WO1991017979A1 - Process for the preparation of 2-n-acylaminopyridines and 2-aminopyridines from 5-oxoalkanenitrile oximes - Google Patents

Process for the preparation of 2-n-acylaminopyridines and 2-aminopyridines from 5-oxoalkanenitrile oximes Download PDF

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WO1991017979A1
WO1991017979A1 PCT/NL1991/000081 NL9100081W WO9117979A1 WO 1991017979 A1 WO1991017979 A1 WO 1991017979A1 NL 9100081 W NL9100081 W NL 9100081W WO 9117979 A1 WO9117979 A1 WO 9117979A1
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formula
group
oxoalkanenitrile
oxime
process according
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PCT/NL1991/000081
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French (fr)
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Anna Maria Cornelia Francisca Castelijns
Peter Johannes Dominicus Maas
Henricus Johannes Arts
Robert Jan Vijn
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Dsm N.V.
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/63—Carboxylic acid nitriles containing cyano groups and nitrogen atoms further bound to other hetero atoms, other than oxygen atoms of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C255/64—Carboxylic acid nitriles containing cyano groups and nitrogen atoms further bound to other hetero atoms, other than oxygen atoms of nitro or nitroso groups, bound to the same carbon skeleton with the nitrogen atoms further bound to oxygen atoms
    • 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
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/38—Nitrogen atoms

Definitions

  • the invention relates to a process for the preparation of 2-N-acylaminopyridines.
  • 2-N-acylaminopyridines are based on the acylation of the corresponding 2-aminopyridines.
  • the 2-aminopyridines required for this synthesis are prepared in the manner described in for example DE-C-374291. In this process a pyridine is aminated with a sodium amide of the general formula NaNHR, where R is hydrogen, aryl, alkyl or a
  • heterocyclic group such as pyridyl or guinolyl, or with a mixture of metallic sodium and a primary amine. On the whole, the reaction takes more than 5 hours.
  • 2-N-acylaminopyridines present the disadvantage that they all proceed via a 2-aminopyridine, which is obtained through amination of the corresponding pyridine.
  • the pyridines used as raw materials in the preparation of these 2-aminopyridines are often not accessible or accessible with difficulty only and the amination reaction takes a long time.
  • R 1 and R 5 an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group,
  • R 2 , R 3 and R 4 hydrogen, an alkoxy group, an aryl group, a heteroaryl or alkyl group or a cycloalkyl group
  • R 1 and R 2 can together form a cycloalkyl group, by treating a 5-oxoalkanenitrile oxime of formula 2,
  • the invention relates to a process for the preparation of 2-aminopyridines from the
  • nalidixic acid is a chemotherapeutic agent.
  • R 1 through R 4 have the meanings given above.
  • R 1 through R 5 in formulas 1-3 and in formulas 4 and 5 to be discussed below may have the meanings given above.
  • R 1 , R 2 , R 3 , R 4 and R 5 may be substituted.
  • substituents in groups R 1 through R 5 use may be made, of all substituents that are inert under the reaction conditions, such as halogenides, alkoxy groups, alkyl groups and aryl groups.
  • R 1 through R 5 may not be too large. Therefore, the size of each of R 1 through R 5 will usually be limited to 15 carbon atoms.
  • R 1 -R 5 examples are: methyl, ethyl, propyl, decyl,
  • R 2 -R 4 isobutyl, phenyl, chlorophenyl, methylcyclohexyl, benzyl, trifluoromethyl, methoxyphenyl and pyridyl.
  • R 2 -R 4 are moreover: methoxy, ethoxy, butoxy, phenoxy and chloromethoxy.
  • the 5-oxoalkanenitrile oximes used as starting compounds in the process according, to the invention are the oximes of formula 2,
  • the oximes can be prepared in any suitable manner.
  • 5-oxoalkanenitrile oximes by reacting a 5-oxoalkanenitrile with hydroxyl ammonium sulphate and treating this mixture with an alkaline solution. This method can also be used to prepare 5-oxoalkanenitrile oximes where R 2 is an acyl group, whether or not substituted, or R 1 is H.
  • the invention also relates to the 5-oxoalkanenitrile oximes of formula 2 where
  • R 1 hydrogen, an alkyl group, a cycloalkyl group
  • R 2 hydrogen, an alkoxy group, an acyl group, an alkyl group or a cycloalkyl group,
  • R 1 and R 2 can together form a cylcoalkyl group
  • R 3 and R 4 hydrogen, an alkoxy group, an alkyl group or a cycloalkyl group with the exception of the compound in which
  • the process according to the invention can also be used to prepare
  • the invention also relates to 2-N-acylaminopyridines of the general formula 1, where
  • R 1 and R 5 an alkyl group or a cycloalkyl group
  • R 2 , R 3 and R 4 hydrogen, an alkoxy group, an alkyl group or a cylcoalkyl group
  • R 1 and R 2 can together form a cycloalkyl group
  • the invention relates to 2-aminopyridines of the general formula 3, where
  • R 1 an alkyl group or a cylcoalkyl group
  • R 2 , R 3 and R 4 hydrogen, an alkoxy group, an alkyl group or a cycloalkyl group
  • the 5-oxoalkanenitrile oximes are treated, in the presence of a strong acid, with an acylating agent that contains at least one R 5 group with the meaning given above.
  • the strong acid that is to be present may be formed in situ or may be added as such to the reaction mixture.
  • acylating agent use may be made of an agent that is an acid halogenide according to formula 4,
  • R 5 - C C - X formula 4 where R 5 has the meaning given above and X is a halogen atom, or use is made of a combination of an acid halogenide of formula 4 and a carboxylic anhydride of formula 5,
  • R' 5 and R' 5 are the same groups as mentioned for R 5 and R' 5 and R" 5 can together form a ring.
  • the combination of an acid chloride and an anhydride as mentioned above is used as an acylating agent.
  • Particularly preferable is the combination of acetylchloride and acetic anhydride.
  • the oxime is dissolved in a carboxylic anhydride.
  • a carboxylic anhydride Preferably, use is made of 2-6 molar equivalents of
  • carboxylic anhydride relative to the amount of oxime, more in particular 2-3 molar equivalents.
  • the temperature maintained during dissolution may vary within wide limits. However, it is preferably kept between -10°C and 20°C. Particularly preferable is a temperature of between 0 and 5°C.
  • the temperature of the reaction mixture is finally kept between 80 and 135°C, preferably between 95 and 105°C.
  • the flow rate of the HCl gas may vary within wide limits. Often, the gas flow is chosen so that complete conversion of the oxime takes place in 3-4 hours.
  • the 2-N-acylaminopyridine formed can now be recovered through, for example, crystallisation.
  • the oxime is dissolved in 1-4 molar equivalents of carboxylic anhydride relative to the oxime.
  • 1-4 molar equivalents of carboxylic anhydride Preferably, use is made of 1-2 molar equivalents of carboxylic anhydride.
  • the temperature during dissolution may vary within wide limits. However, it is preferably kept between -10°C and 20°C. Particularly preferable is a temperature of 0-5°C.
  • carboxylic chloride is supplied in an amount of at least 1 molar equivalent relative to the oxime.
  • the solution is then heated to a temperature of over 40°C, preferably of over 80°C.
  • Particularly preferable is a temperature of 90-110°C.
  • the duration of the heating depends on a number of factors, including the temperature, but usually it lies between 3 and 4 hours.
  • the 2-N-acylaminopyridine can be recovered through distillation or crystallisation.
  • reaction mixture can, for example, be treated with a strong base such as an alkaline solution.
  • a strong base such as an alkaline solution.
  • the 2-aminopyridine formed can then be recovered through distillation or crystallisation.
  • the preparation was effected in the same way as in example 1, except that 2,4-dimethyl-5-oxohexanenitrile was used as a starting material.
  • reaction mixture was stirred for 16 hours at room temperature. After the mixture had separated, the ether phase was separated from the aqueous phase. The aqueous phase was then extracted with the aid of diethyl ether. Then the combined ether phases were dried over MgSO 4 .
  • the preparation was effected in the same manner as in example 4, except that 2-(2-cyanoethyl)cyclohexanone was used as a starting material.
  • the preparation was effected in the same manner as in example 4, except that 4-acetyl-5-oxohexanenitrile was used as a starting material.
  • the aqueous solution was neutralized with a 33 wt.% NaOH solution and then extracted 4x, each time using 50 ml of CH 2 Cl 2 . After drying and evaporation of the organic phase 10.3 g of 2-N-acetylamino-6-methylpyridine was obtained in a yield of 69% relative to the oxime. Melting point 84.5-86°C.
  • reaction mixture was cooled to about 50°C, after which a solution of 26.4 g (0.66 mol) of NaOH in 75 ml of water was added and then the mixture was stirred for 1 hour at 70°C. After this the reaction mixture was cooled to room temperature and extracted 4x, each time using 50 ml of dichloromethane. After drying and evaporation 5.9 g of
  • reaction mixture was cooled to 50°C, after which a solution of 26.4 g (0.66 mol) of NaOH in 75 ml of water was added and the mixture was stirred for 1 hour at 70°C. Then the reaction mixture was cooled to room temperature and extracted 4x, each time using 50 ml of dichloromethane.

Abstract

The invention relates to a process for the preparation of 2-N-acylaminopyridines of formula (1), where R1 and R5 = an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, R2, R3 and R4 = hydrogen, an alkoxy group, an aryl group, a heteroaryl group, an alkyl group or a cycloalkyl group and R1 and R2 can together form a cycloalkyl group, which are prepared by treating a 5-oxoalkanenitrile oxime of formula (2), where R1 through R4 have the meanings given above, in the presence of a strong acid, with an acylating agent that contains at least on R5 group with the meaning given above. The invention moreover relates to a process for the preparation of 2-aminopyridines of formula (3), where R1 through R4 have the meanings given above, from said 2-N-acylaminopyridines. The invention moreover relates to the 5-oxoalkanenitrile oximes of formula (2), including those where R1 = H and R2 is an acyl group, the 2-N-acylaminopyridines of formula (1), and the 2-aminopyridines of formula (3).

Description

PROCESS FOR THE PREPARATION OF 2-N-ACYLAMINOPYRIDINES AND 2-AMINOPYRIDINES FROM 5-OXOALKANENITRILE OXIMES
The invention relates to a process for the preparation of 2-N-acylaminopyridines.
There is a great need for simple, cheap preparation methods for 2-N-acylaminopyridines, which compounds can be used as raw materials for pharmaceutical and agrochemical intermediates and end products.
The known preparation methods for
2-N-acylaminopyridines are based on the acylation of the corresponding 2-aminopyridines. The 2-aminopyridines required for this synthesis are prepared in the manner described in for example DE-C-374291. In this process a pyridine is aminated with a sodium amide of the general formula NaNHR, where R is hydrogen, aryl, alkyl or a
heterocyclic group such as pyridyl or guinolyl, or with a mixture of metallic sodium and a primary amine. On the whole, the reaction takes more than 5 hours.
The known methods for preparing
2-N-acylaminopyridines present the disadvantage that they all proceed via a 2-aminopyridine, which is obtained through amination of the corresponding pyridine.
The pyridines used as raw materials in the preparation of these 2-aminopyridines are often not accessible or accessible with difficulty only and the amination reaction takes a long time.
Moreover, large material streams are required in these preparation methods, which is not attractive from an economic point of view.
The process according to the invention aims to avoid these disadvantages and limitations.
To this effect a 2-N-acylaminopyridine of formula 1 is prepared,
formula 1
where
Figure imgf000004_0002
R1 and R5 = an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group,
R2, R3 and R4 = hydrogen, an alkoxy group, an aryl group, a heteroaryl or alkyl group or a cycloalkyl group
and R1 and R2 can together form a cycloalkyl group, by treating a 5-oxoalkanenitrile oxime of formula 2,
formula 2
Figure imgf000004_0001
where R1 through R4 have the above meanings, in the presence of a strong acid, with an acylating agent that contains at least one R5 group with the above meaning.
Moreover, the invention relates to a process for the preparation of 2-aminopyridines from the
2-N-acylaminopyridines thus obtained. A large number of 2-aminopyridines are raw
materials for pharmaceutical and agrochemical intermediates and end products. For example, 2-amino-6-methylpyridine is used in the preparation of nalidixic acid. Nalidixic acid is a chemotherapeutic agent.
An important known method for the preparation of 2-aminopyridines and the disadvantages involved are
described above.
As the deacylation reaction in the preparation via the 2-N-acylaminopyridines is very simple, these
disadvantages are avoided when a 2-N-acylaminopyridine of formula 1 obtained according to the process of the invention is converted into a 2-aminopyridine of formula 3,
formula 3
Figure imgf000005_0001
where R1 through R4 have the meanings given above.
Groups R1 through R5 in formulas 1-3 and in formulas 4 and 5 to be discussed below may have the meanings given above. R1, R2, R3, R4 and R5 may be substituted. As substituents in groups R1 through R5 use may be made, of all substituents that are inert under the reaction conditions, such as halogenides, alkoxy groups, alkyl groups and aryl groups. For a good development of the process R1 through R5 may not be too large. Therefore, the size of each of R1 through R5 will usually be limited to 15 carbon atoms.
Examples of R1-R5 are: methyl, ethyl, propyl, decyl,
isobutyl, phenyl, chlorophenyl, methylcyclohexyl, benzyl, trifluoromethyl, methoxyphenyl and pyridyl. Examples of R2-R4 are moreover: methoxy, ethoxy, butoxy, phenoxy and chloromethoxy.
The 5-oxoalkanenitrile oximes used as starting compounds in the process according, to the invention are the oximes of formula 2,
formula 2
Figure imgf000006_0001
where R1 through R4 have the meanings given above.
Examples of such 5-oxoalkanenitrile oximes are:
5-oxohexanenitrile oxime,
4-methyl-5-oxohexanenitrile oxime,
2-methyl-5-oxoheptanenitrile oxime,
2,4-dimethyl-5-oxohexanenitrile oxime,
3-methyl-5-oxohexanenitrile oxime,
4-methoxy-5-oxohexanenitrile oxime,
2-(2-cyanoethyl)-cyclohexanone oxime,
2-(2-cyanopropyl)-cyclohexanone oxime,
2-(2-cyanoethyl)-4-methylcyclohexanone oxime,
2-(2-cyanoethyl)-4-methoxycyclohexanone oxime,
2-(1-methyl-2-cyanoethyl)-6-methylcyclohexanone oxime,
2-(2-cyanoethyl)cyclopentanone oxime,
2-(1-methyl-2-cyanoethyl)cyclopentanone oxime and
2-(2-cyanoethyl)-5-methyl-cyclopentanone oxime.
The oximes can be prepared in any suitable manner.
For example, it is possible to prepare the
5-oxoalkanenitrile oximes by reacting a 5-oxoalkanenitrile with hydroxyl ammonium sulphate and treating this mixture with an alkaline solution. This method can also be used to prepare 5-oxoalkanenitrile oximes where R2 is an acyl group, whether or not substituted, or R1 is H.
Examples of this are 5-oxopentanenitrile oxime,
4-methyl-5-oxopentanenitrile oxime,
2-methyl-5-oxopentanenitrile oxime and
3-methoxy-4-methyl-5-oxopentanenitrile oxime. The invention also relates to the 5-oxoalkanenitrile oximes of formula 2 where
R1 = hydrogen, an alkyl group, a cycloalkyl group,
R2 = hydrogen, an alkoxy group, an acyl group, an alkyl group or a cycloalkyl group,
and R1 and R2 can together form a cylcoalkyl group,
R3 and R4 = hydrogen, an alkoxy group, an alkyl group or a cycloalkyl group with the exception of the compound in which
R1 = CH3 or CH2CH3 and R2 through R4 = H.
The process according to the invention can also be used to prepare
2-N-acylaminopyridines. Examples are:
2-N-acetylamino-6-methylpyridine,
2-N-chloroacetylamino-6-methylpyridine,
2-N-benzoylamino-6-methylpyridine,
2-N-acetylamino-5,6-dimethylpyridine,
2-N-acetylamino-3,5,6-trimethylpyridine,
2-N-chloroacetylamino-3,5,6-trimethylpyridine,
2-N-acetylamino-3-methyl-6-ethylpyridine,
2-N-(2-chlorobenzoylamino)-4,6-dimethylpyridine,
2-N-acetylamino-5-methoxy-6-methylpyridine,
2-N-acetylamino-5,6,7,8-tetrahydroquinoline,
2-N-(p-methoxybenzoylamino)-3-methyl-5,6,7,8-tetrahydroquino line,
2-N-acetylamino-6-methyl-5,6,7,8-tetrahydroquinoline,
2-N-chloroacetylamino-6-methoxy-5,6,7,8-tetrahydroquinoline,
2-N-acetylamino-4,8-dimethyl-5,6,7,8-tetrahydroquinoline, 2-N-acetylamino-5,6-cyclopentenopyridine and
2-N-acetylamino-3-methyl-5,6-cyclopentenopyridine.
It can also be used to prepare 2-aminopyridines such as:
2-amino-6-methylpyridine,
2-amino-5,6-dimethylpyridine,
2-amino-3,5,6-trimethylpyridine,
2-amino-6-ethylpyridine, 2-amino-3-methyl-6-ethylpyridine,
2-amino-3-trifluoromethyl-6-ethylpyridine,
2-amino-4,6-dimethylpyridine,
2-amino-4,5,6-trimethylpyridine,
2-amino-6-isopropylpyridine,
2-amino-5-methoxy-6-methylpyridine,
2-amino-5,6,7,8-tetrahydroquinoline,
2-amino-4-methyl-5,6,7,8-tetrahydroquinoline,
2-amino-4,6-dimethyl-5,6,7,8-tetrahydroquinoline,
2-amino-5-methoxy-5,6,7,8-tetrahydroquinoline,
2-amino-5,6-cyclopentenopyridine and
2-amino-3-methyl-5,6-cyclopentenopyridine.
The invention also relates to 2-N-acylaminopyridines of the general formula 1, where
R1 and R5 = an alkyl group or a cycloalkyl group,
R2, R3 and R4 = hydrogen, an alkoxy group, an alkyl group or a cylcoalkyl group
and R1 and R2 can together form a cycloalkyl group,
with the exception of the compounds where R1 through R5 at the same time have the following meanings:
R1 = CH3, R2 through R4 = H and R5 = H, CH3 or CH2-COOET.
Moreover, the invention relates to 2-aminopyridines of the general formula 3, where
R1 = an alkyl group or a cylcoalkyl group,
R2, R3 and R4 = hydrogen, an alkoxy group, an alkyl group or a cycloalkyl group
and R1 and R2 can together form a cycloalkyl group, with the exception of the compound where, at the same time, R1 = CH3 and R2 through R4 = H and the compound where, at the same time, R1, R2 and R4 = CH3 and R3 = H, the compound where, at the same time, R1 and R2 = CH, and R, and R4 = H, the compound where R1 and R4 = CH, and R2 and R3 = H, the compound where R1 and R3 = CH3, and R2 and R4 = H, the compound where R1 = CH3 and R2 and R3 = H and R4 = CH-CH, and also the compound where R- = CH3, R3 = CH-(CH3)2 and R2 and R4 = H. In the process according to the invention the 5-oxoalkanenitrile oximes are treated, in the presence of a strong acid, with an acylating agent that contains at least one R5 group with the meaning given above. The strong acid that is to be present may be formed in situ or may be added as such to the reaction mixture. As acylating agent use may be made of an agent that is an acid halogenide according to formula 4,
Figure imgf000009_0001
R5 - C C - X formula 4 where R5 has the meaning given above and X is a halogen atom, or use is made of a combination of an acid halogenide of formula 4 and a carboxylic anhydride of formula 5,
Figure imgf000009_0002
R'5 - C - O - C - R"5 formula 5
where R'5 and R'5 are the same groups as mentioned for R5 and R'5 and R"5 can together form a ring.
When use is made of an acid halogenide and also when use is made of an acid halogenide together with an acid anhydride a strong acid is formed in situ. It is also possible to use a carboxylic anhydride according to formula 5 as an acylating agent and to add a strong acid as such to the reaction mixture, preferably a halogenous acid, hydrochloric acid being particularly preferable.
Preferably, the combination of an acid chloride and an anhydride as mentioned above is used as an acylating agent. Particularly preferable is the combination of acetylchloride and acetic anhydride. If the sole aim is the preparation of a 2-aminopyridine, R' 5 and R"5 do not have to be the same because in that case the acyl radical is removed anyway. When a 2-N-acylaminopyridine is prepared, R'5 and R"5 will preferably be chosen the same because otherwise a mixture of two 2-N-acylaminopyridines is obtained.
There are a large number of possible embodiments of the process. Examples of suitable embodiments are as
follows: Synthesis of 2-N-acylaminopyridines
The oxime is dissolved in a carboxylic anhydride. Preferably, use is made of 2-6 molar equivalents of
carboxylic anhydride relative to the amount of oxime, more in particular 2-3 molar equivalents.
The temperature maintained during dissolution may vary within wide limits. However, it is preferably kept between -10°C and 20°C. Particularly preferable is a temperature of between 0 and 5°C.
Then the solution is heated while HCl gas is passed through it.
The temperature of the reaction mixture is finally kept between 80 and 135°C, preferably between 95 and 105°C.
The flow rate of the HCl gas may vary within wide limits. Often, the gas flow is chosen so that complete conversion of the oxime takes place in 3-4 hours.
The 2-N-acylaminopyridine formed can now be recovered through, for example, crystallisation.
In a different method the oxime is dissolved in 1-4 molar equivalents of carboxylic anhydride relative to the oxime. Preferably, use is made of 1-2 molar equivalents of carboxylic anhydride. The temperature during dissolution may vary within wide limits. However, it is preferably kept between -10°C and 20°C. Particularly preferable is a temperature of 0-5°C.
Then carboxylic chloride is supplied in an amount of at least 1 molar equivalent relative to the oxime.
Preferably use is made of 1-4 molar equivalents, 1-2 molar equivalents being particularly preferable. The solution is then heated to a temperature of over 40°C, preferably of over 80°C. Particularly preferable is a temperature of 90-110°C. The duration of the heating depends on a number of factors, including the temperature, but usually it lies between 3 and 4 hours.
The 2-N-acylaminopyridine can be recovered through distillation or crystallisation.
Synthesis of 2-aminopyridine
If so desired, the 2-N-acylaminopyridines obtained with the process according to the invention can be converted into the corresponding
2-aminopyridines in a manner known per se.
To this effect the reaction mixture can, for example, be treated with a strong base such as an alkaline solution. The 2-aminopyridine formed can then be recovered through distillation or crystallisation.
Example 1
Preparation of 5-oxohexanenitrile oxime
37.0 grams (0.45 mol) of hydroxyl ammonium sulphate was dissolved in 75 ml of water. 50.2 grams (0.45 mol) of 5-oxohexanenitrile was supplied to this solution. The mixture obtained was then cooled to about 10°C, after which 18.0 grams of NaOH (0.45 mol) in 35 ml of water was added (duration of the addition: 25 minutes), with stirring and cooling. It was ensured that the temperature of the reaction mixture did not rise above 20°C during this addition. After the addition, the reaction mixture was stirred for 2 hours at room temperature. After the mixture had separated, the organic phase was separated from the aqueous phase. The aqueous phase was then extracted with the aid of diethyl ether. Then the combined organic phases were dried over
MgSO4. After the MgSO4 had been removed via filtration, the filtrate was evaporated using a rotavapor. In this manner 48.1 grams was obtained of 5-oxohexanenitrile oxime with a purity of 99% (yield: 84%).
The following values were measured with the aid of 1H-NMR:
a c d e
CH3 - C - CH2 - CH2 - CH2 - C≡ N
Figure imgf000012_0002
1H-NMR (CDCl3/TMS):
δ = 1.5-2.1; m; 6p; Ha + Hd + Hb
δ = 2.1-2.6; m; 4p; Hc + He. The symbols used in the representation of the 1H-NMR results have the following meanings:
p = proton
s = singlet
d = doublet
t = triplet
q = quartet
m = multiplet
(w) = wide
Example 2
Preparation of 2-methyl-5-oxoheptanenitrile oxime
The preparation was effected in the same manner as in example 1, except that 2-methyl-5-oxoheptanenitrile was used as a starting material. Purity: 94%. Yield: 97%. a d e c f
CH3 - CH2 - C - CH2 - CH2 - CH - C ≡ N
Figure imgf000012_0001
1H-NMR (CDCl3/TMS):
δ = 0.90-1.33; m; 6p; Ha + Hb
δ = 1.79; m; 2p; Hc
δ = 2.08-2.68; m; 5p; Hd + He + Hf
δ = 4.90; s (w); 1p; Hh
Example 3
Preparation of 2,4-dimethyl-5-oxohexanenitrile oxime
The preparation was effected in the same way as in example 1, except that 2,4-dimethyl-5-oxohexanenitrile was used as a starting material.
Yield: 93%. Purity: 95%.
Example 4
Preparation of 2-(2-cyanoethyl)-cyclopentanone oxime
25.8 grams (0.31 mol) of hydroxyl ammonium sulphate was dissolved in 50 ml of water. 27.3 grams (0.2 mol) of 2-(2-cyanoethyl)-cyclopentanone dissolved in 50 ml of diethyl ether was added to this solution. The mixture obtained was then cooled to 10°C, after which 12.0 g (0.3 mol) of NaOH in 40 ml of H2O was added, with stirring and cooling (duration of the addition: 20 minutes). It was ensured that the temperature of the reaction mixture did not rise above 20°C during the addition.
After this addition, the reaction mixture was stirred for 16 hours at room temperature. After the mixture had separated, the ether phase was separated from the aqueous phase. The aqueous phase was then extracted with the aid of diethyl ether. Then the combined ether phases were dried over MgSO4.
After the MgSO4 had been removed via filtration the filtrate was evaporated using a rotavapor.
In this manner 26.2 grams of 99% pure
2-(2-cyanoethyl)-cyclopentanone oxime was obtained. Yield:
86%. Example 5
Preparation of 2-(2-cyanoethyl)-cyclohexanone oxime
The preparation was effected in the same manner as in example 4, except that 2-(2-cyanoethyl)cyclohexanone was used as a starting material.
Yield: 59%. Purity: 75%.
Figure imgf000014_0001
1H-NMR (CDCl3/TMS):
δ = 1.5-2.0; m; 9p; Ha
δ = 2.15-2.69; m; 4p; Hb + Hc
δ = 6.68-8.34; s (w); 1p; Hd
Example 6
Preparation of 4-acetyl-5-oxohexanenitrile oxime
The preparation was effected in the same manner as in example 4, except that 4-acetyl-5-oxohexanenitrile was used as a starting material.
Yield: 86%. Purity: 84%.
Example 7
Preparation of 5-oxopentanenitrile oxime
The preparation was effected in the same manner as in example 4, except that 5-oxopentanenitrile was used as a starting material. Yield: 81%. Purity: 93%. e b a c
H - C - CH2 - CH2 - CH2 - C ≡ N
Figure imgf000014_0002
1H-NMR (CDCl3/TMS):
δ = 1.60 - 2.09; m; 2p; Ha
δ = 2.10 - 2.68; m(w); 4p; Hb + Hc
δ = 4.60; s(w); 1p; Hd
δ = 6.63 and 7.31; t; 1p; He
(E + Z isomers)
Example 8
Preparation of 2-N-acetylamino-6-methylpyridine
10.2 grams. of acetic anhydride (0.1 mol) was added to 12.6 grams of 5-oxohexanenitrile oxime (0.1 mol), with cooling in a water/ice bath and stirring. At a temperature of approx. 5°C 10.2 g of acetyl chloride (0.13 mol) was supplied in 15 minutes, with continued cooling in the water/ice bath. Then the reaction mixture was heated to reflux temperature. Once a reflux temperature of about 100°C was reached the reaction mixture was maintained at this temperature. The total reaction time after the reflux temperature was reached was four hours. Then the reaction mixture was cooled to room temperature and poured into 100 ml of water. The aqueous solution was neutralized with a 33 wt.% NaOH solution and then extracted 4x, each time using 50 ml of CH2Cl2. After drying and evaporation of the organic phase 10.3 g of 2-N-acetylamino-6-methylpyridine was obtained in a yield of 69% relative to the oxime. Melting point 84.5-86°C.
Figure imgf000015_0001
1H-NMR (CDCl3/TMS)
δ = 2 .26 ; s ; 3p; Ha
δ = 2 . 42 ; s ; 3p; Hb
δ = 6 .80 ; d; 1p; Hc
δ = 7 .50 ; t; 1p; He
δ = 7. 97 ; d; 1p; Hd
δ = 8.90; s(w); 1p; Hf
Example 9
Preparation of 2-N-acetylamino-5,6-cyclopentenopyridine
25.0 g (0.25 mol) of acetic anhydride was added to 8.0 grams (0.05 mol) of 2-(2-cyanoethyl)cyclopentanone oxime. HCl gas with a temperature of 18-22°C was passed through the solution for 5 hours, with cooling in a
water/ice bath. The reaction mixture was stirred for 16 hours at room temperature. 75 ml of water was added to the reaction mixture, after which it was extracted 4 times, each time using 35 ml of dichloromethane.
Yield: 5%. Melting point: 117.5-118°C.
Figure imgf000016_0001
1H-NMR (CHCl3/TMS)
δ = 2.08; s; 3p; He
δ = 2.78; m(w); 8p; Ha
δ = 8.75; s(w); 1p; Hb
δ = 7.37; d; 1p; Hc
δ = 7.82; d; 1p; Hd Example 10
Preparation of 2-amino-6-methylpyridine
23.5 grams (0.23 mol) of acetic anhydride was added to 12.6 grams (0.1 mol) of 5-oxohexanenitrile oxime, with stirring and cooling in a water/ice bath. Then the reaction mixture was heated to reflux temperature for 4 hours, while at the same time HCl gas was passed through it, said reflux temperature rising to about 100°C.
Then the reaction mixture was cooled to about 50°C, after which a solution of 26.4 g (0.66 mol) of NaOH in 75 ml of water was added and then the mixture was stirred for 1 hour at 70°C. After this the reaction mixture was cooled to room temperature and extracted 4x, each time using 50 ml of dichloromethane. After drying and evaporation 5.9 g of
2-amino-6-methylpyridine was obtained in a yield of 55% relative to the oxime. Example 11
Preparation of 2-amino-6-methylpyridine
10.2 grams (0.1 mol) of acetic anhydride was added to 12.6 grams (0.1 mol) of 5-oxohexanenitrile oxime, with stirring and cooling in a water/ice bath. At a temperature of about 5°C 10.2 g (0.13 mol) of acetyl chloride was supplied in 20 minutes, with cooling in a water/ice bath and stirring. Then the reaction mixture was heated to reflux temperature for 4 hours, said reflux temperature rising from 80°C to about 130°C.
Then the reaction mixture was cooled to 50°C, after which a solution of 26.4 g (0.66 mol) of NaOH in 75 ml of water was added and the mixture was stirred for 1 hour at 70°C. Then the reaction mixture was cooled to room temperature and extracted 4x, each time using 50 ml of dichloromethane.
After drying and evaporation of the organic phase 6.3 g of 2-amino-6-methylpyridine was obtained in a yield of 58% relative to the oxime. Melting point: 41.2-42.4°C.
Figure imgf000018_0001
1H-NMR (CDCl3/TMS):
δ = 2.35; s; 3p; Ha
δ = 4.80; s(w); 2p; Hb
δ = 6.17; d; and 6.34; d; 2p; Hc + Hd
δ = 7.15; t; 1p; He
Example 12
Preparation of 2-amino-6-methylpyridine
40.5 g of chloroacetic anhydride (0.24 mol) was added to 12.6 g of 5-oxohexanenitrile oxime (0.10 mol). Then HCl gas was passed through the solution, with simultaneous heating to 85°C. For the first 45 min. the temperature was kept between 80 and 95°C by means of slight cooling. Then the temperature was kept at 95°C for 3.5 hours. HCl was passed through throughout the whole experiment. Then the reaction mixture was cooled to room temperature, after which a solution of 14 g of NaOH (0.35 mol) in 75 ml of water was added. After this 40 ml of ethanol was added (the addition of ethanol ensures a homogeneous reaction mixture during the hydrolysis). The reaction mixture was then heated to reflux temperature for 2 hours. This was followed by cooling to room temperature, after which the reaction mixture was extracted using 4x 50 ml of dichloromethane. After drying and evaporation of the organic phase the yield of
2-amino-6-methylpyridine was 15% relative to the oxime. Example 13
Preparation of 2-amino-6-methylpyridine
32.5 g of benzoic anhydride (0.14 mol) was added to
18.0 g of 5-oxohexanenitrile oxime (0.14 mol). This mixture was heated to 100°C. At 100°C 26.8 g of benzoyl chloride (0.19 mol) was added within 14 minutes. During the addition, brief cooling in a water bath ensured that the temperature did not rise above 115°C.
After all of the benzoyl chloride had been added the
temperature was maintained at about 100ºC for another 4 hours. This was followed by cooling to room temperature. A solution of 15 g of NaOH (0.38 mol) in 50 ml of water and 50 ml of ethanol was added to the reaction mixture.
The reaction mixture was kept at reflux temperature for 2 hours. Then it was cooled to room temperature and extracted 4x, each time using 50 ml of dichloromethane. After drying and evaporation of the organic phase the yield of
2-amino-6-methylpyridine was 7% relative to the oxime.
Example 14
Preparation of 2-amino-6-methylpyridine
52.0 g of benzoic anhydride (0.23 mol) was added to 12.6 g of 5-oxohexanenitrile oxime (0.10 mol). At the same time HCl gas was supplied and the mixture was heated to 100°C. HCl gas was passed through for 4 hours at 100°C. This was followed by cooling to 50ºC (the reaction mixture would solidify at a lower temperature). A solution of 30 g of NaOH (0.75 mol) in 100 ml of water and 50 ml of ethanol was added to the reaction mixture. The reaction mixture was kept at reflux temperature for 2 hours. Then 50 ml of water was added otherwise an inhomogeneous mixture would be obtained on cooling. After this the mixture was cooled to room temperature and extracted 4x, each time using 50 ml of dichloromethane. After drying and evaporation of the organic phase the yield of 2-amino-6-methylpyridine was 28.1%. The following products were synthesized in a manner similar to that of example 11:
Example 15
2-amino-3,5,6-trimethylpyridine
Boiling point 110°C (14.5 mm Hg); melting point 99-102°C. Yield: 63%.
Figure imgf000020_0002
1H-NMR (CDCl3/TMS):
δ = 2.02; s; 2.11; s; 2.28; s; 9p; Ha + Hb + Hc
δ = 4.25; s(w); 2p; Hd
δ = 6.90; s; 1p; He
Example 16
2-amino-5,6,7,8-tetrahydroquinoline
Melting point: 60.5-62.5°C; yield: approx. 43%
Figure imgf000020_0001
H-NMR (CDCl3/TMS):
δ = 1.78; m(w); 2.66 m(w); 8p; Ha
δ = 4.33; S(w); 2p; Hb
δ = 6.22; d; 1p; Hc
δ = 7.05; d; 1p; Hd. Example 17
2-amino-3-methyl-6-ethylpyridine
Boiling point: 68-70°C (0.55 mm Hg); yield: approx. 43%
Figure imgf000021_0001
1H-NMR (CDCl3/TMS):
δ = 1.24; t; 3p; Ha
δ = 2.03; s; 3p; Hb
δ = 2.60; q; 2p; Hc
δ = 4.60; s(w); 2p; Hd
δ = 6.38; d; 1p; He
δ = 7.08; d; 1p; Hf

Claims

C L A I M S 1. Process for the preparation of 2-N-acylaminopyridines, characterized in that a 2-N-acylaminopyridine of formula 1,
formula 1
Figure imgf000022_0001
where
R1 and R5 = an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, R2, R3 and R4 = hydrogen, an alkoxy group, an aryl
group, a heteroaryl group, an alkyl group, or a cycloalkyl group
and R1 and R2 can together form a cycloalkyl group, is prepared by treating a 5-oxoalkanenitrile oxime of formula 2,
formula 2
Figure imgf000022_0002
where R1 through R4 have the meanings given above, in the presence of a strong acid, with an acylating agent that contains at least one R5 group with the above meaning.
2. Process according to claim 1, characterized in that the acylating agent is an acid halogenide of formula 4, R5 -
Figure imgf000023_0001
C - X formula 4 where R5 has the above meaning and X is a halogen atom.
3. Process according to claim 1 or 2, characterized in that a carboxylic anhydride of formula 5 is also present.
Figure imgf000023_0002
R'5 - C - O - C - R"5 formula 5
where R'5 and R'5 are the same groups as described for R5 and R'5 and R"5 can together form a ring.
4. Process according to claim 3, characterized in that in the carboxylic anhydride of formula 5 R'5 is the same as R"5.
5. Process according to claim 3 or 4, characterized in that the 5-oxoalkanenitrile oxime is dissolved in a
carboxylic anhydride of formula 5 and that an acid chloride of formula 4 is then added.
6. Process according to any one of claims 3-5,
characterized in that the amount of carboxylic anhydride of formula 5 amounts to 1-4 molar equivalents relative to the 5-oxoalkanenitrile oxime and that the amount of acid chloride of formula 4 amounts to 1-4 molar
equivalents relative to the 5-oxoalkanenitrile oxime.
7 . Process according to any one of claims 3-6,
characterized in that the carboxylic anhydride is acetic anhydride.
8. Process according to claim 3, characterized in that the strong acid is added as such to the reaction mixture.
9. Process according to claim 8, characterized in that the 5-oxoalkanenitrile oxime is dissolved in a carboxylic anhydride of formula 5, after which the solution is contacted with the strong acid.
10. Process according to claim 9, characterized in that the 5-oxoalkanenitrile oxime is dissolved in 2-6 molar equivalents of carboxylic anhydride of formula 5.
11. Process according to any one of claims 1-10,
characterized in that the strong acid is hydrochloric acid.
12. Process for the preparation of 2-aminopyridines,
characterized in that a 2-N-acylaminopyridine of formula 2, prepared according to any one of claims 1 to 11, is converted into a 2-aminopyridine of formula 3,
formula 3
Figure imgf000024_0001
where R1 through R4 have the meanings given above,
13. 5-Oxoalkanenitrile oximes of formula 2,
formula 2
Figure imgf000024_0002
where
R1 = hydrogen, an alkyl group, a cycloalkyl group,
R2 = hydrogen, an alkoxy group, an acyl group, an alkyl group or a cycloalkyl group,
and R1 and R2 can together form a cylcoalkyl group, R3 and R4 = hydrogen, an alkoxy group, an alkyl group or a cycloalkyl group with the exception of the compound in which R = C·3 or CH2CH3 and R2 through R4 = H.
14. Process for the preparation of 5-oxoalkanenitrile oximes according to claim 13, characterized in that a
5-oxoalkanenitrile is treated with hydroxyl ammonium sulphate and an alkaline solution.
15. 2-N-acylaminopyridines of formula 1,
formula 1
Figure imgf000025_0002
where
R1 and R5 = an alkyl group, a cycloalkyl group,
R2, R3 and R4 =hydrogen, an alkoxy group, an alkyl group or a cylcoalkyl group
and R1 and R2 can together form a cycloalkyl group, with the exception of the compounds where R1 through R5 at the same time have the following meanings:
R1 = CH3, R2 through R4 = H and R5 = H, CH3 or
CH2-COOET.
16. 2-aminopyridines of formula 3,
formula 3
Figure imgf000025_0001
where
R1 = an alkyl group, a cylcoalkyl group, R2, R3 and R4 = hydrogen, an alkoxy group, an alkyl group or a cycloalkyl group
and R1 and R2 can together form a cycloalkyl group, with the exception of the compound where, at the same time, R1 = CH3 and R2 trough R4 = H and the compound where, at the same time, R1, R2 and R4 = CH3 and R3 = H, the compound where, at the same time, R1 and R2 = CH3 and R3 and R4 = H, the compound where R1 and R, = CH3 and R2 and R3 = H, the compound where R1 and R3 = CH3, and R2 and R4 = H, the compound where R1 = CH3 and R2 and R, = H and R4 = CH2CH3 and also the compound where R, = CH3, R3 = CH-(CH3)2 and R2 and R4 = H.
17. Process for the preparation of 2-N-acylaminopyridines, 2-N-aminopyridines or 5-oxoalkanenitrile oximes as substantially set forth and explained in the examples.
PCT/NL1991/000081 1990-05-18 1991-05-16 Process for the preparation of 2-n-acylaminopyridines and 2-aminopyridines from 5-oxoalkanenitrile oximes WO1991017979A1 (en)

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