CA1083603A - Production of substituted guanidines. - Google Patents
Production of substituted guanidines.Info
- Publication number
- CA1083603A CA1083603A CA305,594A CA305594A CA1083603A CA 1083603 A CA1083603 A CA 1083603A CA 305594 A CA305594 A CA 305594A CA 1083603 A CA1083603 A CA 1083603A
- Authority
- CA
- Canada
- Prior art keywords
- salt
- substituted
- mole
- thiourea
- sulphonic acid
- 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.)
- Expired
Links
- 150000002357 guanidines Chemical class 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 15
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001412 amines Chemical class 0.000 claims abstract description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 17
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- -1 methylenedioxybenzyl Chemical group 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- VLCDUOXHFNUCKK-UHFFFAOYSA-N N,N'-Dimethylthiourea Chemical compound CNC(=S)NC VLCDUOXHFNUCKK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000004803 chlorobenzyl group Chemical group 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 8
- 230000000875 corresponding effect Effects 0.000 abstract description 7
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 abstract description 5
- 229910021529 ammonia Inorganic materials 0.000 abstract description 4
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 229960000443 hydrochloric acid Drugs 0.000 description 7
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 235000009518 sodium iodide Nutrition 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- CRMWDHWPEFVLOU-UHFFFAOYSA-N n,n'-dimethylmethanimidamide Chemical compound CNC=NC CRMWDHWPEFVLOU-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- GKVUQZXKYCDPBJ-UHFFFAOYSA-N N-benzyl-N'-methylmethanimidamide Chemical compound C(C1=CC=CC=C1)NC=NC GKVUQZXKYCDPBJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 238000007790 scraping Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003585 thioureas Chemical class 0.000 description 2
- HWZWLMPFFGWOIJ-UHFFFAOYSA-N 1,2,3-trimethylguanidine;hydroiodide Chemical compound I.CNC(NC)=NC HWZWLMPFFGWOIJ-UHFFFAOYSA-N 0.000 description 1
- ZILSBZLQGRBMOR-UHFFFAOYSA-N 1,3-benzodioxol-5-ylmethanamine Chemical compound NCC1=CC=C2OCOC2=C1 ZILSBZLQGRBMOR-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 150000001450 anions Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000019628 coolness Nutrition 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract of the Disclosure:
A process for the production of substituted guanidines is described, in which a thiourea or isothiourea, the amino groups of which are substituted with substituents of the final substituted guanidine, is oxidized to the correspond-ing formamidine sulphonic acid, which is then reacted with ammonia or, if a further substituent is to be introduced in the final product, with the amine corresponding to said further substituent.
A process for the production of substituted guanidines is described, in which a thiourea or isothiourea, the amino groups of which are substituted with substituents of the final substituted guanidine, is oxidized to the correspond-ing formamidine sulphonic acid, which is then reacted with ammonia or, if a further substituent is to be introduced in the final product, with the amine corresponding to said further substituent.
Description
- ~83E;03 This inven-tion relates -to a new process for -the pro-duction of mono-, di- and trisubs-tituted guanidines of -the formula Rl _ NH - C - NH - R (I) N
wherein each of Rl, R2, and R3 is hydrogen, an alkyl group 9 including cycloalkyl, having 1 to 6 carbon atoms, a phenyl_ alkyl group of not more than 3 carbon atoms in the alkyl part, with the proviso that at leas-t one of Rl, R2, and R shall be different from hydrogen.
Particularly, the compounds of formula I, wherein one of the substituents Rl, R2, and R3 is a benzyl group or a phenylethyl group are known and used therapeu-tically, because they selectively depress sympha-te-tic nerve function and have little or no effect on the parasymphatetic or central nerve functions, cf. the British Patent Specification No. 973,882.
According to the said specification, the compounds may be prepared by the reaction of ammonia or an ammonia deri-vative or a salt thereof with a S-substituted isothiourea or a salt thereof, for example as follows:
Rl-NH Rl-NH
C-SR + R2NH ~ C-NHR2 ~ RSH
+ ~ 2 +
In this scheme, Rl and R2 are as above defined, R is an alkyl group, generally methyl, and X is an anion.
The foully smelling mercap-tans formed in this process have to be removed completely, which may prove difficult and any-way involves a separate purification process.
.' '' 9~
~83~1~3 In the presen-t process, compounds of -the above formula I are produced easily and in good yields from substituted thioureas without formation of thef`oully smelling mercap-tanes of -the known process.
Thus, according to -the invention, a N- or N,N'-substi-tuted thiourea or isothiourea, or a salt -thereof, is oxi-dized to form the corresponding formamidine-sulphonic acid, which is subsequently reacted with ammonia or an amine to yield the desired compound of formula I, as illustrated by the following schemes of reaction, wherein Rl, R2, and R3 are as hereinbefore defined.
Rl_NH Rl_NH
CS + 3 H22 ~----~ C-S03H -~ 3 H20 Rl_NH Rl-NH
C-S03H + R2NH2 > ~C~NH-R2 -~ H2S03 R3 -N ~ R3 -N
It will be noted that dependen-t upon the choice of` the substituents Rl, R2, and R3, the process will yield mono-, di- or -trisubs-tituted guanidines.
As illustrated by the schemes of reaction, hydrogen peroxide is the preferred oxidizing agent, because it forms water by the reaction, but other peroxides may be used.
I'he following examples are illustrative of the present process.
Example 1 A. N-Benzyl-N'-methylformamidine sulphonic acid To a mixture of 100 g of 34.6% hydrogen peroxide (1 mole) " ~8~3 and 200 ml of water were added 45 g (0.25 mole) of N-benzyl-N'-me-thylthiourea in small portions during two hours. The re-action being exothermic, the temperature of the reaction mix-ture was kept below 18C by cooling the reaction vessel in a mix-ture of ice and water.
After the addition of the thiourea derivative, the re-action mixture was left for two hours wi-thout cooling, thus slowly reaching room temperature.
Then, it was again cooled in ice-water, whereby the title compound precipitated as white crystals. The crystals were filtered off and washed with a small volume of cold water and finally with ether. The yield was 44 g (0.19 mole), correspond-ing to 76% of the theoretical yield. The compound mel-ted at 120-125C under decomposition.
B. N-Benzy]-N',N'-dimethyl~uanidinium iodide 4.56 g (0.020 mole) of N-benzyl-N'-methylformamidine sulphonic acid, a 24% solution of 15 ml methylamine in water, and 50 ml of water were mixed, and the mixture was refluxed for 6 hours. Excess of methylamine was removed by suction in vacuum, after which -the volume of the reaction mixture was 50 ml. The mix-ture was acidified with concentrated hydrochloric acid -to a pH between 1 and 2, after which 10 ml of a saturated aqueous solution of NaI and 5 g of solid NaCl were added. The mixture was then left overnight with stirring to yield a cream-coloured precipitate of the title compound. The preci-pitate was filtered off and recrystallized from ethanol to yield 3.5 g (0.01148 mole), corresponding to 57.4% of the theoretical yield. The melting point was 192-194C.
1~836~3 Example 2 N-Benz~1-N',N'-dimethyl~uanidinium iodide A mixture of 3.0 g (0.0197 mole) of N,N'-dime-thylform-amidine sulphonic acid (produced from N,N'-dimethylthiourea in similar manner as described in step A of Example 1), 10 ml (0.092 mole) of benzylamine and 60 ml of water were mixed and refluxed for 3 1/2 hours. Concentrated hydrochloric acid was added to a pH between 1 and 2, and then 10 ml of a saturated aqueous solution of NaI were added. After s-tanding for a short time, an almost white precipitate was formed.
The reaction mixture was cooled for about 2 hours in a mixture of ice and water, when -the precipitate, consisting of the title compound, was fil-tered off and recrystallized from ethanol in a yield of 4.7 g (0.0154 mole) (7~%) with melting point 192-194C.
.
Example 3 N-Benz~1-N'-N"-dimeth~lguanidinium iodide A mixture of 12 g of N,N'-dimethylformamidine sulphonic acid, 20 ml of benzylamine and 120 ml of waterwas stirred overnight at room temperature. The mixturew~s then acidi-fied to pH 1 with hydrochloric acid, and a saturated aqueous solution of sodium iodidewas added. Af-ter stirring and cool-ing for about one hour, the precipitate, consisting of the title compound, was filtered off, washed first with water and then with ether, and finally dried at 30C. The melting point was 195C, and the yield was 19 g (79~).
8~6~313 Example l~
N,N',N"--trimethylguanidinium iodide 15.2 g (0.10 mole) of N,N'-dime-thylformamidine sulphon-ic acid and 75 ml of a 24% aqueous solution of methylamine were dissolved in 250 ml of water. The mixture was refluxed for 3 hours. The surplus of methylamine was sucked off in vacuum, after which concentrated hydrochloric acid was added to give a pH between 1 and 2. Then, a saturated aqueous so-lution of sodium iodide was added, resulting in a white pre-cipitate of the -ti-tle compound. The precipitate was removed by filtration and recrystallized from watèr as shining white needles. The yield was 18.0 g (0.0786 mole, 78.6%) with melting point above 320C.
Example 5 N,N'-dimethyl-N"-(3,4-meth~lenediox~benz~ nidinium iodide 4.56 g (0.030 mole) of N,N'-dimethylformamidine sulphon-ic acid and 18.1 g (0.12 mole) of 3,4-methylenedioxybenzyl-amine were dissolved in 60 ml of water, and the solution was refluxed for 4 1/2 hours. The reaction mixture was then concentrated to a volume of 40 ml, af-ter which concen-trated hydrochloric acid was added to give a pH between 1 and 3, and then 25 ml of a saturated aqueous solution of sodium iodide were added. A white crystalline precipitate of the title compound was formed, filtered off and washed wi-th water. The yield was 8.4 g (0.0241 mole) corresponding to 80.3% of the -theoretical yield, and -the melting point was 211.0-212.0C.
10836~3 Example 6 N-(2-Chlorobenzyl)_N',N"-dime-thyl~uanidinium iodide 4.56 g (0.030 mole) of N,N'-dlrnethylformamidine sulphon-ic acid and 17.0 g (0.12 mole) of 2--chlorobenzylamine were dissolved in 60 ml of water, and the solution was refluxed for 5 1/2 hours. The solution was acidified with concen-trated hydrochloric acid to pH 1-3 and then 25 ml oi~ a sa-turated aqueous solution of sodium iodide were added, where-by a yellow oily substance separated. The reaction mixture was stirred overnight, whereby the separated oil became semi-crystalline. The paren-t lye was decan-ted off, and -the resi-due was washed repea-tedly with ether, whereby all became crystalline. The substance was recrystallized from water, the solution being purified with active carbon 9 the title compound again separating as an oil which, however, rapidly became crystalline by scraping. The yield of the cream-coloured compound was 6.7 g (0.0197 mole, 65.7%) with melt-ing point 157.5-158.5C.
Example 7 N,N'-dimethyl-N"-(4-methoxybenz~ -guanidinium iodide The procedure of Example 5 was repeated using 16.44 g (0.12 mole) of 4-methoxybenzylamine instead of 2-chloro-benzylamine. The title compound, also first separating as an oil, was finally recovered as a white substance in a yield of 5.8 g (0.0173 mole, 57.7%) with melting point 162.0 162.5 C D
336~3 Example 8 N-C~clohexyl-N',N"-dimethyl~uanidin:ium iodide 4.56 g (0,030 mole) of N,N'-dime-thylformamidine sulphon-ic acid and 12.0 g (0.12 mole) of cyclohexylamine were dis-solved in 60 ml of water. The mixture was stirred overnight and then concentrated by evaporation to a volume of about 30 ml. The reaction mixture was then acidified with hydro-chloric acid to pH 2, after which 10 ml of a saturated aqueous solution of sodium iodide were added. An oily sub-stance separated, which rapidly crystallized when scraping.
The solid subs-tance was filtered off and recrys-tallized from water. The white solid, consis-ting of the ti-tle compound, was recovered in a yield of 3.70 g (0.0125 mole, 41.7%) with melting point 195.5-196.0C.
In the present specification the terms "alkyl group", including "cycloalkyl group", and "phenyl-alkyl group" are understood to mean the corresponding substituted or unsub-stituted groups.
wherein each of Rl, R2, and R3 is hydrogen, an alkyl group 9 including cycloalkyl, having 1 to 6 carbon atoms, a phenyl_ alkyl group of not more than 3 carbon atoms in the alkyl part, with the proviso that at leas-t one of Rl, R2, and R shall be different from hydrogen.
Particularly, the compounds of formula I, wherein one of the substituents Rl, R2, and R3 is a benzyl group or a phenylethyl group are known and used therapeu-tically, because they selectively depress sympha-te-tic nerve function and have little or no effect on the parasymphatetic or central nerve functions, cf. the British Patent Specification No. 973,882.
According to the said specification, the compounds may be prepared by the reaction of ammonia or an ammonia deri-vative or a salt thereof with a S-substituted isothiourea or a salt thereof, for example as follows:
Rl-NH Rl-NH
C-SR + R2NH ~ C-NHR2 ~ RSH
+ ~ 2 +
In this scheme, Rl and R2 are as above defined, R is an alkyl group, generally methyl, and X is an anion.
The foully smelling mercap-tans formed in this process have to be removed completely, which may prove difficult and any-way involves a separate purification process.
.' '' 9~
~83~1~3 In the presen-t process, compounds of -the above formula I are produced easily and in good yields from substituted thioureas without formation of thef`oully smelling mercap-tanes of -the known process.
Thus, according to -the invention, a N- or N,N'-substi-tuted thiourea or isothiourea, or a salt -thereof, is oxi-dized to form the corresponding formamidine-sulphonic acid, which is subsequently reacted with ammonia or an amine to yield the desired compound of formula I, as illustrated by the following schemes of reaction, wherein Rl, R2, and R3 are as hereinbefore defined.
Rl_NH Rl_NH
CS + 3 H22 ~----~ C-S03H -~ 3 H20 Rl_NH Rl-NH
C-S03H + R2NH2 > ~C~NH-R2 -~ H2S03 R3 -N ~ R3 -N
It will be noted that dependen-t upon the choice of` the substituents Rl, R2, and R3, the process will yield mono-, di- or -trisubs-tituted guanidines.
As illustrated by the schemes of reaction, hydrogen peroxide is the preferred oxidizing agent, because it forms water by the reaction, but other peroxides may be used.
I'he following examples are illustrative of the present process.
Example 1 A. N-Benzyl-N'-methylformamidine sulphonic acid To a mixture of 100 g of 34.6% hydrogen peroxide (1 mole) " ~8~3 and 200 ml of water were added 45 g (0.25 mole) of N-benzyl-N'-me-thylthiourea in small portions during two hours. The re-action being exothermic, the temperature of the reaction mix-ture was kept below 18C by cooling the reaction vessel in a mix-ture of ice and water.
After the addition of the thiourea derivative, the re-action mixture was left for two hours wi-thout cooling, thus slowly reaching room temperature.
Then, it was again cooled in ice-water, whereby the title compound precipitated as white crystals. The crystals were filtered off and washed with a small volume of cold water and finally with ether. The yield was 44 g (0.19 mole), correspond-ing to 76% of the theoretical yield. The compound mel-ted at 120-125C under decomposition.
B. N-Benzy]-N',N'-dimethyl~uanidinium iodide 4.56 g (0.020 mole) of N-benzyl-N'-methylformamidine sulphonic acid, a 24% solution of 15 ml methylamine in water, and 50 ml of water were mixed, and the mixture was refluxed for 6 hours. Excess of methylamine was removed by suction in vacuum, after which -the volume of the reaction mixture was 50 ml. The mix-ture was acidified with concentrated hydrochloric acid -to a pH between 1 and 2, after which 10 ml of a saturated aqueous solution of NaI and 5 g of solid NaCl were added. The mixture was then left overnight with stirring to yield a cream-coloured precipitate of the title compound. The preci-pitate was filtered off and recrystallized from ethanol to yield 3.5 g (0.01148 mole), corresponding to 57.4% of the theoretical yield. The melting point was 192-194C.
1~836~3 Example 2 N-Benz~1-N',N'-dimethyl~uanidinium iodide A mixture of 3.0 g (0.0197 mole) of N,N'-dime-thylform-amidine sulphonic acid (produced from N,N'-dimethylthiourea in similar manner as described in step A of Example 1), 10 ml (0.092 mole) of benzylamine and 60 ml of water were mixed and refluxed for 3 1/2 hours. Concentrated hydrochloric acid was added to a pH between 1 and 2, and then 10 ml of a saturated aqueous solution of NaI were added. After s-tanding for a short time, an almost white precipitate was formed.
The reaction mixture was cooled for about 2 hours in a mixture of ice and water, when -the precipitate, consisting of the title compound, was fil-tered off and recrystallized from ethanol in a yield of 4.7 g (0.0154 mole) (7~%) with melting point 192-194C.
.
Example 3 N-Benz~1-N'-N"-dimeth~lguanidinium iodide A mixture of 12 g of N,N'-dimethylformamidine sulphonic acid, 20 ml of benzylamine and 120 ml of waterwas stirred overnight at room temperature. The mixturew~s then acidi-fied to pH 1 with hydrochloric acid, and a saturated aqueous solution of sodium iodidewas added. Af-ter stirring and cool-ing for about one hour, the precipitate, consisting of the title compound, was filtered off, washed first with water and then with ether, and finally dried at 30C. The melting point was 195C, and the yield was 19 g (79~).
8~6~313 Example l~
N,N',N"--trimethylguanidinium iodide 15.2 g (0.10 mole) of N,N'-dime-thylformamidine sulphon-ic acid and 75 ml of a 24% aqueous solution of methylamine were dissolved in 250 ml of water. The mixture was refluxed for 3 hours. The surplus of methylamine was sucked off in vacuum, after which concentrated hydrochloric acid was added to give a pH between 1 and 2. Then, a saturated aqueous so-lution of sodium iodide was added, resulting in a white pre-cipitate of the -ti-tle compound. The precipitate was removed by filtration and recrystallized from watèr as shining white needles. The yield was 18.0 g (0.0786 mole, 78.6%) with melting point above 320C.
Example 5 N,N'-dimethyl-N"-(3,4-meth~lenediox~benz~ nidinium iodide 4.56 g (0.030 mole) of N,N'-dimethylformamidine sulphon-ic acid and 18.1 g (0.12 mole) of 3,4-methylenedioxybenzyl-amine were dissolved in 60 ml of water, and the solution was refluxed for 4 1/2 hours. The reaction mixture was then concentrated to a volume of 40 ml, af-ter which concen-trated hydrochloric acid was added to give a pH between 1 and 3, and then 25 ml of a saturated aqueous solution of sodium iodide were added. A white crystalline precipitate of the title compound was formed, filtered off and washed wi-th water. The yield was 8.4 g (0.0241 mole) corresponding to 80.3% of the -theoretical yield, and -the melting point was 211.0-212.0C.
10836~3 Example 6 N-(2-Chlorobenzyl)_N',N"-dime-thyl~uanidinium iodide 4.56 g (0.030 mole) of N,N'-dlrnethylformamidine sulphon-ic acid and 17.0 g (0.12 mole) of 2--chlorobenzylamine were dissolved in 60 ml of water, and the solution was refluxed for 5 1/2 hours. The solution was acidified with concen-trated hydrochloric acid to pH 1-3 and then 25 ml oi~ a sa-turated aqueous solution of sodium iodide were added, where-by a yellow oily substance separated. The reaction mixture was stirred overnight, whereby the separated oil became semi-crystalline. The paren-t lye was decan-ted off, and -the resi-due was washed repea-tedly with ether, whereby all became crystalline. The substance was recrystallized from water, the solution being purified with active carbon 9 the title compound again separating as an oil which, however, rapidly became crystalline by scraping. The yield of the cream-coloured compound was 6.7 g (0.0197 mole, 65.7%) with melt-ing point 157.5-158.5C.
Example 7 N,N'-dimethyl-N"-(4-methoxybenz~ -guanidinium iodide The procedure of Example 5 was repeated using 16.44 g (0.12 mole) of 4-methoxybenzylamine instead of 2-chloro-benzylamine. The title compound, also first separating as an oil, was finally recovered as a white substance in a yield of 5.8 g (0.0173 mole, 57.7%) with melting point 162.0 162.5 C D
336~3 Example 8 N-C~clohexyl-N',N"-dimethyl~uanidin:ium iodide 4.56 g (0,030 mole) of N,N'-dime-thylformamidine sulphon-ic acid and 12.0 g (0.12 mole) of cyclohexylamine were dis-solved in 60 ml of water. The mixture was stirred overnight and then concentrated by evaporation to a volume of about 30 ml. The reaction mixture was then acidified with hydro-chloric acid to pH 2, after which 10 ml of a saturated aqueous solution of sodium iodide were added. An oily sub-stance separated, which rapidly crystallized when scraping.
The solid subs-tance was filtered off and recrys-tallized from water. The white solid, consis-ting of the ti-tle compound, was recovered in a yield of 3.70 g (0.0125 mole, 41.7%) with melting point 195.5-196.0C.
In the present specification the terms "alkyl group", including "cycloalkyl group", and "phenyl-alkyl group" are understood to mean the corresponding substituted or unsub-stituted groups.
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a substituted guanidine having the general formula:
(I) wherein each of R1, R2, R3 is hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 1 to 6 carbon atoms, or a phenylalkyl group having from 1 to 3 atoms in the alkyl part, at least one of R1, R2 and R3 being different from hydrogen or a pharmaceutically acceptable salt of a said substituted guanidine, which comprises oxidizing a thiourea or iso-thiourea, N,N'-substituted with two of the substituents R1, R2 and R3 or a salt thereof to form the corresponding formamidine-sulphonic acid and reacting the formamidine-sulphonic acid with the amine of the third of the substituents R1, R2 and R3 to yield a compound of formula I or the salt thereof.
(I) wherein each of R1, R2, R3 is hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 1 to 6 carbon atoms, or a phenylalkyl group having from 1 to 3 atoms in the alkyl part, at least one of R1, R2 and R3 being different from hydrogen or a pharmaceutically acceptable salt of a said substituted guanidine, which comprises oxidizing a thiourea or iso-thiourea, N,N'-substituted with two of the substituents R1, R2 and R3 or a salt thereof to form the corresponding formamidine-sulphonic acid and reacting the formamidine-sulphonic acid with the amine of the third of the substituents R1, R2 and R3 to yield a compound of formula I or the salt thereof.
2. A process according to claim 1 in which the compound of formula I is reacted with a sodium salt under acidic conditions to form the required salt of the substituted guanidine of general formula I.
3. A process according to claim 1 in which hydrogen peroxide is employed to oxidize the said thiourea or isothiourea.
4. A process as claimed in claim 1, 2 or 3 in which in the reactants R1 and R2 are methyl.
5. A process as claimed in claim 1, 2 or 3 in which in the reactants, R1 and R2 are methyl and R3 is benzyl, methyl, methylenedioxybenzyl, chlorobenzyl, methoxy benzyl, or cyclohexyl.
6. A process as claimed in claim 2 in which the salt is the iodide or chloride.
7. A process according to claim 3, in which N,N'-dimethylthiourea is oxidized with hydrogen peroxide, and the resulting N,N'-dimethylformamidine-sulphonic acid is reacted with benzylamine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB25533/77 | 1977-06-17 | ||
| GB2553377A GB1587258A (en) | 1977-06-17 | 1977-06-17 | Production of substituted guanidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1083603A true CA1083603A (en) | 1980-08-12 |
Family
ID=10229222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA305,594A Expired CA1083603A (en) | 1977-06-17 | 1978-06-16 | Production of substituted guanidines. |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5448714A (en) |
| AU (1) | AU520839B2 (en) |
| CA (1) | CA1083603A (en) |
| DE (1) | DE2826452C2 (en) |
| DK (1) | DK158977C (en) |
| GB (1) | GB1587258A (en) |
| NL (1) | NL187856C (en) |
| NZ (1) | NZ187557A (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6043414U (en) * | 1983-08-29 | 1985-03-27 | 本田技研工業株式会社 | Heater devices for motorcycles, etc. |
| US4656291A (en) * | 1985-03-15 | 1987-04-07 | Mcneilab, Inc. | Process for producing amidine sulfonic acids |
| US4851094A (en) * | 1985-03-15 | 1989-07-25 | Mcneilab, Inc. | Process for producing amidine sulfonic acid intermediates for guanidines |
| US4656270A (en) * | 1985-03-15 | 1987-04-07 | Mcneilab, Inc. | Process for producing guanidines such as linogliride |
| US4693850A (en) * | 1985-03-15 | 1987-09-15 | Mcneilab, Inc. | Methane sulfonic acid derivatives |
| US4781866A (en) * | 1985-03-15 | 1988-11-01 | Mcneilab, Inc. | Process for producing amidine sulfonic acid intermediates for guanidines |
| US5948939A (en) * | 1986-09-10 | 1999-09-07 | Syntex (U.S.A.) Inc. | Selective amidination of diamines |
| EP0260118B1 (en) * | 1986-09-10 | 1991-12-04 | Syntex (U.S.A.) Inc. | Selective amidination of diamines |
| WO1989000563A1 (en) * | 1987-07-17 | 1989-01-26 | The Nutrasweet Company | High potency sweetening agents |
| AU3578489A (en) * | 1988-07-12 | 1990-02-05 | Nutrasweet Company, The | High potency sweetening agents |
| GB9309321D0 (en) * | 1993-05-06 | 1993-06-16 | Wellcome Found | Process for the preparation of ng-monoalkyl-l-arginine derivatives |
| CN102363601A (en) * | 2011-09-20 | 2012-02-29 | 科迈化工股份有限公司 | Method for producing rubber accelerator DGP by using hydrogen peroxide as oxidant |
| CN102363602A (en) * | 2011-09-20 | 2012-02-29 | 科迈化工股份有限公司 | Method for producing vulcanization accelerator DPG with hydrogen peroxide as oxidant |
| CN110407720B (en) * | 2019-08-20 | 2021-07-27 | 西安近代化学研究所 | Synthetic method for preparing substituted guanidine by desulfurizing thiourea under catalysis of iodine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB973882A (en) * | 1959-12-23 | 1964-10-28 | Wellcome Found | Benzyl-guanidines,their preparation and pharmaceutical compositions containing them |
-
1977
- 1977-06-17 GB GB2553377A patent/GB1587258A/en not_active Expired
-
1978
- 1978-06-13 NZ NZ18755778A patent/NZ187557A/en unknown
- 1978-06-14 DK DK265978A patent/DK158977C/en active
- 1978-06-15 JP JP7157778A patent/JPS5448714A/en active Granted
- 1978-06-15 AU AU37154/78A patent/AU520839B2/en not_active Expired
- 1978-06-16 CA CA305,594A patent/CA1083603A/en not_active Expired
- 1978-06-16 NL NL7806526A patent/NL187856C/en not_active IP Right Cessation
- 1978-06-16 DE DE19782826452 patent/DE2826452C2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NL7806526A (en) | 1978-12-19 |
| AU520839B2 (en) | 1982-03-04 |
| DE2826452A1 (en) | 1979-01-11 |
| NZ187557A (en) | 1980-08-26 |
| JPS5748106B2 (en) | 1982-10-14 |
| DK158977B (en) | 1990-08-13 |
| GB1587258A (en) | 1981-04-01 |
| NL187856C (en) | 1992-02-03 |
| DK158977C (en) | 1991-01-21 |
| DE2826452C2 (en) | 1987-01-22 |
| DK265978A (en) | 1978-12-18 |
| NL187856B (en) | 1991-09-02 |
| JPS5448714A (en) | 1979-04-17 |
| AU3715478A (en) | 1979-12-20 |
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