US3184505A - Process for the n-monoacylation of cysteine - Google Patents
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- the present invention is concerned with a novel process for the selective N-monacylation of cysteine.
- the method is highly efiicient by comparison to prior art only common, readily available starting materials, and is adapted for commercial production of N-monoacylated derivatives of cysteine, and particularly those wherein the acyl group corresponds to a mono or dicarboxylic acid having up to 6 carbon atoms.
- the N-acyl derivatives of cysteine typified by N-acetyl-L-cys teine have been reported to possess unique mucolytic properties and are, therefore, of value in therapeutics, particularly in the management of respiratory diseases.
- N-acetylcysteine involves acylation of cystine with an excess of acylating agent to provide N,N'-diacetylcystine which is then reduced to provide the free thiol compound, N-monoacetyl cysteine [M. W. Pirie, et al., Biochemical Journal 25, 614 (1931); ibid 27, 1716 (1933)].
- This method involves reduction as an additional step after acylation. Laborious procedures for isolation of the product are also described. Both add greatly to the expense of this prior process.
- N-acylcysteine can be prepared in high yield and with relatively simple manipulations by treatment of cysteine with one chemical equivalent of an alkanoic acid anhydride having up to 12 carbon atoms, or an alkandioic acid anhydride having up to 6 carbon atoms under such conditions that an alkali metal salt or the ammonium salt of the N-acylcysteine is formed rather than the free carboxylic acid form thereof.
- This is accomplished either by employing an alkali metal salt or the ammonium salt of cysteine as the starting material or by operating on cysteine itself in the presence of a neutralizing agent comprised of an alkali metal or ammonium salt of an acid having a pKa value greater than 3.2.
- This novel process has the further advantage of not racemizing the starting material. That is, if L-cysteine or a salt thereof is used as starting material, the product obtained is an N-acyl-L-cysteine, and not the N-acyl-DL-cysteine.
- the process is carried out by suspending or dissolving the cysteine compound and the buffering agent, if one is used, in a solvent and adding one molecular proportion of the anhydride acylating agent thereto in the temperature range of about 5 to +20 C.
- cysteine compound is meant cysteine itself or an alkali metal or the ammonium salt thereof. If this operation is carried out at temperatures substantially in excess of 20 C., lower yields of product are obtained. Cysteine seems to de compose appreciably at temperatures in excess of 20 C. since the odor of hydrogen sulfide is sometimes apparent on warming.
- the intermediate N-acylcysteine salt formed by the present process is much more stable than the cysteine starting material, and after formation thereof, the reaction mixture is allowed to Warm to room temperature and preferably heated for at least one hour about 40-75 C. to insure completion of the reaction and maximum yield of product.
- cysteine and its salts are subect to oxidative conversion to cystine, it is preferred to conduct the process in the absence of air by employing an inert atmosphere such as nitrogen or other reaction inert gas.
- reaction stable organic solvents organic liquids which do not react with either the anhydride acylating agent, the neutralizing agent if one is used, or the cysteine compound reactant under the conditions of the reaction, that is Within the temperature range of about 5 to C. More specifically it has been found that Water, the lower alkanols, lower alkanediols, and others thereof, as Well as lower aliphatic cyclic others and mixtures thereof are operable.
- Suitable organic solvents include methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, ethylene glycol, propylene glycol, monomethyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, and mixtures thereof with Water, etc.
- Anhydride acylating agents selected from the class consisting of the alkanoic acid anhydrides having up to 12 carbon atoms such as acetic anhydride, propionic anhydride, acetoformic anhydride, butyric anhydride, pentanoic anhydride, and hexanoic anhydride are suitable.
- the cyclic alkanedioic acid anhydrides having up to 6 carbon atoms such as succinic anhydride, methyl succinic anhydride, glutaric acid anhydride, and methyl glutaric anhydride are suitable.
- The. acylation product may be recovered either as the alkali metal or ammonium salt thereof formed as an intermediate, or preferably it may be neutralized by the addition of sufiicient of a strong acid including the mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, and the allcyl and aryl sulf-onic acids to result in formation of the free carboxylic acid form thereof.
- a strong acid including the mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid
- neutralization prior to recovery is generallypreferred, particularly in the preparation of N- acetylcysteine, but the best method of.isolation varies according to the specific compound being prepared and the particular process operating conditions and solvents selected.
- Example L-N-acetyl-L-cysteiue via selective direct acylarz'on in the presence of sodium acetare To a suspension of 35.2 g. (0.2 mole) of L-cys-teine hydrochloride monohydrate stirred in a reaction vessel containing 87 ml. of 91% aqueous tetrahydrofur-an under a nitrogen atmosphere there is added 54.4 g. (0.4 mole) of sodium acetate trihydrate. The mixture is stirred for 20 min. at room temperature to insure neutralization of the hydrochloride salt resulting in the formation of a suspension of equimolar amounts of cysteine and sodium acetate.
- the mixture is then chilled to 36 C. by external cooling and 20 ml. (20.8 g., 0.21 mole) of acetic anhydride is added thereto in dropwise fashion with cooling in the above range.
- the resulting mobile suspension is stirred for six hours at room temperature, allowed to stand over night, and finally heated at reflux (72 C.) for 4 hrs.
- the resulting suspension of sodium N-acetyl-L-cysteinate is then neutralized by treatmentat 510 C. with 8 g. of hydrogen chloride. Resulting sodium chloride is removed by filtration and the product is isolated by distilling the solvent from the filtrate in vacuo and crystallizing the residue from 35 ml. of water, yield 2 6.3 g. (80.6%) of N-acetylcysteine as a white solid, M.P. 109-1 10 C.
- Example 1 two chemical equivalents of sodium acetate, the neutralizing agent, relative to cysteine hydrochloride reactant are used.
- the cysteine compound as defined herein is cysteine itself formed by neutralization in situ of the hydrochloride salt charged to the reaction vessel.
- Example 1 The time periods specified in Example 1 are somewhat arbitrary, having been selected on a convenience basis.
- the preferred minimum heating period after addition of the acetic anhydride is 1 'hr., and the temperature range about40-75 C.
- Example 1 Various other solvents'may be employed in Example 1 with essentially the same results, 70% yield having been obtained employing methanol, 61% yield employing isopropanol, 78% yield employing 90% aqueous isopropanel, 74% yield using 100% tetrahydrof-uran, and 63% yield using water.
- neutralizing agents may be substituted for sodium acetateapart from the amountof :agent'needed to liberate cysteine reactant from its hydrochloride salt on an equimolar basis with substantially the same results: disodium phosphate, dipotassium phosphate, disodiurn citrate, and dipotassium citrate.
- the following neutralizing agents may be substituted for sodium acetate on a one-half molar basis with substantially the same results: trisodium phosphate, tripotassium phosphate, trisodium citrate, and tripotassium citrate. 7
- Example 2 N-acetyl-L-cysteine via selective direct acylation in the presence of trisodium ph0Sphate.Example 1 is repeated substituting 76 g. (0.2. mole) of Na PO 121-1 0 as neutralizing agent for the sodium acetate used in that example. N-acetylcysteine of similar quality and weighing 23.5 g. (72%) is recovered in the fashion specified in that example.
- Example 5 N-succinyl-L-cysteine.
- the procedure of Example :1 is repeated, substituting 20g. (0.2 mole) of succinic anhydride for the acetic anhydride specified in that example.
- Example 4.N-propionyl-L-cysteina-aPropionic anhydride 26.4 g. (0.202 mole) is added slowly during min. at 05 C. to'a stirred suspension of 35.2 g. (0.2 mole) of L-cysteine hydrochloride monohydrate and 3 8.4 g. (0.4 mole) of sodium propionate in 18.2 ml. of water and 80 ml. of tetrahydrofuran under an atmosphere of nitrogen.
- the reaction is then treated as described in Example 1, yield 21.7 g. (61%), M.P. 89-90 C., M1 +24.3 (c., 5 .0, water, adjusted to pH 7 with NaOH).
- N-acyl derivatives of'cysteine' may be prepared by the method of Examples 1 employing the appropriate acid anhydrid es including caproic anhydride, butyric anhydride, et-methyl-succinic anhydride, glutaric anhydr-ide, etc.
- acid anhydrid es including caproic anhydride, butyric anhydride, et-methyl-succinic anhydride, glutaric anhydr-ide, etc.
- DL-cysteine or the pure D-isomer of cysteine may be acylated by this method without racemization and in similar yield.
- Example 5 N-acetyl cysteine via selective N-acylation of sodium cystez'nate.L-cysteine, 24.2 g. (0.2 mole) is added under anat-mosphere of nitrogen at 1015 C. to a freshly prepared solution of 0.2 mole of sodium methoxide in 200 ml. of anhydrous methanol. After solution is complete, the mixture is cooled to 5 to 0 C. and 20 ml. of acetic anhydride is slowly added thereto. The'mixture is then stirred over'night'resulting in a clear solution which is warmed at 50 60 C. :for 4, hrs.
- the resultingsolution of sodium N-acetyl-L-cysteinate is then neutralized by treatment with 3 N methanolic hydro-gen chloride.
- Sodium chloride is removed by filtration, and the solvent dis-tilled from the filtrate in 'vacuo at -50 C.
- the residual oil is dissolved in 35 ml. of Water and set aside in the refrigerator to crystallize.
- the purified product is recovered in two crops totalling 21.5 'g. (67% M.P. 108410 C.
- Example 5 When the procedure of Example 5 is repeated omitting the sodium methoxide in an attempt to efiect acylation of L-cysteine without operating on the sodium salt and without the aid of a neutralizing agent to form a salt of the product as formed, an 11.4% yield of N-acetylcysteine, M.P. 105-108 C., is obtained.
- Example 6.-N-acetylcysteine viaselective 'N-acyla tion of ammonium cysteinata-To' a stirred suspension (under nitrogen) of 35.2 g. (0.2 mole) of L-cysteine hydrocloride monohydrate and 100 ml. of tetrahydrofuran, 28 ml. (0.42 mole) of concentrated aqueous ammonia (28-30% Nil-l sp. gr. at 60 F., 0.8957- 0.9016) is added slowly at 05 C. After stirring overnight at room temperature the mixture is heated under reflux for 4 hrs. While cooling at 05 C., 17 ml. of concentrated hydrochloric acid (36.5-38% hydrogen chloride; sp.
- said process being conducted in the presence of at least one chemical equivalent of a neutralizing agent selected from the group consisting of the alkali metal and ammonium salts of acids having pKa values greater than 3.2 when said cysteine compound is cysteine.
- a neutralizing agent selected from the group consisting of the alkali metal and ammonium salts of acids having pKa values greater than 3.2 when said cysteine compound is cysteine.
- N-monoacyl cysteine salt resulting from said process is neutralized and N- rnonoacyl cysteine is recovered.
- cysteine compound is cysteine and said alkali metal salt is an alkali metal alkanoate.
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Description
methods, requires United States Patent Ofitice 3,ld,5d Patented May 18, ll65 3,184,505 PRGCESS FOR THE N-MONQAC 'LATION 0F CYSTEHIE The present invention is concerned with a novel process for the selective N-monacylation of cysteine. The method is highly efiicient by comparison to prior art only common, readily available starting materials, and is adapted for commercial production of N-monoacylated derivatives of cysteine, and particularly those wherein the acyl group corresponds to a mono or dicarboxylic acid having up to 6 carbon atoms. The N-acyl derivatives of cysteine typified by N-acetyl-L-cys teine have been reported to possess unique mucolytic properties and are, therefore, of value in therapeutics, particularly in the management of respiratory diseases.
When it is attempted to acylate cysteine under either aqueous or anhydrous conditions with conventional acylating agents such as acyl halides, acyl anhydrides, and ketene, it is found that the N,S-diacyl compounds are obtained and that only a very loW yield of the N-monoacyl derivative is obtained even when the amount of acylating agent is limited and other manipulations to favor monosubstitution are employed. As a matter of fact, the only method heretofore described for the preparation of N-acetylcysteine involves acylation of cystine with an excess of acylating agent to provide N,N'-diacetylcystine which is then reduced to provide the free thiol compound, N-monoacetyl cysteine [M. W. Pirie, et al., Biochemical Journal 25, 614 (1931); ibid 27, 1716 (1933)]. This method involves reduction as an additional step after acylation. Laborious procedures for isolation of the product are also described. Both add greatly to the expense of this prior process.
It has now been found that N-acylcysteine can be prepared in high yield and with relatively simple manipulations by treatment of cysteine with one chemical equivalent of an alkanoic acid anhydride having up to 12 carbon atoms, or an alkandioic acid anhydride having up to 6 carbon atoms under such conditions that an alkali metal salt or the ammonium salt of the N-acylcysteine is formed rather than the free carboxylic acid form thereof. This is accomplished either by employing an alkali metal salt or the ammonium salt of cysteine as the starting material or by operating on cysteine itself in the presence of a neutralizing agent comprised of an alkali metal or ammonium salt of an acid having a pKa value greater than 3.2. This novel process has the further advantage of not racemizing the starting material. That is, if L-cysteine or a salt thereof is used as starting material, the product obtained is an N-acyl-L-cysteine, and not the N-acyl-DL-cysteine.
When employing salts of acids having pKa values in excess of 8.4 as neutralizing agents, the corresponding alkali metal or ammonium salt of cysteine most probably forms at the outset and serves as reactant, since the pKa value of cysteine is 8.4. In other Words, when employing an alkali metal or the ammonium salt of cysteine as starting material, it may be provided as such or formed in situ by neutralization of cysteine. No theory as to the identity of the actual reactive intermediate in the process is proposed, however, since it is likely that equilibria are set up in the reaction mixture by virtue of which various reactive ionic and non-ionic species are present.
The process is carried out by suspending or dissolving the cysteine compound and the buffering agent, if one is used, in a solvent and adding one molecular proportion of the anhydride acylating agent thereto in the temperature range of about 5 to +20 C. By cysteine compound is meant cysteine itself or an alkali metal or the ammonium salt thereof. If this operation is carried out at temperatures substantially in excess of 20 C., lower yields of product are obtained. Cysteine seems to de compose appreciably at temperatures in excess of 20 C. since the odor of hydrogen sulfide is sometimes apparent on warming. The intermediate N-acylcysteine salt formed by the present process is much more stable than the cysteine starting material, and after formation thereof, the reaction mixture is allowed to Warm to room temperature and preferably heated for at least one hour about 40-75 C. to insure completion of the reaction and maximum yield of product. p
In view of the fact that cysteine and its salts are subect to oxidative conversion to cystine, it is preferred to conduct the process in the absence of air by employing an inert atmosphere such as nitrogen or other reaction inert gas.
Various solvents have been found to serve satisfactorily in the process, the preferred solvent being tetrahydrofuran containing about 10% by Weight of Water. Water itself and reaction stable organic solvents miscible therewith are operable. By reaction stable organic solvents is meant organic liquids which do not react with either the anhydride acylating agent, the neutralizing agent if one is used, or the cysteine compound reactant under the conditions of the reaction, that is Within the temperature range of about 5 to C. More specifically it has been found that Water, the lower alkanols, lower alkanediols, and others thereof, as Well as lower aliphatic cyclic others and mixtures thereof are operable. Examples of suitable organic solvents include methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, ethylene glycol, propylene glycol, monomethyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, and mixtures thereof with Water, etc.
Anhydride acylating agents selected from the class consisting of the alkanoic acid anhydrides having up to 12 carbon atoms such as acetic anhydride, propionic anhydride, acetoformic anhydride, butyric anhydride, pentanoic anhydride, and hexanoic anhydride are suitable. Similarly the cyclic alkanedioic acid anhydrides having up to 6 carbon atoms, such as succinic anhydride, methyl succinic anhydride, glutaric acid anhydride, and methyl glutaric anhydride are suitable.
The. acylation product may be recovered either as the alkali metal or ammonium salt thereof formed as an intermediate, or preferably it may be neutralized by the addition of sufiicient of a strong acid including the mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, and the allcyl and aryl sulf-onic acids to result in formation of the free carboxylic acid form thereof. Neutralization prior to recovery is generallypreferred, particularly in the preparation of N- acetylcysteine, but the best method of.isolation varies according to the specific compound being prepared and the particular process operating conditions and solvents selected.
The following examples are offered to further illustrate the manner of practicing our invention.
Example L-N-acetyl-L-cysteiue via selective direct acylarz'on in the presence of sodium acetare.To a suspension of 35.2 g. (0.2 mole) of L-cys-teine hydrochloride monohydrate stirred in a reaction vessel containing 87 ml. of 91% aqueous tetrahydrofur-an under a nitrogen atmosphere there is added 54.4 g. (0.4 mole) of sodium acetate trihydrate. The mixture is stirred for 20 min. at room temperature to insure neutralization of the hydrochloride salt resulting in the formation of a suspension of equimolar amounts of cysteine and sodium acetate.
The mixture is then chilled to 36 C. by external cooling and 20 ml. (20.8 g., 0.21 mole) of acetic anhydride is added thereto in dropwise fashion with cooling in the above range. The resulting mobile suspension is stirred for six hours at room temperature, allowed to stand over night, and finally heated at reflux (72 C.) for 4 hrs. The resulting suspension of sodium N-acetyl-L-cysteinate is then neutralized by treatmentat 510 C. with 8 g. of hydrogen chloride. Resulting sodium chloride is removed by filtration and the product is isolated by distilling the solvent from the filtrate in vacuo and crystallizing the residue from 35 ml. of water, yield 2 6.3 g. (80.6%) of N-acetylcysteine as a white solid, M.P. 109-1 10 C.
Analysis.- N, 8.54; SH, 19.9.
It should be noted that in Example 1, two chemical equivalents of sodium acetate, the neutralizing agent, relative to cysteine hydrochloride reactant are used. There fore, inthis example the cysteine compound as defined herein is cysteine itself formed by neutralization in situ of the hydrochloride salt charged to the reaction vessel.
The time periods specified in Example 1 are somewhat arbitrary, having been selected on a convenience basis. The preferred minimum heating period after addition of the acetic anhydride is 1 'hr., and the temperature range about40-75 C.
Various other solvents'may be employed in Example 1 with essentially the same results, 70% yield having been obtained employing methanol, 61% yield employing isopropanol, 78% yield employing 90% aqueous isopropanel, 74% yield using 100% tetrahydrof-uran, and 63% yield using water.
The following salts may be substituted as neutralizing.
agents on a chemical equivalent basis for sodium acetate in the process of Example 1 with substantially the same results: sodium lactate, ammonium lactate, potassium acetate, lithium acetate, ammonium acetate, sodium, potas-sium, and lithium carbonates and bicarbonates, sodium .succinate, potassium succinate, ammonium succinate, so-
dium propionate, potassium propionate, sodium iormate, potassium formate, lithium tormate, and ammonium tormate. The following neutralizing agents may be substituted for sodium acetateapart from the amountof :agent'needed to liberate cysteine reactant from its hydrochloride salt on an equimolar basis with substantially the same results: disodium phosphate, dipotassium phosphate, disodiurn citrate, and dipotassium citrate. The following neutralizing agents may be substituted for sodium acetate on a one-half molar basis with substantially the same results: trisodium phosphate, tripotassium phosphate, trisodium citrate, and tripotassium citrate. 7
When the nitrogen atmosphere is not employed in the process of Example 1, somewhat lower yields are obtained.
Example 2.N-acetyl-L-cysteine via selective direct acylation in the presence of trisodium ph0Sphate.Example 1 is repeated substituting 76 g. (0.2. mole) of Na PO 121-1 0 as neutralizing agent for the sodium acetate used in that example. N-acetylcysteine of similar quality and weighing 23.5 g. (72%) is recovered in the fashion specified in that example.
Example 5.N-succinyl-L-cysteine.The procedure of Example :1 is repeated, substituting 20g. (0.2 mole) of succinic anhydride for the acetic anhydride specified in that example. The product is recovered as anoil which solidifies upon treatment with 4150 ml. of anhydrous ether, yield 41.6 g. (94.2%). It is twice recrystallized from water, yielding a white solid, M.P. 141-142 C., [M =+-4.5 (0., 3.0, water).
. Analysis.- 0, 38.38; H, 5.08; N, 6.03; SH, 14.6. 5
Example 4.N-propionyl-L-cysteina-aPropionic anhydride, 26.4 g. (0.202 mole) is added slowly during min. at 05 C. to'a stirred suspension of 35.2 g. (0.2 mole) of L-cysteine hydrochloride monohydrate and 3 8.4 g. (0.4 mole) of sodium propionate in 18.2 ml. of water and 80 ml. of tetrahydrofuran under an atmosphere of nitrogen. The reaction is then treated as described in Example 1, yield 21.7 g. (61%), M.P. 89-90 C., M1 +24.3 (c., 5 .0, water, adjusted to pH 7 with NaOH).
Analysis.-*N, 7.69; SH, 1816.
Other N-acyl derivatives of'cysteine' may be prepared by the method of Examples 1 employing the appropriate acid anhydrid es including caproic anhydride, butyric anhydride, et-methyl-succinic anhydride, glutaric anhydr-ide, etc. Similarly, DL-cysteine or the pure D-isomer of cysteine may be acylated by this method without racemization and in similar yield.
Example 5.-N-acetyl cysteine via selective N-acylation of sodium cystez'nate.L-cysteine, 24.2 g. (0.2 mole) is added under anat-mosphere of nitrogen at 1015 C. to a freshly prepared solution of 0.2 mole of sodium methoxide in 200 ml. of anhydrous methanol. After solution is complete, the mixture is cooled to 5 to 0 C. and 20 ml. of acetic anhydride is slowly added thereto. The'mixture is then stirred over'night'resulting in a clear solution which is warmed at 50 60 C. :for 4, hrs. The resultingsolution of sodium N-acetyl-L-cysteinate is then neutralized by treatment with 3 N methanolic hydro-gen chloride. Sodium chloride is removed by filtration, and the solvent dis-tilled from the filtrate in 'vacuo at -50 C. The residual oil is dissolved in 35 ml. of Water and set aside in the refrigerator to crystallize. The purified product is recovered in two crops totalling 21.5 'g. (67% M.P. 108410 C.
When the procedure of Example 5 is repeated omitting the sodium methoxide in an attempt to efiect acylation of L-cysteine without operating on the sodium salt and without the aid of a neutralizing agent to form a salt of the product as formed, an 11.4% yield of N-acetylcysteine, M.P. 105-108 C., is obtained.
Attempted acylation of L-cysteine inlaqueous solution with acetic anhydride without the assistance of a neutralizing agent to form a salt of the resulting product, yielded N-acetyl-L-cysteine in 24% yield. This experiment was carried out as described in Example 1 but employing water as solvent and reducing the amount of sodium acetate from 0.4 moleto 0.2. mole, i.e., just suflicient to neutralize the hydrochloride salt of cysteine employed as starting material.
. Example 6.-N-acetylcysteine viaselective 'N-acyla tion of ammonium cysteinata-To' a stirred suspension (under nitrogen) of 35.2 g. (0.2 mole) of L-cysteine hydrocloride monohydrate and 100 ml. of tetrahydrofuran, 28 ml. (0.42 mole) of concentrated aqueous ammonia (28-30% Nil-l sp. gr. at 60 F., 0.8957- 0.9016) is added slowly at 05 C. After stirring overnight at room temperature the mixture is heated under reflux for 4 hrs. While cooling at 05 C., 17 ml. of concentrated hydrochloric acid (36.5-38% hydrogen chloride; sp. gr. at 60 F., 1.18541.1923) is slowly added to the mixture, followed by 250 ml. of tetrahydrofuran. The ammonium chloride which precipitates (17 g.) is separated by filtration. The filtrate is concentrated to give 37 g. of oil, which is dissolved in 25 ml. of water;
The solution is cooled, resulting in crystallization of 21.3 g. (65.3% of N-acetylcysteine of M.P. 105-107 C. and white in color. a p
While several particular embodiments of this invention are shown above, it will be understood, of course,
that the invention is not to be limited thereto, since many j moditications may be made, and it is contemplated,
therefore, by the appended claims, to cover any such modifications as fall within the true spirit and scope of this invention.
What isclaimed is: V
1. The process which comprises reacting a cysteine compound selected 'from the group consisting of cysteine and the alkali metal andammonium salts thereof in a solvent selected from the group consisting of water and. reaction stable organic solvents miscible therewith with one chemical equivalent of an acylating agent selected from the group consisting of alkanoic acid anhydrides having up to 12 carbon atoms, and alkandioic acid anhydrides having up to 6 carton atoms, at from about 5 to ;+20 C., said process being conducted in the presence of at least one chemical equivalent of a neutralizing agent selected from the group consisting of the alkali metal and ammonium salts of acids having pKa values greater than 3.2 when said cysteine compound is cysteine.
2. The process which comprises reacting a cysteine compound selected from the group consisting of cysteine and the alkali metal and ammonium salts thereof in a solvent selected from the group consisting of water and reaction stable organic solvents miscible therewith with one chemical equivalent of an acylating agent selected from the group consisting of alkanoic acid anhydrides having up to 12 carbon atoms, and alkandioic acid anhydrides having up to 6 carbon atoms, at from about -5 to +20 C., and thereafter heating at a temperature of from about 40 to 75 C. for at least one hour, said process being conducted in the presence of at least one chemical equivalent of a neutralizing agent selected from the group consisting of the alkali metal and ammonium salts of acids having pKa values greater than 3.2 when said cysteine compound is cysteine.
3. The process is claim 2 wherein N-monoacyl cysteine salt resulting from said process is neutralized and N- rnonoacyl cysteine is recovered.
4. The process of claim 2 wherein said acylating agent is acetic anhydride.
5. The process of claim 2 wherein said solvent is a lower alkanol.
6. The process of claim 2 wherein said solvent is tetrahydrofuran.
7. The process of claim 2 wherein said cysteine compound is cysteine and said alkali metal salt is an alkali metal alkanoate.
8. The process of claim 7 wherein sodium acetate is employed.
References Qited by the Examiner Smith: J. Org. Chem, vol. 26, pp. 820-3 (1961).
LORRAINE A. WEINBERGER,
Acting Primary Examiner. LEON ZITVER, Examiner.
Claims (1)
1. THE PROCESS WHICH COMPRISES REACTING A CYSTEINE COMPOUND SELECTED FROM THE GROUP CONSISTING OF CYSTEINE AND THE ALKLAI METAL AND AMMONIUM SALTS THEREOF IN A SOLVENT SELECTED FROM THE GROUP CONSISTING OF WATER AND REACTION STABLE ORGANIC SOLVENTS MISCIBLE THEREWITH WITH ONE CHEMICAL EQUIVALENT OF AN ACYLATING AGENT SELECTED FROM THE GROUP CONSISTING OF ALKANOIC ACID ANHYDRIDES HAVING UP TO 12 CARBON ATOMS, AND ALKANDIOIC ACID ANHYDRIDES HAVING UP TO 6 CARBON ATOMS, AT FROM ABOUT -5 TO +20*C., SAID PROCESS BEING CONDUCTED IN THE PRESENCE OF AT LEAST ONE CHEMICAL EQUIVALENT OF A NEUTRALIZING AGENT SELECTED FROM THE GROUP CONSISTING OF THE ALKALI METAL AND AMMONIUM SALTS OF ACIDS HAVING PKA VALUES GREATER THAN 3.2 WHEN SAID CYSTEINE COMPOUND IS CYSTEINE.
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CH276163A CH457490A (en) | 1962-06-18 | 1963-03-05 | Process for the preparation of N-acylcysteines |
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Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4129593A (en) * | 1976-10-19 | 1978-12-12 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler | Process for the production of high purity S-carboxymethyl-L-cysteine |
US4847282A (en) * | 1982-04-19 | 1989-07-11 | Galephar | Mucolytic acetylcysteine salts |
US4918223A (en) * | 1987-08-21 | 1990-04-17 | Degussa Aktiengesellschaft | Method of preparing N-acylated mercapto-alpha-amino acids |
US5350768A (en) * | 1987-11-19 | 1994-09-27 | Aktiebolaget Draco | Derivatives of cysteine |
US5380758A (en) * | 1991-03-29 | 1995-01-10 | Brigham And Women's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
US5580577A (en) * | 1990-01-11 | 1996-12-03 | Herzenberg; Leonard A. | Method of treating the symptoms of human rhinovirus infection |
WO1998030228A1 (en) | 1997-01-13 | 1998-07-16 | Emory University | Compounds and their combinations for the treatment of influenza infection |
WO2010090611A2 (en) | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Taste and odor masked pharmaceutical compositions with high bioavailability |
WO2010090612A1 (en) | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Stable, taste and odor masked pharmaceutical compositions comprising acetylcystein and vitamin c |
WO2011146031A1 (en) | 2010-05-18 | 2011-11-24 | Bilgic Mahmut | Pharmaceutical composition comprising n- acetylcysteine and a xanthine |
WO2012039691A2 (en) | 2010-09-20 | 2012-03-29 | Mahmut Bilgic | Synergic effect |
EP2574333A1 (en) | 2011-09-27 | 2013-04-03 | Friulchem SpA | N-acetylcysteine effervescent tablet and its therapeutical applications |
WO2013055302A1 (en) | 2011-05-16 | 2013-04-18 | Mahmut Bilgic | Effervescent composition comprising n- acetylcysteine and doxophylline or theophylline |
EP2905020A1 (en) | 2014-02-05 | 2015-08-12 | Sanovel Ilac Sanayi ve Ticaret A.S. | Effervescent formulations comprising ibuprofen and N-acetylcystein |
WO2019026073A1 (en) | 2017-08-01 | 2019-02-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | S-nitrosothiol compounds and their combinations with nitrosamine blocking agents for safe food preservation |
CN109503439A (en) * | 2019-01-09 | 2019-03-22 | 中国农业大学 | A kind of preparation method of N-acetyl-L-cysteine |
CN113461580A (en) * | 2021-06-25 | 2021-10-01 | 浙江金华康恩贝生物制药有限公司 | N-acetyl-L-cysteine synthesis method |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE8704542D0 (en) * | 1987-11-19 | 1987-11-19 | Draco Ab | NEW DERIVATIVES OF CYSTEINE |
-
1962
- 1962-06-18 US US202948A patent/US3184505A/en not_active Expired - Lifetime
-
1963
- 1963-03-04 DE DEM55979A patent/DE1260476B/en active Pending
- 1963-03-05 CH CH276163A patent/CH457490A/en unknown
Non-Patent Citations (1)
Title |
---|
None * |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4129593A (en) * | 1976-10-19 | 1978-12-12 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler | Process for the production of high purity S-carboxymethyl-L-cysteine |
US4847282A (en) * | 1982-04-19 | 1989-07-11 | Galephar | Mucolytic acetylcysteine salts |
US4918223A (en) * | 1987-08-21 | 1990-04-17 | Degussa Aktiengesellschaft | Method of preparing N-acylated mercapto-alpha-amino acids |
US5350768A (en) * | 1987-11-19 | 1994-09-27 | Aktiebolaget Draco | Derivatives of cysteine |
US5580577A (en) * | 1990-01-11 | 1996-12-03 | Herzenberg; Leonard A. | Method of treating the symptoms of human rhinovirus infection |
US5380758A (en) * | 1991-03-29 | 1995-01-10 | Brigham And Women's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
WO1998030228A1 (en) | 1997-01-13 | 1998-07-16 | Emory University | Compounds and their combinations for the treatment of influenza infection |
US6013632A (en) * | 1997-01-13 | 2000-01-11 | Emory University | Compounds and their combinations for the treatment of influenza infection |
US6107281A (en) * | 1997-01-13 | 2000-08-22 | Nutri-Quest, Inc. | Compounds and their combinations for the treatment of influenza infection |
WO2010090612A1 (en) | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Stable, taste and odor masked pharmaceutical compositions comprising acetylcystein and vitamin c |
WO2010090611A2 (en) | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Taste and odor masked pharmaceutical compositions with high bioavailability |
WO2011146031A1 (en) | 2010-05-18 | 2011-11-24 | Bilgic Mahmut | Pharmaceutical composition comprising n- acetylcysteine and a xanthine |
WO2012039691A2 (en) | 2010-09-20 | 2012-03-29 | Mahmut Bilgic | Synergic effect |
WO2013055302A1 (en) | 2011-05-16 | 2013-04-18 | Mahmut Bilgic | Effervescent composition comprising n- acetylcysteine and doxophylline or theophylline |
EP2574333A1 (en) | 2011-09-27 | 2013-04-03 | Friulchem SpA | N-acetylcysteine effervescent tablet and its therapeutical applications |
WO2013045566A1 (en) | 2011-09-27 | 2013-04-04 | Friulchem Spa | N-acetylcysteine effervescent tablet and its therapeutical applications |
EP2905020A1 (en) | 2014-02-05 | 2015-08-12 | Sanovel Ilac Sanayi ve Ticaret A.S. | Effervescent formulations comprising ibuprofen and N-acetylcystein |
WO2015117987A1 (en) | 2014-02-05 | 2015-08-13 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Effervescent formulations comprising ibuprofen and n-acetylcystein |
WO2019026073A1 (en) | 2017-08-01 | 2019-02-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | S-nitrosothiol compounds and their combinations with nitrosamine blocking agents for safe food preservation |
US11632972B2 (en) | 2017-08-01 | 2023-04-25 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | S-nitrosothiol compounds and their combinations with nitrosamine blocking agents for safe food preservation |
CN109503439A (en) * | 2019-01-09 | 2019-03-22 | 中国农业大学 | A kind of preparation method of N-acetyl-L-cysteine |
CN113461580A (en) * | 2021-06-25 | 2021-10-01 | 浙江金华康恩贝生物制药有限公司 | N-acetyl-L-cysteine synthesis method |
CN113461580B (en) * | 2021-06-25 | 2023-08-15 | 浙江金华康恩贝生物制药有限公司 | N-acetyl-L-cysteine synthesis method |
Also Published As
Publication number | Publication date |
---|---|
CH457490A (en) | 1968-06-15 |
DE1260476B (en) | 1968-02-08 |
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