PL218006B1 - Process for the preparation of sulphides and N-alkylimide sulphides - Google Patents

Description

The subject of the invention is a process for the preparation of sulfides.

Sulfides belong to the group of very important intermediates and compounds that perform important biological functions. The most famous compound from this group is methionine, which, together with cysteine, are two amino acids belonging to the so-called encoded protein amino acids from which proteins are built in the first stage of their biosynthesis. The -SH group of cysteine is often the center of enzyme activity, both in redox and arylation reactions, and the -CH3 group attached to the sulfur atom in methionine serves to methylate other compounds in biochemical reactions. Certain vitamins are sulfides (e.g. Bi and H), and the sulfide moiety is found in popular β-lactam antibiotics (penicillins and cephalosporins). Sulfides and their mixtures with other compounds are also used as insecticides and fungicides. Aromatic sulfides, such as nitrophenyl and nitrothienyl sulfides, are characterized by bactericidal properties and are used in disinfecting preparations. Due to their intense smell, sulfides are part of the substances used in the production of perfumes and for flavoring food. They are intermediates used in the production of medicinal products with antiepileptic properties, such as Tiafibrate or Tiadenol.

Among the very wide group of sulfides, N-alkylimide sulfides deserve special mention, which are compounds used as substrates in photochemical cyclization reactions (Griesbeck, AG; Olgemoller, M .; Lex, J .; Haeuseler, A .; Schmittel, M. Eur. J. Org. Chem. 2001, 1831-1843), or carried out under the conditions of anionic cyclizations (Włostowski, M .; Jańczewski, D .; Czarnocka, S .; Synoradzki, L. Synlett, 2008, 3198-3202), and the products of their cyclization are heterocyclic compounds with the structure of e.g. isoindolone, which, due to their biological activity, are used in numerous applications as anti-inflammatory drugs (Li, S .; Wang, X .; Guo, H .; Chen, L. Yiyano Gongue 1985, 16 , 543-544; Chem. Abstr. 1986, 105, 6378n), antihypertensive (Ferland, J.-M .; Demerson, CA; Humber, LG Can. J. Chem. 1985, 63, 361-365), drugs in the treatment of leukemia (Taylor, E. C; Zhou, P .; Jenning, LD; Mao, Z ,; Hu, B; Jun, J.-G. Tetrahedron Lett. 1997, 38, 521-524) or antiviral ( Zhaung, ZP; Ku ng, M. P .; Mu, M .; Kung, H. F. J. Med. Chem. 1998, 41, 157-166). Speaking of sulfides, it must not be forgotten that N-alkylimide sulfides can be easily oxidized to the corresponding sulfoxides or sulfones, which are mainly used as intermediates in the production of compounds with high pesticidal activity, especially fungal and bactericidal, and are used to protect green plants and their seed, as described in US patents 5,166,165 and US 3,037,907.

The known method for the preparation of sulfides is based on the reaction of the appropriate thiols with primary or secondary alkyl halides in the presence of a base. This process is carried out in water or in expensive polar solvents. Thiols are reactive compounds and are easily oxidized to disulphides, and their intense and unpleasant smell often makes it difficult to work with them, especially troublesome in the case of dithiols. Due to their high reactivity and susceptibility to oxidation, the process of their alkylation is often unsatisfactory. Polish patent 136279 describes a highly efficient method of alkylating thiols in the presence of poly-substituted guanidine derivatives and amidines.

Methods are known for synthesizing N-alkylimide sulfides from the corresponding N-alkylimide halides which serve as alkylating agents of mercaptocarboxylic acids or their esters in dimethylformamide to potassium carbonate (Griesbeck, AG; Oelgemoller, M .; Lex, J .; Haeuseler, A .; Schmittel, M. Eur. J. Org. Chem. 2002, 1831-L843). This procedure leads to sulfides containing a carboxyl group. The use of dimethylformamide, an expensive, hygroscopic and high boiling solvent, is an obvious drawback of this method.

An alternative route to the synthesis of N-alkylimide sulfides requires the use of N-alkylimide mercaptans and simpler and cheaper alkylating agents in the reaction. N-Alkylimide thiols can be efficiently obtained by reacting the corresponding anhydride with 2-aminoethanethiol hydrochloride (Gullotti, M .; Pintar, A .; Pinciroli, F .; Vigano, RJ Chem. Soc. Dalton Trans. 1989, 1161-1169) or 3-amino-1-propanethiol hydrochloride. N-alkylimide thiols can also be obtained by displacement of the corresponding halide with ammonium bisulfide in an alcoholic solution (Gabriel, S. Chem. Berg. 1889, 22, 1138-1139; Gabriel, S. Chem. Berg. 1891, 24, 1110-1121) . Nevertheless, the yields of such reactions are often unsatisfactory, despite the use of an excess of troublesome hydrosulfide.

PL 218 006 B1

There are also known methods of obtaining sulfides from isothiouronium salts in a two-stage process, in which in the first stage the isothiouronium salts are hydrolyzed to a thiol, and in the second stage the separated mercaptans are subjected to alkylation.

A number of methods for the hydrolysis of isothiouronium salts to the corresponding thiols running in aqueous alkaline solutions have been described in the chemical literature. Typically aqueous solutions of sodium hydroxide (McElhinney, RS; McCormick, JE; Bibby, M. C; Double, JA; Radacic, M .; Dumont, PJ Med. Chem. 1996, 1403-1412) or potassium hydroxide (Bunce, RA ; Peeples, CJ; Jones, PBJ Org. Chem. 1992, 1727-1733), sodium bicarbonate (DeBernardis, JF; Kerkman, DJ; Buckner, SA; Kyncl, JJ; Hancock, AAJ Med. Chem. 1987, 1003-1011 ). Sodium metabisulfite was also used (Kazemekaite, M .; Bulovas, A .; Talaikyt, Z .; Butkus, E .; Railait, V .; Niaura G .; Palaima, A .; Razumas, V .; Tetrahedron Letters 2004, 3551- 3555) or ammonium hydroxide (Naud, C; Calas, P .; Blancou, H .; Commeyras, A.J. Fluor. Chem. 2000, 173-183). This reaction was also carried out in an ethanol solution in the presence of tetraethylpentamine (Barrera, H .; Sola, J .; Vinas, JMJ Chem. Research (S) 1985, 270-271) or an unsymmetrical IV, IV-dimethylethylenediamine (Ed, ML; Prakashwards, NJ; Stemerick, DM; Sunkara, SP; Bitonti, AJ; Davis, GF; Dumont, JA; Bey, PJ Med. Chem. 1990, 1369-1375).

In the case of N-alkylimide isothiouronium salts, their hydrolysis in an aqueous or alcoholic solution of a strong base may lead to undesirable products, opening of the imide ring. Also, the process of alkylation of N-alkylimide thiols requires the reaction to be carried out under very subtle conditions that prevent the opening of the imide ring and the possible hydrolysis of the alkylating agents used, which greatly limits the choice of the base and the appropriate solvent.

The chemical literature describes attempts to directly convert isothiouronium salts into sulfides. Carrying out such a process requires the use of an excess of the starting N-alkylimide isothiouronium salt (1.5 eq) and an excess (2.5 eq) of such an exotic reagent as cesium carbonate in dimethylformamide (Karginov, VA; Yohannes, A .; Robinson, TM; Fahmi, NE; Alibek, K .; Hecht, SM; Bioorg. Med. Chem., 2006, 33-44). The use of an excess of substrates makes it impossible to selectively carry out the process, and the efficiency of the chromatographic purification of the final products, β-cyclodextrin derivatives, was unsatisfactory. Also described is a method for converting an N-alkylimide isothiouronium salt to a sulfide by reaction with potassium hydroxide in methanol (Hunter, R .; Kaschula, CH; Parker, IM; Caira, MR; Richards, P .; Travis, S .; Taute , F .; Qwebani, T. Bioorg. Med. Chem. Lett. 2008, 5277-5279), but requires the use of an excess (1.5 eq) of the alkylating agent (propargyl bromide) and the final sulfide was purified by chromatography. This procedure causes additional problems with the isolation of the products and excludes the usefulness of the method in the case of alkylation with alkylating agents containing ester groups.

Unsatisfactory yields, low alkylation selectivity, difficult solubility of the reactants, and cumbersome purification are problems that have been experienced in attempts to prepare sulfides and N-alkylimide sulfides.

The process of the invention completely eliminates the above problems and removes the step in which the thiol was used as a substrate from the sulfide preparation process.

The method of producing sulfides of the general formula R- (CHY) a- (S) n- (CH2) m- (S) z- (CHY1) b-R1, in which R and R1 are the same or different and represent the groups: alkyl , alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl or heterocyclic containing N, S or O heteroatoms which may be substituted with one or more groups such as alkyl, amide, nitrile, ester, amino, amino, amino , thioalkyl, thioaryl, sulfone, sulfoxide, ketone, aldehyde, nitro, silyl, hydroxy, halogen or poly-substituted phosphorus, and Y and Y1 are the same or different and represent: hydrogen, alkyl, alkenes or alkynyl or such group, as ester containing 1-4 carbon atoms, nitrile, ketone, m is 0 to 6, n is 0 or 1, z is 0 or 1, and b are the same or different from 1 to 10, niz cannot be 0 simultaneously, and when m = 0 then n or z is 0, according to The invention is characterized in that the isothiouronium salts of the general formula Z- (S) n- (CH2) m- (S) z- (C = NH) NH2-HX, where: Z represents the group: - (C = NH) NH2 -HX or a group - (YCH) aR, in which Y and R are as defined above, X is a chlorine, bromine or iodine atom, m, n, z and z is as defined above, is treated with a non-ionic base described by the general formula II or the formula general III, where R2, R3, R4, R5, R6, R7, R8, R9, R10 are alkyl substituents, the same or different, with 1 to 4 carbon atoms or are optionally part of a cyclic or bicyclic system

PL 218 006 B1 in the amount of 2.0 to 2.5 moles of base per 1 mole of isothiouronium salt, in an organic solvent ensuring homogeneity of the reaction mixture, at a temperature of 20 to 50. 4.0-4.5 moles of non-ionic base. Then the alkylating agent of formula R1 (CHY) bX is added, where R1 is chlorine, bromine or iodine, or as defined above, Y, b and X are as defined above in an amount of 1.0 to 1.05 mol ( respectively 2.0-2.1 moles for disols) and carries out the alkylation reaction at 20 to 80 ° C, until the required degree of conversion is obtained.

Preferably the heterocyclic group is imide, most preferably succinimide or phthalimide.

1,1,3,3-Tetramethylguanidine (TMG) is particularly preferably used as the nonionic base. Good results have been obtained with its 2-substituted derivatives. Commercially available 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1 , 3,7-triazabicyclo [4,4.0] dec-5-ene (TBD) and 7-methyl-1,3,7-triazabicyclo [4,4.0] dec-5-ene.

The organic solvent used is a polar protic or aprotic solvent that ensures the homogeneity of the reaction mixture, such as acetone, methanol or other alcohols, acetonitrile. The process can also be carried out in other organic solvents or their mixtures, but the necessary condition is that the reactants are completely soluble before adding the alkylating agent.

The process is carried out under an inert gas atmosphere.

The reaction product can be isolated by isolating the by-product (the hydrohalide of the nonionic base if such falls out of the reaction after the reaction) and then concentrating the filtrate, adding water to the residue and extracting the aqueous phase three times with dichloromethane, chloroform or other solvent. The combined organic phases are dried over anhydrous magnesium sulfate, which is then separated from the reaction mixture by filtration and washed with a solvent. The combined dichloromethane fractions are concentrated under reduced pressure and the crude product is crystallized from a suitable solvent, particularly preferably alcohols such as methanol, ethanol and the like, or distilled under reduced pressure.

In the event that the hydrohalide of the nonionic base does not fall out of solution, the reaction mixture is concentrated under reduced pressure and the above procedure is carried out. In such a case, concentration of the aqueous phase, basification at a temperature below 10 ° C with 30% aqueous NaOH solution to pH 14, extraction and finally distillation under reduced pressure allow the regeneration of an appropriate non-ionic base with an efficiency of up to 83%, which significantly reduces the costs of the process.

In the case of sulfides and disulfides of high molar mass, the reaction product may fall out of the reaction mixture together with the halide of the non-ionic base, then the filtered precipitate is washed with water to obtain the desired product.

The process yield is usually close to quantitative.

The process according to the invention is illustrated by the following examples.

P r z k ł a d 1

Benzylisothiouronium hydrochloride 0.51 g (2.5 mmol) was dissolved in 10 mL of acetone, the mixture was placed under argon, 0.31 g (5.25 mmol) of TMG was added and stirred until complete dissolution by heating the reaction mixture to 35 ° C. Then 0.31 g (2.5 mmol) of benzyl chloride diluted with 5 mL of solvent was added dropwise to the mixture (the dropwise addition was carried out over 20 min). The mixture was heated to 50 ° C and stirred at this temperature for 2 h. After this time, the mixture was cooled to room temperature, a white precipitate was filtered off, which was then washed with 10 mL of acetone. The filtrate was concentrated, 10 mL of water was added, and extracted with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness on an evaporator to give 0.60 g of crude product which was crystallized from hexane-diethyl ether to give 0.50 g of a light yellow solid (93% yield). Dibenzyl sulfide: mp 45-46 ° C (hexane), (lithium: mp 44-47 ° C).

P r z k ł a d 2

Benzylisothiouronium hydrochloride 0.51 g (2.5 mmol) was dissolved in 10 mL of acetone, the mixture was placed under an argon atmosphere, 0.80 g (5.25 mmol) of DBU was added and stirred until completely dissolved while gently warming the reaction mixture to 35 ° C. Then 0.56 g (2.5 mmol) of N- (3-chloropropyl) phthalimide dissolved in 10 mL of solvent was slowly added dropwise to the mixture (the dropwise addition was carried out over 20 min). The mixture was then heated to 50 ° C and stirred at this temperature for 2 h. After that, the mixture was cooled to room temperature, concentrated, added 10 mL of water and extracted with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness on an evaporator to give 0.90 g of crude product which was crystallized from hexane-diethyl ether to give 0.56 g of a light yellow solid (72% yield). Benzyl-3-phthalimidopropyl sulfide: mp 60-61 ° C (hexane-diethyl ether), (lithium: mp 63-64 ° C).

P r z k ł a d 3

2,2-ethylenediisothiouronium hydrochloride 0.85 g (2.5 mmol) was dissolved in 10 mL of acetone, the mixture was placed under argon, 1.21 g (10.5 mmol) of TMG were added and the mixture was stirred while gently warming the reaction mixture to 35 ° C. . Then 1.21 g (5.0 mmol) of N- (3-chloropropyl) phthalimide dissolved in 10 mL of solvent was slowly added dropwise to the mixture (the dropwise addition was carried out over 20 min). The mixture was then heated to 50 ° C and stirred at this temperature for 2 h. After that, the mixture was cooled, and the precipitate that had fallen out of the mixture was filtered off. The precipitate was washed twice with 10 ml of water to obtain 0.75 g of pure product (64% yield).

1,10-di (N-phthalimido) -4,7-dithiadecane: mp 127-128 ° C (acetone), (lithium: mp 128 ° C).

P r z k ł a d 4

3-Phthalimidoethylisothiouronium hydrochloride 2.86 g (10 mmol) was dissolved in 20 mL of acetonitrile, the mixture was placed under argon, 2.42 g (21 mmol) TMG was added and stirred until complete dissolution by gently warming the reaction mixture to 35 ° C. Then 1.23 g (10 mmol) of methyl chloroacetate diluted with 5 mL of solvent was slowly added dropwise to the mixture (addition was carried out over 20 min) while the temperature rose to 35 ° C. The mixture was then heated to 50 ° C and stirred at this temperature for 2 h, the progress of the reaction was monitored by thin-layer chromatography TLC. After that, the mixture was cooled to room temperature, the white precipitate was filtered off, which was then washed with 10 mL of acetonitrile. The filtrate was concentrated, 10 mL of water was added, and extracted with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness on an evaporator to give 2.79 g of crude product which was crystallized from ethanol to give 2.14 g of a light yellow solid (73% yield). Ethyl (2-phthalimidoethylthio) acetate: mp

49-50 ° C (ethanol); ¹ H NMR (CDCl3, 400 MHz) δ / ppm: 7.84 - 7.69 (m, 4H, Pht), 4,21-4,15 (q, 2H, J = 7.2 Hz, OCH ₂₎ , 3.94-3.91 (t, 2H, J = 6.8Hz, NCH ₂ ), 3.29 (s, 2H, SCH ₂ CO), 2.97-2.94 (t, 2H, J = 6.4 Hz, CH2), 1,29-1,25 (t, 3H, J = 7.2 Hz, OCH ₂ CH 3).

P r z k ł a d 5

3-phthalimidopropylisothiouronium hydrochloride 3.01 g (10 mmol) was dissolved in 20 mL acetonitrile, the mixture was placed under argon, 2.42 g (21 mmol) TMG was added and stirred until completely dissolved while gently warming the reaction mixture to 35 ° C. Then 1.09 g (10 mmol) of methyl chloroacetate diluted with 5 mL of solvent was slowly added dropwise to the mixture (addition was carried out over 20 min) while the temperature rose to 35 ° C. The mixture was then heated to 50 ° C and stirred at this temperature for 2 h, while the course of the reaction was monitored by thin-layer chromatography TLC. After that, the mixture was cooled to room temperature, the white precipitate was filtered off, which was then washed with 10 mL of acetonitrile. The filtrate was concentrated, 10 mL of water was added, and extracted with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness on an evaporator to give 2.90 g of a crude product which was crystallized from ethanol to give 2.40 g of a white solid (82% yield).

(3-ftalimidopropylotio) acetate: t _top 50-51 ° C (ethanol); ¹ H NMR (CDCl ₃ , 400 MHz) δ / ppm: 7.84-7.70 (m, 4H, Ar), 3.78 (t, 2H, SCH ₂ , J = 7.2 Hz), 3, 70 (s, 3H, OCH3), 3.22 (s, 2H, CH), 2.67 (t, 2H, CH.-N, J = 7.2Hz), 1.98 (p, 2H, CH -OH-OH ··, J = 7.2 Hz).

P r z k ł a d 6

3-Phthalimidopropylisothiouronium hydrochloride 3.00 g (10 mmol) was dissolved in 20 mL of acetonitrile, the mixture was placed under an argon atmosphere, 2.42 g (21 mmol) of TMG were added and stirred until complete dissolution with gentle warming of the reaction mixture to 35 ° C. Then 1.19 g (10 mmol) of propargyl bromide diluted with 5 mL of solvent was slowly added dropwise to the mixture (addition was carried out over 20 min) while the temperature rose to 35 ° C. The mixture was then heated to 50 ° C and stirred at this temperature for 2 h, the progress of the reaction was monitored by thin-layer chromatography TLC. After that, the mixture was cooled to room temperature, the white precipitate was filtered off, which was then washed with 10 mL of acetonitrile. The filtrate was concentrated,

10 mL of water was added and extraction was carried out with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness on an evaporator to give 2.45 g of a crude product which was crystallized from ethanol to give 1.96 g of a light yellow solid (76% yield). 3-phthalimidopropylpropargyl sulfide: mp _to p 46-47 ° C (ethanol); ¹ H NMR (CDCl3, 400 MHz) δ / ppm: 7,85-7,70 (m, 4H, Ar), 3.80 (t, 2H, SCH2, J = 7.2 Hz), 3.26 ( d, 2H, CH ₂ C = J = 2.6Hz), 2.73 (t, 2H, CH - N, J = 7.2Hz), 2.18 (t, 1H, C = CH, J = 2.6 Hz), 2.00 (p, 2H, CH ₂ Cl CH ₂ , J = 7.2 Hz).

P r z k ł a d 7

3-succinimidoethylisothiouronium hydrobromide 1.41 g (5 mmol) was dissolved in 15 mL of methanol, the mixture was placed under an argon atmosphere, 1.21 g (10.5 mmol) TMG was added and stirred until complete dissolution with gentle warming of the reaction mixture to 35 ° C. Then 0.54 g (5 mmol) of methyl chloroacetate diluted with 5 mL of the solvent was slowly added dropwise to the mixture (the addition was carried out over 20 min). The mixture was heated to 50 ° C and stirred at this temperature for 1 h while the progress of the reaction was monitored by thin-layer TLC. Thereafter, the mixture was cooled to room temperature and the solvent was distilled off in vacuo. 10 mL of water was added to the oily residue and extracted with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness by evaporation to give 1.17 g of crude product which was crystallized from ethanol to give 0.80 g of a white solid (69% yield). 2- (suscynimidoetylotio) acetate: t _top 33-34 ° C (methanol); ¹ H NMR (CDCl ₃ , 400 MHz) δ / ppm: 3.76 (t, 2H, CH; N, J = 6.8 Hz), 3.74 (s, 3H, OCH3), 3.28 (s , 2H, CH _2), 2.88 (t, 2H, SCH _2, J = 6.8 Hz), 2.74 (s, 4H, CH ₂ CI ±).

P r z k ł a d 8

3-succinimidoethylisothiouronium hydrobromide 1.41 g (5 mmol) was dissolved in 15 mL of acetone, the mixture was placed under an argon atmosphere, 1.21 g (10.5 mmol) TMG was added and stirred until complete dissolution with gentle warming of the reaction mixture to 35 ° C. Then 0.68 g (5 mmol) of ethyl 2-chloropropanoate diluted with 5 mL of solvent was slowly added dropwise to the mixture (the dropwise addition was carried out over 20 min). The mixture was heated to 50 ° C and stirred at this temperature for 1 h while the progress of the reaction was monitored by thin layer chromatography TLC. After the mixture was cooled to room temperature, the white precipitate of tetramethylguanidinium hydrogen bromide (a by-product) was filtered off, which was then washed with 10 mL of acetone. The filtrate was concentrated, 10 mL of water was added, and extracted with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness on an evaporator to give 2.45 g of a crude product which was crystallized from ethanol to give a white solid with a yield of 51%.

(2-sukcynimidoetylotio) -2-propionate: t _top 39-40 ° C (ethanol); ¹ H NMR (CDCl ₃ , 400 MHz) δ / ppm: 3.74 (t, 2H, Cl ± N, J = 6.8 Hz), 4.15 (q, 2H, OCH ₂ ), 3.52 ( q, 1H, CH, J = 6.8 Hz), 2.87 (t, 2H, SCH _2, J = 6.8 Hz), 2.74 (s, 4H, CH ₂ CI ±), 1.43 (d, 3H, J = 6.8 Hz, CHCH3), 1.28 (t, 3H, J = 6.8 Hz, OCH ₂ CH 3).

P r z k ł a d 9

3-succinimidoethylisothiouronium hydrobromide 1.41 g (5 mmol) was dissolved in 15 mL of acetone, the mixture was placed under argon, 1.21 g (10.5 mmol) TMG was added and stirred until complete dissolution was achieved by gently warming the reaction mixture to 35 ° C. Then 0.60 g (5 mmol) of propargyl bromide diluted with 5 mL of solvent was slowly added dropwise to the mixture (dropwise addition was carried out over 20 min). The mixture was heated to 50 ° C and stirred at this temperature for 1 h while the progress of the reaction was monitored by thin-layer TLC. After the mixture was cooled to room temperature, the white precipitate was filtered off with tetramethylguanidinium bromine (a by-product), which was then washed with 10 mL of acetone. The filtrate was concentrated, 10 mL of water was added, and extracted with chloroform (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, which was then filtered off and washed with 20 mL of chloroform. The filtrate was again concentrated to dryness on an evaporator to give 1.00 g of crude product which was crystallized from ethanol to give 0.74 g of a light yellow solid (75% yield). 2-succinimidoethylpropargyl sulfide: mp 36-37 ° C (ethanol); ¹ H NMR (CDCl 3, 400 MHz) δ / ppm: 3.75 (t, 2H, NCH ₂ , J = 6.8 Hz), 3.32 (d, 2H, CH ₂ C = J = 2.6 Hz ), 2.95 (t, 2H, CH ₂ s, J = 6.8 Hz), 2.74 (s, 4H, CH-O, '2.27 (t, 1 H, C = CH,

Claims (7)

1. The method of producing sulfides of the general formula R- (CHY) a- (S) n- (CH2) m- (S) z- (CHY1) b-R1, in which R and R1 are the same or different and represent the groups : alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl or heterocyclic containing N, S or O heteroatoms which may be substituted with one or more groups such as alkyl, amide, nitrile, ester, amino , alkoxy, thioalkyl, thioaryl, sulfone, sulfoxide, ketone, aldehyde, nitro, silyl, hydroxy, halogen or multi-substituted phosphorus, and Y and Y1 are the same or different and are: hydrogen, alkyl, alkenyl or alkynyl or such groups such as ester containing 1-4 carbon atoms, nitrile, ketone, m is 0 to 6, n is 0 or 1, z is 0 or 1, and b are the same or different from 1 to 10, where n and n cannot be simultaneously 0, and when m = 0 then n or z is 0, z wy using isothiouronium salts characterized in that the isothiouronium salts of the general formula Z- (S) n- (CH2) m- (S) z- (C = NH) NH2-HX, where: Z is the group: - (C = NH) NH2-HX or the group - (YCH) aR, in which Y and R are as defined above, X is chlorine, bromine or iodine, m, n, z and z are as defined above, are treated with a non-ionic base described by the general formula I R5 Formula I or general formula II Formula II where R2, R3, R4, R5, R6, R7, R8, R9, R10 are alkyl substituents, the same or different, with 1 to 4 carbon atoms or are part of a cyclic or bicyclic system in an amount from 2.0 to 2.5 moles of base to 1 mole of isothiouronium salt, or 4.0-4.5 moles of base per 1 mole of isothiouronium disole, in an organic solvent ensuring homogeneity of the reaction mixture, at a temperature of 20 to 50 ° C, and then added there is an alkylating agent of the formula R1 (CHY1) bX where R1 is chlorine, bromine or iodine, or as defined above, Y1, b and X are as defined above in an amount of 1.0 to 1.05 moles or 2.0 - 2.1 moles for disols, and the alkylation reaction is carried out at a temperature of 20 to 80 ° C, until the desired conversion is obtained. 2. The method according to p. The process of claim 1, wherein R and / or R 1 is an imide group. 3. The method according to p. The process of claim 1, wherein R and / or R1 is a succinimide or phthalimide group. 4. The method according to p. The process of claim 1, wherein the non-ionic base is 1,1,3,3-tetramethylguanidine (TMG) or its 2-substituted derivatives, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) , 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,3,7-triazabicyclo [4,4,0] dec-5-ene (TBD) and 7-methyl-1 , 3,7-triazabicyclo [4,4.0] dec-5-ene. PL 218 006 B1 5. The method according to p. The process of claim 1, wherein the organic solvent is a polar protic or aprotic solvent. 6. The method according to p. The process of claim 1, wherein acetone, acetonitrile, methanol, ethanol, propanol, isopropanol, butanol or 2-butanone are used as the solvent. 7. The method according to p. 3. The process of claim 1, wherein the process is carried out in a gas atmosphere