CA1085846A - Process for producing 3-substituted 1,2,4-triazines - Google Patents
Process for producing 3-substituted 1,2,4-triazinesInfo
- Publication number
- CA1085846A CA1085846A CA295,345A CA295345A CA1085846A CA 1085846 A CA1085846 A CA 1085846A CA 295345 A CA295345 A CA 295345A CA 1085846 A CA1085846 A CA 1085846A
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- CA
- Canada
- Prior art keywords
- triazine
- benzyl
- substituted
- phenyl
- aminoethylhydrazine
- 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.)
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Abstract
ABSTRACT OF THE DISCLOSURE
A process for producing 3-substituted 1,2,4-triazines comprising reacting a nitrile with a 2-amino-ethylhydrazine in the presence of a catalytic amount of a transition metal salt selected from iron salts and zinc salts, or elemental sulfur.
A process for producing 3-substituted 1,2,4-triazines comprising reacting a nitrile with a 2-amino-ethylhydrazine in the presence of a catalytic amount of a transition metal salt selected from iron salts and zinc salts, or elemental sulfur.
Description
Various substituted 1,4,5,6-tetrahydro-1,2,4-triazines are des-cribed as having antidepressant properties in United States Patent 3,471,486.
In general the compounds are prepared by reacting an imino ester hydrohalide dissolved in glacial acetic acid, methanol or ethanol with a 2-aminoalkyl-hydrazine. This method of preparing the compounds is tedious and gives poor yields making the overall procedure uneconomical for commercial production.
The present invention is directed to a new synthetic route which can be used to prepare triazines of the type described above.
In related art substituted 2-amidazolines have been synthesized by the cycliæation of a diamine with a nitrile in the presence of elemental sul~ur. Nippon Kaguku Zasshi 1968, 89 ~8), 780 ~Chem Abs. 70:19983q.) The present invention is directed to a process of preparing a 3-substituted 1,2,4-triazine which comprises reacting a nitrile with a 2-amino- ;
ethylhydrazine or substituted 2-aminoethylhydrazine in the presence of a catalytic amount of a transition metal salt selected from iron salts and zinc -salts, or elemental sulfur. The process is particularly useful in preparing a triazine having the general formula ~ H
R-N ~ N
- CH
A / B
wherein R is hydrogen or methyl and A and B independently represent hydrogen, an alkyl group of from 1 to 5 carbon atoms, phenyl9 substituted phenyl, benzyl, or substituted benzyl. Substituents on the phenyl and benzyl rings described above may include almost any group which will not react with hydra-zine under the conditions of the reaction process. Such substituents include halogen atoms, and lower alkyl, lower alkoxy, nitro, naphthyl and pyridyl groups. As used herein lower alkyl and alkoxy refers to a group having from , 1 to 3 carbon atoms.
The reaction of the nitrile with 2-aminoethylhydrazine can be carried out in a suitable solvent system, usually a high boiling alcohol, but the reaction can also be carried out in the absence of solvent by simply mixing the reactants together with a catalytic amount of a transition metal salt or elemental sulfur. The reaction usually proceeds more rapidly in the absence of solvent, but when the product is made in large batches, it is often desirable to use some solvent to lower the viscosity of the reactants to facilitate mixing. As used herein the term catalytic amount refers to the amount of transition metal salt or elemental sulfur required to convert equi-molar amounts of the hydrazine and the nitrile to the 1,2,4-triazine product. -The transition metal salts3 ferric chloride and zinc acetate were found to give satisfactory results. Elemental sulfur is particularly preferred because of its ready availability, and it evolves out of the reaction mass leaving only trace amounts in the final product.
The general reaction described above may be represented as follows R A
In general the compounds are prepared by reacting an imino ester hydrohalide dissolved in glacial acetic acid, methanol or ethanol with a 2-aminoalkyl-hydrazine. This method of preparing the compounds is tedious and gives poor yields making the overall procedure uneconomical for commercial production.
The present invention is directed to a new synthetic route which can be used to prepare triazines of the type described above.
In related art substituted 2-amidazolines have been synthesized by the cycliæation of a diamine with a nitrile in the presence of elemental sul~ur. Nippon Kaguku Zasshi 1968, 89 ~8), 780 ~Chem Abs. 70:19983q.) The present invention is directed to a process of preparing a 3-substituted 1,2,4-triazine which comprises reacting a nitrile with a 2-amino- ;
ethylhydrazine or substituted 2-aminoethylhydrazine in the presence of a catalytic amount of a transition metal salt selected from iron salts and zinc -salts, or elemental sulfur. The process is particularly useful in preparing a triazine having the general formula ~ H
R-N ~ N
- CH
A / B
wherein R is hydrogen or methyl and A and B independently represent hydrogen, an alkyl group of from 1 to 5 carbon atoms, phenyl9 substituted phenyl, benzyl, or substituted benzyl. Substituents on the phenyl and benzyl rings described above may include almost any group which will not react with hydra-zine under the conditions of the reaction process. Such substituents include halogen atoms, and lower alkyl, lower alkoxy, nitro, naphthyl and pyridyl groups. As used herein lower alkyl and alkoxy refers to a group having from , 1 to 3 carbon atoms.
The reaction of the nitrile with 2-aminoethylhydrazine can be carried out in a suitable solvent system, usually a high boiling alcohol, but the reaction can also be carried out in the absence of solvent by simply mixing the reactants together with a catalytic amount of a transition metal salt or elemental sulfur. The reaction usually proceeds more rapidly in the absence of solvent, but when the product is made in large batches, it is often desirable to use some solvent to lower the viscosity of the reactants to facilitate mixing. As used herein the term catalytic amount refers to the amount of transition metal salt or elemental sulfur required to convert equi-molar amounts of the hydrazine and the nitrile to the 1,2,4-triazine product. -The transition metal salts3 ferric chloride and zinc acetate were found to give satisfactory results. Elemental sulfur is particularly preferred because of its ready availability, and it evolves out of the reaction mass leaving only trace amounts in the final product.
The general reaction described above may be represented as follows R A
2 2 2 C - CN
B
/ Sulfur k' or ~ transition R-N ~ I ;`
CH
A / \ B
As noted above sulfur was found to be the preferred catalyst in carrying out the process which is the subject of the present invention. The reaction is generally carried out at a temperature of from 70 to 100C with 2Q from 85 to g5C being preferred. Lower temperatures are operable but the rate of reaction is slowed do~n. Temperatures above about 120C cause the hydrazine/sulfur complex to vaporize out of the reaction mixture and lead to decreased yields and the formation of impurities. `
sJ~
The various nitrile intermediates are prepared by known procedures described in ~he literature. See for instance Synthesis 441-456 (1973);
J. Org. Chem. 36, 2948 (1971), and Tetrahedron Letters No. 14, pp. 1509-1511 (1966). Also the 2-amino-ethyl hydrazines are prepared according to litera-ture methods.
The compound 3~ 2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4~
triazine is an effective antidepressant drug. Production of this compound in experimental developmental studies in both small laboratory and large production size batches using the process of this invention has been carried out and are summarized below.
The compound 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine is most conveniently prepared by a two step synthesis, thesecond step .
being the novel process which is the subject of this invention. In the first step the intermediate 2,3-diphenylpropionitrile is produced by a phase trans-fer catalysis reaction involving benzyl cyanide and benzyl chloride in the presence of aqueous sodium hydroxide. This reaction is preferably effected in the presence of a quaternary ammonium salt as the catalyst. A suitable quaternary ammonium salt is benzyl triethylammonium chloride. Reactions of this general type are well documented in the literature. See Synthesis, 441-456, August 1973 and Polish Patent 47,950 (CA61 : 14593q). In the second step the 2,3~diphenylpropionitrile and 2-aminoethylhydrazine are cyclized in the presence of sulfur to yield the 3-(1,2-diphenylethyl)-134,5,6-tetrahydro-1,2,4-triazine. The triazine readily may be converted to the hydrohalide salt if desired by acidification with a pre-selected hydrohalide. The intermediate ni~rile can be produced by other known methods (see, for example, Tetrahedron Letters No. 14, pp 1509-1511, 1966) and such intermediates are entirely satisfactory for use in the second step of the synthesis described above.
The following examples will serve to further clarify the present invention and will serve to illustrate certain preferred embodiments thereof;
:~ .
4~
however, they are not to be construed as a limitation upon the scope of the invention.
Example 1: Preparation of 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-tria ine monohydrochloride Step one: A reaction vessel consisting of a 2 liter round bottom flask fitted with a mechanical stirrer, thermometer, nitrogen inlet and reflux condenser was charged with 585 g (574 ml; 5.0 moles) of benzyl cyanide, 250 ml of 50% sodium hydroxide and 12.5 g (0.055 mole; 4.4 mole %) of benzyl- - -triethylammonium chloride. While maintaining the temperature at about 50C
in a cool water bath, 224.4 g (1.77 mole) of benzyl chloride was slowly added dropwise over a period of about one hour. The reaction mass was stirred for an additional one hour after which 400 ml of deionized water was added to ~ -dissolve the sodium chloride and caused a separation of the aqueous and or-ganic layers. In this step if an emulsion formed, methylene chloride was added. The organic layer was distilled to separate the 2,3-diphenylpropionit- ;~
rile from the other reactants and impurities. The identity of the compound ;
was confirmed by elemental analysis, NMR, IR, and mass spectrophotometry data.
~tep two: The nitrile intermediate prepared in step one (35.0 g~
0.169 mole) was heated under nitrogen with 0.379 gram (0.012 gram-atom, 7 `
mole %) of sulfur to about 70C in a lO0 ml round bottom flask until the sulfur dissolved ~about 2 hours). The reaction vessel was charged with 25.4 grams (0.338 moles; 2 equiv.) of 2-aminoethylhydrazine. The temperature was increased to about 100C and held for about five hours. The reaction mass was cooled to about 50C after which 75 ml of toluene was added followed by extraction with 75 ml of water. Absolute alcohol (35 ml) was added and the mixture refluxed while hydrogen chloride was bubbled into the flask. The
B
/ Sulfur k' or ~ transition R-N ~ I ;`
CH
A / \ B
As noted above sulfur was found to be the preferred catalyst in carrying out the process which is the subject of the present invention. The reaction is generally carried out at a temperature of from 70 to 100C with 2Q from 85 to g5C being preferred. Lower temperatures are operable but the rate of reaction is slowed do~n. Temperatures above about 120C cause the hydrazine/sulfur complex to vaporize out of the reaction mixture and lead to decreased yields and the formation of impurities. `
sJ~
The various nitrile intermediates are prepared by known procedures described in ~he literature. See for instance Synthesis 441-456 (1973);
J. Org. Chem. 36, 2948 (1971), and Tetrahedron Letters No. 14, pp. 1509-1511 (1966). Also the 2-amino-ethyl hydrazines are prepared according to litera-ture methods.
The compound 3~ 2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4~
triazine is an effective antidepressant drug. Production of this compound in experimental developmental studies in both small laboratory and large production size batches using the process of this invention has been carried out and are summarized below.
The compound 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine is most conveniently prepared by a two step synthesis, thesecond step .
being the novel process which is the subject of this invention. In the first step the intermediate 2,3-diphenylpropionitrile is produced by a phase trans-fer catalysis reaction involving benzyl cyanide and benzyl chloride in the presence of aqueous sodium hydroxide. This reaction is preferably effected in the presence of a quaternary ammonium salt as the catalyst. A suitable quaternary ammonium salt is benzyl triethylammonium chloride. Reactions of this general type are well documented in the literature. See Synthesis, 441-456, August 1973 and Polish Patent 47,950 (CA61 : 14593q). In the second step the 2,3~diphenylpropionitrile and 2-aminoethylhydrazine are cyclized in the presence of sulfur to yield the 3-(1,2-diphenylethyl)-134,5,6-tetrahydro-1,2,4-triazine. The triazine readily may be converted to the hydrohalide salt if desired by acidification with a pre-selected hydrohalide. The intermediate ni~rile can be produced by other known methods (see, for example, Tetrahedron Letters No. 14, pp 1509-1511, 1966) and such intermediates are entirely satisfactory for use in the second step of the synthesis described above.
The following examples will serve to further clarify the present invention and will serve to illustrate certain preferred embodiments thereof;
:~ .
4~
however, they are not to be construed as a limitation upon the scope of the invention.
Example 1: Preparation of 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-tria ine monohydrochloride Step one: A reaction vessel consisting of a 2 liter round bottom flask fitted with a mechanical stirrer, thermometer, nitrogen inlet and reflux condenser was charged with 585 g (574 ml; 5.0 moles) of benzyl cyanide, 250 ml of 50% sodium hydroxide and 12.5 g (0.055 mole; 4.4 mole %) of benzyl- - -triethylammonium chloride. While maintaining the temperature at about 50C
in a cool water bath, 224.4 g (1.77 mole) of benzyl chloride was slowly added dropwise over a period of about one hour. The reaction mass was stirred for an additional one hour after which 400 ml of deionized water was added to ~ -dissolve the sodium chloride and caused a separation of the aqueous and or-ganic layers. In this step if an emulsion formed, methylene chloride was added. The organic layer was distilled to separate the 2,3-diphenylpropionit- ;~
rile from the other reactants and impurities. The identity of the compound ;
was confirmed by elemental analysis, NMR, IR, and mass spectrophotometry data.
~tep two: The nitrile intermediate prepared in step one (35.0 g~
0.169 mole) was heated under nitrogen with 0.379 gram (0.012 gram-atom, 7 `
mole %) of sulfur to about 70C in a lO0 ml round bottom flask until the sulfur dissolved ~about 2 hours). The reaction vessel was charged with 25.4 grams (0.338 moles; 2 equiv.) of 2-aminoethylhydrazine. The temperature was increased to about 100C and held for about five hours. The reaction mass was cooled to about 50C after which 75 ml of toluene was added followed by extraction with 75 ml of water. Absolute alcohol (35 ml) was added and the mixture refluxed while hydrogen chloride was bubbled into the flask. The
3-(1,2-diphenylethyl)-1,4-5~6-tetrahydro-1,2,4-triazine monohydrochloride crystallized out and was filtered off then washed with a 90/10 toluene/
ethanol mixture. The product was dried in vacuo. Elemental analysis, X-ray ~-crystallography, NMR, and mass spectrophotometry were used to confi~rm the structure.
~5~6 Using the general procedure outlined above, a number of related compounds were prepared having the general structure ~ NH
R~ HCl ( )n wherein n is the integer 1 or 2. These compounds are shown in Table 1 below.
. T A B L E 1 ~:
Example No. R R' R'' M.p. C
2 H 4-Cl H 212-3 :~;
3 H 4-F 4-OCH3 145-7 - :
ethanol mixture. The product was dried in vacuo. Elemental analysis, X-ray ~-crystallography, NMR, and mass spectrophotometry were used to confi~rm the structure.
~5~6 Using the general procedure outlined above, a number of related compounds were prepared having the general structure ~ NH
R~ HCl ( )n wherein n is the integer 1 or 2. These compounds are shown in Table 1 below.
. T A B L E 1 ~:
Example No. R R' R'' M.p. C
2 H 4-Cl H 212-3 :~;
3 H 4-F 4-OCH3 145-7 - :
4 H H 4-CH3 217-9 ~ 5 H 3-CH3 H 184-6 7 H 3-Cl H 144-6 8 H H 3-CH3 177-8.5 .:: :
9 H 4-F H 220-2 .;
H 3,4-di CH3 H 211-3 . 11 H 2,6-di Cl H 135-8 . ~:
12 H 3,4-di Cl H 224-5 :`
13 H 3-F H 233-5 ..
Other compounds which are prepared are the following~
Example No. R R' R'' ~:
14 CH3 H H .
H H 2-naphthyl 17 H 4-NO H ; .
18 H H l-naphthyl -19 H 3,4-di OCH3 H
H l-naphthyl H
21 H 2-pyridyl H
22 H 4-pyridyl H ;
2~ H 2-naphthyl H
24 H 2-naphthyl2-naphthyl i84~6 In addi~ion to the compounds listed above, compounds which do not fit the general formula of Table 1 were prepared using the process of the invention. The compounds include: 3~ (1,3-benzodioxol-5-yl)-2-phenylethyl)-1,4,5,6-tetrahydro-192,4-triazine monohydrochloride; 1,4,5,6-tetrahydro-3-~2-naphthalenylmethyl)-1,2,4-triazine monohydrochloride; and 3-(2-(4-chloro-phenyl)-1-((4-methylphenyl)sulfonyl)ethyl)-1,4-5,6-tetrahydro-1,2,4-triazine.
Example 25 Using essentially the same procedures outlined above, two batches containing 25.5 kg and 26.5 kg of 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride were produced. The crude yield was found to be 65.1% and 70.0%, respectively. Following recrystallization from ethanol the yield of purified product was 42.5% and 53.1%, respectively.
It was found that the sulfur catalyst could be added directly to the melted nitrile without the lengthy heating needed to dissolve the sulur -in step two of the reaction. Thus overall batch time was significantly re-duced from that of Example 1 above.
I
,
9 H 4-F H 220-2 .;
H 3,4-di CH3 H 211-3 . 11 H 2,6-di Cl H 135-8 . ~:
12 H 3,4-di Cl H 224-5 :`
13 H 3-F H 233-5 ..
Other compounds which are prepared are the following~
Example No. R R' R'' ~:
14 CH3 H H .
H H 2-naphthyl 17 H 4-NO H ; .
18 H H l-naphthyl -19 H 3,4-di OCH3 H
H l-naphthyl H
21 H 2-pyridyl H
22 H 4-pyridyl H ;
2~ H 2-naphthyl H
24 H 2-naphthyl2-naphthyl i84~6 In addi~ion to the compounds listed above, compounds which do not fit the general formula of Table 1 were prepared using the process of the invention. The compounds include: 3~ (1,3-benzodioxol-5-yl)-2-phenylethyl)-1,4,5,6-tetrahydro-192,4-triazine monohydrochloride; 1,4,5,6-tetrahydro-3-~2-naphthalenylmethyl)-1,2,4-triazine monohydrochloride; and 3-(2-(4-chloro-phenyl)-1-((4-methylphenyl)sulfonyl)ethyl)-1,4-5,6-tetrahydro-1,2,4-triazine.
Example 25 Using essentially the same procedures outlined above, two batches containing 25.5 kg and 26.5 kg of 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride were produced. The crude yield was found to be 65.1% and 70.0%, respectively. Following recrystallization from ethanol the yield of purified product was 42.5% and 53.1%, respectively.
It was found that the sulfur catalyst could be added directly to the melted nitrile without the lengthy heating needed to dissolve the sulur -in step two of the reaction. Thus overall batch time was significantly re-duced from that of Example 1 above.
I
,
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a 3-substituted-tetrahydro 1,2,4-triazine which comprises reacting a nitrile with 2-aminoethylhydrazine or substituted 2-aminoethylhydrazine in the presence of a catalytic amount of a transition metal salt selected from iron salts and zinc salts, or elemental sulfur.
2. The process of Claim 1 wherein the 2-aminoethylhydrazine is represented by the formula and the nitrile is represented by the formula wherein R is hydrogen or methyl and A and B independently represent hydrogen, an alkyl of from 1 to 5 carbon atoms, phenyl, substituted phenyl, benzyl, or substituted benzyl; said substitutions on the phenyl and benzyl rings being selected from the group consisting of halogen atoms and lower alkyl, lower alkoxy, nitro, naphthyl, and pyridyl groups.
3. The process of Claim 2 wherein R is hydrogen, A is benzyl or substituted benzyl, and B is phenyl or substituted phenyl.
4. The process of Claim 3 wherein the nitrile 2,3-diphenylpropioni-trile is reacted with 2-aminoethylhydrazine.
5. A process for preparing 3-(1,2-diphenyl-ethyl)-1,4,5,6-tetrahydro-1,2,4-triazine which comprises reacting benzyl cyanide with benzyl chloride to produce 2,3-diphenylpropionitrile and cyclizing the 2,3-diphenylpropioni-trile with 2-aminoethylhydrazine in the presence of a catalytic amount of elemental sulfur to give 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine.
6. The process of Claim 5 further comprising the step of acidifying the 3-(1,2-diphenylethyl)-1,4,5-tetrahydro-1,2,4-triazine with a hydrohalide to produce a hydrohalide salt thereof.
7. The process of claim 1 to 3 wherein the reaction between the 2-aminomethylhydrazine and the nitrile is carried out at a temperature between 70 and 100°C.
8. A process as in claim 3 in which 3-(2-(4-chlorophenyl)-1-phenethyl)-1,4,5,6-tetra hydro-1,2,4-triazine is prepared by reacting 2-(4-chlorophenyl)-3-phenyl propionitrile with 2-amino ethyl hydrogen and wherein the process further comprises the step of acidifying with a hydrogen halide to obtain the hydro-halide salt thereof.
9. A process as in claim 3 in which 3-(1-(4-methyl-phenyl)-2-phenethyl)-1,4,5,6-tetrahydro-1,2,4-triazine is pre-pared by reacting 2-(4-methylphenyl)-3-phenylpropionitrile with 2-aminoethylhydrazine and wherein the process comprises the step of acidifying with a hydrogenhalide to obtain the hydrohalide salt thereof.
10. A process as in claim 1, 2 or 3, wherein the transition metal salt is ferric chloride or zinc acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA295,345A CA1085846A (en) | 1978-01-20 | 1978-01-20 | Process for producing 3-substituted 1,2,4-triazines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA295,345A CA1085846A (en) | 1978-01-20 | 1978-01-20 | Process for producing 3-substituted 1,2,4-triazines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1085846A true CA1085846A (en) | 1980-09-16 |
Family
ID=4110585
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA295,345A Expired CA1085846A (en) | 1978-01-20 | 1978-01-20 | Process for producing 3-substituted 1,2,4-triazines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1085846A (en) |
-
1978
- 1978-01-20 CA CA295,345A patent/CA1085846A/en not_active Expired
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