DE1088047B - Process for the production of protoanemonin and its homologues - Google Patents

Description

Process for the production of protoanemonin and its homologues Es is known from acetylacrylic acid in the presence of acetic anhydride as a dehydrating agent Means to split off water to obtain protoanemonin. In this way of working must, however, acetic anhydride as a dehydrating agent in the @; # excess can be used, see Journal American Chemical Society, Vol. 68, 1946, p. 2510 until 2513.

According to Ch. Grundmann and E. Kober, see Journal American Chemical Society, Vol. 77, 1955, pp.2332 and 2333, protoanemonin is obtained if one adds levulinic acid the ring closure to the angelicalactone in the dibromovalerolactone and then out this splits off 2 moles of hydrogen bromide by treatment with tertiary amines. This The process is disadvantageous because the dehydrogenation takes place in two stages via an addition of bromine and subsequent elimination of hydrogen bromide as a result of the corrosive effect the hydrobromic acid requires special technical efforts. Also is the bromination is associated with a considerable consumption, since stoichiometric amounts Bromine must be implemented. These bromine losses can only be caused by an additional Work-up procedures for the hydrogen bromide are avoided.

It is also known that according to H. 1V1. Walton, see Journal Organic Chemistry, Vol. 22, 1957, pp. 312 to 315, succeeds in producing protoanemonin analogs to produce using a cumbersome and multi-stage process. For example a diene such as cyclopentadiene or anthracene with maleic acid monochloride monomethyl ester implemented by the Diels-Alder process to give the corresponding diene adduct. This The adduct is converted into a derivative of the γ-ketocarboxylic acid ester by a Grignard reaction transferred, then saponified the ester derivative and then the free acid in acetic anhydride in the presence of sodium acetate or hydrochloric acid into the lactone converted. The cleavage of the diene adduct finally results in the protoanemonine analog and get the diene used.

These known methods are not readily available on an industrial scale feasible, as the yields are not acceptable due to the multistage procedure can be expected. It has now been found that protoanemonin can be obtained in a very simple manner or its homologues are obtained by y-ketocarboxylic acids or their esters at increased Temperature either simultaneously or in succession over dehydrogenation and dehydration catalysts directs.

The method of the invention now provides a simple technical one viable route to the production of protoanemonin and its homologues from γ-ketocarboxylic acids or their esters or derivatives open. Either the γ-ketocarboxylic acids are used or their esters or derivatives directly by splitting off hydrogen and water into the protoanemonin and its homologues via or the γ-ketocarboxylic acids are first dehydrated or their esters or derivatives and cleaves from the dehydrogenation products formed Water is removed or, in reverse of this procedure, the γ-ketocarboxylic acids are first cleaved or their esters or derivatives, and then dehydrate the resulting dehydration products.

These three different procedures are explained in terms of formulas using propionyl propionic acid. In the procedure indicated according to route II, the elimination of water in the first stage leads to the lactones. The dehydration product can, of course, contain all three possible isomeric lactones, i.e. hexen-(2) -olide- (1,4), hexen- (3) -olide- (1,4) and hexen- (4) -olide- (1 , 4), contained side by side in varying proportions. When carrying out the process according to route II or III, both the intermediates obtained in the first stage can be separated off, but the reaction mixtures formed can also be processed further directly. It is of course also possible to use γ-ketocarboxylic acid lactones obtained in other ways as starting materials for the process and to convert them into protoanemonin and its homologues by subsequent dehydration.

When performing the procedure on the specified in the equation Route I is used as the starting material aliphatic γ-ketocarboxylic acids or their Esters or derivatives, such as levulinic acid, levulinic acid methyl ester or ethyl ester, Propionyl propionic acid, propionyl propionic acid methyl ester or. -äthylsster.

When carrying out the process according to reaction path II and III of the formula scheme one uses the same starting materials or on route II, As already mentioned, the lactonization of these γ-ketocarboxylic acids or their esters or derivatives available compounds, e.g. B. the 1,4-pentenolides or 1,4-hexenolides, such as pentene- (3) -olide- (1,4) (= a-angelicalactone), pentene- (2) -olide- (1,4) (=, B-angelicalactone), pentene- (4) -olide- (1,4), hexen- (3) -olide- (1,4), Hexen- (2) -olide- (1,4), hexen- (4) -olide- (1,4) or mixtures thereof.

To carry out the process, depending on the reaction route, one after the other or side by side, those commonly used for dehydration and dehydration Catalysts used.

As catalysts for the dehydrogenation and dehydration of the y-ketocarboxylic acids or their esters can be used simultaneously in addition to the known metallic dehydrogenation catalysts, e.g. B. the platinum metals, such as palladium, platinum and nickel, especially phosphates in a mixture with alkali or Alkaline earth oxides as catalysts, which are also applied to supports such as aluminum oxide could be.

Among the possible catalysts, those made of silicic acid or aluminum oxide, which contain about 20% phosphoric acid, of calcium-nickel-phosphate, of γ-aluminum oxide to which 10% palladium is applied, of activated carbon, have proven particularly suitable, to which 20% palladium is applied, furthermore from silica gel, the 20% nickel and 10 /, chromium or 501, copper, 150 /, nickel and 10 [0 chromium or 501, copper, 160/0 nickel and 0.80 It contains manganese, and 98% copper, which contains small admixtures of barium, chromium, and zinc.

However, these catalysts are also used for the dehydrogenation of the three isomers Pentenolide- and hexenolide- (1,4) suitable in the gas state.

As catalysts for the dehydrogenation of the dehydration products according to reaction path II of the equation, the hitherto customary ones can generally be used known dehydration catalysts can be used.

For example, the metals palladium, platinum, nickel, Copper in metallic form or on inert carriers, e.g. B. on aluminum oxide; Silica gel, Use pumice stone, charcoal or fuller's earth applied. The weight ratio the metals applied to the supports can vary between 0.5 and 40%; A content of 10 to 30%, based on the total amount, is particularly favorable of the catalyst.

When using metallic dehydrogenation catalysts, especially those which are applied to supports, it is advantageous, the catalysts expedient under the respective reaction conditions beforehand by treatment in a stream of hydrogen to activate.

The oxides of V. and VI are also suitable for dehydration. Subgroup of the periodic system as well as mixed catalysts, the z. B. to consist predominantly of zinc oxide and small amounts of non-volatile alkali or alkaline earth salts of inorganic acids and / or alkali or alkaline earth oxides or hydroxides. But you can also use the oxides of the metals of V. and VI. Subgroup of the periodic system, z. B. vanadium, chromium, molybdenum, Tungsten and uranium, as well as other oxides, e.g. B. zinc oxide, aluminum oxide, especially add the well-known y-aluminum oxide, magnesium oxide, bismuth oxide and thorium oxide.

The dehydration of the dehydration products, which one according to the reaction mode II receives, i.e. the dehydration of the lactones, but can also be in the liquid state are executed. Raney nickel and Raney copper are also suitable as catalysts for this. It is advantageous to use the dehydrogenation catalysts in this procedure however, the quinones or the quinone derivatives, e.g. B. of o-chloranil, p-chloranil, 2,3-dichloro-5,6-dicyano-1,4-benzoquinones.

You can arrange the catalysts in the reaction vessel or after move through the reaction vessel using the fluidized bed process. But it is also possible the catalysts in granulated, powdery or pill form in swirling and swirling Keep moving.

The process is carried out at an elevated temperature. One works with the reactants in the gaseous state, one expediently selected Temperature range from 250 to 600 ° C, advantageously between 350 and 500 ° C. In contrast it is expedient to work with the liquid reactants in the temperature range from 70 to 180 ° C, advantageously between 100 and 150 ° C.

The procedure is both under diminished, normal and at increased pressure. When performing the dehydration of the starting materials in the gas state it is advantageous to work under reduced pressure, e.g. B. at 30 to 500 mm of mercury pressure, especially between 100 and 300 mm. But you can also at dehydrate under normal or elevated pressure. Will the dehydration of the starting materials carried out in the gas state, the starting materials can be put directly into the catalyst chamber introduce or upstream a suitable vaporizer in which the starting materials heated and evaporated, whereupon they are in vapor form, optionally together with inert gases, are introduced into the catalyst space. The use of inert Gases is, for example, catalytic in the implementation of either of the two Process stages according to reaction path II or III in the fluidized bed process are expedient, because the vapors from the starting material to be dehydrated or from the water are split off will mostly not be enough to keep the catalytic converters swirling in up and down Keep moving. You can use the inert gases used for support run in a cycle. It can be particularly useful in the case of dehydration, the Dehydration when the starting materials are carried out once through the reaction vessel not to let it run completely, but rather. the dehydration only up to one to carry out certain sales. In this case one reduces by known technical Measures, z. B. the reduction of the catalyst space or the Path through the catalyst room, the residence time of the substances in the catalyst room. But you can also increase the conversion by diluting the starting materials to be converted reduce. So you can, for example, in the dehydration of the starting materials Mix in inert gases in the gas state or add solvents in the liquid state.

As solvents are, for. B. suitable: hydrocarbons such as xylene, Alcohols such as tertiary butanol, ethers such as dioxane, chlorinated hydrocarbons such as Tetrachlorethylene.

According to the method of the invention it is possible to use protoanemonin and its homologues, e.g. B. Methylprotoanemonin to produce in a continuous manner. But you can also, if it is appropriate, according to the formula given in the formula Reaction pathways work partly continuously and partly batchwise. So can one z. B. in the direct production of methyl protoanemonine from propionyl propionic acid this in a mixture with 5 to 10% steam, continuously in steam form, if necessary in the presence of inert gases, introduce into the reaction vessel and over the catalyst to lead. But you can also directly into the feed mixture from the outside via the Add dropwise the reaction vessel heated to the boiling point. With the direct introduction the starting materials can be placed in the reaction vessel heated above the boiling point an inert organic solvent, e.g. B. hydrocarbons, such as benzene, Also introduce petroleum ether or alcohols into the reaction chamber.

Inert solvents are mainly understood to mean those that Do not trigger any side reactions under the reaction conditions, i.e. neither yourself are dehydrated nor react with the starting materials to split off water are suitable.

The reaction mixture becomes appropriate after the completion of the reaction chilled or quenched. The reaction mixture is advantageously cooled with a cold aqueous solution of a stabilizing agent, e.g. B. of hydroquinone, Pyrogallol, phenthiazine, ascorbic acid or their mixtures. A special embodiment consists z. B. is that the hot reaction gases directly into a cold one sprayed in aqueous solution of the stabilizers mentioned, whereby the reaction gases the protoanemonin or its homologues are deposited and stabilized at the same time. But you can also quench the reaction gases with water and the stabilizers add afterwards or otherwise cool and liquefy the gases.

The reaction mixtures are worked up, for. B. by fractional Distillation. The crude mixture is expediently distilled under reduced pressure. The substances accessible after the process are valuable pharmaceuticals. example 1 145g ß-propionyl-propionic acid are mixed with 3% boric acid and under Heated to reflux for about 1 hour. The mixture is then turned into a water jet pump in a vacuum A mixture of water and hexen- (3) -olide- (1,4) via an attached packed column distilled off. After separating the aqueous layer and drying the hexene (3) solide (1,4) with anhydrous sodium sulfate that is distilled in vacuo. With KP-3 .. = 50 up to 52 ° C., 112 g of hexen- (3) -olide- (1,4) are obtained, which is 90% of theory.

In a vertical tube 60 cm long and 45 mm in diameter are 200 cm3 of a catalyst containing 20% copper and 0.7% chromium on silica contains as a carrier, fixedly arranged. Through this pipe one leads in the course of 8 Hours at 350 ° C and 760 mm mercury pressure 112 g hexen- (3) -olide- (1,4). At the bottom At the end of the reaction tube, the gas mixture is collected in a separator and cooler. Fractional distillation of the crude mixture gives a bp "= 86 bis 92 ° C 79 g of unreacted hexenolide, which can be reused, and at Bp "= 115 to 120 ° C. 28 g of methyl protoanemonine. A small amount of residue remains in the vessel. The yield of methyl protoanemonine corresponds to 86% of theory a conversion of 29.5 u /., based on converted hexen- (3) -olide- (1.4). example 2 In the same device as in Example 1, in the course of 7 hours 112 g hexen- (4) -olide- (1,4) at 400 to 410 ° C and 50 mm mercury pressure over a Catalyst containing 10% palladium on aluminum oxide as a support, passed. After 65 g of unconverted hexen- (4) -olide- (1,4) are obtained at a boiling point of 100 up to 105 ° C 41 parts of methyl protoanemonine. At a conversion of 42 ° / a is the Yield over 89% of theory. Example 3 As in example 1, 112g hexen- (2) -olide- (1,4) at 390 ° C and 300 mm mercury pressure in the course of 6 hours over a palladium-carbon dehydrogenation catalyst, which contains 20 0 / a of palladium, passed. 39 g of methyl protoanemonine are obtained Bp. "= 120 to 125 ° C and 61.5 g of unconverted hexen- (2) -olide (1,4). The yield is 79 "/ o with a conversion of about 450 /,. Example 4 As in Example 1 are 112 g of hexen- (2) -olide- (1,4) at 350 ° C. and 760 mm of mercury pressure in the course of 7 hours via a catalyst containing 1.5% palladium on aluminum oxide as a carrier, directed. 15 g of methyl protoanemonine are obtained in addition to 90 g of unreacted hexenolide. The yield is 68%, the conversion 19.5%.

Example 5 As in Example 1, 112 g of hexen- (2) -olide- (1,4) at 350 ° C and 76 Ω mm mercury pressure passed over a catalyst, the 20% Contains copper and 0.7% chromium on silicon dioxide as a carrier. 23 g are obtained Methyl protoanemonine and 79.4 g of unreacted hexenolide. The yield is 70.6 ° / o, the conversion 29 ° / o.

Example 6 As in Example 1, 112 g of hexen- (2y-olide- (1,4) im Run of 6 1/2 hours at 350 ° C and 400 mm mercury pressure over a catalyst which contains 20111, nickel and calcium phosphate. 17 g of methyl protoanemonine are obtained and 92 g of unreacted hexenolide. The yield is 85% and the conversion 17.5 ° / o.

Example 7 As in Example 1, 7.12 g of hexen- (4) -olide (1,4) are passed over a catalyst in the course of 6 hours at 350 ° C and 250 mm mercury pressure, which contains 5% copper, 15% p contains nickel and 101, chromium silicon dioxide as a carrier. In addition to 96.6 g of unreacted hexenolide, 12 g of methyl protoanemonine are obtained. This corresponds to a yield of 740/0 and a conversion of 14.5%.

Example 8 As in Example 1, 112 g of hexen- (3) -olide- (1,4) are passed over a catalyst containing 5% copper, 160/0 at 300 ° C. and 760 mm mercury pressure in the course of 8 hours Contains nickel and 0.80 /, manganese applied to silicon dioxide as a carrier. 19 g of methyl protoanemonine and 88 g of unreacted hexenolide are obtained. This corresponds to a yield of 79% of theory with a conversion of 210/0. Example 9 After the preparation of the hexene (3) solide (1,4)! obtained from 140 g of levulinic acid in a yield of 82% of theory = 98 g of pentene- (3) -olide- (1,4) with a boiling point of 12 mm = 55 to 56 ° C.

In the device described in Example 1 are in the course of 6 hours at 370 ° C and 400 mm mercury pressure 98 g of pentene- (2) -olide- (1,4) over a catalyst containing 10 0/0 palladium on aluminum oxide as a support, given.

During work-up, the solid reaction product is separated off and recrystallized. 28 g of anemonine with a melting point of 150 ° C. are obtained. The liquid one Mixture is fractionally distilled; at KP-1.5 = 85 ° C, another 12 go g protoanemonin about. At bp 15 = 89 to 90 ° C, 49 parts of unreacted are obtained Pentenolide back. This corresponds to a yield of 81.5%, of which 24.5% is protoanemonin and 57 0/0 are anemonine. The conversion is about 50%. Example 10 As in the example 1, 98 g of pentene- (3) -olide- (1,4) are obtained in 7 hours at 450 ° C. and 50 mm Mercury pressure passed over a catalyst, the 20 0/0 palladium on granular Contains coal. The reaction mixture is worked up as in Example 9 and is obtained 24 g of anemonine with a melting point of 151 ° C., 44 g of unreacted pentenolide with a boiling point. " = 55 to 56 ° C and 18 g of protoanemonin with a boiling point of 12 = 80 ° C. The yield is about 78 ° / 0, of which 33.40 / 0 is protoanemonine and 44.5% is anemonine. The turnover is at 56 0/0. Example 11 is obtained in the same way in the presence of a catalyst from 20 0/0 copper and 0.7 0/0 chromium on silicon dioxide as a carrier made from 98 g pentene- (3) -ohd- (1.4) 32 g of anemonin and 6 g of protoanemonin and 36 parts of unreacted pentenolide. The yield is 73%, of which 11.3% are protoanemonine and 61.6% are anemonine. The conversion is 53%.

Example 12 In 400 cm3 of xylene, 112 g of hexen- (3) -olide- (1,4) and 245 g of chloranil refluxed for 1 hour with stirring. After the termination After the reaction, the solution is filtered off from the precipitate and the solvent is distilled off away. The residue is fractionally distilled. One obtains with a Kp.0,0a = 37 to 40 ° C 70 g of pure methyl protoanemonine, not = 1.5319. The yield is 63.5 0/0 of theory, based on hexen- (3) -olide- (1,4). .

Example 13 In 400 cm3 of xylene, 112 g of hexen- (2) -olide- (1,4) and 245 g of chloranil boiled under reflux with stirring for 1/2 hour: The work-up takes place as in Example 12. In addition to 51 g of unreacted hexenolide 42 are obtained g methylprotoanemonin. The conversion corresponds to 54.50 / 0; the yield is 69%.

Example 14 In a vertical pipe 1 m long and 45 mm diameter is 400 cm3 of a catalyst containing nickel and calcium phosphate, firmly arranged. 50 cm3 of a mixture that consists of 95% propionyl propionic acid and 5% water. The reaction temperature is 470 ° C, the pressure is 200 mm of mercury. At the lower end of the reaction tube the gas mixture is collected in a separator and cooler. You get every hour 28 g of methyl protoanemonine with b.p. "= 115 to 120 ° C in addition to 15.5 g of unreacted Propionylpropionic acid, KP-25 = 125 to 130 ° C, obtained by fractional distillation be separated. The conversion is 65 "1" and the yield is 90.50 / 0. The space-time yield is 1.5 to 2 kg per liter of catalyst per day. Example 15 In the presence of a Catalyst containing 20% phosphoric acid on aluminum oxide as a support according to the procedure described in Example 14 from. Propionyl propionic acid hourly 15 g methyl protoanemonine with b.p. 25 = 115 to 120 ° C, 9 g hexen- (2) -olide- (1,4) with b.p. 26 = 120 to 125 ° C and 17.5 g of unreacted propionylpropionic acid with b.p. 25 = 125 to 130 ° C. The conversion is 610/0, the yield of methyl protoanemonine is 52.5 0/0, of hexen- (2) -olide- (1,4) 300/0, the total yield thus 82.5 0/0. example 16 In a vertical tube 60 cm long and 45 mm in diameter 200 cms of a catalyst containing 10 0/0 palladium on aluminum oxide as a carrier, firmly arranged. This pipe is used for 6 hours at 400 to 410 ° C and 150 mm mercury pressure passed 158 g of ethyl propionyl propionate. at after working up, 10 g of methyl protoanemonine are obtained by fractional distillation, 24 g hexen- (2) -olide- (1,4) and 78.5 g propionyl-propionic acid.

In place of the ethyl propionyl propionate, 144 g of ethyl levulinate are used implemented. In the work-up, 20 g of anemonine have been separated off by fractional distillation 5 g of protoanemonine at b.p. "= 85 ° C, 13 g of pentene- (2) -olide- (1.4) at bp "= 85 to 95 ° C and 65 g of levulinic acid at bp" =. 150 to 1600C. example 17 Under the test conditions of Example 16, when using a Calcium nickel phosphate catalyst 116 g of levulinic acid at 470 ° C and 250 mm mercury pressure passed over the catalyst in 6 hours. Just below the reaction space a cold, aqueous 20% hydroquinone solution is injected into the reaction tube. The reaction gases are quenched and separated in a separator. One achieves thereby a stabilization of the rather volatile protoanemonin,. so that the Dimerization is largely suppressed. One obtains after separating the Crystal fraction of 8 parts of anemonine, corresponding to a yield of 110/0 Theory, by fractional distillation at b.p.iS = 85 ° C 49 parts protoanernonine, corresponding to a yield of 67%, theoretically, and at b.p. "= 154 to 160 ° C 43 parts of unreacted levulinic acid. The conversion is 63 0/0 ..

One uses a catalyst that contains 20 0/0 phosphoric acid on silica contains, one obtains 4 g anemonin, 43 g protoanemonin and 11 g Pentene- (2) -olide- (1,4).

Example 18 A test arrangement as shown in Example 14 is used. In the vertical pipe that has the same quantities contains the same catalyst as in Example 14, within 1 hour 50 cc of B-n-propyl levulinic acid, which still contains about 5% water, was added dropwise. The reaction temperature is kept at 480 ° C, the pressure is set to 200 mm mercury silver column a. At the lower end of the reaction tube, the gas mixture is in one Separator and cooler collected. After working up, the liquid ones are obtained Reaction products 12 g of n-propylprotoanemonine, b.p. 1 = 63 to 68 ° C, in addition to 20 g not converted 8-n-propyl levulinic acid, boiling point 25 = 160 to 170 ° C.

Claims (5)

PATENT CLAIMS: 1. Process for the production of protoanemonin and its homologues, characterized in that aliphatic γ-ketocarboxylic acids or their esters in liquid or gaseous state at elevated temperature either simultaneously or successively over known dehydrogenation and dehydration catalysts. 2. The method according to claim 1, characterized in that one propionyl propionic acid or levulinic acid at elevated temperature and under reduced pressure over catalysts conducts that contain nickel and calcium phosphate. 3. The method of claim 1; characterized in that one propionyl propionic acid ester at elevated temperature and passes under reduced pressure over a catalyst containing 10% palladium contains on aluminum oxide as a carrier. 4. The method according to claim 1 to 3, characterized characterized in that the dehydrogenation and / or elimination of water in the presence performed by water vapor as an inert gas. 5. The method according to claim 1 to 4, characterized in that the hot reaction gases are quenched with cold water, contains the stabilizing agent in dissolved form. Publications considered: Journal of the American Chemical Society, Vol. 68, 1946, pp. 2510-2513; Vol. 77, 1955, Pp. 2332 and 2333; Journal Organic Chemistry, Vol. 22, 1957, pp. 312-315.