JPS5939416B2 - Process for producing nitroarylacetic acid ester and its derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing nitroarylacetic acid esters and derivatives thereof.

There are known techniques for making PrOfen-type drugs or other substances having relatively complex aryl groups attached to the α-carbon of substituted or unsubstituted acetic acids.

For example, U.S. Pat. No. 3,775,427 (Adams et al.), 3
959364 (Armitage et al.) and 42785
No. 16 (ZaikO et al.), various starting materials were synthesized into FlurbiprOfen, i.e., 2-(
2-Fluoro-4-biphenylyl)propionic acid and similar compounds with anti-inflammatory, analgesic and antipyretic properties; 3-Chloro 4-(3-
pyrrolinyl)phenyl]-propionic acid”, Expert
iential vol. 29, p. 938 (1972) describes, inter alia, ethyl 2-(3-chloro-4nitrobenzene).
teaches the production of these anti-inflammatory agents (also known as PirprOben) via propionate intermediates: US Pat. No. 4,239,901 (
Rainer) is a pyrazolyl compound with anti-inflammatory properties.
We show that phenyl and pyrazolinyl-1-phenylacetic acids can be synthesized from various intermediates, including polychloronitrobenzene acetate; and indoprofen (
IndOprOfen), i.e., 2-[4-(1,3 dihythro-1-oxo-2H-isoindol-2-yl)
phenyl]propionic acid, and indobuphene (In
It is known that 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]butyric acid can be prepared from the appropriate 2-(4nitrobenzene)-α-alkyl acetic acid. It is.

Nitroarylacetic acids and their esters, as well as their amino derivatives, have been found to be particularly useful intermediates for the synthesis of these pharmaceuticals.

However, in the past, a disadvantage of using them as pharmaceutical intermediates has been the difficulty of producing them by conventional techniques. Even the preferred procedure for making them is Example 23 of U.S. Pat. No. 3,868,391 (Carney et al.).
and Rainer's Example 16, both examples required several days at reflux to accomplish a small portion of their synthesis. indicates to use. It would clearly be a welcome contribution to the art to provide a method for the synthesis of nitrobenzene acetate and analogs and derivatives thereof in a simple and facile manner. The object of the present invention is to provide a method for producing nitroarylacetic acid esters in a simple and easy manner with high selectivity and moderate to good yields.

Another object is to provide new and improved methods for preparing ester derivatives. For these and other purposes, (a) nitroaromatic compounds are
reacting with a substituted acetate in a substantially anhydrous aprotic solvent and in the presence of a base, thereby causing nucleophilic substitution of the ester on the unsubstituted ring carbon of the nitroaromatic compound, during which The α substituent acts as a leaving group, thereby forming a nitroarylacetate, and (b) where appropriate, this is achieved by converting the nitroarylacetate into the desired derivative thereof. . The nitroaromatic compounds that can be utilized in the practice of this invention are: (1) they have at least one nitro substituent on the aromatic ring; (2) they have at least one nitro substituent on the aromatic ring; two substitutable hydrogens on the aromatic ring to which the nitro group is attached, and (3) substituents that would interfere with the desired nucleophilic substitution reaction, such as -NH2,
Includes various compounds such as -0H, -SH, -NHR, etc., which do not have substituents with acidic protons.

Therefore, the nitroaromatic compounds that can be utilized have one or more simple or fused 5- or 6-membered rings and contain no substituents other than nitro substituents, or contain various inert Substituents: halo, alkyl, alkoxy, alkylmercapto, trifluoromethyl, dialkylamino, dialkanoylimino, cyano, dialkylcarbamoyl, alkylsulfonyl, dialkylsulfamoyl, alkoxyalkyl, haloalkyl, cycloalkyl, halocycloalkyl, The alkyl chain in the etc. substituent generally includes compounds containing any substituent that does not interfere with the desired nucleophilic substitution reaction, such as one that is a lower alkyl chain.

("Lower alkyl" herein refers in its conventional sense to an alkyl group containing up to about 6 carbon atoms). If the nitroaromatic compound contains one or more rings, such inert substituents may be directly or indirectly on the same ring as the ring bearing the nitro substituent and/or on the ring bearing the nitro substituent. It is on the bonding ring. When the aromatic ring having the required nitro substituent is a 6-membered ring,
There will be at least one substitutable hydrogen in the para or ortho position to the carbon having the nitro substitution; and it is preferred to have a substitutable hydrogen in the para position.

Nitroaromatic compounds having a five-membered ring should have a substitutable hydrogen on a carbon adjacent to the carbon bearing the nitro substituent or separated by two ring atoms.

According to one embodiment of the invention, nitroaromatic compounds are compounds that do not have . . . rogens on the aromatic ring with the necessary nitro group.

Illustrative of such compounds are nitropyridine-
N-oxide, 5-nitroisoquinoline, 5- and 6
- Heterocyclic compounds containing 5- or 6-membered rings, preferably with aromatic character, such as nitroquinoline, 2-nitrothiophene, etc.; fused ring aromatic compounds, such as 1- and 2-nitronaphthalene; 2- , 3-, and 4-nitrobiphenyl, 2-3- and 4-benzylnitrobenzene, 2-nitrodiphenyl ether, etc.; and nitrobenzene, 2
Methylnitrobenzene, 2.3-, 2.5- and 3.
5-dimethylnitrobenzene, 2,4- and 2,6-
Diethylnitrobenzene, 3,4-dibutylnitrobenzene, 1,2- and 1,3 dinitrobenzene, 2,6
-dinitrotoluene, 1,2,3- and 1,2,4-
Trinitrobenzene, 2-nitro-N-N-diethylaniline, 4-nitro-N-ethylacetanilide, 2-
It is an aromatic compound containing a single simple ring such as nitrobenzyl cyanide, 2-nitrophenyl acetate, and the like.
According to another embodiment of the invention, nitroaromatic compounds are compounds having at least one single-portion substituent on the aromatic ring with the required nitro group.

Examples of such compounds are 2-3- and 4-chloronitrobenzene; 2,3-, 2,4, 2,5- 2,6-
, 3,4- and 3,5-dichloronitrobenzene; various trichloronitrobenzenes; similar fluoro, bromo and iodo compounds; various dimethyl-, diethyl-
, and dibutylnitrobenzene, nitrobiphenyl,
Benzylnitrobenzene, nitronaphthalene, di- and trinitrobenzene, nitro-N-N-diethylaniline, nitrodiphenyl ester, nitro-N-ethylacetanilide, nitrobenzyl cyanide, nitrophenyl acetate, nitropyridine-N-oxide, Nitroquinoline, ditroisoquinoline, nitrothiophene,
and one or more aruchloro, fluoro,
The like have bromo or iodo substituents and contain at least one substitutable hydrogen in the appropriate position. Preferred mono- and nitroaromatic compounds are those in which the mono- and chloro-substituents are fluoro, chloro, or bromo, as they tend to be removed for iodo substituents under the conditions of the substitution reactions of the present invention. Most preferred are fluoro or chloro. In some cases, the polynitroaromatic reactant undergoes a substitution reaction whereby one of the nitro groups is replaced by an ester reactant. Therefore, this potential for competitive reactions should be kept in mind when selecting polynitroaromatics for use in this process. Preferred nitroaromatic compounds in each of the above-described embodiments of the invention are nitrobenzenes having a substitutable hydrogen in the para position to the nitro group, which means that the nucleophilic substitution reaction of the invention is highly selective towards the para position. The use of such compounds therefore leads to the production of nitrobenzene acetates, which are ideally suited for the synthesis of anti-inflammatory agents of the type described in the above-mentioned references. .

Even the more preferred mono-nitrobenzenes are those having the halo substituent in the ortho position to the nitro group. Particularly preferred halonitrobenzenes are 2-chloronitrobenzene and 2-fluoronitrobenzene, which can be used with high selectivity to 2-[3-chloro-4-(3-pyrrolinyl)phenyl]propionic acid, 2
It is readily converted to products such as mono(2-fluoro-4-biphenylyl)-propionic acid and related anti-inflammatory agents. A particularly preferred non-...rogenated nitroaromatic compound is nitrobenzene, which has a high selectivity of 2-[4
-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]propionic acid, 2-[4-(
It is readily converted into pharmaceutically active agents such as 1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]butyric acid, and analogs thereof. The α·α-[u-substituted acetate esters that can be used in the practice of this invention also include a variety of compounds that can be generally represented by the following formula: where L is a residue; (preferably chloro) or more preferably hydrocarbyl (e.g. alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, etc.) or hydrocarbyl (e.g.
alkoxyalkyl, aryloxyalkyl, alkoxyaryl, alkoxycycloalkyl, etc.) groups, which most preferably contain up to about 10 carbons; and R' is a hydrocarbyl group, which preferably contains about 1
It contains up to 0 to 5 carbons and is most preferably an alkyl group.

Illustrative residues L include mono, aryloxy, no)roaryloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, haloalkylthio, halocycloalkylthio, haloarylthio, . -alkoxy, cycloalkoxy, aralkoxy, haloalkoxy, halocycloalkoxy, mono-roaralkoxy, and the like, as well as in the literature, e.g.
i, etc., [Nucleophilic Substitution of Hydrogen in Aromatic Nitro Compounds], TetrahedrOnLettersl37
Vol. 3495-8 (1978) and MalcOs.
Z.A. et al., “Substitute substitution of hydrogen in aromatic nitro compounds by acetonitrile derivatives”, JournalOfO
rganic Chemistryl volume 45, 1534-
5 (1980).

If the residue is an organic group, it is generally desirable that the group does not contain more than about 10 carbons (although this does not remain in the product), even if the organic residue has a higher carbon content. However, the implementation of the present invention is satisfactory.

Preferably the residue is halo, ie chloro, bromo, fluoro or ino-odo; and more preferably chloro or bromo and most preferably chloro.
Some examples of α・α-[wou-converted acetate esters that can be used are methyl, ethyl, propyl, isopropyl, butyl,
α-chloropropionates such as t-butyl, cyclohexyl, phenyl, and benzyl 2-chloropropionate; the corresponding α-furomopropionate; and other α-substituted monocarboxylic acid esters, such as methyl 2-chloropropionate; Monomethylmercaptopropionate; Ethyl 2-butylmercaptopropionate, Methyl 2-phenoxybutyrate, Phenyl 2-methylmercaptopropionate, Butyl 2-cyclohexylmercaptovalerate, Methyl 2-(4-Fluorofu) (enoxy)propionate, and the like. α-halo-α-halohydrocarbyl acetate, i.e. at least 3
Esters of α-halomonocarboxylic acids containing 5 carbons are particularly preferred, although analogous esters in which the α 1 . . . mouth substituent is replaced by other residues as described above are also highly desirable. In another highly preferred embodiment of the invention, the α·α-[u-substituted acetate is an α·α dihaloacetate, most preferably an α·α-dichloroacetate, which is in the α-position. leading to the formation of products with reactive mono-oral substituents, such as those corresponding to the formula: where X is halo, preferably chloro; R is a hydrocarbyl group, preferably up to about 10 carbon and n is an integer from 1 to 3).

Such products allow easy synthesis of various final products. Most preferably the nitro group is in the para position to the ester substituent, but it may also be placed in the ortho position. Examples of aprotic solvents that can be used in the process of the invention include diethyl ether, dibutyl ether, 1-ethoxyhexane, tetrahydrofuran, 1.
4-dioxane, 1,3-dioxolane, diglyme, 1
Ethers such as 2-diethoxyethane, anisole, etc.; tertiary such as pyridine, N-ethylpiperidine, triethylamine, tributylamine, N-N-diphenyl-N-methylamine, N-N dimethylaniline, etc. amines; and other aprotic solvents. However, preferred aprotic solvents are dipolar aprotic solvents such as dimethylsulfoxide, N-N-dimethylformamide, N-N-dimethylacetamide, dimethylsulfone, tetramethylenesulfone, N-methylpyrrolidone, and the like. It is. Bases useful in the practice of this invention include all bases strong enough to activate the ester reactants, such as calcium hydride to calcium oxide, calcium hydroxide, barium hydroxide to barium oxide, magnesium hydroxide, Contains alkaline earth metal compounds such as zinc hydroxide, etc.

However, the base is preferably an alkali metal compound, such as an organic alkali metal compound, an alkali metal hydride, an alkali metal hydroxide, an alkali metal oxide, an alkali metal amide, or an alkali metal alcoholate, examples of which include butyllithium, fluoride, etc. enyllithium, ethyl sodium, amyl sodium, butyl potassium, benzyl potassium, sodium dimsylate
(i.e. sodium salt of diethyl sulfoxide), sodium hydride, potassium hydride, sodium hydroxide,
Contains potassium hydroxide, potassium oxide, sodium amide, potassium amide, lithium diisopropylamide, sodium methoxide, potassium t-butoxide, sodium salt of monomethyl ether of ethylene glycol, sodium phenoxide, and the like. . The use of sodium hydride or potassium hydride will usually prove to be the most convenient and economical. The use of alkali metal compounds as bases
It allows the choice of using the alkali metal compound alone or in conjunction with a phase transfer catalyst such as a quaternary ammonium salt, ethylene glycol, or a suitable CrOwn ether.

When using a phase transfer catalyst: 1) The alkali metal compound may generally or specifically be any of the alkali metal compounds listed above, although the type of alkali metal compound used determines the type of crown ether, i.e. preferably The lithium base utilized is generally 12-crown-4
Requires the use of an ether, and the sodium base is generally 1
(2) the reaction medium can be any of the aprotic solvents listed above, or benzene, It may be an inert liquid hydrocarbon such as toluene, xylene, hexane, heptane, isooctane, or the like. When using an alkali metal hydride, especially a high purity alkali metal hydride, as the base, it is desirable to include a small amount of a transfer agent such as water, alcohol, or the like in the system.

It is believed that the transfer agent reacts with the hydride to form small amounts of alkali metal hydroxides or alcoholates. The nitroarylacetic acid ester synthesis of the present invention is carried out in a substantially anhydrous reaction system, thus using small amounts of water (which is itself consumed by reaction with the alkali metal hydride) as a transfer agent. Unless otherwise specified, the components of the reaction system should be combined and kept under a dry, inert atmosphere.
Therefore, although it is possible to carry out the process in the presence of air, it is desirable to maintain the reaction system under an atmosphere of dry nitrogen or the like. Since the reaction itself is usually exothermic, its initiation can be easily ascertained by observing the exotherm produced, and the reactants are usually allowed to combine at ambient temperature and, if desired, as required in the case. The temperature can be increased or decreased to match. : Toroaromatic compounds and α・α
The -[u-converted acetate esters can be used in amounts to provide a stoichiometric excess of either of the reactants or stoichiometric amounts of each.

However, when using a stoichiometric excess of nitroaromatics, the amount of product obtained is limited by the amount of ester used, so it is not possible to use a stoichiometric excess of ester. desirable. The amount of base used is preferably such that it provides at least 2 molar equivalents per mole of nitroaromatic compound, since the use of smaller amounts will result in one reaction but one base becomes the limiting agent. The mode of addition of the components of the reaction system is not particularly critical.

Therefore, the nitroaromatic compound is added to the mixture of other materials, the base is added to the mixture of other materials, the reactants are added to the mixture of base and aprotic solvent, and all four components are simultaneously added to the reaction zone. or similar methods are advantageous. Reactions usually proceed very rapidly, so
There is no need for long reaction times. The reaction is usually complete within about a few minutes or at ambient temperature within a few hours. If derivatives of nitroaromatic acetates are desired, they can be converted to the desired derivatives using conventional techniques.

Thus, for example: (4) alkyl 2-(4-nitrobenzene) propiotinate or alkyl 2-(3-chloro-4-nitrobenzene) synthesized by the method of the invention;
Propionate is hydrogenated to alkyl 2-(4-aminobenzene) propionate, which in turn reacts with phthalic anhydride to form alkyl 2-(4-phthalimidophenyl) propionate, which is reduced and It is hydrolyzed to 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-12yl)-phenyl]propionic acid. (8) Alkyl 2-(3-chloro-4-nitrobenzene)propionate synthesized by the method of the present invention is hydrolyzed to give 2-(3-chloro-4-nitrobenzene)propionic acid, which is sequentially converted into 2-( 4-aminobenzene) propionic acid, reacted with phthalic anhydride to form 2-(4-phthalimidophenyl) propionic acid, and reduced to 2-[4-(1,3-dihydro-1-oxo-1) 2H-isoindol-2-yl)-phenyl]propionic acid, and selectively alkyl 2-(4-
Propionate (amino-3-fluorobenzene) was prepared, which was then converted into Gomber
g-Bachmann) reaction to replace the amino group with a phenyl group and alkyl 2(2-fluoro-4-
Make 2-(biphenylyl) propionate and add it to 2-(
It can be hydrolyzed to 2-fluoro-4-biphenylyl)propionic acid.

The particular conventional techniques used to convert nitroaromatic acetate esters into their various derivatives are not critical.

It may sometimes be desirable to use certain specialized techniques for the preparation of derivatives, such as those described by Carne, supra.
y et al. and Carnery et al., the disclosures of which are hereby incorporated by reference. However, despite the individual techniques used to convert them into various derivatives, the present simplification of nitroaromatic acetate synthesis simplifies all methods for making the derivatives. And it becomes more efficient and economical. As mentioned above, the present invention is particularly advantageous in providing an easier and more economical means for the synthesis of pharmaceuticals and other chemical products that can be made from nitroaromatic acetate esters.

Such products include those mentioned above, as well as U.S. Pat.
868391;3936467;3993763;39
97669;4010274;4118504;412
6691; 4163788 and 4239901.

The following examples are given to illustrate the invention and are not intended to limit it.

Synthesis example of nitroaromatic acetate 1 3.0 ml (26 mmol) in a flame-dried flask
of 2-chloronitrobenzene, 2.9 ml (26 mmol) of methyl 2-chloropropionate and 25 ml of NN-dimethylformamide, which had been previously dried on 3-Angstrom molecular sieves.

The flask was held in water and 1.5 t (31 mmol) of sodium hydride was added as a 50% slurry in hydrocarbon oil in portions over 20 minutes. The reaction mixture turned red when the first increasing portion of sodium hydride was added and then turned deep purple when more base was added. After the entire amount of sodium hydride was added to the flask, the mixture was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then poured into 1N HCl and extracted with portions of diethyl ether to form ether layers which were combined, extracted with water, dried over MgSO4 and stripped to give a black oil. A small amount of the oil was analyzed by gas chromatography/mass spectrometry (GC/MS) and found to contain a product with the empirical formula ClOHlOClNO4. Another small amount was subjected to preparative thin layer chromatography and brown color analysis of the isolated product was consistent with the compound methyl 2-(3-chloro-4-nitrobenzene)propionate. Example 2 A flame drying flask was flushed with nitrogen to provide an inert atmosphere and charged with 5.1 t (110 mmol) of a 50% dispersion of sodium hydride in hydrocarbon oil.

Sodium hydride was dissolved in 15 ml of petroleum ether (boiling point 35
The flask was then charged with 15 mL of N-N-dimethylformamide that had been dried over 3-Angstrom molecular sieves. It is then added dropwise over 20 minutes to form a reaction mixture of a solution of 6 ml (51 mmol) of 2-chloronitrobenzene and 6 ml (53 mmol) of methyl 2-chloropropionate in 10 ml of N-N-dimethylformamide. Ivy. During the dropwise addition the mixture turned purple and became hot. After the addition was complete, the reaction mixture was stirred for a further 15 minutes, poured into 200 ml of 1N HCl and extracted three times with 150 ml portions of diethyl ether. Combining the ester layer, Mg
Dry over SO4 and concentrate to give a black oil which was chromatographed on a 2007 silica gel column eluting with 30% methylene chloride/70% Petroleum. The appropriate fractions were combined and concentrated to give 8.27 material, which was 94% (GC area %) or 7.77
Example 3 2-chloronitrobenzene/2-chloropropionate/N-N-dimethylformamide solution over 30 minutes Example 2 was repeated except that the reaction mixture was maintained at 25-30 DEG C. by occasional cooling with an ice/water bath during the addition, and stirring of the reaction mixture was continued for 30 minutes after the dropwise addition was complete.

The reaction mixture was then poured into 150ml of 1N HCl and extracted with four 150ml portions of diethyl ether. The ether layers were combined, dried over MgSO4, and concentrated to give an oil, which was purified from 15y silica gel (230
-400 mesh). This was applied to a column of 2007 silica and eluted with 30% dichloromethane/70% petroleum ether under nitrogen pressure to give a 0.65%
7 of unreacted 2-chloronitrobenzene and 8.47 of methyl 2(3-chloro-4-nitrobenzene)propionate were obtained, which was about a 68% yield. Example
4 300 η (6,3 mmol) of 50% sodium hydride dispersion in hydrocarbon oil and 5
7TL1 of N-N-dimethylformamide was charged.

The flask was then charged with 2 ml f) 0.56 ml (4.8 mmol) of 2-chloronitrobenzene and 0.65 ml (5.0 mmol) in N-N-dimethylformamide.
of ethyl 2-promopropionate was added dropwise over 5 minutes. When the first drop of this solution was added, the mixture turned orange-red; and after about 5 minutes, the dropwise addition was complete, the mixture turned deep purple, and a significant exotherm was observed. Then a second portion of sodium hydride (4
．． 2 mmol) was added and further exotherm was observed. A small portion of the reaction mixture was then partitioned between 1N HCl and diethyl ether. Analysis of the ether layer by GC/MS revealed that ethyl 2-(3-chloro-4-nitrobenzene)
It showed that propionate was formed. Example 5 A flame dried flask was flushed with nitrogen to provide an inert atmosphere and a 60% dispersion of sodium hydride in mineral oil 7
5Tf19 (1.9 mmol) was charged.

This was washed three times with 2 ml of petroleum ether (boiling point 35-60°C) and slurried in 1.0 ml of N-N-dimethylformamide. 1.0 m1f) A solution of 103 m9 (0.65 mmol) of 2-chloronitrobenzene and 126η (0.65 mmol) of ethyl 2-phenoxypropionate in N-N dimethylformamide is added dropwise to the sodium hydrogen slurry. and stir the resulting purple mixture for 45 minutes, then 20 minutes.
111 of 1N HCl.

The aqueous mixture was extracted three times with 20 TrL1 portions of diethyl ether, and the ether layers were combined, dried over MgSO4, concentrated, and placed on a 2 mm silica gel thin layer chromatography (TLC) plate. Elution with 50% petroleum ether/50% dichloromethane was 4.6 m9 of 2
-Chloronitrobenzene gave 15η of ethyl 2-phenoxypropionate and 53η of ethyl 2-(3-chloro-4-nitrobenzene)propionate.

Example 6 A 60% dispersion of sodium hydride in mineral oil was prepared in a flask under a flame-dried nitrogen atmosphere.
millimoles) and add this 3 times to 2ml of petroleum ether (
Wash with boiling point 35-6'C) and 1.0mlf)N-N
- Slurried in dimethylformamide.

A solution of 100 η (0.635 mmol) 4-chloronitrobenzene and 83 η (0,677 mmol) methyl 2-chloropropionate in 10 ml (7) N-N-dimethylformamide was then added dropwise to the slurry. The resulting purple mixture was then stirred for 15 minutes and poured into 20 ml of 1N HCl. 3 aqueous mixture
Extracted twice with 20 ml portions of diethyl ether, and the ether layers were combined, dried over MgSO4, concentrated, and placed on a 2 mm silica gel TCL plate. 50%
Elution of the plate with petroleum ether/50% dichloromethane resulted in 43Tn9 of 4-chloronitrobenzene and 1
3 gave immediate methyl 2-(2-nitro-5-chlorobenzene)propionate.

Example 7 14 in a flame-dried flask under nitrogen atmosphere
0η (1.24 mmol) potassium t-butoxide,
23η (0,064 mmol) of dibenzo 18-crown-6 ether and 1.0 ml of toluene were charged.

While stirring the mixture vigorously in a room temperature water bath, 1.
106η (0.670 mmol) in 0 ml of toluene
of 2-chloronitrobenzene and 124η (0.63
A solution of ethyl 2-promobutyrate (3 mmol) was added dropwise. The resulting purple mixture was stirred for 5 minutes and poured into 20 ml of 1N HCl. The aqueous mixture was then extracted with three 20 ml portions of diethyl ether, and the ether layers were combined and dried over MgSO4.
Concentrated and plated onto 2 mm silica gel TLC plates. Elution of the plate with 60% petroleum ether/40% dichloromethane gave 45η of 2-chloronitrobenzene and 27η of ethyl 2(3-chloro-4-nitrobenzene)butyrate.

Example 8 A flame-dried flask was flushed with nitrogen to provide an inert atmosphere and treated with 2 ml of a 50% sodium hydride dispersion in mineral oil.
．． 8t (58 mmol) was charged.

Add this 3 times to 10ml of petroleum ether (boiling point 35-60
Rinse at 20 ml (7) N.
Slurried in N-dimethylformamide and placed on ice/
Cooled in a water bath. A solution of 3.77 (26 mmol) 2-fluoronitrobenzene and 3.67 (29 mmol) methyl 2-chloropropionate in 5 ml (71) N-N-dimethylformamide is stirred dropwise. Added to sodium hydride slurry over 15 minutes.

After the addition was complete, the cooling bath was removed but reapplied periodically to maintain the temperature of the reaction mixture below 30°C while the mixture was stirred for an additional 30 minutes. The reaction mixture was then diluted with 1
Pour into 50 ml of cold 1N HCl and extract the resulting aqueous mixture with three 100 ml portions of diethyl ether. The ether layers were combined, dried over MgSO4, and concentrated to give an orange oil of 7.87. 1507
Chromatography of this oil on a column of 230-400 mesh silica gel was performed using methyl 2-(3-fluoro-
317 fractions containing 4-nitrobenzene) propionate (eluted with 40% dichloromethane/60% petroleum ether) were obtained.

Example 9 3.67 (0.09 moles) of 60% NaH in mineral oil were placed under nitrogen into a flame-dried flask equipped with a mechanical stirrer.

Add 15ml each of petroleum ether (boiling point 35-60℃)
), dried in a stream of nitrogen, and washed 3 times with 25 ml (7
) Slurried in N-N-dimethylformamide (stored over 3 angstrom molecular sieves). Then 5.0f in 5ml (7)N-N dimethylformamide
7 nitrobenzene (0.041 mol) and 5.5f! 10 drops of a solution of methyl 2-chloropropionate (0.045 mol) were added to the NaH slurry. After about 3 minutes, the mixture turned deep purple and an exotherm was observed, indicating that the reaction had begun. 22 while dropping the remainder of the reaction solution.
NaH was added for 1 minute and an ice-water bath was periodically applied to the flask, thereby maintaining the temperature between 20 and 30°C. After the addition was complete, the mixture was stirred for 15 minutes at 20-30°C and then 200 ml. , into 1N HCl. The aqueous mixture was extracted with three 150 ml portions of diethyl ether. The ether layers were combined, dried (magnesium sulfate), and concentrated to give 1Of a brown oil. Gas chromatographic analysis of this oil revealed that it contained 6.9% nitrobenzene and 54% methyl 2-(
It was shown that it contained 4-nitrobenzene) propionate. 4.67 96% methyl 2-(4-nitrobenzene) propionate (0.5 mm at 1125° C.) was distilled from the oil. Example 10 The reaction was carried out as described in Example 9, but elaborated as follows: the reaction mixture was poured into 200 ml of water and the resulting aqueous mixture (PHI 2.9) was poured three times successively. 150ml each petroleum ether (boiling point 35-60
°C), 3 times at 150mf, toluene, 3 times at 150m
Extracted once with diethyl ether and three times with 150 ml portions of dichloromethane.

Gas chromatography analysis revealed that virtually all methyl 2
-(4-nitrobenzene)propionate was shown to be present in the petroleum ether extract. These were combined, dried (magnesium sulfate) and concentrated to give a 3.77 oil containing 59% methyl 2-(4nitrobenzene)propionate. 94% methyl 2-(4-nitrobenzene) propionate (0.0f) from oil.
5 mm, 125°C) was distilled. Example 11 Another reaction was carried out as in Example 9 with the following precautions: the reaction mixture was poured into 200 ml of water and 96% sulfuric acid was added to a pH of 6.9. I added up to.

The resulting aqueous mixture was subsequently extracted with three 150 ml portions of petroleum ether (boiling point 3560° C.), three times with 150 ml portions of toluene, three times with 150 TIl portions of diethyl ether and three times with 150 ml portions of dichloromethane. Gas chromatographic analysis showed that virtually all of the methyl 2-(4-nitrobenzene) propionate was contained in the petroleum ether extract. These were combined, dried (magnesium sulfate), and concentrated to 7
It gave an oil of 4,47 containing 1% methyl 2-(4nitrobenzene)propionate. Example 12 The reaction mixture prepared as in Example 9 was worked up as follows: The reaction mixture was poured into 200 ml of water and 96% sulfuric acid was added until the pH was 2.9.

The resulting aqueous mixture was then diluted three times with 150 ml portions of petroleum ether (boiling point 3560° C.), three times with 150 TILI portions of toluene, and three times with 150 ml portions of diethyl ether.
and three times with 150 ml portions of dichloromethane. Gas chromatography analysis showed that most of the methyl 2-(4-nitrobenzene) probionate was in the petroleum ether extract, but some was in the toluene extract. The petroleum ether layers were combined, dried with magnesium sulfate, and concentrated to 72% methyl 2
-4,8 containing (4-nitrobenzene)propionate
t of oil was given. The toluene extracts were combined, dried over magnesium sulfate, and concentrated to 3.5 t containing 5.0% methyl 2-(4-nitrobenzene) propionate.
of oil. Example 13 The following work-up procedure was applied to another reaction mixture prepared as in Example 9: The reaction mixture was poured into a solution of 1.25 ml of 95% sulfuric acid in 200 ml of water.

Approximately 3 ml of black oil settled to the bottom of the aqueous mixture and was removed. Add 10 ml of oil to petroleum ether (boiling point 35-6
0° C.) three times and the petroleum ether layers were combined and dried over magnesium sulfate. The dried layer was concentrated to give a 1.3y oil (Fraction 1) containing 72% methyl 2-(4-nitrobenzene)propionate (
(by gas chromatography analysis). The aqueous mixture was extracted with three 150Tn portions of petroleum ether and the organic layers were combined, dried (magnesium sulfate) and concentrated to 2.7f oil containing 77% methyl 2-(4-nitrobenzene)propionate ( This gave fraction 2). The black oil that had separated from the water was then recombined with the aqueous layer and the resulting mixture was extracted with three 150 ml portions of diethyl ether. The ether layers were combined, dried (magnesium sulfate) and concentrated to 5.3 t of oil containing 39% methyl 2-(4-nitrobenzene)-propionate (
Fraction 3) was given. Example 14 18.0y of 60% NaH (0.450
mol) and 100 ml of N-N-dimethylformamide (stored over 3 angstrom molecular sieves).

The resulting slurry was mixed with 25.07 ml of nitrobenzene (0
．． 203 mol) and 27.5f of methyl 2-chloropropionate (0.224 mol) were added. After about 6 minutes the mixture turned deep purple and showed an exotherm.
This indicated the start of the reaction. Add remaining reactant solution dropwise for 30 min.
to the NaH slurry for several minutes and an ice-water bath was periodically applied to the flask, thereby increasing the temperature to 20 and 30°C.
I kept it between. After the addition is complete, stir the mixture for 20 minutes.
Stir at -30°C and pour into 1 stand of 1N HCl. The aqueous mixture was extracted with three 500 ml portions of dichloromethane. The organic layers were combined, dried (magnesium sulfate), and concentrated to give 1427, a black liquid. 79.1ff from this liquid) N-N-dimethylformamide (Fraction 1, 10ml 130-70℃)
followed by distillation of 34.6t of orange oil (Fraction 2, 10m
71L (165-180°C) was distilled, which contained 7.0% nitrobenzene (by gas chromatography analysis), 75%
% methyl 2-(4-nitrobenzene) propionate (by gas chromatographic analysis) and some mineral oil (observed as an insoluble upper layer). Synthesis of derivatives Example 15 207 fraction 2 obtained in Example 14, i.e. 157 (72 mmol) of methyl 2-(4
-nitrobenzene)-propionate and the resulting mixture was stirred vigorously under nitrogen and cooled in a 25°C water bath.

The mixture became homogeneous after 20 minutes. After 90 minutes, the mixture was extracted with three 30 ml portions of dichloromethane and the aqueous layer was stirred at 50° C. under aspirator vacuum to remove residual dichloromethane.

The aqueous solution was cooled in an ice-water bath and 37% HCl was added dropwise to pH 7. Excluding the cooling bath, 200ηCal
gOnCPG decolorizing carbon (-70 mesh) was added, the mixture was stirred for 10 minutes, and the carbon was passed through Celite. The filtrate was cooled in an ice-water bath and 37% HCl was added to PHI.

The precipitated solid was filtered off, washed with 25 ml of cold 1N HCl and dried over phosphorus pentoxide for 19 hours at 1 mm.
7 of 2-(4-nitrobenzene)propionic acid (melting point 8
3-85°C). Example 16 Fraction 2 from Example 13 [2.7f oil containing 77% methyl 2(4-nitrobenzene)propionate]
was added to 5 ml of 5N NaOH and the resulting heterogeneous mixture was stirred vigorously for 1.5 h under nitrogen.

During this time the mixture became homogeneous. This was extracted with three 10 ml portions of dichloromethane and the organic layers were combined, dried over magnesium sulfate, and concentrated to 88% nitrobenzene and 2% methyl 2-(4-nitrobenzene)-propionate (gas chromatographed). One analysis gave an oil containing 0.377). The aqueous layer was cooled with an ice-water bath and acidified with 37% HCl. The precipitated solid was filtered off and dried under high vacuum overnight.
of crude 2-(4-nitrobenzene)propionic acid (melting point 64-68°C). Example 171.0y (3
．． 7 mmol) of methyl 2-(3-chloro-4-nitrobenzene)-propionate (91% purity by GC)
, 0.377 (4.5 mmol) anhydrous sodium acetate, and 0.1% 7% palladium on carbon in 15 ml methanol was hydrogenated in a stirred vessel at 50 psig for 16 hours.

The mixture was then filtered and the catalyst was washed twice with 5 ml portions of 1-"tanol. The filtrate was concentrated under vacuum and the residue was partitioned between 20 ml of dichloromethane and 20 ml of saturated sodium bicarbonate solution. MgSO layer
4 and concentrated to give a 0.667 oil containing 89% methyl 2-(4-aminobenzene) propionate by GC. Example 18 5.07 (45 mmol) in a flame-dried flask under nitrogen
of potassium t-butoxide and condensed 50 d of ammonia into the flask using a dry ice condenser to obtain a solution of base in refluxing ammonia.

2.7t (22 mmol) of nitrobenzene and 2.7t
(A mixture with 22 mmol of methyl 2-chloropropionate was added dropwise to the ammonia solution and the mixture was allowed to react for 15 minutes.

Then 2.5 t of ammonium chloride was added and the ammonia was evaporated. The residue was taken up in 150 ml of 1N HCl and the aqueous mixture was extracted three times with 100 ml each of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated to give 4.7y of oil.
Gas chromatographic analysis (using an internal standard) of this oil revealed that it contained 2.8 tons (61%) of methyl 2-(4-nitrobenzene) propionate.
Example 19 Nine types of synthesis were performed by reacting a nitroaromatic compound with methyl 2-chloropropionate in the presence of sodium hydride from which mineral oil had been previously washed off using pentane.

In each case, 2 equivalents of sodium hydride and 1-2 m1f) DMF were placed in a flame-dried flask under nitrogen. A solution of 1 equivalent each of the nitroaromatic compound and chloroester in 1-2 ml of DMF was then added dropwise and the resulting solution was stirred for 15 minutes before being poured into 20-40 ml of 1N HCl. The aqueous mixture was extracted three times with 20-40 ml each of diethyl ether, the ether layers were collected, dried over magnesium sulfate and concentrated to give a mixed crude product. The crude product was purified by preparative thin layer chromatography. The nitroaromatic compound used,
The obtained products and yields are shown in Table 1. Example 21 Using the method described in Example 19, nitrobenzene and allyl 2-chloropropionate were reacted.

The product obtained with a yield of 39% was allyl 2-(4-nitrobenzene)propionate. Example 22 Nitrobenzene and t-butoxide were prepared using the method described in Example 19 except that sodium hydride was replaced with potassium t-butoxide.
-butyl 2-chloropropionate.

The product obtained with a yield of 53% was t-butyl 2-(4-nitrobenzene)propionate. Example 23 A solution of 2.97 (26 mmol) of potassium t-butoxide in 20 ml of N--N dimethylformamide (DMF) was made in a flame-dried flask under nitrogen and cooled in an ice-water bath.

Next, to this catalyst solution, ]W2. 30t (13 mmol) of 93% 2-phenoxynitrobenzene and 1
．． A solution of 6y (13 mmol) in methyl 2-chloropropionate was added dropwise and the resulting purple mixture was stirred for 15 minutes at 00-5°C before 200 ml of 1N HCl was poured. This aqueous mixture was diluted with 15 each of diethyl ether.
Extracted 3 times with 0ml. The extract layers were combined, dried over magnesium sulfate, and concentrated to yield 6.0 tons of red oil. Dichloromethane 40%/petroleum ether (boiling point 35
. The oil was chromatographed on 1007 silica gel (230-400 mesh) using a 60% mixture of A fraction containing -3-phenoxybenzene) propionate was obtained. Part B Methyl 2-(4-nitro-3-phenoxybenzene)propionate 1.07, 7% palladium on carbon 0.
17 and 20 ml of absolute ethanol.
Hydrogenated under psig hydrogen pressure for 1 hour, filtered and concentrated to give a 0.967 oil.

According to the results of thin layer chromatography and NMR analysis of this oil, it contained only methyl 2-(4-amino-3 phenoxybenzene) propionate. Part C: A solution of 0.207 (0.74 mmol) of methyl 2-(4-amino-3-phenoxybenzene)propione in 1.0 ml of dry tetrahydrofuran (THF) was dissolved in THF.
4. It was added dropwise into a refluxing solution of 0.18 ml (1.3 mmol) of isoamyl nitrite in Oml.

The resulting mixture was heated at reflux temperature for 1.5 hours, then cooled to room temperature and concentrated. The residue was subjected to preparative thin layer chromatography to obtain 0.0327 (16%) methyl 2-(
3-phenoxybenzene) propionate was obtained. Example 23 60% dispersion of sodium hydride in mineral oil 0.107 (2
．． 5 mmol) into a flame-dried flask under nitrogen.

This was washed three times with 1 ml each of quartz ether (boiling point 35F-60C) and slurried in 2.0 ml (7) DMF. Methyl 2-chloropropionate 0 in 2 ml DMF
．． A solution of 15t (1.3 mmol) and 0.24y (1.3 mmol) of 2-nitrotrifluoromethylbenzene was added dropwise into the sodium hydride slurry. The resulting purple mixture was stirred at room temperature for 15 minutes and then poured into 20me of 10% hydrochloric acid. The aqueous mixture was extracted three times with 20 ml each of diethyl ether, the ether layers were combined, dried over magnesium sulfate and concentrated.
The residue was purified by preparative thin layer chromatography, and 0.12
7 (35%) of methyl 2-(4-nitro-3-fluoromethylbenzene)propionate was obtained. Example 24 Example 23 was repeated except that 2-nitrotrifluoromethylbenzene was replaced with 3-nitrotrifluoromethylbenzene.

This process resulted in the formation of 37η (11%) of methyl 2-(4-nitro-2-trifluoromethylbenzene)propionate. Example 25 2-nitrotrifluoromethylbenzene 0.247(1
．． 3 mmol) to 2-nitrobiphenyl 0.25y(1
．． Example 23 was repeated except that 3 mmol was used.

By this method, 36η (11%) of methyl 2-(2-
Nitro-5-biphenyl)propionate was formed. Example 26 2-nitrotrifluoromethylbenzene 0.24y(1
．． 3 mmol) to 0.21 t of 2-nitroacetophenone
Example 23 was repeated except that (1.3 mmol) was substituted.

When the obtained residue was analyzed by gas chromatography-mass spectrometry, it was found that methyl 2-(3-acetyl-4-nitrobenzene) propionate was present. Example 27 60% sodium hydride 0.157 (368 mmol), methyl 2-chloropropionate 0.15 t (1.
3 mmol) and 2-nitrobenzoic acid 0.217 (1.
The procedure of Example 23 was repeated using 3 mmol).

When the residue obtained after the operation was analyzed by gas chromatography, it was found that methyl 2 of 36Tf19 (11%)
The presence of -(3-kayleboxy-4nitrobenzene)propionate was observed. Example 28 Potassium t-butoxide 0.287 (2.5 mmol)
, methyl 2-chloropropionate 0.157 (1.3
mmol) and 3-nitrotoluene 0.177 (1.3
The procedure of Example 23 was repeated using (mmol).

The residue obtained after the end of the operation was purified by preparative thin layer chromatography to obtain 30 mCl (11%) of methyl 2-(2-methyl-4-nitrobenzene)propionate. The invention is susceptible to significant modification within the spirit and scope of the claims.

Claims (1)

Claims: 1. Reacting a nitroaromatic compound with an α·α-disubstituted acetic acid ester in a substantially anhydrous aprotic solvent and in the presence of a base, thereby converting the ester into a nitroaromatic compound. A method characterized in that nucleophilic substitution is carried out on the unsubstituted ring carbon of , during which the α-substituent functions as a leaving group, thereby producing a nitroarylacetic acid ester. 2. The method according to claim 1, further characterized in that the nitroaromatic compound is a compound having no halogen on an aromatic ring having a nitro group. 3. The method according to claim 1, further characterized in that the nitroaromatic compound is a halonitroaromatic compound having a halo substituent on the aromatic ring having a nitro group. 4. The method of claim 1, further characterized in that the nitroaromatic compound is mononitrobenzene having an unsubstituted position para to the nitro group. 5. The method according to claim 4, further characterized in that the mononitrobenzene is nitrobenzene. 6. The method according to claim 4, further characterized in that the mononitrobenzene is 0-halonitrobenzene. 7. The method of claim 1, further characterized in that the α·α-disubstituted acetate is an α-halomonocarboxylic acid ester containing at least 3 carbons in the acid moiety. 8(a) the nitroaromatic compound is mononitrobenzene having an unsubstituted position para to the nitro group, and (b) α
- the α-disubstituted acetate is an α-halomonocarboxylic acid ester containing at least 3 carbons in the acid moiety, (c) the solvent is a dipolar aprotic solvent, and (d
2. The method of claim 1 further characterized in that:) the base comprises an alkali metal compound, and (e) the nitroaromatic acetate is 2-(4-nitrobenzene)acetate. 9(a) mononitrobenzene is nitrobenzene,
(b) the α·α-disubstituted acetate is an alkyl α-chloro or α-bromopropionate, (c) the base is sodium hydride or potassium hydride, and (d) the nitroarylacetate is Alkyl 2-(
9. The method according to claim 8, further characterized in that it is 4-nitrobenzene) propionate. 10 (a) the mononitrobenzene is 0-halonitrobenzene, (b) the α·α-disubstituted acetate is an alkyl α-chloro- or α-bromopropionate, and (c) the base is sodium hydride or 9. The method of claim 8, wherein the nitroarylacetic acid ester is potassium hydride and further characterized in that (d) the nitroarylacetic acid ester is an alkyl 2-(3-halo-4-nitrobenzene)propionate. 11. The method of claim 10, further characterized in that the 110-halonitrobenzene is 0-fluoronitrobenzene. 12 Claim 1 further characterized in that the 0-halonitrobenzene is 0-chloronitrobenzene.
The method described in item 0. 13(A) Reacting nitrobenzene with alkyl α-chloro- or α-bromopropionate to form alkyl 2-
(4-nitrobenzene)-propionate and (B) hydrolyzing the alkyl 2-(4-nitrobenzene)-propionate to 2-(4-nitrobenzene)propionic acid. The method described in. 14 (A) 2-chloronitrobenzene is reacted with an alkyl α-chloro- or α-bromopropionate to form an alkyl 2-(3-chloro-4-nitrobenzene)propionate and (B) an alkyl 2-(3- Chloro-4-nitrobenzene)propionate to 2-(3-
2. The method of claim 1 further comprising hydrolysis to chloro-4-nitrobenzene)propionic acid.