CA1290754C - Method of manufacturing benzoguanamine derivatives - Google Patents
Method of manufacturing benzoguanamine derivativesInfo
- Publication number
- CA1290754C CA1290754C CA000538701A CA538701A CA1290754C CA 1290754 C CA1290754 C CA 1290754C CA 000538701 A CA000538701 A CA 000538701A CA 538701 A CA538701 A CA 538701A CA 1290754 C CA1290754 C CA 1290754C
- Authority
- CA
- Canada
- Prior art keywords
- iii
- alcohol
- dicyandiamide
- manufacturing
- tertiary
- 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 - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
Abstract
ABSTRACT
A method of manufacturing a benzoguanamine derivative of the formula (III):
A method of manufacturing a benzoguanamine derivative of the formula (III):
Description
~9~
The present invention relates to a method of preparing a ~enzoguanamine clerivative of formula (III):
Cl m ) Compound (III) and pharmaceutically acceptable salts thereof have an anti-ulcerative activity and are useful as an anti-ulcer drug. The maleate salt of (III) has a marked anti-ulcerative action which is useful as a starting material for preparing other drugs.
The conventional method for manufacturing compounds of the benzoguanamine type comprises reacting a henzonitrile with dicyandiamide in a high-boiling alcohol in the presence of an alkali catalyst (cf. Org. Syn. Coll. Vol. IV, 78). For example, in Japanese Patent 1,017,236, 2,5-d;chlorobenzo-nitrile is reacted with dicyandiamide in methyl cellosolve in th~ presence of potassium hydroxide catalyst to provide compound (III).
The present inventors have found that a very small amount of a hyproduct is present when compound (III) is ~9~
manufactured by the above known method. It has been confirmed that, ln accordance with the above known method, this byproduct comprises 2 to 4% of the final product.
When a compound is to be used as a drug, it is necessaxy that byproducts must be removed, even if they are as small as 2 to 4~. However, several purification steps are required for such removal, and during the purification operation there is a loss in the yield of compound (III).
The byproduct was isolated and was found to be compound tIV) below which is the reaction product of the 2,5-dichloro- benzonitrile starting material with the methyl cellosolve solvent, When cyclohexanol was used as the solvent in place of methyl cellosolve, it was found that compound (V) below was produced as a byproduct.
Cl / NH2 Cl / NH2 (~ ~/~N ~--~N
ocH2-cH2-oCH3 0{~
~IV) ( V ) It is believed that byproducts (IV) and (V) are formed by a reaction between the 2,5-dichlorobenzene and the solvent, whereby the 2-chloro atom is replaced by the residue of an alcohol, followed by reaction of the 2-substituted benzonitrile with dicyandiamide to form the byproduct (IV) or ~90~5~
(V), which decreases the yield of (III). It is therefore desired to pxovide a process of preparing (III) in which:
(l) no proclucts other than the desired ~III) are produced by the reaction of 2~5-dichlorohenzonitrile with dicyandiamide; and (2) a higher yield of the product (III) is obta~ned as compared with the known methods.
The present invention now provides a process for preparing compound (III) in which a tertiary alcohol is used as a solvent in the reaction between 2,5-dichlorobenzonitril~
and dicyandiamide.
Suitable tertiary alcohols useful in the present invention are tertiary alkanols, preferably having from about 4 to about 10 carbon atoms in the alkyl moiety, such as tert-butyl alcohol and tert-amyl alcohol.
There is no general restriction as to the amount o~
the tertiary alcohol to be used, but it is preferred to use about 10 times (v/w) or even more of the tertiary alcohol than the starting 2,5-dlchlorobenzonitrile.
The alkali catalyst may be an alkali metal hydroxi~e or other alkali as used in the known methods of preparing (III), and the amount o~ the catalyst may be the same as o~
similar to that used in the known methods. Preferably, the amount of the alkali catalyst is from about 4 to about 20 molar % of the 2,5-dichlorobenzonitrile.
The present invention may be carried out under an~
suitable conditions without any particular limitations.
Preferably, the reaction temperature ls about 80C and the reaction time is from about 8 to about 12 hours.
The reaction mechanism of the present invention not entirely understood, but it is helie~ed the steric hindrance of the tertiary alcohol prevents or minimizes it~
reaction with the 2-chloro atom of the starting 2,5-di~hlorc-benzonitrile. Thus, while the conventional method using methyl cellosolve results in the formation of 2 to 4% of hyproduct, no byproducts are produced at all in the present invention.
The method of the present invention is thus useful in providing a pure pharmaceutical product.
The present invention is illustrated in the following examples:
Example 1.
2,5-Dichlorobenzonitrile (5 g; 0.00291 mole) and 35 g (0.1416 mole) of dicyandiamide were placed in a 100 ml fo~r-necked flask e~uipped with a stirrer, thermometer and stopper, 50 ml of tert-butanol was added thereto, and stirring was started keeping the temperature at 80C. Potassium hydroxide (120 mg; 0.0021 mole) was added thereto and the mixture was made to react at 80C for 10 hours.
After the reaction, the mixture was cooled overni~ht and, on the next day, the white crystals that had separated out therefrom were collected by filtration, washed with tert-butanol, warm water and toluene, and dried to give 7.08 g of desired ~III), i.e. 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine. Yield: 95%.
The procluct was analyzed in accordance with the following procedure and found to contain no byproduct at all.
Analytical_Procedure For High Performance Liquid Chromato~ra~nY
Columns: Nucleosil 5 C18 40O x 25 cm Mobile Phase: Acetonitrile-Water-Glacial Acetic Acid (85:300:1.2) 1.0 ml/min Column Temperature: 25C
Wavelength Checked: 230 mm Rxample 2.
The procedure of Example 1 was repeated usin~ tert-amyl alcohol as the solvent. The particulars were as follows:
2,5-Dichlorobenzonitrile 5 g (0.0291 mole) Dicyandiamide 35 g (0O0416 mole) Potassium hydroxide120 mg (0.0021 mole) Solvent: tert-Amyl alcohol (50 ml~
Reaction temperature: 80C
React.ion time: 10 hours Yi.eld: 7 g (94%~
Analytlcal result: After analysis by high performance liquid chromatography, no impurity was found to have been produced.
75~
The procedure of Example 1 was repeated using methyl cellosolve and cyclohexanol as the solvents in Reference Examples 1 and 2 below. The particulars are as follows:
Reference Example 1.
2,5-Dichlorobenzorlitrile 5 g (0.0291 mole) Dicyandiamide 35 g (0.0416 mole~
Potassium hydroxi.de120 mg (0.0021 mole~
Solvent: Methyl cellosolve (50 ml) Reaction temperature: 80C
Reaction time: 10 hours Yield: 6.3 g (85%) Analytical result: Using high performance liquid chromatography, 2.6% of impurity (IV) was found by area percentage.
Reference Example 2.
2,5-Dichlorobenzonitrile 5 g (0.0291 mole) Dicyandiamide 35 g (0.0416 mole) Potassium hydroxide120 ml (0.0021 mole~
Solvent: Cyclohexanol (50 ml) Reaction Temperature: 80C
Reaction Time: 10 hours Yield: 6~18 g (83~) Analyti.cal result: Using high performance liquid ~-chromatography, 3.~% of impurity (V) was found by a~ea percentage. ,-r ~
The present invention relates to a method of preparing a ~enzoguanamine clerivative of formula (III):
Cl m ) Compound (III) and pharmaceutically acceptable salts thereof have an anti-ulcerative activity and are useful as an anti-ulcer drug. The maleate salt of (III) has a marked anti-ulcerative action which is useful as a starting material for preparing other drugs.
The conventional method for manufacturing compounds of the benzoguanamine type comprises reacting a henzonitrile with dicyandiamide in a high-boiling alcohol in the presence of an alkali catalyst (cf. Org. Syn. Coll. Vol. IV, 78). For example, in Japanese Patent 1,017,236, 2,5-d;chlorobenzo-nitrile is reacted with dicyandiamide in methyl cellosolve in th~ presence of potassium hydroxide catalyst to provide compound (III).
The present inventors have found that a very small amount of a hyproduct is present when compound (III) is ~9~
manufactured by the above known method. It has been confirmed that, ln accordance with the above known method, this byproduct comprises 2 to 4% of the final product.
When a compound is to be used as a drug, it is necessaxy that byproducts must be removed, even if they are as small as 2 to 4~. However, several purification steps are required for such removal, and during the purification operation there is a loss in the yield of compound (III).
The byproduct was isolated and was found to be compound tIV) below which is the reaction product of the 2,5-dichloro- benzonitrile starting material with the methyl cellosolve solvent, When cyclohexanol was used as the solvent in place of methyl cellosolve, it was found that compound (V) below was produced as a byproduct.
Cl / NH2 Cl / NH2 (~ ~/~N ~--~N
ocH2-cH2-oCH3 0{~
~IV) ( V ) It is believed that byproducts (IV) and (V) are formed by a reaction between the 2,5-dichlorobenzene and the solvent, whereby the 2-chloro atom is replaced by the residue of an alcohol, followed by reaction of the 2-substituted benzonitrile with dicyandiamide to form the byproduct (IV) or ~90~5~
(V), which decreases the yield of (III). It is therefore desired to pxovide a process of preparing (III) in which:
(l) no proclucts other than the desired ~III) are produced by the reaction of 2~5-dichlorohenzonitrile with dicyandiamide; and (2) a higher yield of the product (III) is obta~ned as compared with the known methods.
The present invention now provides a process for preparing compound (III) in which a tertiary alcohol is used as a solvent in the reaction between 2,5-dichlorobenzonitril~
and dicyandiamide.
Suitable tertiary alcohols useful in the present invention are tertiary alkanols, preferably having from about 4 to about 10 carbon atoms in the alkyl moiety, such as tert-butyl alcohol and tert-amyl alcohol.
There is no general restriction as to the amount o~
the tertiary alcohol to be used, but it is preferred to use about 10 times (v/w) or even more of the tertiary alcohol than the starting 2,5-dlchlorobenzonitrile.
The alkali catalyst may be an alkali metal hydroxi~e or other alkali as used in the known methods of preparing (III), and the amount o~ the catalyst may be the same as o~
similar to that used in the known methods. Preferably, the amount of the alkali catalyst is from about 4 to about 20 molar % of the 2,5-dichlorobenzonitrile.
The present invention may be carried out under an~
suitable conditions without any particular limitations.
Preferably, the reaction temperature ls about 80C and the reaction time is from about 8 to about 12 hours.
The reaction mechanism of the present invention not entirely understood, but it is helie~ed the steric hindrance of the tertiary alcohol prevents or minimizes it~
reaction with the 2-chloro atom of the starting 2,5-di~hlorc-benzonitrile. Thus, while the conventional method using methyl cellosolve results in the formation of 2 to 4% of hyproduct, no byproducts are produced at all in the present invention.
The method of the present invention is thus useful in providing a pure pharmaceutical product.
The present invention is illustrated in the following examples:
Example 1.
2,5-Dichlorobenzonitrile (5 g; 0.00291 mole) and 35 g (0.1416 mole) of dicyandiamide were placed in a 100 ml fo~r-necked flask e~uipped with a stirrer, thermometer and stopper, 50 ml of tert-butanol was added thereto, and stirring was started keeping the temperature at 80C. Potassium hydroxide (120 mg; 0.0021 mole) was added thereto and the mixture was made to react at 80C for 10 hours.
After the reaction, the mixture was cooled overni~ht and, on the next day, the white crystals that had separated out therefrom were collected by filtration, washed with tert-butanol, warm water and toluene, and dried to give 7.08 g of desired ~III), i.e. 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine. Yield: 95%.
The procluct was analyzed in accordance with the following procedure and found to contain no byproduct at all.
Analytical_Procedure For High Performance Liquid Chromato~ra~nY
Columns: Nucleosil 5 C18 40O x 25 cm Mobile Phase: Acetonitrile-Water-Glacial Acetic Acid (85:300:1.2) 1.0 ml/min Column Temperature: 25C
Wavelength Checked: 230 mm Rxample 2.
The procedure of Example 1 was repeated usin~ tert-amyl alcohol as the solvent. The particulars were as follows:
2,5-Dichlorobenzonitrile 5 g (0.0291 mole) Dicyandiamide 35 g (0O0416 mole) Potassium hydroxide120 mg (0.0021 mole) Solvent: tert-Amyl alcohol (50 ml~
Reaction temperature: 80C
React.ion time: 10 hours Yi.eld: 7 g (94%~
Analytlcal result: After analysis by high performance liquid chromatography, no impurity was found to have been produced.
75~
The procedure of Example 1 was repeated using methyl cellosolve and cyclohexanol as the solvents in Reference Examples 1 and 2 below. The particulars are as follows:
Reference Example 1.
2,5-Dichlorobenzorlitrile 5 g (0.0291 mole) Dicyandiamide 35 g (0.0416 mole~
Potassium hydroxi.de120 mg (0.0021 mole~
Solvent: Methyl cellosolve (50 ml) Reaction temperature: 80C
Reaction time: 10 hours Yield: 6.3 g (85%) Analytical result: Using high performance liquid chromatography, 2.6% of impurity (IV) was found by area percentage.
Reference Example 2.
2,5-Dichlorobenzonitrile 5 g (0.0291 mole) Dicyandiamide 35 g (0.0416 mole) Potassium hydroxide120 ml (0.0021 mole~
Solvent: Cyclohexanol (50 ml) Reaction Temperature: 80C
Reaction Time: 10 hours Yield: 6~18 g (83~) Analyti.cal result: Using high performance liquid ~-chromatography, 3.~% of impurity (V) was found by a~ea percentage. ,-r ~
Claims (4)
EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:
1. A method of manufacturing a benzoguanamine derivative of the formula (III):
(III) which comprises reacting 2,5-dichlorohenzonitrile with dicyandiamide in a tertiary alcohol in the presence of an alkali catalyst.
(III) which comprises reacting 2,5-dichlorohenzonitrile with dicyandiamide in a tertiary alcohol in the presence of an alkali catalyst.
2. The method according to claim 1, wherein said tertiary alcohol is a tertiary alkanol.
3. The method according to claim 2, wherein said tertiary alkanol has from about 4 to about 10 carbon atoms.
4. The method according to claim 1, wherein said tertiary alcohol is tert-butyl alcohol or tert-amyl alcohol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61/135,196 | 1986-06-10 | ||
| JP61135196A JPH072726B2 (en) | 1986-06-10 | 1986-06-10 | Method for producing benzoguanamine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1290754C true CA1290754C (en) | 1991-10-15 |
Family
ID=15146092
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000538701A Expired - Lifetime CA1290754C (en) | 1986-06-10 | 1987-06-03 | Method of manufacturing benzoguanamine derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPH072726B2 (en) |
| KR (1) | KR950005204B1 (en) |
| AT (1) | AT395713B (en) |
| CA (1) | CA1290754C (en) |
| ES (1) | ES2005249A6 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187928A (en) * | 2016-08-02 | 2016-12-07 | 安徽省逸欣铭医药科技有限公司 | A kind of preparation method of irsogladine maleate |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6150362A (en) * | 1997-12-12 | 2000-11-21 | Henkin; Jack | Triazine angiogenesis inhibitors |
| KR101289575B1 (en) * | 2012-09-07 | 2013-07-24 | 박충만 | The roast chicken manufacture method |
| KR101896105B1 (en) * | 2017-08-28 | 2018-09-07 | 최용선 | Process for preparing Food formulation with rolled type |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1441904A (en) * | 1974-02-18 | 1976-07-07 | Nippon Shinyaku Co Ltd | Benzoguanamine derivatives |
| JPS5925765B2 (en) * | 1981-08-04 | 1984-06-21 | 日本新薬株式会社 | Peptic ulcer treatment agent |
-
1986
- 1986-06-10 JP JP61135196A patent/JPH072726B2/en not_active Expired - Lifetime
-
1987
- 1987-06-03 CA CA000538701A patent/CA1290754C/en not_active Expired - Lifetime
- 1987-06-08 ES ES8701678A patent/ES2005249A6/en not_active Expired
- 1987-06-09 AT AT0144887A patent/AT395713B/en not_active IP Right Cessation
- 1987-06-10 KR KR1019870005855A patent/KR950005204B1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187928A (en) * | 2016-08-02 | 2016-12-07 | 安徽省逸欣铭医药科技有限公司 | A kind of preparation method of irsogladine maleate |
| CN106187928B (en) * | 2016-08-02 | 2019-06-07 | 安徽省逸欣铭医药科技有限公司 | A kind of preparation method of irsogladine maleate |
Also Published As
| Publication number | Publication date |
|---|---|
| KR880000411A (en) | 1988-03-25 |
| ATA144887A (en) | 1992-07-15 |
| KR950005204B1 (en) | 1995-05-19 |
| JPH072726B2 (en) | 1995-01-18 |
| ES2005249A6 (en) | 1989-03-01 |
| JPS62292771A (en) | 1987-12-19 |
| AT395713B (en) | 1993-02-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 20001016 |