GB2188318A - Preparation of pyridine derivatives - Google Patents

Preparation of pyridine derivatives Download PDF

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Publication number
GB2188318A
GB2188318A GB08705472A GB8705472A GB2188318A GB 2188318 A GB2188318 A GB 2188318A GB 08705472 A GB08705472 A GB 08705472A GB 8705472 A GB8705472 A GB 8705472A GB 2188318 A GB2188318 A GB 2188318A
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Prior art keywords
compound
general formula
group
optionally substituted
compounds
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GB08705472A
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GB8705472D0 (en
GB2188318B (en
Inventor
David Phillip Astles
Andrew Flood
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Shell Internationale Research Maatschappij BV
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Shell Internationale Research Maatschappij BV
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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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/98—Nitrogen atom
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

Abstract

A process for the preparation of a compound of formula <IMAGE> in which R<1> represents a hydrogen atom or an optionally substituted alkyl or cycloalkyl group, R<2> represents an optionally substituted alkyl or cycloalkyl group, each of R<3> and R<4> independently represents an optionally substituted alkyl or cycloalkyl group, and each of R<5> and R<6> independently represents an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl group, which comprises reacting a hydrazone compound of the general formula <IMAGE> with a dicarboxylate compound of the general formula <IMAGE> The compounds of formula I may be deaminated to form the compounds of formula IV <IMAGE> The compounds of formulae (I) and (IV) are also claimed.

Description

SPECIFICATION Preparation of heterocyclic compounds This invention relates to the preparation of certain substituted dihydropyridine and pyridine compounds, and to novel dihydropyridine compoundsperse. Such compounds are useful as intermediates for the preparation of herbicidal pyridyl imidazolinone compounds.
Pyridyl imidazolinone compounds have been disclosed as herbicides and plant growth regulants in various documents. For example EP-A-41 623 discloses a wide range of such compounds and their use as herbicides, whilst EP-A-41 624 discloses their use as plant growth regulants. Among the compounds each of these specifications specifically discloses are 2-(5-isopropyl-5-methyl-4-oxo-2-im idazolin-2-yl)-5-ethyl- nicotinic acid and 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-5-methyl-nicotinic acid.
EP-A-95105 discloses that such pyridyl imidazolinone compounds may be synthesized from 2,3-pyridine carboxylic anhydrides and it is known that the dicarboxy compounds from which such anhydrides are readily prepared may themselves be prepared by subjecting quinoline compoundsto oxidising conditions.
EP-A-1 61221 claims that compounds offormula A
may be prepared by reacting a hydrazone offormula B with a maleic acid derivative of formula C, to form a compound offormula D
from which H-NRgR10 is removed. A wide range of possibilities is claimed for moieties R1 to Era0.
The moietyX ofthecompounds offormula C is a chlorine or bromine atom, in orderforthe reactionto produce the dihydropyridyl compounds D. The presenceof a base is stated to be preferable, and is employed in all the examples, to take up the hydrochloric or hydrobromic acid formed. The deamination is effected by use of acid in dioxan.
In the compounds of the examples of EP-A-1 61221 the groups R2 and R4 always represent a joint moiety, which is usually a group of formula
R usually being phenyl, a-cyanoalkyl orcx-carbamoylalkyl. In one examplethejoint moiety is an oxygen atom.
EP-A-161221 is concerned moreover to providethe 2,3-pyridine carboxylic anhydridesfrom which pyridyl imidazolinone compounds may be synthesised. The way such anhydrides are prepared, according to EP-A 161221, involves the ring opening ofthe pyridyl compounds derived bydeamination ofthe compounds of formula Din which R3 and R4jointly represent a group offormula
with loss of the compound R-NH2, to form dicarboxy compounds, followed by dehydration.
The compounds offormula C required for the reactions disclosed in EP-A-1 61221 must themselves be synthesised and this may be achieved by treatment of maleic acid anhydride with a compound offormula R-NH2, followed by treatment with acetic anhydride, followed by halogenation (see EP-A-41 624).
The present invention relates to a simple process for the preparation of dihydropyridine compounds, from which such 2,3-pyridine carboxylic anhydride compounds may readily be prepared.
According to the present invention there is provided a process forthe preparation of a compound ofthe general formula
in which R1 represents a hydrogen atom or an optionally substituted alkyl or cycloalkyl group, R2 represents an optionally substituted alkyl or cycloalkyl group, each of R3 and R4independently represents an optionally substituted alkyl or cycloalkyl group, and each of R5 and R6 independently represents an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl group, which comprises reacting a hydrazone compound ofthe general formula
with a dicarboxylate compound of the general formula
Whereas the prior art provides a route to 2,3-pyridine carboxylic anhydrides which requires a large number of steps from maleic acid anhydride, involving inter alia,theformation of a ring compound containing a group
halogenation, base catalysed addition, acid catalysed deamination, and ring-opening of the resulting compound with loss ofthe compound R-NH2, the present invention offers a simple and direct route to those compounds which does not require halogenation, the use of a base, or a ring-opening step with resulting loss of material.
In accordance with the process of the present invention, an alkyl, alkenyl or alkyl group preferably has 1 to 6, especially 1 to 4 carbon atoms, whilst a cycloalkyl group preferably has 3 to 8 carbon atoms. An aryl group is preferably phenyl and an aralkyl group preferably benzyl. When a group is substituted, possible substituents may include for example halogen atoms, CIA alkoxy or haloalkoxy groups, hydroxy, cyano, amino, alkylamino, phenyl, phenoxy, carboxy and alkoxycarbonyl groups. In general, however, unsubstituted groups are preferred for each substituent R2to R6, and preferably unsubstituted C1-4 alkyl groups,with methyl and ethyl being the most preferred groups, whilst R1 is preferably a hydrogen atom.
Preferablythe reaction takes place in an inert organic solvent, such astetrahydrofuran, acetonitrileor dioxan, or suitably an alkylated benzene such astoluene orxylene. The reaction may take place in the range O"C to the refluxtemperature (which may suitably be from 70 Cto 140"C depending on the solvent used), and advantageously takes place in the range 50 Ctothe reflux temperature, most preferably at the refluxtem erature.
It is preferred that the hydrozone is in a molar excess over the dicarboxylate, although the reaction may proceed adequately if this is not the case. In general, a preferred molar ratio of hydrazone to dicarboxylate is in the range 1:1 to 2: 1, especially 1:1 to 1.5:1.
In another aspectthe invention relates to compounds offormula I perse.
Acompound ofthe general formula 1may be converted to a pyridinecompound ofthegeneralformula
underthe deamination conditions. Preferably the reaction takes place in an inert organic solvent, such as benzene, toluene orxylene, in the presence of a catalyst such as palladium or platinum, which may conveni- ently be carried by a charcoal substrate. Preferably, the reaction takes place at elevated temperature, suitably in the range 50"C to the reflux temperature, most preferably the reflux temperature.
In other aspect the present invention relates to the novel pyridine compoundsperse, with the exception of 5-methyl-2,3-pyridine dicarboxylic acid, diethyl ester.
The compounds of the general formula IV may be used to generate herbicidal pyridyl imadazolinyl compounds, for example by converting them, in aqueous sodium hydroxide, to the corresponding dicarboxylic acids, converting the acids to the acid anhydrides, suitably by refluxing the acids in the presence of acetic anhydride, and thence by the methods disclosed in EP-A-95105.
The invention will now be further described with reference to the following Examples.
Example 1 Preparation of 1-dim ethylamino-2, 3-dicarboxy-5-meth yldih ydrop yridine, dim ethyl ester Di methyl acetylene dicarboxylate (17.39; 0.122mol) and 2-methylprop-2-enal dimethylhydrazone(l 5.0g; 0.134mol) were added to 20ml of dry toluene. The reaction mixture was refluxed under a nitrogen atmosphere for 1 hour. The solvent was evaporated off. Column chromatography on silica using 35-40% (v/v) ethyl acetate/n-hexane as eluantyield the title compound as a yellow oil (6.9g), which crystallized on refrigeration (mp. c.50 C).
Analysis Required (%) 56.7 C 7.1 H 11.0 N Found (%) 56.5 C 7.2 H 11.0 N Example2 Preparation of 1-dimeth ylamino-2,3-dicarboxy-5-eth yldih ydrop yridine, dimeth yl ester Dimethyl acetylene dicarboxylate (20.5g; 0.144mol) and 2-ethylprop-2-enal dimethyl hydrazone (20.0g; 0.1 59mop) were added to 25ml of drytoluene. The reaction mixture was refluxed for 1 hour. The solvent was removed by evaporation. Column chromatography on silica using 40.5%(v/v) ethyl acetate/n-hexane as eluantyielded the title compound as an orange oil (7.79).
Analysis Required (%) 58.2 C 7.5 H 10.4 N Found (%) 56.8 C 7.7 H 9.6 N Example 3 Preparation of2,3-dicarboxy-5-methylp yridine, dimethylester The title compound of Example 1 (6.5g)was dissolved in 50ml ofdrytoluene and 5% w/w palladium on charcoal (0.69) was added, as catalyst. The reaction mixture was refluxed for 14 hours with replenishment of the catalyst every 2 hours. The reaction was filtered and the solvent was evaporated off to leave a red-brown oil (7.0g). Column chromatography on silica using 40% (v/v) ethyl acetate/n-hexane as eluantyielded the title compound (3.35g) as a solid, m.p. 59-60%.
Analysis Required(%) 58.9C 3.1 H 8.6N Found (%) 58.7 C 3.7 H 8.0 N Example 4 Preparation of23-dicarboxy-5-ethylpyridine, dimethyl ester The title compound of Example 2 (7.459) was dissolved in 75ml of drytoluene and 5%w/w palladium on charcoal (0.75g) was added, as catalyst The reaction mixture was refluxed under a nitrogen atmosphere for 21 hours, with replenishment of the catalyst after 17 and 19 hours. The reaction mixture was filtered and the solvent evaporated. Column chromatographyofthe resulting oil (6g) on silica using 35-40%(v/v) ethyl acetate/n-hexane yielded the title compound as an orange oil (3.49).
Analysis Required (%) 59.2 C 5.8 H 6.3 N Found (%) 57.by 5.8 H 6.5 N When the above procedure was repeated 3.499 ofthetitle compound was produced from 4.69 ofstarting material.
The following Example illustrates howa compound offormula IV may be converted to an acid anhydride compound, which may be used to synthesise a pyridyl imidazolinyl compound of EP-A-95105.
Example5 Preparation of2,3-carboxy-5methyIpyridine, anh ydride The title compound of Example 3 (7.95g) was added to 10% wlw aqueous sodium hydroxide (35ml). The reaction mixture was refluxed for 11/2 hours and cooled. Concentrated hydrochloric acid was added until the pH of the reaction mixture was 2. A light brown precipitate which formed on cooling was filtered off and dried (2.1 5g). Further hydrochloric acid was added until the pH was 1. The further precipitate which formed (0.959) was filtered off and dried.
The 2.159 precipitate (2,3-dicarboxy-5-methylpyridine) was dissolved in acetic anhydride (35ml; density, 1.082g/l). The reaction mixture was refluxed for 21/2 hours. The acetic anhydride was separated first by evaporation then by a hot water bath and vacuum pump leaving a pale grey solid.
Analysis Required(%) 58.9C 3.1 H 8.6N Found (%) 58.7 C 3.7 H 8.0 N

Claims (9)

1. A process forthe preparation of a compound of the general formula
in which R' represents a hydrogen atom or an optionally substituted alkyl or cycloalkyl group, R2 represents an optionally substituted alkyl or cycloalkyl group, each of R3 and R4 independently represents an optionally substituted alkyl or cycloalkyl group, and each of R5andR6independently represents an optionally substitu- ted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl group, which comprises reacting a hydrazone compound ofthe general formula
with a dicarboxylate compound of the general formula
2.A process according to claim 1, wherein R' represents a hydrogen atom and each of R2 to R5 independently represents a C1 4 alkyl group.
3. A process according to claim 2, wherein each of R3 to R6 represents a methyl group and R2 represents a methyl or ethyl group.
4. A process according to any preceding claim in which the hydrozone is in a molar excess overthe dicarboxylate.
5. A process according to any preceding claim wherein the reaction takes place in an inert organic solvent in the range 50"C to the reflux temperature.
6. A process according to any preceding claim, which is followed by the deamination of the compound of the general formula I, to form a compound of the general formula
7. A process substantially as hereinbefore described with reference to the Examples.
8. A compound of the general formula I, as defined in any of claims 1 to 3.
9. A compound of the general formula IV, as defined in claim 6, but not 5-methyl-2,3-pyridinecarboxylic acid, diethyl ester.
GB8705472A 1986-03-10 1987-03-09 2,3-pyridine dicarboxylic acid derivatives Expired - Fee Related GB2188318B (en)

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GB868605868A GB8605868D0 (en) 1986-03-10 1986-03-10 Preparation of heterocyclic compounds

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GB8705472D0 GB8705472D0 (en) 1987-04-15
GB2188318A true GB2188318A (en) 1987-09-30
GB2188318B GB2188318B (en) 1990-02-14

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GB8705472A Expired - Fee Related GB2188318B (en) 1986-03-10 1987-03-09 2,3-pyridine dicarboxylic acid derivatives

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BE (1) BE1003158A5 (en)
CH (1) CH671762A5 (en)
DE (1) DE3707530A1 (en)
FR (1) FR2595354B1 (en)
GB (2) GB8605868D0 (en)
NL (1) NL8700324A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2549894C2 (en) * 2008-12-08 2015-05-10 Басф Се Method for producing substituted 5-methoxymethylpyridine-2, 3-dicarboxylic acid derivatives

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Publication number Priority date Publication date Assignee Title
DE19518739A1 (en) * 1995-05-22 1996-11-28 Basf Ag N-aminopyridone derivatives
JP2019502729A (en) * 2016-01-22 2019-01-31 ダウ アグロサイエンシィズ エルエルシー Process for producing 4-alkoxy-3-hydroxypicolinic acid

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EP0067511A3 (en) * 1981-05-19 1983-04-06 Imperial Chemical Industries Plc Method of inducing tillering using pyridine derivatives, and some of the pyridines themselves, process for preparing them and agricultural compositions containing them
US4748244A (en) * 1984-05-11 1988-05-31 Ciba-Geigy Corporation Process for the preparation of pyridine-2-3-dicarboxylic acid derivatives, and novel 1-amino-1,4-dihydropyridine-2-3-diarboxylic acid derivatives
BR8502364A (en) * 1984-05-21 1986-01-21 American Cyanamid Co PROCESS FOR THE PREPARATION OF PYRIDINE 2,3-DICARBOXYLATES, 5-REPLACED, 6-REPLACED AND 5,6-DISSUBSTITUTED
US4754033A (en) * 1984-08-10 1988-06-28 Ciba-Geigy Corporation Process for producing pyridine-2,3-dicarboxylic acid derivatives; and novel 1-amino-1,2,3,4-tetrahydropyridine-2,3-dicarboxylic acid derivatives and 1,4-dihydropyridine-2,3-dicarboxylic acid derivatives
EP0221023A3 (en) * 1985-10-25 1988-11-09 Ciba-Geigy Ag Process for the preparation of pyridine-2-carboxylic-acid derivatives and 1-amino-1,4-dihydropyridine-2-carboxylic-acid derivatives
US4723011A (en) * 1985-10-28 1988-02-02 American Cyanamid Company Preparation of substituted and disubstituted-pyridine-2,3-dicarboxylate esters

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2549894C2 (en) * 2008-12-08 2015-05-10 Басф Се Method for producing substituted 5-methoxymethylpyridine-2, 3-dicarboxylic acid derivatives

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Publication number Publication date
BE1003158A5 (en) 1991-12-17
JP2631644B2 (en) 1997-07-16
GB8705472D0 (en) 1987-04-15
GB8605868D0 (en) 1986-04-16
GB2188318B (en) 1990-02-14
JPH08198852A (en) 1996-08-06
DE3707530A1 (en) 1987-09-17
NL8700324A (en) 1987-10-01
JPH0832683B2 (en) 1996-03-29
CH671762A5 (en) 1989-09-29
FR2595354A1 (en) 1987-09-11
FR2595354B1 (en) 1993-11-26
JPS62212368A (en) 1987-09-18

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Effective date: 19950309

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PCNP Patent ceased through non-payment of renewal fee

Effective date: 20000309