KR810001413B1 - Process for preparing 2,3-dichloro-4-(2-thenoyl)phenoxy acetic acid - Google Patents

Abstract

Title compd.(ticrynafen) useful as a diuretic was prepd. from glycerol ether deriv. (compd.I). Thus, compd. I esterified to yield compd. II (R1, R2 = C1-5 alkanoyl, carbomethoxy, carboethoxy, carbonyl, thiocarbonyl), the product was reacted with thenoyl chloride or bromide in the existence of Lewis acid more than 1 mol to give compd. III which was hydrolised with acid or alkali to give diol compd. (IV), and oxidation of IV gave title compd.

Description

Method for preparing 2-3-dichloro-4- (2-tenoyl) -phenoxyacetic acid

The present invention is directed to a novel process for preparing 2,3-dichloro-4- (2-tenoyl) phenoxyacetic acid (ticrinafen) useful as a diuretic. The process proceeds with certain novel cyclic esters and diols.

Ticlinafen has been prepared by a synthetic method of Friedel-Craft condensation with tenoyl chloride before the O-C-C structure of the oxiatic acid side chain is formed. (US Pat. No. 3,758,506 and G. Thuillieretal, Eur. J. Med. Chem. O (6) 625, (1974)), the most recently discovered intermediates of these materials which are part of the present invention are 3- (2). , 3-dichlorophenoxy) -1, 2-propanediol 2,4-isomer (BJ Ludwig. J. Am. Chem. Soc. 74, 1935) 2,6-isomer (French Patent No. 2,056,296) 3, 4-isomer (BR Baker. J. Med. Chem. 14 793, 1971). Cyclic carbonates include 2-monochloro, US Pat. No. 3,168,525 and 4-mono-chloro (Y.M. Beasley. J. Pharm. Pharmacd 9 10 (1956).

The order in which the compound of this invention changes is as follows.

Wherein X is thio (= S) or preferably oxo (= O). An important step in the synthesis process is the Friedel-Crafts reaction, IV-V. The new part of the whole process is from III to Ⅷ.

The novel intermediate of the present invention has the structure

또는 티오카르보닐

이고 R은 테노일 또는 수소이다. R이 테노일(C₄H₃SCO-)R₁및 R₂가 수소이고 함께 취해질 때 카르보닐 또는 티오카르보닐인 구조식 Ⅷ의 화합물이 바람직하다.Wherein R ₁ and R ₂ when taken together are both hydrogen or carbonyl

Or thiocarbonyl

And R is tennoyl or hydrogen. Preferred are compounds of formula VII, wherein R is tenoyl (C ₄ H ₃ SCO-) R ₁ and R ₂ are hydrogen and carbonyl or thiocarbonyl when taken together.

, O-카르보메토옥시

또는 O-카르보에토옥시

에스테르를 생성하게 된다.The first step (III → IV) of the synthesis protects two hydroxyl groups of 3- (2,3-dichlorophenoxy) -1,2-propanediol (III) from the reaction during the successive Friedel-Craft acylation step. In order to esterify the two groups. The process is carried out in standard O-acylation reactions using acyl halides or acyl anhydrides known in the art. Indeed, when a cleavable ester group is formed and sometimes used in combination with materials similar to the above, O-lower, lower alkyl (R ₃ ) is a compound having up to 5 carbon atoms, such as formate, acetate or propionate derivatives Alkyl carbonyl

, O-carbometooxy

Or O-carboetooxy

To produce an ester.

Cyclic esters, thiocarbonates and carbonates represented by compound IV are preferred because they have already been determined and are produced in high yields. Cyclic carbonate is used to convert 3- (2,3-dichlorophenoxy) -1,2-propanediol (III) in the presence of an excess of dimethyl in the presence of an alkali metal base such as sodium bicarbonate or potassium bicarbonate or sodium carbonate or potassium carbonate. Or by reacting with diethyl carbonate. Most preferably, the reaction mixture is heated to reflux for 2-6 hours. Crystalline carbonate (IV) is isolated and purified by methods known in the art. Phosgene or thiophosgene can be used for the inert organic solvent and lower alkyl chloro formate can also be used.

The second step (IV → V) of the synthesis is a novel Friedel-Craft acylation step in which tennoyl chloride is reacted with esterified diol under standard Friedel-Craft conditions. In this step, when 1 molar equivalent of Friedel-Craft catalyst, which is a conventional Lewis acid such as aluminum chloride, an acylation reaction is not induced. In general, when 3-5 molar equivalents are used, high yields of preferred esters such as 3- [2,3-dichloro-4- (2-tenoyl) -phenoxyl] -propanediol-1,2-carbonate Can be generated as The properties of the alcoholic substituents on the carbonium ions in the transition state are critical to the efficiency of the acylation and the P-direction of the resulting acyl group.

In esterified carbonium water bodies of the Pradel-Craft reaction, especially esterified starting materials such as cyclic carbonates provide high yields of the preferred isomers.

The most preferred reaction state is to react the ester in methylene chloride with 4 molar equivalents of aluminum chloride for 1-12 hours while heating from room temperature to reflux. If necessary, the reaction product is separated by a standard separation process.

The third step (V → VI) of this process is to remove the protective ester group using a weak acid or alkaline hydrolysis state by methods known in the art. The fourth step (VI → VIII) of this reaction is to oxidize the propanediol side chain of 3- [2,3-dichloro-4- (2-tenoyl) -phenoxy] -propanediol-1,2. The oxidation reaction is carried out using an oxidant which converts the 1,2-propylene diol moiety into the acetic acid co-operative without any effect on the thiophene ring. It is more preferable to use chromic acid dissolved in acetic acid in the temperature range of room temperature to about 75 ° until the reaction is completed. Other oxidizing agents used to produce ticlinafen are permanganate, manganese dioxide, iodate / permanganate, and oxidation catalysts used in catalytic oxidation are cobalt acetate or precious metal catalysts.

Ester (V) can also be directly oxidized to ticlinafen without undergoing a hydrolysis step, but yields are low.

Cyclic carbonates, for example, produce ticyclinafen when reacted with chromic acid under steam bath temperature. In addition, the reaction product produced at each stage of the synthesis reaction described above can be isolated, purified or used according to the choice of the machine. The product of hydrolysis (V → VI) needs to be separated.

Using the reaction sequences described herein, it is possible to produce inexpensive chemicals and high yields of diuretics, ticrinafen (thienic acid), without introducing unnecessary environmental hazards. The important intermediate (IV), which is the starting material for the Friedel-Craft acylation reaction, can be prepared by another synthetic process that does not have any process advantages other than those described herein.

The following examples illustrate this reaction. The unit of temperature is Celsius.

Example 1

With a mixture of 652 g of 2,3-dichlorophenol (4.0 m), 483.52 g of allyl bromide (4.0 m) and 1 L of methanol in 1 L of methanol, a mixture of 914.4 ml (400 m) of 25% sodium methooxide / methanol React. The mixture is continued to reflux and heat for 8-10 hours until T.L.C.analysis (chloroform-methanol 95: 5) indicates the reaction is complete.

The mixture is cooled to 30 ° and poured into 5 l of water. Extraction with ether followed by washing, drying and evaporation yielded 698.15 g of crumb 3- (2,3-dichlorophenoxy) -propane.

Example 2

To 25.5 g (0.125 m) of 2- [2,3-dichlorophenoxy] -propane dissolved in 150 ml of 97% formic acid is added 24 g of 30% hydrogen peroxide (0.211 m). The mixture is stirred at room temperature for 18 hours to homogenize the reaction mixture.

Add 1 liter of water to the solution and collect the solid. The solid is dissolved in 200 ml of ethanol containing 21.1 g of potassium hydroxide dissolved in 21 ml of water and then heated to reflux for 2 hours. Ethanol was removed from the reaction mixture under reduced pressure, and then the residue was diluted with water and extracted with ether. Dry ether is evaporated to yield 27 g of crumb 3- [2,3-dichloro phenoxy] -1,2-propanediol. Recrystallization from 60 ml of chloroform gives 22.3 g (75%) of diol. Melting Point 98-100 °: IR (New Sol) 3400cm ^-1 : NMR (DMSO-d ₆ ) δ 3.5 (t, 2H, 3.7-4.1 (m, 3H), 4.7 (t, 1H) 5.0 (d, 1H), 7.2 (m, 3H): m / e 236

Analysis result: C _θ H ₁₀ Cl ₂ O ₃

Calculated Value: C 45.61 H 4.25 Cl 29.91

Found: C 45.61 H 4.21 Cl 29.54

Example 3

22.33 g (0.0918 m) of diol produced in Example 2 is dissolved in 90 ml of diethyl carbonate and 0.5 g of sodium bicarbonate is added to the solution. The mixture is heated to reflux for 6 hours. Upon cooling, the purification step was carried out by collecting acicular 3- [2,3-dichlorophenoxy] -propanediol-1,2-carbonate (17.4 g, 70%, melting point 108-110 ° C.) deposited on the mixture. Use in the next step without going through. IR (New sol) 1760 cm ⁻¹ , NMR (DMSO-d ₆ ) δ 4.3-4.8 (m, 4H), 5.2 (m, 1H), 7.2 (m, 3H) m / e 262.

The sample is recrystallized from isopropanol for analysis.

Analysis result: C ₁₀ H ₈ Cl ₂ O ₄

Calculated Value: C 45.66 H 3.07 Cl 26.95

Found: C 45.46 H 3.24 Cl 26.72

Example 4

50 g (0.19 m) of ester produced in Example 3 are dissolved in 420 ml of methylene chloride and 30.6 g of 2-thiophenecarboxylic acid (tenoyl) chloride (0.21 m) is added to the solution. 111.5 g (0.84 m) of aluminum chloride is slowly added to the reaction mixture for 1 hour. The reaction mixture is heated at reflux for 1 hour, cooled, cooled with water and heated again for 1 hour. The methylene chloride layer is separated and washed in the order of water, 10% sodium hydroxide and water. The dry organic layer is evaporated to yield 61.8 g (59%) of crumb 3- [2,3-dichloro-4- (2-tenoyl) -phenoxy] -propanediol-1,2-carbonate. Recrystallization with ethyl acetate gave 46.3 g of compound having a melting point of 125 °: IR (New Sol) 1800, 1660 cm ^-1 : NMR (DMSO-d ₆ ) δ 4.6 (m, 4H), 5.3 (m, 1H), 7.5 (m, 4 H), 8.2 (d, 1 H) m / e 372.

Analysis result: C ₁₅ H ₁₀ Cl ₂ O ₅ S

Calculated: C 48.27 H 2.70 Cl 19.00 S 8.59

Found: C 48.39 H 2.89 Cl 18.74 S 8.41

Example 5

51 g (0.135 m) of Friedel-Craft product produced in Example 4 are suspended in 300 ml of 10% sodium hydroxide and heated in a steam bath for 1 hour. The cooled reaction mixture is filtered and washed with water to yield 35 g (75%) of crumb 3- [2,3-dichloro-4- (2-tenoyl) phenoxy] -propanediol. The solids are treated with charcoal and recrystallized with chloroform to yield 28.4 g of diol having a melting point of 119 °: IR (New Sol) 3380, 3250, 1650 cm ^-1 , NMR (DMSO-d ₆ ) S 3.6 (t, 2H ), 3.8-4.3 (m, 3H), 4.7 (t, 1H), 5.1 (d, 1H), 7.5 (m, 4H), 8.2 (d, 1H): m / e 346.

Analysis result: C ₁₄ H ₁₂ Cl ₂ O ₄ S

Calculated: C 48.43 H 3.48 Cl 20.42 S 9.23

Found: C 48.26 H 3.44 Cl 20.06 S 9.15

Example 6

The product of Example 5 (10.44 g, 0.03 m) is suspended in 150 ml of acetic acid. To the suspension, 17.88 g (0.06 m) of Na ₂ Cr ₂ O ₇ .6H ₂ O dissolved in 40-50 ° of chromic acid [81 ml of H ₂ O and 24 g of H ₂ SO ₄ were added dropwise for 1 hour. The reaction mixture is stirred for 1 hour and then diluted to 3 L with the addition of water. The solid is filtered off, washed with water and dissolved in 1.2 l of ether. The ether is extracted with 5% sodium bicarbonate. The solid and aqueous layer formed are acidified and then extracted with ether. The ether decolorized with charcoal is dried and evaporated to yield 4.5 g of crumb 3- [2,3-dichloro-4- (2-diethyl carbonyl) phenoxy] acetic acid (ticrinafen). (Melting point 148 °), recrystallized with dichloroethane to give 3.7 g of a compound having a 150-150.5 ° melting point: IR (New Sol) 1660, 1750 cm ^-1 , NMR (DMSO-d ₆ ) δ 5.0 (S, 2H), 7.5 (m, 4H), 8.2 (d, 1H).

Analysis result: C ₁₃ H ₈ Cl ₂ O ₄ S

Calculated Value: C 47.15 H 2.43 Cl 21.41 S 9.68

Found: C 47.38 H 2.64 Cl 21.46 S 9.65

Example 7

A mixture of 0.746 g (0.006 m) of cyclic carbonate and 20 ml of acetic acid produced in Example 4 is reacted with 1.79 g of sodium chromate hydrate on steam bath, 16 g of sulfuric acid, and 5.9 ml of steam bath for 5 hours. The mixture is cooled and added to sodium bicarbonate solution. The mixture is acidified and extracted with ether. The ether extract is extracted with sodium bicarbonate solution and 0.039 g of thycrinaphene is separated with aqueous acid.

Example 8

11.9 g (0.05 m) of the product of Example 2 was heated in reflux toluene with 4.45 g (0.025 m) of N, N-thiocarbonyl-diimidazole for 30 min. The solution is cooled, washed with water, dried and evaporated to yield 3- (2,3-dichlorophenoxy) -propanediol-1,2-thiocarbonate. The product is treated in the manner described above to produce ticrinafen.

Example 9

The following oxidation reaction to produce ticyclinafen proceeded at room temperature using the product of Example 5. The reaction product is analyzed by comparative thin layer chromatography (T.L.C).

A. diol (0.347 g): manganese dioxide (3 g): acetone

B. Diol (0.347 g): sodium carbonate (1.189 g): sodium and iodide (1.71 g), potassium permanganate salt (0.025 g): t-butanol

C. diol (0.347 g): potassium permanganate salt (1.589): 10% sodium hydroxide (10 ml)

Claims (1)

The following compound of formula (I) is esterified by consumption reaction to obtain an ester compound of the following formula (II), and the ester compound of formula (II) mentioned above under Friedel-Craft conditions in which at least one mole of Lewis acid catalyst is added. Reacted with tenoyl chloride or bromide to obtain a diol ester compound of the following formula (III) and then hydrolyzing the diol ester compound of the following formula (III) under an acid or alkaline state to produce a diol compound of the following formula (IV) A process for preparing 2,3-dichloro-4-2 (-tenoyl) -phenoxyacetic acid according to the following formula (V), wherein the diol compound of formula (IV) is oxidized with a diol oxidizing agent.

In the above structural formula R ₁ and R ₂ are lower alkanoyl, carbomethoxy, carboethoxy of 1-5 carbon atoms which are identical to each other or carbonyl or thiocarbonyl when taken together.