WO1995017387A1 - A novel process for preparing n''-cyano-n'-(4-pyridyl)-n-(1,2,2-trimethylpropyl)-guanidine - Google Patents

A novel process for preparing n''-cyano-n'-(4-pyridyl)-n-(1,2,2-trimethylpropyl)-guanidine Download PDF

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Publication number
WO1995017387A1
WO1995017387A1 PCT/HU1994/000061 HU9400061W WO9517387A1 WO 1995017387 A1 WO1995017387 A1 WO 1995017387A1 HU 9400061 W HU9400061 W HU 9400061W WO 9517387 A1 WO9517387 A1 WO 9517387A1
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Prior art keywords
formula
cyano
pyridyl
trimethylpropyl
guanidine
Prior art date
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PCT/HU1994/000061
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French (fr)
Inventor
József Reiter
László Pongó
Original Assignee
EGIS Gyógyszergyár Rt.
Priority date (The priority date 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 date listed.)
Filing date
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Priority claimed from HU9303711A external-priority patent/HU213116B/en
Application filed by EGIS Gyógyszergyár Rt. filed Critical EGIS Gyógyszergyár Rt.
Priority to PCT/HU1994/000061 priority Critical patent/WO1995017387A1/en
Priority to AU13261/95A priority patent/AU1326195A/en
Publication of WO1995017387A1 publication Critical patent/WO1995017387A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the invention refers to a novel process for preparing W'-cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-guanidine of the formula
  • the compound of the formula I is known under the international non-proprietory name pinacidil and has very favourable hypotensive activity.
  • R' represents a 4-pyridyl or a 1,2,2-trimethylpropyl group, is reacted with an amine of the formula
  • R" stands for a 1,2,2-trimethylpropyl or a 4-pyridyl group, but R" and R' cannot have the same meaning.
  • R' is as defined above, X stands for a halo, an alkylthio or an alkoxy group, is reacted with an amine of the formula
  • R" is as stated above.
  • the latter process is also rather hazardous to the environment, since, if the starting compound is an isourea derivative of the formula VIII, wherein X is a halo such as chloro, this rather unstable compound is prepared by means of corrosive halogenides e.g. thionyl chloride, phosphorous oxychloride etc. that are harmful to the health. If an isourea derivative of the formula VIII, wherein X represents an alkylthio group, is reacted with the amine of the formula VII, mercaptane - a toxic gas - is released as a byproduct.
  • cyanamide salt such as lea (II)-cyanamide.
  • the reaction proceeds only with a heavy metal salt of 5 cyanamide. Heavy metal salts represent a serious hazard to the environment and they can be removed from the product of the synthesis with difficulties to obtain a pharmaceutical product that corresponds to the quality
  • pinacidil cannot be prepared by the known processes in an economical way that would be acceptable for the environment.
  • the aim of the invention is to provide a simple and economical process for the preparation of pinacidil which process is not detrimental to the environment.
  • reaction is performed at a temperature of 0 to 120 °C in the presence of an organic solvent.
  • the organic solvent can be a polar or apolar, protic or aprotic organic solvent.
  • alkanols such as isopropanol, ethers such as tetrahidrofuran or 2-methoxyethanol, or halogenized hydrocarbons such as dichloroethane proved to be advantageous.
  • An excess of the amine of the formula III 5 can be used as an organic solvent, too.
  • reaction partners are taken in an equimolar amount or the amine of the formula III is employed in an excess, suitably up to three times the equimolar quantity.
  • the product of the formula I can be separated in a very simple way, generally as the monohydrate, since, if the organic solvent is evaporated and the residue is diluted with water, pinacidil monohydrate crystallizes. Then, the crystals are separated by filtration.
  • the phenol remaining in the aqueous mother liquor can be extracted with an organic solvent and used, optionally after purification, for an organic synthesis e.g. for the preparation of the compound of the formula
  • the starting N-cyano-N 1 -(4-pyridyl)-O-phenyl-isourea c of the formula II is a novel compound that can be prepared by reacting diphenyl N-cyano-carbonimidate of the formula XI with 4-aminopyridine. The reaction can be performed in either the presence, or the absence of an organic
  • the organic solvent can be a polar or apolar, protic or aprotic solvent. It is preferred to use chlorinated hydrocarbons such as dichloromethane or chloroform, or ethers such as tetrahydrof ran, diethyl ether, diethylene glycol dimethyl ether or 2-methoxyethanol as the reaction medium. In this case the reaction is usually performed at room temperature to the boiling point of the solvent. If the compound of the formula XI is reacted with chlorinated hydrocarbons such as dichloromethane or chloroform, or ethers such as tetrahydrof ran, diethyl ether, diethylene glycol dimethyl ether or 2-methoxyethanol as the reaction medium. In this case the reaction is usually performed at room temperature to the boiling point of the solvent. If the compound of the formula XI is reacted with chlorinated hydrocarbons such as dichloromethane or chloroform, or ethers such as tetrahydrof ran, diethyl ether, diethylene glycol di
  • the diphenyl N-cyano-carbonimidate of the formula XI and the 4-aminopyridine are suitably reacted in an equimolar amount, or one of them is used in a slight excess.
  • the process of the invention can be performed in an extremely simple way, the yield is nearly theoretical.
  • the starting compounds are easily prepared or commercially available.
  • the process of the invention is very economical and harmless to the environment.
  • Example 1 The process of Example 1 is repeated with the exception that, instead of 0,1 moles, 20.2 g (0.2 moles) of 2-amino- -3, 3-dimethylbutane are used. Thus, 25.3 g (96 %) of the o title compound are obtained, m.p.: 163-165 C.
  • Example 1 The process of Example 1 is repeated with the exception 5 that, instead of 0.1 moles, 30.3 g (0.3 moles) of 2-amino- -3 ,3-dimethylbutane are employed and the reaction mixture is not boiled but kept at room temperature for 3 hours under stirring. Thus, 22.6 g (86 %) of the title compound
  • Example 5 The process of Example 2 is repeated with the exception that, instead of 2-propanol, 100 ml of tetrahydrofuran are used. Thus, 23.4 g (89 %) of the title compound are obtained, m.p.: 163-165 C.
  • Example 5
  • Example 2 The process of Example 2 is repeated with the exception that, instead of 2-propanol, 80 ml of dichloroethane are employed. Thus, 21.1 g (80 %) of the title compound are obtained, m.p.: 163-165 °C.
  • Example 7 The process of Example 2 is repeated with the exception that, instead of 2-propanol, 80 ml of diethylene glycol dimethyl ether are used and the reaction mixture is stirred for 1 hour at 100 °C. Thus, 22.1 g (84 %) of the title compound are obtained, m.p.: 163-165 C.
  • Example 7
  • N-Cyano-N' -(4-pyridyl)-O-phenyl-isourea A mixture of 16.7 g (0.07 moles) of diphenyl cyano- -carbonimidate, 6.6 g (0.07 moles) of 4-aminopyridine and 35 ml of tetrahydrof ran is stirred at 50 °C for 1 hour. At first, the reactants dissolve, then the product crystallizes. The reaction mixture is cooled to 10 C, the crystals are filtered, washed twice with 10 ml of cold tetrahydrofuran each time, then dried at 50 °C. 13 g

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention discloses a novel process for preparing pinacidil i.e. N''-cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-guanidine of formula (I), having hypotensive activity. According to the novel process, N-cyano-N'-(4-pyridyl)-O-phenyl-isourea of formula (II) is reacted with 2-amino-3,3-dimethylbutane of formula (III) at a temperature of 0 to 120 °C in the presence of an organic solvent.

Description

A novel process for preparing N"-cyano-N'-(4-pyridyl)- -N-(1,2,2-trimethylpropyl)-guanidine
The invention refers to a novel process for preparing W'-cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-guanidine of the formula
Figure imgf000003_0001
through reacting an N-cyano-N'-(4-pyridyl)-isourea derivative with 2-amino-3,3-dimethylbutane of the formula
Figure imgf000003_0002
The compound of the formula I is known under the international non-proprietory name pinacidil and has very favourable hypotensive activity.
From DE-OS 25 57 438, several processes are known for the preparation of pinacidil. According to one known process, the carbodiimide derivative of the formula
Figure imgf000003_0003
is reacted with the cyanamide of the formula
H2N-CN
if desired, in the presence of a tertiary amine catalyst. The drawback of the known process is that the starting compound of the formula IV is not available easily since a strong poison - phosgene - is needed for the preparation thereof. On the other hand, it is well known that a general method for the preparation of carbodiimides requires the use of mercury oxide and carbon disulfide, both being hazardous to the environment.
In accordance with a further known process, a cyano- carbodiimide derivative of the formula
VI
RN=C=N-CN
wherein R' represents a 4-pyridyl or a 1,2,2-trimethylpropyl group, is reacted with an amine of the formula
R •NH, VII
wherein R" stands for a 1,2,2-trimethylpropyl or a 4-pyridyl group, but R" and R' cannot have the same meaning. Again, the preparation of the starting cyanocarbodiimide derivative of the formula VI is a problem.
According to a further known process, an isourea derivative of the formula
R— NH— C — X
II NCN
VIII
wherein R' is as defined above, X stands for a halo, an alkylthio or an alkoxy group, is reacted with an amine of the formula
VII
R ■NH.
wherein R" is as stated above. The latter process is also rather hazardous to the environment, since, if the starting compound is an isourea derivative of the formula VIII, wherein X is a halo such as chloro, this rather unstable compound is prepared by means of corrosive halogenides e.g. thionyl chloride, phosphorous oxychloride etc. that are harmful to the health. If an isourea derivative of the formula VIII, wherein X represents an alkylthio group, is reacted with the amine of the formula VII, mercaptane - a toxic gas - is released as a byproduct. Finally, if an isourea derivative of the formula VIII, wherein X stands for an alkoxy group, is employed, due to the low reactivity of the alkoxy group (J. Heterocycl. Chem., 2JL, 61 /1984/) the reaction with the amine of the formula VII leads to a poor yield and a great number of byproducts are obtained. Moreover, even the starting compound can be prepared through a complicated reaction route, very uneconomically (J. Heterocycl. Chem., L , 61 /1984/).
According to a still further known process, a compound 5 of the formula
Figure imgf000006_0001
0 wherein X is as stated above, is reacted with the cyanamide of the formula V. However, in the preparation of the compound of the formula IX, similar difficulties are met as in the preparation of the carbodiimide of the formula 5 ιv.
In accordance with a further known process, the thiourea of the formula
Figure imgf000006_0002
is reacted with a cyanamide salt such as lea (II)-cyanamide. The reaction proceeds only with a heavy metal salt of 5 cyanamide. Heavy metal salts represent a serious hazard to the environment and they can be removed from the product of the synthesis with difficulties to obtain a pharmaceutical product that corresponds to the quality
0 requirements.
To sum it up, pinacidil cannot be prepared by the known processes in an economical way that would be acceptable for the environment.
The aim of the invention is to provide a simple and economical process for the preparation of pinacidil which process is not detrimental to the environment.
It was found that the above aim is fulfilled through reacting an N-cyano-N'-(4-pyridyl)-isourea derivative with 2-amino-3,3-dimethylbutane of the formula III, in which the N-cyano-N'-(4-pyridyl)-isourea derivative is N-cyano- N '-(4-pyridyl)-0-phenyl-isourea of the formula
Figure imgf000007_0001
and the reaction is performed at a temperature of 0 to 120 °C in the presence of an organic solvent.
Owing to the high reactivity of the phenoxy group in the starting compound of the formula II, the reaction with the amine of the formula III proceeds easily resulting in the formation of pinacidil with a nearly theoretical yield.
In the process of the invention the organic solvent can be a polar or apolar, protic or aprotic organic solvent. During the experiments, alkanols such as isopropanol, ethers such as tetrahidrofuran or 2-methoxyethanol, or halogenized hydrocarbons such as dichloroethane proved to be advantageous. An excess of the amine of the formula III 5 can be used as an organic solvent, too.
In general, the reaction partners are taken in an equimolar amount or the amine of the formula III is employed in an excess, suitably up to three times the equimolar quantity. The product of the formula I can be separated in a very simple way, generally as the monohydrate, since, if the organic solvent is evaporated and the residue is diluted with water, pinacidil monohydrate crystallizes. Then, the crystals are separated by filtration. The phenol remaining in the aqueous mother liquor can be extracted with an organic solvent and used, optionally after purification, for an organic synthesis e.g. for the preparation of the compound of the formula
Figure imgf000008_0001
The starting N-cyano-N1 -(4-pyridyl)-O-phenyl-isourea c of the formula II is a novel compound that can be prepared by reacting diphenyl N-cyano-carbonimidate of the formula XI with 4-aminopyridine. The reaction can be performed in either the presence, or the absence of an organic
0 solvent. The organic solvent can be a polar or apolar, protic or aprotic solvent. It is preferred to use chlorinated hydrocarbons such as dichloromethane or chloroform, or ethers such as tetrahydrof ran, diethyl ether, diethylene glycol dimethyl ether or 2-methoxyethanol as the reaction medium. In this case the reaction is usually performed at room temperature to the boiling point of the solvent. If the compound of the formula XI is reacted with
4-aminopyridine in the absence of an organic solvent, the compounds are melted together, in general, at about 100 °C.
The diphenyl N-cyano-carbonimidate of the formula XI and the 4-aminopyridine are suitably reacted in an equimolar amount, or one of them is used in a slight excess.
The compound of the formula XI, the 4-aminopyridine and the amine of the formula III are commercially available.
The process of the invention can be performed in an extremely simple way, the yield is nearly theoretical.
The starting compounds are easily prepared or commercially available. Thus, the process of the invention is very economical and harmless to the environment.
The invention is further elucidated by means of the following Examples.
Example 1
N"-Cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-
-guanidine monohydrate 23.8 g (0.1 moles) of N'-cyano-N-(4-pyridyl)-0-phenyl- isourea are dissolved in 100 ml of 2-propanol, and, to the solution obtained, 10.1 g (0.1 moles) of 2-amino-3,3- 5 -dimethylbutane are added. The reaction mixture is boiled for 1.5 hours under stirring, then cooled to room temperature and the solvent is evaporated under reduced pressure. To the remaining oily product 250 ml of distilled water are added, then stirred for 2 hours. The crystalline 0 product that precipitates is filtered and recrystallized from a mixture of one volume of acetone and one volume of water. Thus, 18.7 g (71 %) of the title compound are obtained, m.p.: 163-165 C.
Example 2 5 N"-Cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-
-guanidine monohydrate
The process of Example 1 is repeated with the exception that, instead of 0,1 moles, 20.2 g (0.2 moles) of 2-amino- -3, 3-dimethylbutane are used. Thus, 25.3 g (96 %) of the o title compound are obtained, m.p.: 163-165 C.
Example 3
N"-Cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-
-guanidine monohydrate
The process of Example 1 is repeated with the exception 5 that, instead of 0.1 moles, 30.3 g (0.3 moles) of 2-amino- -3 ,3-dimethylbutane are employed and the reaction mixture is not boiled but kept at room temperature for 3 hours under stirring. Thus, 22.6 g (86 %) of the title compound
0 are obtained, m.p.: 163-165 °C.
Example 4
N"-Cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)- -guanidine monohydrate
The process of Example 2 is repeated with the exception that, instead of 2-propanol, 100 ml of tetrahydrofuran are used. Thus, 23.4 g (89 %) of the title compound are obtained, m.p.: 163-165 C. Example 5
N"-Cyano- '-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-
-guanidine monohydrate
The process of Example 2 is repeated with the exception that, instead of 2-propanol, 80 ml of dichloroethane are employed. Thus, 21.1 g (80 %) of the title compound are obtained, m.p.: 163-165 °C.
Example 6
N"-Cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-
-guanidine monohydrate The process of Example 2 is repeated with the exception that, instead of 2-propanol, 80 ml of diethylene glycol dimethyl ether are used and the reaction mixture is stirred for 1 hour at 100 °C. Thus, 22.1 g (84 %) of the title compound are obtained, m.p.: 163-165 C. Example 7
N"-Cyano-N'-(4-pyridyl)-N-(1,2,2-trimethylpropyl)-
-guanidine monohydrate
A mixture of 2.38 g (0.01 moles) of N'-cyano-N-(4- -pyridyl)-0-phenyl-isourea and 3.03 g (0.03 moles) of 2- -amino-3,3-dimethylbutane are stirred for 2 hours in an oil bath of 100 C. To the melt obtained, 25 ml of water are added, then stirred for 2 hours. The crystalline product precipitated is filtered and recrystallized from a mixture of one volume of acetone and one volume of water. Thus, 1.70 g (64 %) of the title compound are obtained, m.p.: 163-165 °C. Preparation of the starting compound:
N-Cyano-N' -(4-pyridyl)-O-phenyl-isourea A mixture of 16.7 g (0.07 moles) of diphenyl cyano- -carbonimidate, 6.6 g (0.07 moles) of 4-aminopyridine and 35 ml of tetrahydrof ran is stirred at 50 °C for 1 hour. At first, the reactants dissolve, then the product crystallizes. The reaction mixture is cooled to 10 C, the crystals are filtered, washed twice with 10 ml of cold tetrahydrofuran each time, then dried at 50 °C. 13 g
(78 %) of the title compound are obtained, m.p.: 164-166 o,-

Claims

Claims :
1. A process for preparing N"-cyano-N' -(4-pyridyl ) 5 -N-(l,2,2-trimethylpropyl)-guanidine of the formula
Figure imgf000013_0001
10 through reacting an N-cyano-N'-(4-pyridyl)-isourea derivative with 2-amino-3,3-dimethylbutane of the formula
Figure imgf000013_0002
in which the N-cyano-N1-(4-pyridyl)-isourea derivative is N-cyano-N'-(4-pyridyl)-O-phenyl-isourea of the formula
20
Figure imgf000013_0003
_-. and the reaction is performed at a temperature of 0 to 120 C in the presence of an organic solvent.
2. A process of Claim 1 in which the organic solvent is an excess of 2-amino-3,3-dimethylbutane of the formula
30 III.
3. N-Cyano-N'-(4-pyridyl)-0-phenyl-isourea of the formula II.
PCT/HU1994/000061 1993-11-22 1994-12-20 A novel process for preparing n''-cyano-n'-(4-pyridyl)-n-(1,2,2-trimethylpropyl)-guanidine WO1995017387A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/HU1994/000061 WO1995017387A1 (en) 1993-11-22 1994-12-20 A novel process for preparing n''-cyano-n'-(4-pyridyl)-n-(1,2,2-trimethylpropyl)-guanidine
AU13261/95A AU1326195A (en) 1993-11-22 1994-12-20 A novel process for preparing n''-cyano-n'-(4-pyridyl)-n-(1,2,2-trimethylpropyl)-guanidine

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HU9303711A HU213116B (en) 1993-11-22 1993-11-22 A new process for producing n``-cyano-n`-(4-pyridyl)-n-(1,2,2-trimethyl-propyl)-guanidine
HUP9303711 1993-12-22
PCT/HU1994/000061 WO1995017387A1 (en) 1993-11-22 1994-12-20 A novel process for preparing n''-cyano-n'-(4-pyridyl)-n-(1,2,2-trimethylpropyl)-guanidine

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0354553A2 (en) * 1988-08-09 1990-02-14 E.R. SQUIBB & SONS, INC. Aryl cyanoguanidines: potassium channel activators and method of making same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0354553A2 (en) * 1988-08-09 1990-02-14 E.R. SQUIBB & SONS, INC. Aryl cyanoguanidines: potassium channel activators and method of making same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 102, No. 11, issued 1985, March 18 (Columbus, Ohio, USA), HANSEN E.T. et al., "Synthesis of N-alkyl-N'-cyano-N'-4-pyridylguanidines from 4-pyridyldithiocarbamic Acid Via N-alkyl-N'-4-pyridylthioureas or Via 4-pyridylcyaniminothio-carbamic Acid", page 561, Abstract No. 95505e; & SYNTH. COMMUN., *
CHEMICAL ABSTRACTS, Vol. 89, No. 13, issued 1978, September 1978 (Columbus, Ohio, USA), PETERSEN H.J. et al., "Synthesis and Hypotensive Activity of N-alkyl-N'-cyano-N'-pyridylguanidines", page 35, Abstract No. 99710d; & J. MED. CHEM., 1978, 21(8), 778-81 (Eng). *

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