JPS6245549A - Production of 3,6-dichloro-2-hydroxyacetophenone - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the titled compound useful as an intermediate for medicines, agricultural chemicals, etc., in good yield as a whole without forming unnecessary isomers, by hydrolyzing a novel 5,8- dichromone. CONSTITUTION:A novel substance expressed by formula I (R<1> is H or OH; R<2> is H or alkoxycarbonyl, provided that at least one of R<1> and R<2> is H), e.g. 5,8-dichromone expressed by formula Ia, is hydrolyzed by the conventional method to advantageously obtain 3,6-dichloro-2-hydroxyacetophenone. The above- mentioned novel substance can be produced from a compound expressed by formula II, and for example, the above-mentioned exemplified compound can be produced by passing through compound expressed by formulae III-IV or further a compound expressed by formula V in 3-4 steps or passing through a compound expressed by formula VI (R is alkyl) in 2 steps.

Description

[Detailed description of the invention]

3.6, which is important as a raw material for pharmaceuticals, agricultural chemicals, etc.
-Nokrjo -2-Human [7ki>acetopheno>7)
Regarding manufacturing methods. Ikira's technology sales 23 + 6- Fukuroro 2-Hydroxy/Acetate:
- The following method is known as a manufacturing method for ~77. The reaction of 2.5-sochlorophenol with acetylene ester methyl ester was also achieved by ring-closing the maleic acid ester core in the presence of 4sulfur and 2-carboxyne-5,8. −;; Lead chlorochromone and further add water to hole 11 using alkali to decompose water 1. The method of manufacturing [one thing ヱ'I is jjt]: I am, q fl. This method has the disadvantages of a long number of steps, an expensive acetylene/carboxylic acid methyl ester used as a reagent, and a low overall yield of 35.2%. 2) Prczem, Chem, 58. 533
(1979) discloses a method in which 2,5-dichlorophenol acetate and aluminum chloride are reacted at 155-165°C for 1.5 hours. The stated yield of this reaction is 57%, but since the phenolic hydroxyl group is isolated by methylation, the reaction solution is treated as it is, and the separation from the by-product 2,5-cyclor+-4-hydroxyacetophenone is difficult. The downside is the lack of consideration. Furthermore, the yield also suffers from a lack of accuracy. 3) J. Indian Chem, Soc, 1982
．． This reaction is almost the same as the reaction in 2) of No. 77-79, but the reaction product is separated by steam distillation. A method for obtaining 3,6-dichloro-2-hydroxyacetophenone by heating 2,5-dichlorophenol acetate in the presence of aluminum chloride and acetic anhydride in a solvent such as nitrohenzene has been disclosed. The yield of this reaction was 42%, which is unsatisfactory. For the purpose of synthesizing 3,6-cyclo2-hydroquinacetophenol, the present inventors selectively introduced an acetyl group into the 1 to 1-positions of 25-dichlorophenol. Taking into account the difficulty of 5,8-dichlorochromone derivative, it is hydrolyzed to obtain the desired 3-dichlorochromone derivative.
, 6-cyclo-2-hydroquinoacetophenone [As a result of detailed puncturing, the present invention was completed. That is, the present invention provides a 5,8-dichloro compound represented by the general formula: It relates to a method for producing 3,6-phthalol-2-hydroxy/acetophenone, which is characterized by hydrolyzing chromones (I>). In the above definition, alkoxycarbonyl refers to meF-quincarbonyl, ethquincarbonyl, propoquincarbonyl, Butquincarbonyl C. Means lower alkoxycarbonyl.Hydrolysis is carried out in a conventional manner with an acid or base at room temperature to the boiling point of the solvent.The solvent is water or water and an organic solvent (for example, methanol). , ethanol, isopropanol, acetone, oxane, dimethylformamide, dimethylformoquine). It is obtained through the process shown in the formula. (Left below) (VI) (IA)
(V) (wherein R represents lower alkyl (for example, methyl, ethyl, propyl, butyl, etc.)) Process A (1) 2,5-dichlorophenol (II) to 3-
Ha

[React with copropionic acid to produce 3-(2,5-dichlorophenyloxy)propion 9(111). This reaction may be carried out by heating at 50 to 110°C in the presence of a strong base such as sodium hydroxide or potassium hydroxide. As a solvent, water or water and an organic solvent (for example, oxane,
A mixed solvent of methylformamide (methanol, ethanol, etc.) is used. Here, as the 3-halopropionic acid, 3-chloropropionic acid and 3-bromopropionic acid can be used, and in place of 3-halopropionic acid, β
- A similar objective can be achieved using propiolactone. (2) 3-(2,5-dichlorophenylokine)propionic acid (III) obtained in the above (1) is allowed to react with polyphosphoric acid to lead to a closed ring product (1v). This reaction may be carried out without solvent by heating at 80 to 120'C. Instead of polyphosphoric acid, other condensing agents may be used, such as phosphorus pentoxide, sulfuric acid, and mixtures thereof. (3) - The closed ring product (Iv) obtained in the above (2) is converted into 3-bromo-5,8-cyclo-2,3-ene hydrotanic compound (1 mon m).This reaction is carried out in a suitable solvent. (For example, ether, chloroform, acetic acid, etc.) at room temperature T (1
0 to 30°C) by the action of bromine. (4) The 3-bromo compound (■) obtained in (3) above was subjected to a dehydrobromination reaction to give 5.8-t [Jrochromo].(1
a). This reaction is ace) nitrile, /','-f
This is carried out using tetraethylammonium chloride, DBU (1,5-/azahicyclo[5°4.0]undecene-5) in a suitable solvent such as diformamide, but generally the boiling point of the solvent is about 7°C. Heated to -? That's good. (5) Dehydrate the ring-closed product (1v) obtained in (2) above.
9 reactions were carried out to obtain 5.8 and 10 chromones (18). This reaction is carried out by adding trityl alcohol in lifluoroacetic acid and heating to reflux. Process B (6) β- to 2,5-dichlorophenol (11)
3-(2,5-link[lophenyloxy)acrylic acid alkyl ester (VI) is obtained by reacting the main acrylic acid alkyl ester. This reaction is carried out in an appropriate solution in the presence of a strong base such as sodium chloride.
For example, 7'1. Ru. Examples of the alkyl ester moiety of β-menluoquine acrylic alkyl ester include methyl ester, ethyl ester, propyl ester, and isopropyl ester. The product m) obtained here contains cis isomer, trans isomer, and seven combinations thereof; however, in the next reaction, the nos isomer and trans isomer may be used separately, or the mixture may be used as is. You may. The alkyl esters quenched in (7) and (6) are hydrolyzed at room temperature using an alcoholic alkali hydroxide (for example, thorium hydroxide) in a conventional manner. Add polyphosphoric acid to the carboxylic acid and add 100'
When heated to C, the desired 5.8-7 chlorochromone (Ia) is obtained. Process C (8) Reacting 2,5-dichlorophenol (II) with chloromethylene alkyl ester
,...Nicely obtained VII). This reaction consists of 1-lium hydride, sodium methoxyamide, sodium methoxyhydride,
dimethylbormamide in the presence of a strong base such as l-',
・＼＼→）゛Mesenshin phosphortriamide and other organic products
t'? ! It may be carried out in a medium at room temperature. (9) Add polyphosphoric acid to the ester (t/II) obtained in (8) above and heat it to 100°C to obtain 2,5-dichlorochromone-3-carboxylic acid alkyl ester (1b).
lead to. Process D (10) 2,5-Dichlorophenol (II>) is reacted with malonic acid to produce malonυ mono(2,5-cyclo[I phenyl) ester (VIII).This reaction is performed using ether, Hensen, etc. Malonic acid is reacted with thionyl chloride in an organic solvent to yield malonic acid monochloride (ζ), which is then reacted with 2,5-dichlorophenol (11). This reaction can be carried out by heating to about the boiling point of the solvent. (11), the malonic acid half ester obtained in (10) (■11 step) was reacted with phosphorus pentachloride in a liquid gastrointestinal solution to form 7U acid, and then ferric chloride was added to this. By reacting with the Friedel-Crafts reaction catalyst, Fl
target and t65.8-fucrol 2-hydroquine r fusei
(IC) ( 5 , 8 − /chloro [tautomeric y4 isomer of j-4-hydroquinocumarin)]. What is the To2 reaction? It is an I+0 thermal reaction and can be carried out by heating to 50-70°C. The features of the present invention are as follows. a) M3Q nip of 3.6>chloro-2-hydroxyacetophonone, 5,8-ink [10 chromone 1 permeation! ! (I) does not produce unnecessary isomers because the base part of the acetyl group is fixed.b) 5.8-';'Chlorocro7ane derivative It is indeed a new substance. C) The yield of each step is overall excellent. d) The production method of the present invention is industrially advantageous compared to conventional methods. Embodiments of the present invention are shown below. Example 1 a) 9.2 g of 3-chloropropionic acid was dissolved in a solution consisting of 7 g of sodium hydrogen carbonate and 10 ml of water, and then 10.58 g of 2,5-cyclophenol and 30% potassium hydroxide solution were dissolved. Add a solution of λ for 3 hours). Add 10% hydrochloric acid to the reaction solution to adjust the pH to 1, and extract with a needle. The ether layer is washed with an aqueous sodium bicarbonate solution, and the ether layer is concentrated to recover 4.50 g of 2.5-cyclophenol. The alkaline washing solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ether. The extract is washed with saturated brine, dried, and concentrated to obtain crude crystals mainly consisting of 3-(2,5-dichlorophenyloxy/)propionic acid. This was washed with hot petroleum ether to obtain 8.60 g of colorless crystals. Yield 56.4%. Melting point: 1450-146°C (recrystallized from a chloroform-benzene mixture). URL/max(CHCI-): 2400-36
00.1720cm-'NMR (CDCI, -acetone): 82.85 (2H, t, J=6Hz), 4.33 (2
H, t, 6Hz). 6, 77-7, 43 (3H, m> Note that 3-77 c+ +: + β- in place of propionic acid
When using propiolactone, the target substance is 5.76%
obtained in a yield of . b) A mixture of 4.29 g of 3-(2,5-dic[corophenyloxy)propionic acid and 43 ml of polyphosphoric acid is heated at 100° C. for 12.5 hours. Add 200 ml of ice water to the reaction solution and extract with benzene. The benzene layer was washed with 5% sodium hydroxide solution, washed with water, dried over Glauber's salt, concentrated under reduced pressure, and concentrated to 5.8-/chloro2.
．． Obtain 3.29 g of hydrochromone 3. Yield: 8
3.1%. When this crystal is recrystallized from benzene-petroleum ether, it becomes colorless crystal with a melting point of 66.0-67.0@C. IRL/max(CHCI,): 1700.15
80cm-'NMR,S (CDCI, ): 2,87(2H,j, J=6Hz), 4.62(2
H, t, J=6Hz). 6.90.7.40 (2H, ABq, J=8)1z)c
) 5.8; Chloro-2,3-7 hydrochromone 3 1.
0.028 g of bromine and 10 ml of ether.
Gradually add 255ml and stir at room temperature for 3 hours). The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel and eluted with benzene. The eluate was concentrated under reduced pressure, and 3-bromo-5,8-cyclo2.3
-1.179 g of dihydrochromone are obtained. Yield: 84.
1%. Melting point 1185-1195°C (recrystallized from benzene-petroleum ether). IRV max (CHC1+): 1700.15
80cm-'NMR, 8 (CDCI+): 4.51-4.84 (3) 1. m), 6.99.7.4
1 (2H, ABq, J = 8Hz) d) 3-Bromo-5,8-j cyclo2,3-nohydrochromone 224 mg of tetraethylammonium chloride is added to a solution of 4200 mg of acetonitrile and 10 ml of acetonitrile.
mg was added thereto, and the mixture was stirred for 58 hours under heating at 71E. The reaction solution was concentrated under reduced pressure, 10 ml of water was added to the residue, and the mixture was heated at room temperature for 10 ml.
Stir for a minute. The precipitated crystals are collected, washed with water, and dried to obtain 129 mg of 5,8-dichlorochromone. Yield 88.7%. Melting point: 129.0-133.0°C. IRL/max (CHC1+): 1660.1
587 cm-'NMR, δ (CDCI, ). 6.32.7.79<2t(,ABq,J=6Hz)
, 7.27.7.56 (2H, ABq, J=9Hz) e) 5.8-',; 100 mg of chromone 10%
Add 2 ml of sodium hydroxide and heat the mixture at 60°C for 1 hour.
Stir for an additional 1.5 hours at 100°C. The reaction solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to give 2.6-/chloro-2-hydroxyacetophyl as yellow crystals.
Get non-mutual. This product was purified by silica gel chromatography, and the point B was +4. Yellow crystals at s ~ 56.0°C 76
Get m3. Yield 797%. Example 2 Trifluoric acid% 5.8-cyclo2,3- in 2 ml
Add 3217 mg of sohydrochromone and 390 mg of trityl alcohol, and reflux for 40 hours. The reaction solution is concentrated under reduced pressure, 10 ml of water and 5 ml of an aqueous sodium bicarbonate solution are added to the residue, and the mixture is extracted with benzene. The residue is chromatographed on a gel/gel, eluting with Hensen-Hensen-ethyl acetate (5:1 v/v). The eluate was concentrated under reduced pressure to obtain 5182m of 5,8-nochlorochromone.
get g. Yield 84.6%. Melting point 1310-1340°
C0 (blank below) Example 3 C] a) 50°6 petomization size thorium (f, oil suspension, suspension) 0,
A mixture of 576 g and 10 ml of dry trimethylformamide
7 volumes of 1.63 g of 2,5-chlorophenol and 2 ml of dry trimethylformamide were added dropwise to water-cooled F, and stirred for 30 minutes. To this, β-7, xyacrylic acid ethyl ester 3.623 (purity 64
%) under water cooling for 1 hour, and further stirred at 28°C for 4 hours. The reaction solution was dissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and dried under pressure. The residue was transferred to a column chromatogram using a gel and subjected to Hensenupa\xane (10°1 v/v).
and benzene. Reduce the pressure of the eluate 1. shrunken,
10.19g (yield 7.28%)
) and trans-3-(2,5-cyclor1 phenyloxy/)acrylic acid ethyl ester 8 1.18 g (
Yield: 45.1%). 7 IRvmax (CHCI,): 1700.1
650.1580.1470゜1160, 109109
O' NMR, 8 (CDCI, ) + 1.29 (3t (, t
, J=7Hz), 4.21(2H,q, J near Hz>,
5.25.6.73 (IH, d, J=7Hz each) 8 IRvmax (C1 (C1s): 1710.16
50.1632.1576°1470.1110cm-
'NMR,S (CDCI,): 1.29(3H,t
, J-7Hz), 4.20 (2H, q, J=7)1z)
, 5.5.7.68 (IH, d, J = 13 Hz each) b)/Su 3-(2,5-dichloro[-1 phenylokino)acrylic acid ethyl ester 7 0.15 g, 0, IN
6 ml of sodium hydroxide solution and 20 ml of methanol
The solution consisting of is stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was adjusted to pH 1 with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated under reduced pressure, and cis-
3-(2,5-cyclophenyloxy)acrylic i0
．． Obtain 13g. Add 4 ml of polyphosphoric acid to this, t, 1
Heated at 00℃ for 17 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. Reduce the pressure of the organic layer to 1. After evaporation, the residue was subjected to column chromatography on Rikagelt and eluted with benzene. 5. Evaporate the eluate under reduced pressure.
589 mg of 8-dichlorochromone is obtained. Yield 72.4
%. Melting point 129-130°C. c) trans-3-(2,5-dichlorophenyloxy/
) When treated similarly to b) using acrylic acid ethyl ester 8 0.15&, 5.8-dichlorochromone 5
Get 6 mg. Note that trans-3-(2,5-dichlorophenyloxy)acrylic acid ethylnisder 80.
When polyphosphoric acid is added to 15g and heated directly, 5.8-
24 mg of chlorochromone is obtained. Example 4 a) 50% sodium hydride 1, ″) t, (mineral oil suspension) 0
A solution of 163 g of 2,5-dichlorophenol in dry methylformamide was added dropwise to a mixture of 576 g of 2.5-dichlorophenol and 10 ml of dry methylformamide under water cooling.
Stir for a minute. 2.48 g of chloromethylene malonic acid diethyl ester was added dropwise to this mixture at 10 to 15°C.
Stir for 3 hours. Pour water into the reaction solution and extract with ethyl acetate. The ethyl acetate layer was dried with anhydrous magnesium sulfate,
Concentrate under reduced pressure. The residue was subjected to column chromatography on Norica gel and eluted with benzene. Collect the eluate containing the target substance,
Concentration under reduced pressure yields 113.23 g of ethyl nisder 3-(2,5-cyclophenyloquine)-2-ethquine carbonyl acrylate as a colorless oil. Yield 969%. IRvmax(CHCI, ) + 1710.163
5.1570.14621140, 108108O' NMR, l; (CDCI,): 1.30 (
6H, m), 4.30 (4H, m), 7.0-7, 5 (
3H,m), 7.67(IH,5)b) 3-(2,5
Add 10 ml of polyphosphoric acid to 1.5 g of ethyl Nisder (-cyclophenyloquine)-2-ethoquinocarbonylacetate and heat at 100°C for 17 hours. After cooling, water was poured into the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer is washed with water and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, and the melting point was 118-1.
3-ethoxycarbonyl-5,8- as crystals at 20°C
0.16 g of dichlorochromone 12 is obtained. LRvmax (CHC1+): 1740.171
0.1670.1620°1582cm-' NMR, S (CDC1+): 1.37<3H,
t, ]=7Hz>, 4.40 (2H. q, J=7Hz), 7.38.7.65 (each L
H. ABq, 9Hz> c) 0.15 g of 3-ethoxycarbonyl-5,8-dichlorochromone, 1.6 ml of IN aqueous sodium hydroxide solution
and 4 ml of methanol, and the mixture is refluxed for 8 hours. The reaction solution was poured into water, adjusted to pH 1 with 10% hydrochloric acid, and extracted with ethyl. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under pressure. The residue was subjected to column chromatography on silica gel, and the melting point was 53-55°.
38 mg of 2.6-7chloro-2-hydroxyace)phenone was obtained as crystals of C. Example 5 a) Add 105 ml of anhydrous ether and 12.7 ml of thionyl chloride to 16.5 g of malonic acid and heat for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous ether L (60 ml).
1: Dissolve, add 23.4% of 2,5-dichlorophenol, and heat under reflux for 3 hours. The reaction solution was washed with water and extracted with an aqueous sodium bicarbonate solution. The aqueous layer is neutralized with hydrochloric acid, and the precipitate is back extracted with ether. Dry the ether layer with Glauber's salt and concentrate. The residue was dissolved in chloroporum-n-hexane (1
:1v/v), melting point 109.0-112.
22.1 g of malonic acid mono(2,5-dichlorophenyl) ester is obtained as crystals of OoC. Yield 61.1%
. Elemental analysis Calculated value (%) as C, H, O, C1: C, 43, 40: H, 2, 43: C
1, 28, 47 fruit 7su (α wealth (%>: C, 42
,98:H,2,40:C1,28,66IRv m
ax(CHCI,li: 1580.1725.
1780°2400-3440cm-'MS M"=248 NMR, 8 (CDC1+): 3.71 (2H, s>
, 7.00-7.45 (3H, m). 7,79(LH,brs) b) 1.25 g of malonic acid mono(2,5-dichlorophenyl) ester, 1.69 g of phosphorus pentachloride and 19 ml of nitrohenzene are mixed and the mixture is stirred at 55° C. for 2 hours. After cooling, 2.69 g of ferric chloride was added, and the mixture was stirred at 85°C for 5.5 hours. Add 20ml of concentrated hydrochloric acid and ice water to the reaction solution! Add 50ml of the mixture and extract with ether. The ether layer was washed with water and extracted with a saturated aqueous solution of hydrogen carbonate. The water stone is brought to pH 1 with hydrochloric acid and extracted with ether. The ether layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, concentrated, and 5,8-dichloro-
0.776 g of 2-hydroginchromone ('J. Melting point: 255-265°C. Elemental analysis C,) 1.0. CI1%H,0 calculated value (%)
I C,45,89;H,1,93:C1,30,1
0 actual θυ value (%): C, 45,83; H, 2,03
:C1,30,63M5 M"232 IRvmax(Nujol): 1710cm-'N
MR,S (CDC1+): 5.67 (1) 1.
s), 7.37.7.75 (2H. ABq, J-9Hz > b) 5.8-Cycloro-2-hydroquine chromone 231
mg is dissolved in a solution consisting of 0.24 g of sodium hydroxide and 5 ml of water and refluxed for 8 hours. After cooling, the reaction solution was diluted with 1
Adjust the pH to 1 with 0% hydrochloric acid and extract with acetic acid ester. Wash the acetate ester with water, dry it with anhydrous sulfur,
Reduce pressure a. The residue was subjected to column chromatography on licage gel and eluted with Hensen. The eluate was concentrated under reduced pressure to obtain 170 mg of 3,6-cyclo2-hydroxyacetophenone. Yield 82.9%. Example 6 3.26 g of 2.5-cyclophenol and 3.49 g of malonic acid dichloride were added to 1110th nitrohembine 32
ml and stirred at 55°C for 3 hours. Add 10.71 g of ferric chloride to this and stir at 85° C. for 3 hours. To the reaction solution, add fj, 20 ml of hydrochloric acid, and 1 ml of ice water.
Add 00ml of the mixture and extract with ether. ether] with an aqueous sodium bicarbonate solution. After adjusting the aqueous layer to pH 1, it is extracted with ether. The needle layer was washed with water, dried, concentrated, and diluted with 5°8-cyclo2-
2.80 g of hydroxychromone is obtained. Yield 60.6%
.

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents hydrogen or hydroxy, and R^2 represents hydrogen or alkoxycarbonyl. However, R^1
At least one of and R^2 is hydrogen. ) A method for producing 3,6-dichloro-2-hydroxyacetophenone, which comprises hydrolyzing a compound represented by: (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents hydrogen or hydroxy, and R^2 represents hydrogen or alkoxycarbonyl. However, R^1
At least one of and R^2 is hydrogen. ).