CN1067379C - Process of 5-(substituted methyl)-2,3-pyridinedicarboxylic acids - Google Patents
Process of 5-(substituted methyl)-2,3-pyridinedicarboxylic acids Download PDFInfo
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- CN1067379C CN1067379C CN98103644A CN98103644A CN1067379C CN 1067379 C CN1067379 C CN 1067379C CN 98103644 A CN98103644 A CN 98103644A CN 98103644 A CN98103644 A CN 98103644A CN 1067379 C CN1067379 C CN 1067379C
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Abstract
A method for the preparation of 5-(substituted methyl)-2,3-pylidinedicarboxylic acids having the following formula, wherein Z and Z1 are hydrogen, A is oxygen, and R7 is an alkyl group having 1 to 3 carbon atoms.
Description
Patent application of the present invention is dividing an application of application for a patent for invention CN93105332.3.
The invention belongs to organic chemistry filed, relate to the synthetic of substituent methyl pyridine dicarboxylic acid compound.
U.S. Patent No. 5,064,842; 5,137,889; 5,063,237 and 5,034,395 disclose some has the dichloropyridine derivative of pharmaceutical activity.U.S. Patent No. 5,125,961 have described the substituted pyridine herbicides of You isoxazolyl on 3.European patent application No.0299362 discloses the method for preparing pyridine 2,3 dicarboxylic acid from ketene compound and amino diester compound.European patent application No.0461401 discloses from the dichloromaleic acid dialkyl and has prepared pyridine-2, the method for 3-dicarboxylic acid dialkyl and derivative thereof.
An object of the present invention is to provide at high purity 5-(substituent methyl)-2 useful as intermediates 5 in the preparation of 3-pyridine dicarboxylic acid class, 6-two replacement-3-picolyl ammonium halide compounds.
Of the present invention also have a purpose to provide preparation 5, the method for 6-two replacement-3-picolyl ammonium halide compounds and from 5, and 6-two replacement-3-picolyl ammonium halide compounds prepare 5-(substituent methyl)-2, the method for 3-pyridine dicarboxylic acid compounds.
The present invention relates to 5 of molecular formula I, 6-two replacement-3-picolyl ammonium halide compounds
Wherein
Z is a hydrogen or halogen;
Z
1Be hydrogen, halogen, cyano group or nitro;
X is Cl, Br, I or R
3SO
3
R
3Be C
1-C
4Alkyl or can be arbitrarily selectively by 1-3 C
1-C
4Alcoxyl base class, C
1-C
4The phenyl that alkyls, nitro, cyano group or halogen atom replace;
Y and Y
1Be independent O R separately
4, NR
4R
5Or (YY when connecting together
1) be-O-,-S-or-NR
6-;
R
4And R
5Be hydrogen independently separately,
Can be arbitrarily selectively by C
1-C
4Alkoxyl group replaces, or by can be arbitrarily selectively by 1-3 C
1-C
4Alkyl, C
1-C
4The C that phenyl replaced that alkoxyl group or halogen atom replace
1-C
4Alkyl,
Can be arbitrarily selectively by 1-3 C
1-C
4Alkyl, C
1-C
4The phenyl that alkoxyl group or halogen atom replace;
R
6Be hydrogen or C
1-C
4Alkyl;
Q is
R, R
1And R
2Be C independently separately
1-C
4Alkyl, and when linking together, R and R
1Can form five yuan or six-ring, wherein RR
1Represent with following formula :-(CH
2) n-, can be arbitrarily selectively by O, S or NR
10Be interrupted, n is an integer 3,4 or 5, if R
2Be C
1-C
4Alkyl; Z
2Be O, S or NR
10R
10Be C
1-C
4Alkyl; And R
11And R
12Be independently hydrogen, halogen, C separately
1-C
4Alkyl or C
1-C
4Alkoxyl group, and when linking together, R
11And R
12Can form saturated or undersaturated five yuan or six-ring, this ring can be arbitrarily selectively by O, S or NR
10Be interrupted, and can be arbitrarily selectively by 1-3 halogen atom, C
1-C
4Alkyl or C
1-C
4Alkoxyl group replaces.
The effective ways and these compounds that the invention still further relates to preparation high purity formula I compounds are preparing 5-(substituent methyl)-2 shown in the high purity formula II, the application in the method for 3-pyridine dicarboxylic acid compounds.
Wherein, Z is a hydrogen or halogen; Z
1Be hydrogen, halogen, cyano group or nitro; A is O or S; And R
7Be the C that can selectively be replaced arbitrarily by phenyl
1-C
4Alkyl, wherein phenyl can be arbitrarily selectively by 1-3 C
1-C
4Alkyl or halogen atom replace, or can be at random by 1-3 C
1-C
4The phenyl that alkyl or halogen atom replace,
X is that the formula I compounds of Cl or Br can prepare like this: in the presence of first solvent, selectively in the presence of catalytic amount group initiator, be preferably in 0 ° of-100 ℃ of temperature range, with formula III compound 5-methyl-2,3-pyridine dicarboxylic acid analog derivative
(wherein Z, Z
1, Y and Y
1As mentioned above), generate the first ' mixture that contains formula IV compounds with the halogenating agent reaction
(wherein Z, Z
1, Y and Y
1As mentioned above, X is Cl or Br), the consumption of selection halogenating agent makes the output of formula IV b compounds minimum.Then, in the presence of second solvent, be preferably in about 0 ℃ of-100 ℃ of temperature range, with described the first ' mixture and at least 1.0 molar equivalent C
1-C
4Three alkanamines, can be at random by 1-3 C
1-C
4Alkyl, C
1-C
4Five yuan of replacing of alkoxyl group or halogen atom to the hexa-atomic saturated or undersaturated heterocyclic amine of 5-14 unit reacts, shown in the production I 5, and 6-two replacement-3-picolyl ammonium halide compounds, the preparation method illustrates in the flow process I.
The flow process I
Aforesaid method is effective especially for the preparation of following formula I compounds, and Z is a hydrogen in these compounds; Z
1Be hydrogen; X is Cl or Br; Y and Y
1Be independent O R separately
4R
4Be C
1-C
4Alkyl; And R, R
1And R
2Be independently methyl or ethyl separately, or if no R
2, R and R
1The nitrogen-atoms that is connected with them is joined together to form pyridine ring.
The preferable formula I compound prepared with method of the present invention is ((5,6-dicarboxyl-3-pyridyl) methyl) trimethylammonium bromide, dimethyl ester; ((5,6-dicarboxyl-3-pyridyl) methyl) trimethylammonium bromide, diethyl ester; ((5,6-dicarboxyl-3-pyridyl) methyl) pyridine bromide, dimethyl ester; 1-((5,6-dicarboxyl-3-pyridyl) methyl)-4-picoline bromide, dimethyl ester; 1-((5,6-dicarboxyl-3-pyridyl) methyl) pyrazine bromide, dimethyl ester; 1-((5,6-dicarboxyl-3-pyridyl) methyl) pyridazine bromide, dimethyl ester; 1-((5,6-dicarboxyl-3-pyridyl) methyl) quinoline bromide, dimethyl ester; 1-((5,6-dicarboxyl-3-pyridyl) methyl) isoquinoline 99.9 bromide, dimethyl ester; 3-((5,6-dicarboxyl-3-pyridyl) methyl)-4,5-dimethylthiazole bromide, dimethyl ester; 3-((5,6-dicarboxyl-3-pyridyl) methyl)-4-methyl thiazole bromide, dimethyl ester; And 1-((5,6-dicarboxyl-3-pyridyl) methyl)-3-Methylimidazole bromide, dimethyl ester; And 1-((5,6-dicarboxyl-3-pyridyl) methyl) benzothiazole bromide, dimethyl ester.
By filtering or use water extraction, separablely go out highly purified formula I compounds.
The amine that can be used for the inventive method is an alkanamine, can be randomly by 1-3 C
1-C
4Alkyl, C
1-C
4Saturated and the 5-14 membered unsaturated heterocycle amine of 5-6 unit that alkoxyl group or halogen atom replace.Preferable amine is C
1-C
4Three alkanamines, 5 or 6 yuan of saturated heterocyclic amine and 5-14 membered unsaturated heterocycle amine, wherein heterocyclic ring system contains 1-3 nitrogen-atoms, and can at random contain sulphur or oxygen on heterocyclic ring system.
Better amine comprises the alkanamine class, Trimethylamine 99 and triethylamine; The saturated heterocyclic amine comprises pyridines, picoline class, pyrazine class, pyridazine class, triazines, quinoline, iloquinoline derivative, imidazoles, benzothiazoles and benzimidazoles, and they can be at random by 1-3 halogen atom, C
1-C
4Alkyl or C
1-C
4Alkoxyl group replaces; And the unsaturated heterocycle amine, as pyrrolidines, piperidines, piperazines, morpholine class, thiazolidines and parathiazan class.
The consumption of halogenating agent depends on reactive mode (in batches to continuous) and is used to reclaim the recirculation step of unreacted starting material matter.Typically, batch reaction is used about 0.3-0.8 molar equivalent halogenating agent, and in successive reaction, beginning only needs the halogenating agent of less molar equivalent.
The halogenating agent that can be used for the inventive method comprises N-bromosuccinimide, 1,3-two bromo-5,5-dimethyl acetylurea, bromine, chlorine, t-butyl hypochlorite's salt, SULPHURYL CHLORIDE, sulfuryl bromide, N-chlorosuccinimide etc.Preferable halogenating agent is chlorine, bromine, N-bromosuccinimide, 1,3-dibromo 5,5-T10 and SULPHURYL CHLORIDE.The group initiator that is applicable to the inventive method comprises 2,2 '-Diisopropyl azodicarboxylate, 2,2 '-azo two (2-methylbutyronitrile), 2,2 '-azo two (2, the 4-methyl pentane nitrile), 1,1 '-azo two (cyclohexanenitrile) (1,1 '-azobis (cyclohex-anecarbonitrile)), organic and inorganic peroxide such as hydrogen peroxide, benzoyl peroxide etc., the photochemistry width of cloth is penetrated etc., with 2,2 '-azo two (isopropyl cyanide) and 2,2 '-azo two (2-methylbutyronitrile) is preferable.Can be used for the C of the inventive method
1-C
4In the three alkanamine classes, Trimethylamine 99 and triethylamine are arranged.
The solvent that can be used for the inventive method comprises halogenated hydrocarbon such as Ethylene Dichloride, tetracol phenixin etc., halogenated aryl hydrocarbon class such as chlorobenzene, dichlorobenzene etc., oil of mirbane, acetate, water and alcohols such as methyl alcohol, ethanol, n-propyl alcohol etc., and the mixture of above-mentioned solvent.First solvent comprises chlorobenzene, dichlorobenzene and tetracol phenixin and chlorobenzene and methanol mixture preferably.Second solvent comprises methyl alcohol, ethanol, chlorobenzene preferably.
The other method for preparing some formula I compound is the flow process II of face as follows:
The flow process II
Wherein, Z, Z
1, R
3, Y and Y
1As top described about the formula I.
Equally, can prepare other formula I compounds with reaction formula shown in the flow process II:
The flow process III
Wherein, Z, Z
1, Y and Y
1As top described about the formula I, X is I or R as mentioned above
3SO
3
Perhaps, make formula IV mixture, can prepare R, R by containing amino substituent anionite-exchange resin
1Or R
2C
1-C
4A formula I compound that is connected on the polymer materials in the alkyl.Very advantageously, formula IV b and IV c compound do not react with resin thereby are removed.High purity ammonium halide compound is further reacted, obtain formula II compound.
At preparation high purity formula II compounds 5-(substituent methyl)-2, in the method for 3-pyridine dicarboxylic acid class, formula I compound of the present invention is an intermediate.Formula II compounds can be by preparing as the below: in the presence of organic solvent, be preferably in 0 ° of-110 ℃ of temperature range formula I compounds 5 as mentioned above, the formula V alkoxide or the thioether reactant of 6-two replacements-3-picolyl ammonium halides and at least 1.0 molar equivalents
R
7A-M
+
R in (V) formula V
7With A such as top described about the formula II, M is basic metal such as sodium or potassium, generate first mixture, in about 20 ℃ of-120 ℃ of temperature ranges, described first mixture is further reacted with at least 2.0 molar equivalent bucks, generate second mixture, be adjusted to below 2.5 with the pH value of acid again described second mixture, 5-shown in the production II (substituent methyl)-2,3-pyridine dicarboxylic acid compounds.This preparation method illustrates in the flow process IV.
The flow process IV
Aforesaid method of the present invention is for preparation Z and Z
1For hydrogen, A are O or S, R
7Be C
1-C
4The high purity formula II compound of alkyl is effective especially.A preferable formula II compound with this method preparation of the present invention is a 5-methoxymethyl-2, the 3-pyridine dicarboxylic acid.
By filtering or with the detachable II compounds of suitable solvent extraction.In sepn process, suitable extraction solvent comprises tetrahydrofuran (THF) and uses separately with alcohol that water can not dissolve each other or mix use with toluene.
The buck that is applicable to the inventive method comprises aqueous sodium hydroxide solution, potassium hydroxide aqueous solution etc.The acid that can be used for the inventive method comprises that ore deposit acid is as sulfuric acid, hydrochloric acid etc.
The organic solvent that can be used for the inventive method comprises acetonitrile, tetrahydrofuran (THF), aromatic hydrocarbons, R
7OH alcohols (R wherein
7As top described about the formula II) etc.Inert organic solvents comprises corresponding to above-mentioned formula II R preferably
7Alcohols such as methyl alcohol and ethanol.
Perhaps, but by the corresponding diester class of following reaction preparation formula II compound shown in the flow process V:
The flow process V
Wherein Z, Z
1, R
7, A, Q, X and M as mentioned above; R
4For can be randomly by C
1-C
4The C that alkoxyl group or phenyl replace
1-C
4Alkyl, wherein phenyl can be at random by 1-3 C
1-C
4Alkyl, C
1-C
4Alkoxyl group or halogen atom replace, or are can be at random by 1-3 C
1-C
4Alkyl, C
1-C
4The phenyl that alkoxyl group or halogen atom replace.
High purity formula II compound can be used for preparing weedkiller 2-shown in the structural formula VI (2-tetrahydroglyoxaline-2-yl) pyridine compounds as initial substance
R wherein
8Be C
1-C
4Alkyl; R
9Be C
1-C
4Alkyl or C
3-C
6Cycloalkyl;
Work as R
8And R
9When linking together with the carbon atom that links to each other with them, can represent can be at random by methyl substituted C
3-C
6Cycloalkyl; Z is a hydrogen or halogen; Z
1Be hydrogen, halogen, cyano group or nitro; A is O or S; R
7The C that can selectively be replaced arbitrarily by phenyl
1-C
4Alkyl, wherein phenyl is can be arbitrarily selectively by 1-3 C
1-C
4Alkyl or halogen atom replace, or
Can be arbitrarily selectively by 1-3 C
1-C
4The phenyl that alkyl or halogen atom replace; Reach and work as R
8And R
9When representing different substituents, the optically active isomer that forms by them.
Very advantageously, the product (being formula VI compound) that makes from formula II compound with the inventive method is more than the purity nice and high of the formula VI compounds that obtains with prior art.
In order to be beneficial to the further the present invention of understanding, provide the following examples, they are done detailed especially elaboration.Unless defined in claim, the present invention is therefore not restricted.Term NMR refers to nucleus magnetic resonance, and HPLC refers to high pressure liquid chromatography.
Embodiment 1
With N-bromosuccinimide preparation ((5,6-dicarboxyl-3-pyridyl) methyl)
The trimethylammonium bromide dimethyl ester
Under nitrogen, with 5-methyl-2,3-pyridine dicarboxylic acid dimethyl ester (523g, 2.5mol) mixture heating up to 85 in chlorobenzene (2440ml) ℃.Under 80-90 ℃, through 1 hour with N-bromosuccinimide (356g, 2.0mol) and 2,2 '-(12.5g, mixture 0.076mol) is added in the reaction mixture Diisopropyl azodicarboxylate.Behind reinforced the finishing, reaction mixture 80 ℃-90 ℃ insulations 1 hour, is cooled to ambient temperature overnight, dilute with water.Isolate organic layer,, be cooled to 10 ℃ with the methyl alcohol dilution, and the adding Trimethylamine Anhydrous (180ml, 1.8mol).Under 5 °-10 ℃, reaction mixture was stirred 3 hours, filter, obtain solid.With this solid dried overnight in vacuum drying oven, obtain title product, be a white solid (429g, mp200 ℃ of-208 ℃ of decomposition).
By above-mentioned steps, but with 5-methyl-2,3-pyridine dicarboxylic acid diethyl ester replacement 5-methyl-2,3-pyridine dicarboxylic acid dimethyl ester, obtaining ((5,6-dicarboxyl-3-pyridyl) methyl) trimethylammonium bromide diethyl ester, is a white solid (mp156 ° of-161 ℃ of decomposition).
Embodiment 2
With 1,3-two bromo-5,5-dimethyl beta-lactam preparation ((5,6-dicarboxyl-3-pyridyl)
Methyl) trimethylammonium bromide dimethyl ester
Under nitrogen, with 5-methyl-2,3-pyridine-dimethyl dicarboxylate (104.5g, 0.5mol) mixture heating up to 85 in chlorobenzene (470ml) ℃.At 80 ℃-90 ℃, through 30 minutes with 1,3-two bromo-5,5-dimethyl beta-lactam (71.5g, 0.25mol) and 2,2 '-(2.5g, mixture 0.015mol) is added in the reaction mixture Diisopropyl azodicarboxylate.Behind reinforced the finishing, reaction mixture is kept 80 °-85 ℃ reach 3.5 hours, be cooled to room temperature, wash with water and drying.Dried organic mixture is diluted with methyl alcohol, be cooled to 10 ℃, and the adding Trimethylamine Anhydrous (17.4g, 0.29mol).Under 10 ℃-36 ℃, the reaction mixture stirring is spent the night, filter, get a solid.Wash this solid with chlorobenzene, vacuum-drying gets title product, is a white solid (74.4g, 200 ° of-208 ℃ of decomposition of mp).
Embodiment 3
5-(methoxymethyl)-2, the preparation of 3-pyridine dicarboxylic acid
Under nitrogen, with the methanol solution of 25% sodium methylate (270g, 1.25mol) and ((5,6-dicarboxyl-3-pyridyl) methyl) trimethylammonium bromide dimethyl ester (347g, the mixture heating up of methanol solution 1.00mol) (650ml) refluxed 1 hour.(80.0g, 2.0mol), it is 100 °-105 ℃ that reaction mixture is distilled to retort to add entry (11) and sodium hydroxide.Reaction mixture is cooled to room temperature, is 1.5-2 with the sulphur acid for adjusting pH value, filters, and gets a solid.Wash this solid with water, dry in vacuum drying oven, get title product, be that a white solid (mp161 °-162 ℃) is analyzed through HPLC, its purity is higher than 99%.
Embodiment 4
5-(brooethyl)-2, the preparation of 3-pyridine dicarboxylic acid dimethyl ester
With 5-methyl-2,3-pyridine dicarboxylic acid dimethyl ester (30.0g, 0.143mol), N-bromosuccinimide (32.0g, 0.18mol) and 2,2 '-(0.9g, 0.0055mol) mixture of tetrahydro-carbon liquid (200ml) was 80 ℃ of heating 1.5 hours for Diisopropyl azodicarboxylate.Add 2,2 again '-(0.9g 0.0055mol), with reaction mixture reflux 2 hours, is cooled to room temperature and filters Diisopropyl azodicarboxylate.With tetracol phenixin washing filter thing.Merging filtrate and washing lotion wash with water, and vacuum concentration gets an oily matter.HPLC shows that this oily matter contains 57% title product, 16%5-methyl-2, and 3-pyridine dicarboxylic acid dimethyl ester and 23%5-two brooethyls-2,3-is than diphosphoglyceric acid dimethyl ester.
Embodiment 5
((5,6-dicarboxyl-3-pyridyl) methyl)
The preparation of pyridinium tribromide compound dimethyl ester
In nitrogen, oily matter (32.0g) and pyridine (9.2g that embodiment is made, 0.12mol) mixture heating up in dehydrated alcohol refluxed 2 hours, be cooled to room temperature and filter filter cake washing with alcohol, 50 ℃ of vacuum-dryings, get title product, be a solid (18.1g), analyze that its purity is higher than 99% through HPLC.
Embodiment 6
In ethanol, prepare ((5,6-dicarboxyl-3-pyridyl) with Trimethylamine Anhydrous
Methyl) trimethylammonium bromide dimethyl ester
Under nitrogen, will be cooled to 5 ℃ by the mixture of embodiment 4 gained oily matter (100g) in dehydrated alcohol, (16g 0.27mol), stirs reaction mixture 3 hours down at 5 ℃, filters to add Trimethylamine Anhydrous.The filter cake washing with alcohol, dry air gets title product, is a white solid (49.1g).
Embodiment 7
5-(methoxymethyl)-2, the preparation of 3-pyridine dicarboxylic acid dimethyl ester
With the methanol solution of 25% sodium methylate (320.0g, 1.5mol) and (5,6-dicarboxyl-3-pyridyl) methyl) trimethylammonium bromide dimethyl ester (160.0g, methanol solution 0.5mol) (650ml) mixes, reflux is 6 hours under nitrogen.Reaction mixture is cooled to 5 ℃, adds acetate (90g) and water (200ml).Vacuum is removed methyl alcohol, adds water, with this mixture of dichloromethane extraction.Merge organic extracting solution, use 5% sodium hydrogen carbonate solution and water washing in succession, vacuum concentration gets a clarified liq (83.2g), uses
1The HNMR spectrum analysis is accredited as title product.
According to above-mentioned steps, but with ((5,6-dicarboxyl-3-pyridyl) methyl) pyridine bromide dimethyl ester substitute [(5,6-dicarboxyl-3-pyridyl) methyl) the trimethylammonium bromide dimethyl ester, title product, be a clarified liq.
Embodiment 8
5-(methoxymethyl)-2, the preparation of 3-pyridine dicarboxylic acid
Under nitrogen, with 5-(methoxymethyl)-2, (60.0g, 0.25mol) (50.0g, mixture 0.63mol) heated 2 hours down at 90-110 ℃ 3-pyridine dicarboxylic acid dimethyl ester, boiled off the first alcohol and water with 50% aqueous sodium hydroxide solution.Reaction mixture is cooled to 10 ℃, regulates pH to 2.0, filter, get a solid with sulfuric acid.Wash this solid with water, vacuum-drying gets title product, is a white solid (44.3g, mpl61 °-162 ℃).
Embodiment 9
2,3-pyridine dicarboxylic acid, 5-(aromatic amine) monobromomethane, the preparation of dimethyl ester
Under nitrogen, in the 250ml flask, add the table listed reaction solvent of I (100ml dehydrated alcohol or 200ml methyl alcohol/chlorobenzene 50/50 mixed solution), rough 5-one bromo methyl cycloheptapyridine-2 of 30g, 3-dimethyl dicarboxylate (recording purity through HPLC is 57%) and 0.1 mole of listed aromatic amine of table I.Mixture heating up is refluxed and be incubated about 5 hours.Under 40-60 ℃ of vacuum, remove reaction solvent.The residue obtained room temperature that is cooled to, the organic solvent that is decided to be " slurry agent " (" slurry solvent) with table in the I is made into slurry.Then mixture is filtered, filter cake washs with about 50ml slurry agent.The resulting crystalline forms solid is surveyed fusing point in 50 ℃ of following vacuum-dryings, uses
1H,
13C, NMR and
13C ATP1 NMR fixed structure.
The table I
4-methyl-2,3-dimethyl dicarboxylate's fragrant amine salt
Table I (continuing)
Claims (10)
1. preparation has the 5-substituent methyl-2 of following structural formula, the method for 3-pyridine dicarboxylic acid compound
Wherein Z is a hydrogen;
Z
1Be hydrogen;
A is O; And
R
7Be C
1-C
4Alkyl,
The method is characterized in that:
In the presence of organic solvent, will have 5 of following structural formula, 6-two replacement-3-picolyl ammonium halide compounds
Wherein
Z is a hydrogen;
Z
1Be hydrogen;
X is Cl, Br or I;
Y and Y
1Be OR independently of one another
4
R
4Be hydrogen or C
1-C
4Alkyl;
Q is
R, R
1And R
2Be C independently of one another
1-C
4Alkyl,
Z
2Be S or NR
10
R
10Be C
1-C
4Alkyl; And
R
11And R
12Be hydrogen or C independently of one another
1-C
4Alkyl, when linking together, R
11And R
12Can form saturated or undersaturated six-ring,
The alkoxide cpd that has following structural formula with at least 1.0 molar equivalents reacts
R
7A-M
+
R wherein
7With A as mentioned above, M is a basic metal, generates first mixture, described first mixture is further reacted with at least 2.0 molar equivalent bucks, generate second mixture, below the pH regulator to 2.5 of acid described second mixture, generate 5-substituent methyl-2,3-pyridine dicarboxylic acid compound.
2. by the described method of claim 1, wherein buck is selected from aqueous sodium hydroxide solution and potassium hydroxide aqueous solution; Acid is selected from sulfuric acid and hydrochloric acid; Organic solvent is R
7OH alcohol, wherein R
7According to claim 1; The temperature of first mixture is 20 ℃-110 ℃, and the temperature of second mixture is 20 ℃-120 ℃.
3. by the described method of claim 2, wherein R
7OH alcohol is selected from methyl alcohol and ethanol.
4. by the described method of claim 1, wherein
Z is a hydrogen;
Z
1Be hydrogen;
A is O;
R
7Be C
1-C
4Alkyl;
X is Cl or Br;
Y and Y
1Be OR independently of one another
4
R
4Be C
1-C
4Alkyl;
Q is
R, R
1And R
2Be methyl or ethyl independently of one another; And R
11And R
12Be hydrogen or C independently of one another
1-C
4Alkyl, when linking together, R
11And R
12Saturable or unsaturated six-ring.
5. by the described method of claim 4,5-substituent methyl-2 wherein, 3-pyridine dicarboxylic acid compound is a 5-methoxyl group-2, the 3-pyridine dicarboxylic acid.
6. the method for claim 1, its Chinese style I compound prepares in the following way:
In first solvent, selectively in the presence of the group initiator, will have the 5-methyl-2 of following structural formula, 3-pyridine dicarboxylic acid compound
Wherein
Z is a hydrogen;
Z
1Be hydrogen;
Y and Y
1Be OR independently of one another
4
R
4Be hydrogen or C
1-C
4Alkyl,
With the halogenating agent reaction, generate the first ' mixture of the compound that contains following structural formula
Wherein Z, Z
1, Y and Y
1As mentioned above, X is Cl or Br, in second solvent, described the first ' mixture and at least 1.0 molar equivalents is had the amine reaction of following structural formula
Wherein R, R
1And R
2Be C independently of one another
1-C
4Alkyl; Z
2Be S or NR
10R
11And R
12Be hydrogen or C independently of one another
1-C
2Alkyl, when connecting together, R
11And R
12Can form saturated or unsaturated six-ring;
Generation has 5 of following structural formula, 6-two replacement-3-picolyl ammonium halide compounds
Wherein Z, Z
1, X, Y and Y
1As mentioned above;
R, R
1And R
2Be C independently of one another
1-C
4Alkyl;
Z
2Be S or NR
10
R
10Be C
1-C
4Alkyl; And
R
11And R
12Independently be hydrogen or C separately
1-C
4Alkyl, when linking together, R
11And R
12Can form saturated or unsaturated six-ring.
7. by the described method of claim 6, it is characterized in that: wherein the group initiator is a catalytic amount; The amount of halogenating agent is at least 0.3 molar equivalent; Halogenating agent is selected from N-bromo amber imide, 1,3 two bromo-5,5-dimethyl beta-lactam, chlorine, bromine, sulfuryl bromide and SULPHURYL CHLORIDE; The group initiator is selected from 2,2 '-Diisopropyl azodicarboxylate, 2,2 '-azo two (2-methylbutyronitrile), 2,2 '-azo two (2, the 4-methyl pentane nitrile) and 1,1-azo two (ring acetonitrile); Amine is selected from Trimethylamine 99 and triethylamine; The temperature of first mixture is 0 ℃-100 ℃.
8. by the described method of claim 6, wherein first solvent is selected from tetracol phenixin and chlorobenzene; Second solvent is selected from chlorobenzene and R
7OH alcohol, wherein R
7As mentioned above.
9. by the described method of claim 8, wherein R
7OH alcohol is selected from methyl alcohol and ethanol.
10. by the described method of claim 6, wherein
Z is a hydrogen;
Z
1Be hydrogen;
A is O;
R
7Be C
1-C
4Alkyl;
X is Cl and B;
Y and Y
1Be OR independently of one another
4
R
4Be C
1-C
4Alkyl;
Q is
R, R
1And R
2Be methyl or ethyl independently of one another; And R
11And R
12Be hydrogen or C independently of one another
1-C
4Alkyl, when connecting together, R
11And R
12Can form saturated or unsaturated six-ring.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/960,749 US5288866A (en) | 1991-12-20 | 1992-10-14 | 5,6-disubstituted-3-pyridylmethyl ammonium halide compounds useful for the preparation of 5- (substituted methyl)-2,3-pyridinedicarboxylic acids |
| US07/960,749 | 1992-10-14 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93105332A Division CN1042333C (en) | 1992-10-14 | 1993-04-30 | 5,6-disubstituted-3-pyridiylmethyl ammonium halide compounds useful, for the preparation of 5-(substituted methyl)-2,3-pyridinedicarboxylic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1190094A CN1190094A (en) | 1998-08-12 |
| CN1067379C true CN1067379C (en) | 2001-06-20 |
Family
ID=25503566
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93105332A Expired - Lifetime CN1042333C (en) | 1992-10-14 | 1993-04-30 | 5,6-disubstituted-3-pyridiylmethyl ammonium halide compounds useful, for the preparation of 5-(substituted methyl)-2,3-pyridinedicarboxylic acids |
| CN98103644A Expired - Lifetime CN1067379C (en) | 1992-10-14 | 1998-01-13 | Process of 5-(substituted methyl)-2,3-pyridinedicarboxylic acids |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93105332A Expired - Lifetime CN1042333C (en) | 1992-10-14 | 1993-04-30 | 5,6-disubstituted-3-pyridiylmethyl ammonium halide compounds useful, for the preparation of 5-(substituted methyl)-2,3-pyridinedicarboxylic acids |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN1042333C (en) |
| RU (1) | RU2090558C1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA103502C2 (en) * | 2008-11-13 | 2013-10-25 | Басф Се | Process for manufacturing 5,6-disubstituted-3-pyridylmethyl ammonium bromides |
| TWI506019B (en) * | 2008-12-08 | 2015-11-01 | Basf Se | Process for manufacturing substituted 5-methoxymethylpyridine-2,3-dicarboxylic acid derivatives |
| TWI537252B (en) * | 2011-01-25 | 2016-06-11 | 陶氏農業科學公司 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates |
| CN103613535A (en) * | 2013-11-26 | 2014-03-05 | 潍坊先达化工有限公司 | Synthesis method of 5-(methoxy methyl)-2,3-pyridine dimethyl dicarboxylate |
| CN105777623A (en) * | 2016-02-29 | 2016-07-20 | 北京颖泰嘉和生物科技股份有限公司 | Method for preparing pyridine side chain methyl quaternary ammonium compound |
| CN109467531A (en) * | 2017-09-08 | 2019-03-15 | 沈阳科创化学品有限公司 | A kind of preparation method of substituted pyridines dicarboxylic acid derivatives |
| CN113061125B (en) * | 2019-12-13 | 2022-11-01 | 沈阳中化农药化工研发有限公司 | Preparation method of imidazolidinone compound |
| CN113968814A (en) * | 2020-07-22 | 2022-01-25 | 帕潘纳(北京)科技有限公司 | Method for preparing 5-bromomethyl-2, 3-pyridine carboxylic acid dimethyl ester |
| CN114478477A (en) * | 2022-01-27 | 2022-05-13 | 江苏中旗科技股份有限公司 | Synthesis process of imazamox |
| CN114933561A (en) * | 2022-05-09 | 2022-08-23 | 沈阳万菱生物技术有限公司 | Preparation method of 5-substituted-2, 3-pyridine dicarboxylic ester compound and quaternary ammonium salt thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0299362A1 (en) * | 1987-07-08 | 1989-01-18 | Daiso Co., Ltd. | Process for preparing pyridine-2,3- dicarboxylic acid compounds |
| EP0461403A1 (en) * | 1990-06-15 | 1991-12-18 | American Cyanamid Company | Process for the preparation of dialkyl pyridine-2,3-dicarboxylate and derivatives thereof from dialkyl dichlorosucciante |
-
1993
- 1993-04-30 CN CN93105332A patent/CN1042333C/en not_active Expired - Lifetime
- 1993-05-11 RU RU93005302A patent/RU2090558C1/en active
-
1998
- 1998-01-13 CN CN98103644A patent/CN1067379C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0299362A1 (en) * | 1987-07-08 | 1989-01-18 | Daiso Co., Ltd. | Process for preparing pyridine-2,3- dicarboxylic acid compounds |
| EP0461403A1 (en) * | 1990-06-15 | 1991-12-18 | American Cyanamid Company | Process for the preparation of dialkyl pyridine-2,3-dicarboxylate and derivatives thereof from dialkyl dichlorosucciante |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1190094A (en) | 1998-08-12 |
| CN1094398A (en) | 1994-11-02 |
| RU2090558C1 (en) | 1997-09-20 |
| CN1042333C (en) | 1999-03-03 |
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