath to give 14.39 of 2, 4, 4-trimethyl-2-ethyl thiazolidine as a white crystal (yield 32.8%).
The crystal has a melting point of 102"C.
EXAMPLE 12
A solution of 24.09 of sodium hydroxide in 40 ml of water is treated with 1 0.2g of hydrogen sulfide with cooling in an ice bath for adsorption thereof. 42.49 of 2-aminoethyl hydrogensulfate and 200 ml of methyl ethyl ketone are added thereto. Thus obtained mixture is allowed to react for 3 hours at 90"C in an autoclave.
After the end of reaction, the reaction mixture is allowed to cool to room temperature.
Thereafter the procedure described in Example 1 is repeated to yield 26.lug of 2-rnethyl-2-ethyl thiazolidine (yield 66.4%).
EXAMPLE 13
To 58.6g of 2, 2-dimethylthiazolidine obtained in Example 2, a solution of 53.79 of 35% hydrochloric acid in the same amount of water is added dropwise with cooling in an ice bath.
The mixture is heated, then a release of acetone takes place at 56"C, this heating treatment is further continued until a distillation temperature reaches to 99 C. This treatment requires a duration of about 2 hours and a half for completion. The residual reaction solution is concentrated to almost dryness under reduced pressure. The resulting residue is added with 100 ml of isopropyl alcohol and then the mixture is cooled and filtered to give a white crystal. Thus obtained crystal is dried at 40 C under reduced pressure, further dried on phosphorus pentoxide for one night, then 55.lg of cysteamine hydrochloride is obtained (yield 97.0%), 98.90% pure, m.p. 68.2"C.
EXAMPLE 14
A mixture prepared in such a way that 88.7g of 47% hydrobromic acid is diluted 1.3-fold with water is added dropwise with cooling by ice to 58.69 of 2, 2-dimethylthiazolidine. Thus obtained mixture is treated as described in Example 13, resulting in 76.4g of cysteamine hydrobromide (yield 96.7%), 98.75% pure, m.p. 41.5"C.
EXAMPLE 15
The operation is conducted under the same conditions as those of Examples 13, but 2, 2dimethylthiazolidine is replaced by 65.6g of 2-methyl-2-ethylthiazolidine obtained in Example 1, yielding 54.89 of cysteamine hydrochloride (yield 96.5%), 98.87% pure, m.p. 68.3"C.
EXAMPLE 16
To 80.0g of 2-methyl-2-isobutylthiazolidine obtained in accordance with Example 2, a solution prepared in such a way that 53.79 of 35% hydrochloric acid is diluted with the same amount of water is added dropwise with cooling in an ice bath. The resulting mixture is added with 50 ml of benzene and heated at reflux for a period of two hours with stirring. The benzene phase is separated and the aqueous phase is again added with 50 ml of benzene with shaking for extraction. The reaction solution, obtained by the above wash treatment with benzene, is concentrated to almost dryness under reduced pressure. The resulting residue is added with 100 ml of isopropyl alcohol and then the mixture is cooled and filtered to give a white crystal. Thus obtained crystal is dried at 40"C under reduced pressure, further dried on phosphorus pentoxide for one night, then 55.99 of cysteamine hydrochloride is obtained (yield 98.4%), 98.85% pure, m.p. 68.5"C.
EXAMPLE 17
Employing the procedure set forth in Example 16, and using respectively 2, 5-dimethyl-2ethyl thiazolidine and 2, 4, 4-trimethyl-2-ethyl thiazolidine obtained in Example 10 and 11 as a starting material in place of 2-methyl-2-isobutylthiazolidine yields respectively the corresponding hydrochlorides of cysteamine derivatives.
Claims (6)
1. A process for preparing a mineral acid salt of cysteamine of the formula:
wherein:
R3, R4, R5 and Re are hydrogen or lower alkyl; and
X is a mineral acid radical, comprising hydrolysing a 2,2-disubstituted thiazolidine of the formula:
wherein:
R, and R2, which may be the same of different, are each straight or branched chain alkyl groups of from one to ten carbon atoms or phenyl groups, or R, is joined with R2 to form a ring; and
R3, R4, R5 and Re are as defined above, with mineral acid in the presence of water.
2. The process defined in claim 1 wherein said 2,2-disubstituted thiazolidine is prepared by reacting aminoalkyl hydrogensulphate of the formula:
wherein:
R3, R4, R5 and Re are as defined in claim 1 with a compound having hydrosulphide ion (-SH), in the presence of ketone of the formula:
wherein:
R, and R2 are as defined in claim 1.
3. A process for preparing a mineral acid salt of cysteamine, according to any one of
Examples 1 to 1 7 hereinbefore.
4. A process according to claim 1, substantially as hereinbefore described.
5. Mineral acid salts of cysteamine whenever prepared by the process claimed in any of claims 1 to 4.
6. A method of preparing a thiazolidine of general formula:
in which R1, R2, R3, R4, R5 and R6 are as defined in claim 1, said method comprising: reacting an aminoalkyl hydrogensulphate of formula
wherein R3, R4, B5 and Re are as defined in claim 1, with a compound containing a hydrosulphide ion, in the presence of a ketone of formula:
where R, and R2 are as defined in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8392279A JPS568358A (en) | 1979-07-04 | 1979-07-04 | Production of cysteamine mineral acid salt |
| JP15813079A JPS5681574A (en) | 1979-12-07 | 1979-12-07 | Preparation of 2,2-disubstituted thiazolidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2054573A true GB2054573A (en) | 1981-02-18 |
| GB2054573B GB2054573B (en) | 1983-07-06 |
Family
ID=26424956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8021313A Expired GB2054573B (en) | 1979-07-04 | 1980-06-30 | Salts of cysteamine |
Country Status (7)
| Country | Link |
|---|---|
| CH (1) | CH643825A5 (en) |
| DE (1) | DE3025461A1 (en) |
| ES (1) | ES492879A0 (en) |
| FR (1) | FR2460926A1 (en) |
| GB (1) | GB2054573B (en) |
| IE (1) | IE49614B1 (en) |
| IT (1) | IT1145439B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0054409A1 (en) * | 1980-12-12 | 1982-06-23 | Fine Organics Limited | Preparation of thiazolidine derivatives |
| CN104910128A (en) * | 2015-06-02 | 2015-09-16 | 安徽兴东化工有限公司 | Preparation method of 2,2-dimethyl thiazolidine |
| WO2023126376A2 (en) | 2021-12-27 | 2023-07-06 | Recordati Industria Chimica E Farmaceutica S.P.A. | Process for the preparation of cysteamine bitartrate and product so obtained |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3742265A1 (en) * | 1987-12-12 | 1989-06-22 | Basf Ag | METHOD FOR PRODUCING CYSTEAMINE ACID ADDITION SALTS |
| US5256362A (en) * | 1989-07-14 | 1993-10-26 | Nippon Shokubai Co., Ltd. | Method for production of granular cysteamine hydrochloride |
| IE67043B1 (en) * | 1989-07-14 | 1996-02-21 | Nippon Catalytic Chem Ind | Granular cysteamine hydrochloride and method for production thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD51641A (en) * | ||||
| JPS5441569B2 (en) * | 1971-09-30 | 1979-12-08 | ||
| CH577272A5 (en) * | 1972-07-04 | 1976-07-15 | Givaudan & Cie Sa | |
| JPS5251308A (en) * | 1975-10-22 | 1977-04-25 | Wakunaga Yakuhin Kk | Process for preparation of cysteamines |
| DE2812400C2 (en) * | 1978-03-21 | 1984-10-31 | The Dow Chemical Co., Midland, Mich. | Process for the preparation of N- (2-mercaptoethyl) alkanamides and 2-mercaptoethylamine hydrochlorides |
-
1980
- 1980-06-17 IE IE1248/80A patent/IE49614B1/en unknown
- 1980-06-27 ES ES492879A patent/ES492879A0/en active Granted
- 1980-06-30 GB GB8021313A patent/GB2054573B/en not_active Expired
- 1980-07-02 IT IT49141/80A patent/IT1145439B/en active
- 1980-07-02 CH CH508980A patent/CH643825A5/en not_active IP Right Cessation
- 1980-07-03 FR FR8014791A patent/FR2460926A1/en active Granted
- 1980-07-04 DE DE19803025461 patent/DE3025461A1/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0054409A1 (en) * | 1980-12-12 | 1982-06-23 | Fine Organics Limited | Preparation of thiazolidine derivatives |
| CN104910128A (en) * | 2015-06-02 | 2015-09-16 | 安徽兴东化工有限公司 | Preparation method of 2,2-dimethyl thiazolidine |
| WO2023126376A2 (en) | 2021-12-27 | 2023-07-06 | Recordati Industria Chimica E Farmaceutica S.P.A. | Process for the preparation of cysteamine bitartrate and product so obtained |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3025461A1 (en) | 1981-01-29 |
| ES8105276A1 (en) | 1981-06-01 |
| ES492879A0 (en) | 1981-06-01 |
| GB2054573B (en) | 1983-07-06 |
| IT1145439B (en) | 1986-11-05 |
| IE801248L (en) | 1981-01-04 |
| CH643825A5 (en) | 1984-06-29 |
| IE49614B1 (en) | 1985-10-30 |
| IT8049141A0 (en) | 1980-07-02 |
| FR2460926B1 (en) | 1985-04-26 |
| FR2460926A1 (en) | 1981-01-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 20000629 |