CS231862B1 - Manufacturing process of alkyl 2-<substituted fenoxy>alcanoate - Google Patents

Description

The invention relates to a process for the preparation of alkyl 2- (substituted phenoxy) alkanoates of the general formula I shown in the drawing, wherein R represents hydrogen or chlorine, bromine, fluorine or trifluoromethyl, alkoxy containing from 1 to 2 carbon atoms, R ¹ represents alkyl containing 1 to 3 carbon atoms, R is hydrogen or alkyl of 1 to 3 carbon atoms and n is 1 to 3 »

The aforementioned esters of the formula I are used in the synthesis of phosphonates / S. Roberts, RF Newton in the book Prostaglandins and Thromboxanes, Butterworths Scientifio, London, 1982, JS Bindra, R. Bindra in the book Prostaglandin Synthesis, Academic Press, including New York 1977 /, through which it is introduced into the prostanoid molecule by a modified Wittig reaction. omega-string.

Prostanolides containing a phenoxy group in the omega chain exhibit 1 to 2 orders of magnitude higher activity and act almost specifically without undesirable side effects. They have found wide application in veterinary medicine (Cloprostenol, Fluprostenol, Fenprostalen) and human medicine (eg. Sulproston.

The known processes for the preparation of the abovementioned compounds of the general formula I have a number of disadvantages. First, an alkali salt of substituted phenoxyacetic acid is prepared from phenol, chloroacetic acid and sodium hydroxide, which is esterified after liberation to the acid by a classical procedure (see, e.g., J. Amer. Chem. Soc. 70, 2849 (1948), J. Amer. Chem. Soc. 65, 1555 (1943).

In this reaction, the sodium salt of hydroxyacetic acid is formed as an undesirable substance. The separation of this component increases the laboriousness of the entire synthesis and reduces the yields. Other methods utilize the reaction of substituted phenol with ethyl chloroacetate in the presence of potash and sodium iodide in acetone (see fr. U.S. Pat. No. 2,321,277, GB Pat. No. 1,521,747], wherein the molar ratio of the components is 1: 1.06: 1.04: 1.01.

After completion of the reaction, the reaction mixture was poured into ice water acidified with hydrochloric acid and the product extracted with ethyl acetate. This process has the disadvantages of high consumption of sodium iodide, ethyl acetate and acetone.

Furthermore, it is relatively laborious and therefore economically disadvantageous. These patents do not protect the preparation of these compounds, but are only given in the Examples section for the preparation of a single specific substance, ethyl 3-nitrophenoxyacetate.

A process for the preparation of an alkyl 2- (substituted phenoxy) alkanoate by reacting a substituted phenol of formula (II) wherein Ran is as defined above with an alkyl 2-haloalkanoate of formula (III)

XCH-COOR

(.2 / 111 /,

Wherein R and R are as defined above and

X denotes halogen, preferably chlorine or bromine, according to the invention, characterized in that the reaction proceeds in the presence of an alkali carbonate and a catalytic amount of an alkali metal iodide in an aliphatic ketone containing 3 to 6 carbon atoms, preferably 2-propanone, 2-butanone or 3-pentanone at 50 to 150 ° C.

The molar ratio of the reactants is 1: 1 to 1.2: 1 to 1.1: 0.05 to 0.2. After completion of the reaction, the precipitated inorganic salts are filtered off, washed with the solvent used in the reaction, and the solvent is distilled off under reduced pressure and used again in the next experiment.

A small amount of water is added to the distillation residue (the remaining inorganic salts are dissolved) and the product is extracted into an organic solvent, preferably into dichloroethane, chloroform, benzene or toluene.

The combined extracts are washed successively with 2-5% sodium hydroxide solution, water and dried with an inorganic desiccant, preferably sodium or magnesium sulfate. Solvents were distilled off and the product of formula I was distilled off.

The process of the invention simplifies the process of product isolation, reduces labor and increases yields. Furthermore, it uses a substantially smaller amount of relatively expensive alkali metal iodide to condense, which only serves to convert the alkyl alpha-chloroalkanoate to the more reactive alkyl alpha-iodoalkanoate, which upon reaction with the substituted phenolate yields the alkali iodide. For this reason, it is sufficient to add only a catalytic amount of an alkali iodide to the reaction.

This method further allows very simple solvent recovery and reduces wastewater treatment costs. From the above advantages, the economic advantageousness of the above process for the preparation of the compounds of the general formula (X) is obvious.

Example 1

Methyl phenoxyacetate

Phenol mixture / 28.3 g; 0.3 mol), potash (45.6 g); 0.33 mol), and potassium iodide (10 g); 0.06 mol (in 120 ml of 2-propanone was heated to boiling and then methyl chloroacetate (36.1 g, 0.33 mol) was added dropwise over 30 minutes.

After 4.5 hours of heating (reaction progress was monitored by gas chromatography), the reaction mixture was cooled, the solid inorganics were filtered off with suction, washed with 2-propanone (20 ml) and the solvents were distilled off under reduced pressure from the filtrate.

To the distillation residue was added 15 ml of water (dissolution of 2-residue of inorganic salts), the organic phase was separated and the aqueous extracted with 3 x 30 ml of benzene. The combined organics were washed successively with 5% sodium hydroxide solution (50 ml), water (50 ml) and dried over magnesium sulfate.

After evaporation of solvent was by distillation afforded 40.5 g / 81% / of the product of the formula I / R "-H, R ^1» CH _3, R ² «H n-1 / t 113 to 114 ° C at a pressure of 1.33 kPa. The literature reports 130 ° C at 1.87 kPa.

Example 2

Methyl (3-trifluoromethylphenoxy) acetate

To the boiling mixture of 25 g (154.2 millimoles) of 3-trifluoromethylphenol, 23.45 g (169.7 moles) of potassium carbonate and 5.15 g (31 moles) of potassium iodide in 65 ml of 2-butanone was added 15 minutes. 5 g (179.7 mmol) of methyl chloroacetate and heated for an additional 6 hours.

After analogous workup as in Example 1 yielded 32.1 g / 88.6% / product of formula I wherein R RszCFy esCHj, R e = ² .H n »l, TV 119 to 121 ° C at The literature reported 101 ° C at 400 Pa.

Example 3

Ethyl (3-trifluoromethylphenoxy) acetate

To a mixture of 4.8 g of 3-trifluoromethylphenol, 4.55 g of sodium carbonate and 1 g of potassium iodide in 5 ml of 3-pentanone was added boiling 3.8 g of ethyl chloroacetate and heated for a further 3 hours.

After analogous workup as in Example 1 was obtained 7.05 g of product of formula I wherein R »CF _3, R ¹ -.C ₂ H _5, R ² ~ H, n" = d, the TV 125 to 127 ° C at a pressure of 1.36 kPa, the structure of which is in accordance with the infrared spectrum, the presence of the band at 1735 cm ^-1 corresponds to the valence vibration of CO in the ester function.

Example 4

Ethyl 2- (2,4-dichlorophenoxy) propionate

To a boiling mixture of 16.3 g (100 mmol) of 2,4-dichlorophenol, 14.1 g (105 mmol) of anhydrous potassium carbonate, 0.83 g (5 mmol) of anhydrous potassium iodide in 50 ml of 2 / butanone was added during 15 minutes. After 19 hours of boiling, the reaction mixture was worked up as in Example 1.

2

22.05 g (84.5%) of the product of formula (I) in which R @ 1, R @ 1 -, R @ 1 --CH2 --N @ 1, 128-130 DEG C. at 1.06 kPa were obtained. The infrared spectrum contains a band at 1725 cm ^-1 confirming the presence of the COOC ₂ H ₅ group.

Example 5

Methyl (3-chlorophenoxy) acetate

To a solution of 3.85 g of 3-chlorophenol, 4.55 g of potash, 0.5 g of sodium iodide in 20 ml of 2-propanone, 3.3 g of methyl chloroacetate was added to reflux and refluxed for 5 more hours. the precipitated inorganic salts were aspirated, washed with 5 ml of the same solvent, the solvents were distilled off and 3 ml of water were added to the residue, the organic phase was separated and the aqueous extracted with 2 x 3 ml of dichloroethane.

The combined organics were washed with 5% sodium hydroxide solution, water and dried over anhydrous sodium sulfate. After distilling off the solvents, 5.5 g (95%) of the product 12 of the general formula (I), where R @ 1, R @ 1 --CH @ 1, R @ 1 -, n @ -1, which was 96% by gas chromatography, were obtained. Distillation yielded 5.1 g of b.p. 119-121 ° C at 0.5 kPa. The infrared spectrum is consistent with the standard.

Example 6

Ethyl 2- (2,4,5-triohlorophenoxy) propionate

To a boiling mixture of 19.7 g (100 mmol) of 2,4,5-trichlorophenol, 14.8 g (110 mmol) of anhydrous potash, 0.8 g of sodium iodide in 150 ml of 2-propanone was added 15.0 minutes over 15 minutes. _χ g 2-ethyl chlorpropionanu.

The reaction mixture was heated to boiling for 3 hours, and after working up analogously to Example 1, 26.4 (89%) of a viscous oily product of the formula I were obtained at 141-145 ° C at a pressure of 1.05 kPa, the purity of which was 98.3% (determined by gas chromatography). The infrared spectrum is present band 1725 cm ¹ - corresponds to the presence C00C ₂ H ₅ group.

Example 7

Methyl 2- (3-fluorophenoxy) butanoate

3-Fluorophenol (9.4 g> 83.9 mmol) was dissolved in 50 ml of 2-propanone, then potash (12.8 g, 92.6 mmol) and potassium iodide (2.8 g, 16.9) were added. 14.4 g (94.8 mmol) of methyl 2-bromobutanoate was added over 20 minutes while stirring and boiling the reaction mixture.

Following an analogous procedure as in Example 1 yielded 12.1 g of product of formula I wherein R .3-F, R ¹ = »CH 3, R ² - C 2 H _5, n = -l, TV 110 to 114 ° C. Pro (212.2) calculated: 62.25% H, 6.17% H, found: 62.43% C, 6.24% H.

In the mass spectrum, the ion species with m / z values of 212, 153, 112, 95, 59 and in the infrared spectrum bands at 2,980, 2,963, 1,725, 1,615, 1,595, 1,490 and 1,138 cm ^-1 are in accordance with the proposed structure.

Example 8

Methyl (4-ethoxyphenoxy) acetate

To a mixture of 13.8 g (0.1 mol) of 4-ethoxyphenol, 15.2 g (0.11 mol) of potash, 3.3 g of potassium iodide in 40 ml of 2-propanone was added, as in Example 1, 12 g of methyl chloroacetate .

After analogous work-up, 14.5 g of b.p. 150 DEG-152 DEG C. at 1.5 kPa.

The mass spectrum contains ionic species at m / z values: 198, 139, 137, 121, 59 and characteristic bands were found in the infrared spectrum at 2,985, 2,960, 2,855, 1,725, 1,620, 1,598, 1,490 and 1,155 cm ¹ . These spectral data confirm the proposed structure.

Claims (4)

A process for the preparation of alkyl 2- (substituted phenoxy) alkanoates of the general formula I, wherein R represents hydrogen or chlorine, bromine, fluorine or trifluoromethyl, alkoxy having 1 to 2 atoms R 2 is hydrogen or alkyl of 1 to 3 carbon atoms, n is 1 to 3, by reacting a substituted phenol of formula II, wherein R and n are as defined above, with alkyl 2 - a haloalkanoate of formula III 'X-CH-COOR ¹ (111), wherein R and R are as defined above and X is chlorine or bromine, using basic compounds and in an organic solvent environment, characterized in that the reaction is carried out with carbonate of an alkali metal in the presence of a catalytic amount of an alkali iodide in an aliphatic ketone containing 3 to 6 carbon atoms at a temperature of 50 to 150 ° C, wherein the molar ratio of substituted phenol: alkyl nalogenoalkanoate: alkali metal carbonate: alkali metal iodide is 1: 1.0 to 1.2: 1.0 to 1.1: 0.05 to 0.2, after which the inorganic salts precipitated after the reaction have been filtered off, regenerate the aliphatic ketone The product of formula (I) is isolated by extraction into an organic solvent with purification distillation. 2. A process according to claim 1, wherein the alkali carbonate is sodium or potassium carbonate. 3. The process according to claim 1, wherein the aliphatic ketone is 2-propanone, 2-butanone or 3-pentanone. 4. A process according to claim 1, wherein the organic solvent is dichloroethane, chloroform, benzene or toluene.