GB2035313A - Preparation of N-cyano-N'-methyl- N''-(2-mercaptoethyl)-guanidine - Google Patents
Preparation of N-cyano-N'-methyl- N''-(2-mercaptoethyl)-guanidine Download PDFInfo
- Publication number
- GB2035313A GB2035313A GB7937081A GB7937081A GB2035313A GB 2035313 A GB2035313 A GB 2035313A GB 7937081 A GB7937081 A GB 7937081A GB 7937081 A GB7937081 A GB 7937081A GB 2035313 A GB2035313 A GB 2035313A
- Authority
- GB
- United Kingdom
- Prior art keywords
- cyano
- methyl
- guanidine
- mercaptoethyl
- process according
- 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.)
- Granted
Links
- ZORWZOOZJGMSTE-UHFFFAOYSA-N 1-cyano-2-methyl-3-(2-sulfanylethyl)guanidine Chemical compound N#CNC(=NC)NCCS ZORWZOOZJGMSTE-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 5
- 229960003151 mercaptamine Drugs 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- MHGGQXIPBPGZFB-UHFFFAOYSA-N methyl n-cyano-n'-methylcarbamimidothioate Chemical compound CSC(=NC)NC#N MHGGQXIPBPGZFB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- PDWPOXKSTFGRIT-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1h-imidazole;hydrochloride Chemical compound Cl.CC=1NC=NC=1CCl PDWPOXKSTFGRIT-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical group NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003792 electrolyte Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 abstract description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 abstract description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002024 ethyl acetate extract Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- AZGNFIUHXWRRAE-UHFFFAOYSA-N 2-cyano-1-methyl-1-(2-sulfanylethyl)guanidine Chemical compound SCCN(C)C(N)=NC#N AZGNFIUHXWRRAE-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000003969 polarography Methods 0.000 description 1
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/43—Y being a hetero atom
- C07C323/44—X or Y being nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
N-cyano-N'-methyl-N''-(2- mercaptoethyl)-guanidine is made by the hydrogenolysis of 2,2'- dithiobisethyl-(N-cyano-N'-methyl)- guanidine so that no change occurs in the guanidine residue. Preferred electrolytic and chemical hydrogenolyses are disclosed.
Description
SPECIFICATION
Preparation of N-cyano-N'.methyl-N"-(2-mercapto-ethyl)-guanidine Description
The present invention relates to a process for preparing N-cyano-N'-methyl-N '-(2-mercaptoethyl)-guanidine by the hydrogenolysis of 2,2'-dithiobis-ehtyl-(N-cyano-N'-methyl)-guanidine. N-cyano-N'-methyl-N"-(2mercaptoethyl)-guanidine is useful as an intermediate for the preparation of N-cyano-N'-methyl-N"-[2-(5 methy-imidazole-4-yl)-methyl-thio-ethylj-guanidine, the latter being an active substance in the treatment of gastric and duodenal ulcers.
It is well known that N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine can be prepared by the reaction of cysteamine and N-cyano-N',S-dimethyl-isothiourea in the presence of sodium hydroxide (Dutch
Published Patent Application 75.10344).
It has now been found that N.cyano-N'-methyl-N'-(2-mercaptoethyl)-guanidine can be prepared readily and in quantitative yields by hydrogenolizing 2,2'-dithiobisethyl-(N-cyano-N'-methyl)-guanidine.
In carrying out the process of the invention, 2,2'-dithiobisethyl-(N-cyano-N'-methyl)-guanidine of the formula:
preferably obtained by the reaction of cysteamine and N-CYANO-N', S-dimethylisothiourea, is hydrogenolyzed to N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine under such conditions that no change takes place in the cyanoguanidine residue.
In carrying out the process according to the present invention, 2,2'-dithiobis-(N-cyano-N'-methyl)- guanidine, which preferably is obtained by the condensation of cysteamine and N-cyano-N',Sdimethylisothiourea in an alcohol, e.g. Cm no at the boiling temperature for 2 to 3 hours, is advantageously suspended in liquid ammonia; after the addition of 6 to 9 equivalents of sodium, the ammonia is evaporated, the residue is dissolved in water, acidified to pH 4 and N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine is isolated in a conventional manner.
Preferred ways of conducting the hydrogenolysis of 2,2'-dithiobisethyl-(N-cyano-N'-methyl)-guanidine also include the use of lithium aluminium hydride in an organic solvent, potassium sulphide or sodium sulphide in an aqueous or alcoholic medium as well as electrolytically.
The invention can also employ other methods leading to the same result as stated above.
The process of the invention is advantageous, in that repeated dimerisation during the reaction is no longer possible and a pure product is obtained in high yields.
The process is illustrated by the following Examples, which should not be considered as a limitation of the present invention.
Example 1
Cysteamine (4.89, 0.062 mole) and N-cyano-N',S-dimethyl-isothiourea (8.0g, 0.062 mole) were added to ethanol (100 ml). The reaction mixture was heated for 2.5 hours at 75" -78"C while stirring. Ethanol was evaporated and the residue, when necessary, was recrystallized from an organic solvent. 2,2'-dithiobisethyl- (N-cyano-N'-methyl)-guanidine (7.879,82%), m.p. 258"-160"C, was obtained.
Example 2
2,2'-Dithiobisethyl-(N-cyano-N'-methyl)-guanidine (1.57g, 0.005 mole) was suspended in liquid ammonia (30 ml) and sodium (0.929, 0.04 mole) was added in portions. The excess of sodium was removed by adding small amounts of ammonium chloride. Ammonia was evaporated off, the residue was dissolved in water (8 ml) and acidified to pH 4 with 10% hydrochloric acid. The aqueous solution was extracted three times with ethyl acetate (25 ml each time). Ethyl acetate extract was dried over sodium sulphate and, after evaporation,
N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine (1.579,99%) was obtained in the form of a viscous colourless oil having the same physical constants as the authentic sample.
Example 3
2,2'-Dithiobisethyl-(N-cyano-N'-methyl)-guanidine (0.59, 0.0016 mole) was added to a suspension of lithium aluminium hydride (0.149, 0.0038 mole) and dry ether (30 ml). The reaction mixture was refluxed for 2 hours, whereafter 5% hydrochloric acid was carefully added drop by drop to achieve pH 4. The ether layer was separated and the acidic aqueous layer was extracted three more times with ethyl acetate (20 ml each time). The combined ether extracts and ethyl acetate extracts were dried over sodium sulphate and, after evaporation, N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine (0.3769,75%) was obtained.
Example 4
A solution of Na2S.9H20 (0.5g, 0.002 mole + excess 5%) in water (10 ml)was added to a suspension of 2,2'-dithiobisethyl-(N-cyano-N'-methyl)-guanidine (0.314g, 0.001 mole) in water (10 ml). The reaction mixture was heated at 800-900C for 2 hours, then cooled and extracted three times with ethyl acetate (10 ml each time). The aqueous part was acidified to pH 4 with 1 N HCI and extracted three more times with ehtyl acetate (10 ml each time). The combined ethyl acetate extracts were dried over sodium sulphate and, after evaporation, N-cyano-N'-methyl-N"-(2-mercapthoethyl)-guanidine (0.21g, 66%) was obtained.
Example 5
A solution of Na2S.9H20 (0.5g, 0.002 mole + excess 5%) in water (3 ml) was added to a solution of 2,2-dithiobisethyl-(N-cyano-N'-methyl)-guanidine (0.3149, 0.001 mole) in ethanol (20 ml). The reaction mixture was refluxed for 2 hours, ethanol was evaporated and the aqueous part was further treated as in
Example 4. N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine (0.1 8g, 57%) was obtained.
Example 6
2,2'-Dithiobisethyl-(N-cyano-N'-methyl)-guanidine (0.3149, 0.001 mole) was added to 0.1 N potassium chloride solution (50 ml) and was electrolytically reduced in a 100 ml cell, while conducting nitrogen through the reaction solution. A constant current of 0.05 A was applied by means of a mercury cathode of 20 cm2 at the bottom of the cell and a centrally-located lead anode (anolyte was 10% sulphuric acid) at a temperature of 20"C. Catholyte and anolyte were separated by a synthetic diaphragm and the catholyte was agitated by means of a magnetic stirrer. The course of the reaction can be monitored by polarography or thin layer chromatography (chloroform: methanol = 9:3). After the reaction was completed, the aqueous solution was extracted three times with ethyl acetate (25 ml each time).The ethyl acetate extract was dried over sodium sulphate and then evaporated to dryness. N-cyano-N '-methyl-N"-(2-mercaptoethyl)-guanidine (0.1 86g, 59%) was obtained in the form of a colourless viscous oil.
Example 7
Analogously to the process described in Example 6, with the only difference that it was operated in methanolic solution under the addition of sodium chloride (0.39) and that the product was isolated in such a way that after the completed reaction, methanol was evaporated to dryness and the residue dissolved in water (5 ml) and acidified to pH 4 with hydrochloric acid, after extraction with ethyl acetate, the product (0.2369,75%) was obtained in the form of a colourless viscous oil.
Example 8
Analogously to the process as described in Example 6, with the only difference that the reaction was carried out in methanol under the addition of 5-methyl-4-chloromethyl imidazole hydrochloride (0.3329, 0.002 mole) as electrolyte and the product was isolated as in Example 7, the product (0.2439,77%) was obtained in the form of a colourless viscous oil.
Claims (7)
1. A process for preparing N-cyano-N '-methyl-N"-(2-mercaptoethyl)-guanidine, wherein 2,2'dithiobisethyl-(N-cyano-N'-methyl)-guanidine of the formula:
is hydrogenolyzed to N-cyano-N '-methyl-N"-(2-mercaptoethyl)-guanidine under such conditions that no change takes place in the cyanoguanidine residue.
2. A process according to claim 1, wherein the condensation is carried out in an alcohol.
3. A process according to claim 1 or 2, wherein the 2,2'-dithiobisethyl-(N-cyano-N'-methyl)-guanidine is obtained by the condensation of cysteamine and N-cyano-N',S-dimethylisothiourea.
4. A process according to any preceding ciaim, wherein the hydrogenolysis is carried out with sodium in liquid ammonia, with lithium aluminium hydride in ether, with sodium sulphide in water or dilute ethanol or electrolytically in an aqueous or alcoholic solutuion using a metal cathode in a current of nitrogen.
5. A process according to claim 4, wherein, in electrolytic production, potassium chloride, sodium chloride or 5-methyl-4-chloromethyl imidazole hydrochloride is used as the electrolyte.
6. A process according to claim 1, substantially as herein described.
7. N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine, when made by a process according to any preceding claim.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU255178A YU41127B (en) | 1978-11-02 | 1978-11-02 | Process for obtaining n-cyano-n-methyl-n-(2-mercaptoethyl)-guanidine |
| YU36579A YU41615B (en) | 1979-02-15 | 1979-02-15 | Process for obtaining n-cyano-n-methyl-n"-(2-mercaptoethyl)-quanidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2035313A true GB2035313A (en) | 1980-06-18 |
| GB2035313B GB2035313B (en) | 1983-01-06 |
Family
ID=27130733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7937081A Expired GB2035313B (en) | 1978-11-02 | 1979-10-25 | Preparation of n-cyano-n'-methyl-n''-(2-mercaptoethyl)-guanidine |
Country Status (5)
| Country | Link |
|---|---|
| AT (1) | AT368991B (en) |
| CH (1) | CH645098A5 (en) |
| DE (1) | DE2944257A1 (en) |
| GB (1) | GB2035313B (en) |
| IT (1) | IT1192784B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2122612A (en) * | 1982-06-16 | 1984-01-18 | May & Baker Ltd | Cystamine derivatives |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0623179B2 (en) * | 1986-09-01 | 1994-03-30 | 三井石油化学工業株式会社 | Cyanoguanidine derivative and method for producing the same |
| JPH0623180B2 (en) * | 1987-02-17 | 1994-03-30 | 三井石油化学工業株式会社 | Cyanoguanidine derivative and method for producing the same |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1533380A (en) * | 1974-09-02 | 1978-11-22 | Smith Kline French Lab | Process for the preparation of heterocyclic substituted thioureas and h-cyanoguanidines |
-
1979
- 1979-10-25 GB GB7937081A patent/GB2035313B/en not_active Expired
- 1979-10-25 CH CH960479A patent/CH645098A5/en not_active IP Right Cessation
- 1979-10-29 IT IT69110/79A patent/IT1192784B/en active
- 1979-10-31 AT AT0702779A patent/AT368991B/en not_active IP Right Cessation
- 1979-11-02 DE DE19792944257 patent/DE2944257A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2122612A (en) * | 1982-06-16 | 1984-01-18 | May & Baker Ltd | Cystamine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CH645098A5 (en) | 1984-09-14 |
| DE2944257A1 (en) | 1980-05-14 |
| GB2035313B (en) | 1983-01-06 |
| IT1192784B (en) | 1988-05-04 |
| IT7969110A0 (en) | 1979-10-29 |
| AT368991B (en) | 1982-11-25 |
| ATA702779A (en) | 1982-04-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |