DE2806424A1 - PROCESS FOR THE PREPARATION OF THE DIESTERS OF ALPHA-ACETYL-ALPHA'-METHYLSERNSTEINIC ACID - Google Patents

Description

The Upjohn Company
Kalamazoo, Mich., V.St.A.

Process for the preparation of diesters of O ^ -acetyl- ^ ¹ -methylsuccinic acid

The invention relates to processes for the production of succinic acid ester derivatives and the use of these succinic acid ester derivatives in processes for the production of valuable acid compounds, in particular the invention relates to an improved process for the production of esters of (X-acetyl-Qc ¹ -methylsuccinic acid, which are found as intermediates in the production of Esters of CX-Methy 1-0 "? -Acetyl-Of" - (5-methyl-3-oxohexyl) succinic acid, which in turn are used in the production of valuable drugs such as ibuprofen, flurbiprofen and the like.

It is known that diethyl-Ctf-acetyl-O? ¹ -methyl succinate can be produced in about 63% yield by reacting ethyl acetoacetate with ethyl (X-bromopropionate in the presence of sodium hydroxide, potassium iodide and water (compare "Zh. Pukl. Khim." Volume 38 (2), pages 436 to 437) (1965) ref. In "Chem. Abs." Volume 62, 13037c). From "J. Chem. Soc." (London), pages 4633 to 4640 (1970) it is known that the same diester is about 47% pure Yield can be prepared by reacting ethyl acetoacetate with ethyl β £ -bromopropionate in the presence of sodium in ethanol. Similar references can be found in "Chem. Abs." Volume 54, 10852h, "Chem. Abs." Volume 49, 1565c by "J. Chem. Soc. "(London), 3313 (1953) and" Chem. Abs. "Vol. 38, 2332 of

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"J. Ind. Chem. Soc." Volume 20, pages 173 to 177 (1943). However, it has been shown that neither the aqueous basic system nor the ethanolic basic systems the described alkylation using the cheaper ethyl-2-chloropropionate instead of the ethyl-2-bromopropionate allow. It has been shown that the 2-chloropropionate ester at moderate temperatures (40 ° to 50 ° C) does not allow any noticeable alkylation reaction to take place. Under more drastic temperature conditions, when using Although this base system consumes 2-chloropropionate and acetoacetic ester starting materials, it finds However, only a small amount of diethyl Q <-acetylsX-methylsuccinic acid ester is present in the reaction product. This suggests that this valuable succinic ester intermediate is something is unstable and is further converted to undesirable and useless by-products in the reaction mixture.

Further information regarding the use of fr-acetyl- (X-methylsuccinic acid esters in processes for the production of valuable medicinal acid compounds can be found in the GB-PS 1,265,800 and the BE-PS 820,267.

The invention was based on the object of developing an improved and more economically feasible process for the preparation of esters of "X-acetyl-Ot! -Methy! Succinic acid, which can be carried out under process conditions in which decomposition of the ester product is largely prevented and the formation and stability of such ester products in the respective reaction mixtures can be maximized and which allows the use of cheaper starting materials. Furthermore, according to the invention, QC-methyl-Oi ¹ -acetyl-Oi - (5-methyl-3-oxohexyl) succinic acid esters should exceed those described in more detail

809833/0592

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CX-Acetyl-Of -methylsuccinic acid diester produced will.

According to the invention it has been shown that esters of Ot-acetyl- (X'-methylsuccinic acid can be obtained in improved yield from acetoacetic acid esters and O-chloro- or "X-bromopropionic acid esters" by alkylation reaction under conditions which allow the formation of the O (-acetyl-0c ' -methylsuccinic diesters and their degradation to less useful materials can practically not promote.The inventive method consists in a reaction of an ester of acetoacetic acid with an ester of one of the O-halopropionic acids mentioned in a practically non-polar, aprotic, organic liquid solvent medium in Presence of a solid / liquid phase transfer catalyst, a catalytic amount of iodide ions and an end protonizing base in a solid form which is practically anhydrous and has a high surface area for a ^{time sufficient to form the Qt-acetyl-1} -methylsuccinate base in the reaction mixture Reaction mixture ka nn per se in the context of chemical processes · further processed. In such a process, the Ot-acetyl-Oi ¹ -methylsuccinic acid ester contained in the reaction mixture is mixed with vinyl isobutyl ketone (or the corresponding Mannich base in the presence of an alkylating agent) and an alkali metal base to form the ester of the Ot-methyl-Qt ¹ acetyl (y - (5-methyl-3-oxohexyl) succinic acid, which is a non-cyclic aliphatic precursor of the known pharmaceutical acid ibuprofen, is reacted for a sufficient period of time. The ibuprofen is then obtained by heat treatment in accordance with GB-PS 1.265.800, BE -PS 820,267 and U.S. Patent Application Serial No. 622,130.

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The invention thus relates to a process for the preparation of diesters of O ^ -acetyl-O ^ '- methylsuccinic acid, which is characterized in that an ester of acetoacetic acid is determined in a practically non-polar, aprotic, organic liquid with a dielectric constant at a temperature of 25 ° C, below about 11 at a temperature of about 50 ⁰ C to the reflux temperature of the mixture in the presence of a deprotonizing base of a surface corresponding to a particle size below at least about 0.246 mm (60 mesh) with an ester of a & -halopropionic acid , the halogen part of which consists of chlorine or bromine, is converted until the respective diester of Ci-acetyl-cl ¹ -methylsuccinic acid is formed.

According to the invention, it has been shown that when working in the manner described, the better stabilizing basic conditions are achieved which ^{are necessary for the formation of the iX-acetyl-ίλ 1} -methylsuccinic diesters from the cheaper 2-chloropropionic acid esters. It has been shown that under otherwise identical conditions (78 ^o C, K ₃ CO ₃ as base, potassium iodide as iodide ion supplier and the commercial product "Aliquat 336" as phase transfer agent) the diethyl O-acetyl-Oc'-methylsuccinate in Absolute ethanol has a half-life of about 2 hours, whereas in toluene (according to the invention) it has a half-life of over 70 hours. According to the invention it has been found that the alkylation of the acetoacetic ester

acid with the 2-bromopropionic / or 2-chloropropionic acid ester in toluene or heptane or an equivalent non-polar, liquid organic medium using dry, ground alkali metal carbonate, a phase transfer catalyst and potassium iodide to a yield of over 70% in Ä-acetyl-Ot ^1- methylsuccinic diester with only 2.6% o-alkylation and 2.9% formation of

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Enol-lactone by-products leads. When using solvents such as methylene chloride in the context of a corresponding process, the amount of Ot-acetyl-OC ¹ -methylsuccinic acid ester product obtained is reduced, this being 20 to 30% o-alkylated product of the formula:

0 CO ₂ -Alk
CO ₂ -AIk

(VII)

Alk for the alkyl ester group, e.g. ethyl group, which is

cannot be separated easily, is contaminated. In the context of the method according to the invention, however, runs the alkylation of the acetoacetate with the 2-bromopropionate or 2-chloropropionate to form the Qc-acetyl-Oc'-methylsuccinic acid diester largely from.

Thus, the described chemistry ultimately leads to an improved chemical that is valuable in practice Process for making valuable 2-arylalkanecarboxylic acid drugs. Esters and acids thereof valuable for agriculture are obtained in a smooth reaction process from inexpensive aliphatic chemicals.

The acetoacetic ester starting materials are known. Which ester is used in detail is not critical (compare GB-PS 1,265,800). With the ester

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it should be one which is soluble in the practically non-polar, organic liquid medium. C - to C _fi esters are particularly popular, the ethyl ester being preferred. The OL-bromopropionic acid and Cft-chloropropionic acid ester starting materials are also known. Which particular ester group is used is not critical, but an ester should be used which is soluble enough in the practically non-polar, organic, liquid solvent medium to be able to react. The C-- to C _g -alkyl esters are particularly popular, the ethyl ester being preferred.

The practically non-polar organic liquids serve in the context of the process according to the invention as solvents for the ester reactants. The organic liquid compounds or mixtures thereof are those with dielectric constants, determined at a temperature of 25 ^° C., of about 11 or below, preferably below 5 (see, for example, Lange's Handbuch der Chemie, 9th edition (1956), Pages 1222 to 1225). Examples of liquid solvents suitable for this purpose are benzene, toluene, xylene, cyclohexane, heptane, nonane, chloroform, bromobenzene and the like. Preferred non-polar aprotic solvents in the context of the process according to the invention are toluene and mixtures thereof.

As solid / liquid phase transfer media are used in usually quaternary ammonium, sulfonium or phosphonium salts used. These promote contact between the solid and liquid substances in the mixture. Examples

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_{for such phase transfer} agents are tetra- (C ₁ - to C 1fi -alkyl) ammonium halides, such as tetrabutylammonium bromide, and other known quaternary salts available for this purpose, as well as crown ethers (see US-PS 4,001,279) and the references cited above, Sulphonium (R ₃ S ⁺ ) salts, e.g. the tris (Cj- to Cg-alkyl) sulphonic acid, di (C ₁ - to C ₁ "-alkyl) phenylsulphonium salts, for example trimethylsulphonium iodide, trisdodecylsulphonium sulphate, di-octadecylmethylsulphonylsulphonium chloride, and di-octadecylmethylsulphonium chloride -p-toluylsulfonium sulfate and the like, and phosphonium (R ₄ P) salts, for example the tetra (C ₁ - to C ₁ g-alkyl) phosphonium and mixed alkylarylphosphonium salts, for example tetrabutylphosphonium chloride, trimethylpheny! phosphonium iodide, methyltriphenylphosphonium A commercial example of such a phase transfer agent is the commercial product "Aliquat 336", which presumably consists of tricaprylylmethylammonium chloride.

The iodide ions can be in any economically justifiable, soluble form are made available in at least a catalytic amount. Alkali metal iodides are preferred, e.g. sodium and potassium iodides. Ammonium iodide and alkaline earth metal iodides, e.g. calcium iodide, can may also be used, but they are used for economic reasons and for reasons of less effectiveness less preferred. Iodide ions can also come from the iodide ions of a phase transfer agent. The catalytic amount of iodide ions is usually small and corresponds to one, based on the ester reactants sub-molar amount.

The deprotonizing base, for example alkali metal carbonates, orthophosphates, -C ₁ - to Cg alkoxides, hydroxides and the like (generally in contrast to Lewis bases),

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should be used in at least approximately stoichiometrically equivalent amounts for both ester reactants reach. The deprotonating base is preferably oven dried to have at least the majority of it to remove adhering water. It can be used as a finely ground powder with a particle size below about 0.246 mm (60 mesh), preferably less than about 0.147 mm,

or in any other equivalent form of high contact surface, e.g. as highly porous pressed granulate, Tablets, pellets and the like. Which are used in the reaction mixtures as a deprotonizing base have the power to work.

The reaction mixture containing the constituents mentioned is stirred or otherwise agitated in order to ensure sufficient contact of the liquid and solid constituents of the mixture for the time required to complete the reaction as far as possible. Although it is possible to work at temperatures below 50 ^° C., the reaction times here are generally too slow to be acceptable for carrying out the process on an industrial scale. When using the ethyl esters as reactants, optimal results are achieved if the reaction mixture is stirred at a temperature of about 75 ° to 100 ° C. for about 6 hours.

The O <r-acetyl- \ H'-methylsuccinic acid diesters can, if desired, be isolated from the reaction mixture in a conventional manner. However, since the diester obtained in each case generally serves as an intermediate for a further reaction, such a preparation in pure form is generally not necessary.

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Another advantage in the production of the (^ -acetyl- ^ 'methy! Succinic acid esters in the manner described is that here in the same vessel and solvent, in which also the relevant OC-acetyl- * '-methylsuccinic acid ester was prepared, from it in the simplest way the & -acetyl-Qt- £ (5-methy 1-3-oxo) hexylJ- (V methy! succinic acid ester can be produced. The latter ester is known from BE-PS 82O.26 7. He represents an intermediate in the manufacture of ibuprofen, a commercially available anti-inflammatory or drug-adverse drug acid.

The method according to the invention consequently enables a complex chemical process sequence with one Minimum equipment and time required. This chemical process sequence follows the following reaction scheme:

Deprotonizing Base (K2CO3) \

Cl)

CO ₂ et

X
(H)

l) isobutyl vinyl ketone

CO ₂ et

+ KX

2) KOH; 3) Polar solution

middle

or

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- 14 N (Et) ₂

2) Me ₂ SO ₄ (IM) I-

further K ₂ CO ₃ polar solvent

In the reaction scheme:

(IV)

Et ethyl,

X chlorine or bromine and

Me ₂ SO ₄

Dimethyl sulfate.

When the reaction of the acetoacetic acid ester (I) and the Ot-halopropionic acid ester (II) to the Ό * · -acetyl-Qtf methylsuccinic acid ester (III) has ended in solution, the mixture containing the ester (III) can be mixed with either isobutyl vinyl ketone per se and a base plus a polar solvent or a N, N-di (C. was), plus an alkylating agent such as di (C, - to Cg ~ * alkyl) sulfate, for example dimethyl sulfate, or a C ₁ - to Cg alkyl iodide, e.g. methyl iodide, and another deprotonizing base, which is used to convert the alkylated Mannich- Base to isobutyl vinyl ketone in situ and to catalyze the Michael reaction between the isobutyl vinyl ketone and the O-acetyl-O'-methylsuccinic acid diester derivative (III) in the presence of any polar solvent added, preferably a C ..- to Cg-alkano l or a Ν, Ν-bis- (C ..- to Cg-alkyl) formamide, is treated.

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280642A

If the Mannich base, for example N, N-diethyl-N- (5-methyl-3-oxohexy-Damin, to the CX-acetyl- (X'-methyl succinic acid diester to form the (X-acetyl-ty.- (5 -methyl-3-oxohexyl) -CiL ¹ -methylsuccinic diester (IV) is added, the addition of further deprotonating base, for example potassium carbonate, is preferably limited as much as possible, namely to an amount not more than that required to produce the OW \ cetyl- <X'-methylsuccinic acid diester (III) itself was used, because at a high (apparent) pH value, the V-acetyl-OC ¹ -methylsuccinic acid ester intermediate (III) is caused by the alkylating agent, for example dimethyl sulfate , O-alkylated is. When the Isobutylvinylketon is generated in situ, dimethyl sulphate is preferably at low temperatures, for example at temperatures from 0 ° to 5 ⁰ C, was added, in order to suppress a Ν, Ν-dialkyl-N-methylamine Eliininierung. The latter could, since it consumes dimethyl sulfate, at h higher temperatures occur. Only after the Mannich base has quaternized and essentially disappeared (determined by gas / liquid chromatography or another equivalent analytical method on a sample of the reaction mixture), a more polar organic liquid solvent, preferably a C ₁ - to C --- Alkanol, e.g. Ethanol, or an N ₇ NC ₁ - to Cg dialkylformamide, and further deprotonizing base, for example potassium carbonate or potassium hydroxide, added to the Michael reaction between the Mannich base and the Qi-acetyl- <X ^g -methylsuccinic acid diester (III) to set in motion. When the added deprotonating base has brought the apparent pH to about 11.5, the Michael reaction begins. At a pH of around 13, acceptable aldolization occurs. The addition

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of the polar solvent, for example a C ₁ - to C _fi -alkanol such as ethanol, is required for the Michael reaction. The polar solvent, for example the alcohol, is added after the quaternization of the Mannich base has ended, so that dimethyl sulfate is no longer consumed by the alcohol or another polar solvent. The size (ie surface area), dryness and agitation of the deprotonating base, for example potassium carbonate, are important for the reproducibility of this heterogeneous reaction. Control of this quaternization, addition of base and addition of polar solvent is, however, not difficult if one is aware of the parameters described. The amount of deprotonizing base which is necessary to establish the pH value required for the start of the Michael addition can be predicted within an error limit of about 1%.

For example, if the vinyl ketone intermediate is isobutyl vinyl ketone, which is used to make ibuprofen is used, is produced by distillation or pyrolysis of the Mannich base hydrochloride (cf. GB-PS 1,265,800, BE-PS 820,267 and "Tetrahedron Letters", 4739 (1968)) should refer to a use of Dimethyl sulfate can be dispensed with. Distilled isobutyl vinyl ketone is also used by T. A. Spencer et al in "The Course of the Mannich Reaction with

Methyl Isobutyl Ketone "in" J. Org. Chem. "Volume 32,

Page 1234 (1967). When the Isobutylvinylketon or other vinyl ketone is used directly, is in this second stage of the process äthanolischesKaliumhydroxid a rapidly acting and effective base catalyst. The ethanolic potassium hydroxide is slowly into the solution of Ot-acetyl-Qc ¹ methy3bemsteinsäurediesters in the non-polar solvent-

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809338/0592

tel registered. The base, for example ethanolic potassium hydroxide, acts in such a way that it converts the phase transfer agent, for example the commercial product Aliquat 336 or tetrabutylammonium bromide, which was used in the production of the O ^ acetyl-iX ¹ -methylsuccinic diester (III), into quaternary ammonium hydroxide. This favors the formation of the non-cyclic Michael adduct, for example of dialkyl-O-acetyl-0? - (5-methyl-3-oxohexyl) - <>'- methy! Succinic acid ester (IV), which is then used in the production of Ibuprofen is used.

A continued base treatment of the reaction mixture to form the Ot-acetyl-Q ^ (5-methyl-3-oxohexyl) -O * ¹ methylsuccinic acid ester (IV) from the Oc-acetyl-Cfc'methylsuccinic acid diester (III) and the isobutyl vinyl ketone leads to an aldol condensation with formation of the corresponding esters of 2- (4-isobutyl-2-oxocyclohex-3-enyl) propionic acid (V)

H ₃ C COOR

(V)

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, 809838 / 05S2

and O-methyl - ^ '- (4-isobutyl-2-oxo-cyclohex-3-enyl) succinic acid (VI)

(Vl)

CH
H ₃ C COOR

In the formulas, R stands for the remainder of the respective ester group and / or for hydrogen of the corresponding one Acids per se, which are also intermediate products in the production of ibuprofen.

The non-cyclic diester (IV) can be known in a conventional manner Way, for example, by extraction and distillation, are isolated. The esters (IV), (V) or (VI) or any mixtures thereof and their free acids can be used as intermediates in their manufacture use of ibuprofen. The intermediate property of the succinic acid diester (IV) results implicitly from GB-PS 1.265.800 and explicitly from BE-PS 820.267. Beyond that improved process for the preparation of the succinic diester (IV) as an intermediate in the preparation of ibuprofen in US patent applications serial Nm. 622.130 and 689.366.

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The following examples are intended to explain the invention in more detail.

example 1

75 mmoles (9.51 ml) ethyl acetoacetate, 75 mmoles (9.48 ml) Ethyl CX chloropropionate, 13.8 g ground potassium carbonate particle size about 0.146mm (about 100 mesh), 1.0g potassium iodide, 1.0g tetrabutylammonium bromide and 90 ml of toluene are filled into a 250 ml three-necked flask and heated in a 100 ° C. Bath stirred for about 6 hours. A sample of the reaction mixture is then subjected to gas / liquid chromatography analyzed on a 1.82 m long column (2% OV 17). It was found that diethyl Qi-methyl-fX '-acetyl succinate was formed in 71.8% (theoretical) yield. This toluene solution of diethyl D \ -methyl- & '-acetylsuccinate is directly suitable for further processing in the production of other valuable compounds, e.g. of ibuprofen, which is a well-known anti-inflammatory or anti-inflammatory drug acid.

Example 2 - Preparation of diethyl-O-acetyl-Ot ¹ -methyl-

succinate and using the reaction mixture of the ester obtained to form Diethyl - & - methyl-O '- (5-methyl-3-oxohexyl) - &' acetyl succinate

1.0 g of the commercial product Aliquat 336 (tricaprylyl methylainmonium chloride), 35.0 ml of toluene, 9.51 ml (75 mmol) of ethyl acetoacetate, 9.48 ml (75 mmoles) of ethyl chloropropionate, 1.0 g Potassium iodide with a particle size of <0.246 mm «60 mesh) and 100 milliequivalents (13.8 grams) of oven dried potassium carbonate a particle size of 0.175 mm are in a 250 ml, with a cooler, a mechanical

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Stirrer and a thermometer equipped three-necked flask filled. After that, the mixture is used to ensure the formation of diethyl - ^ - acetyl-CX'-methylsuccinate Stirred without noticeable decomposition by further heating for about 6 hours at a temperature of 75 ° to 80 ° C.

After adding 7.5 ml of ethanol, the mixture is cooled to a temperature of 0 ⁰ C and 20.0 with the Mannich base is N, N-diethyl-N- (5-methyl-3-oxohexyDamin ml of a 90% purity offset.

Then 16.0 ml (172 mmol) of dimethyl sulfate for 1, 3 h under controlling the temperature to be added to a value below about 3 ⁰ C. The mixture is stirred min and 20 h 5, wherein the temperature gradually from 0 ° to 31 ⁰ C in about 62 min allowed to rise and is then cooled over 4 h again to a value of 20 ° to 24 ⁰ C. Meanwhile, 8.8 g of potassium carbonate are added in four portions (24 minutes, 44 minutes, 1 hour and 10 minutes and 1 hour and 40 minutes) after the start of the reaction. After the reaction mixture was allowed to stand overnight at a temperature of -5 ⁰ C, it is stirred again for 2 hours at a temperature of 15 ° to 20 ° C to ensure that the reaction is complete as possible.

For working up, the reaction mixture obtained is mixed with 50 ml of water, whereupon the aqueous and organic phase can be allowed to separate. The aqueous phase is washed with 40 ml of toluene. The toluene phases are washed twice with 35 ml of saturated brine (NaCl solution) each time. To that in the organic To neutralize the product mixture contained in the phase even more completely, there is a third, fourth and fifth

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Washed times with 22 ml of saturated brine each time. The pH value drops from 12.6 to 6.5. However, these additional washes are not essential. The toluene phases are combined with one another, dried over sodium sulfate, concentrated and then distilled. The distillate is collected in five fractions. Fractions 2, 3 and 4 of a Kp range of 154 ° to 176 ⁰ G contain the product in a total weight of 19.074 g, corresponding to 50.8 mmoles (67.7% yield based on ethyl acetoacetate) diethyl QC-methyl-1- 0'- (5-methyl-3-oxohexyl) -0 $ "-acetyl succinate. On the other hand, the non-distilled crude mixture can also be used directly in the ibuprofen synthesis.

Example 3 - Preparation of Diethyl-Oi-methyl-Oc ¹ -acetyl-OC ¹ - (5-methyl-3-oxohexyl) succinate from Diethyl-Or-acetyl-Oi ¹ -methylsuccinate and vinyl isobutyl ketone produced

105.5 ml (50 mmol) solution of diethyl-O-acetyl-öt'-methylsuccinate in toluene, which had been prepared according to Example 2 in a 250 ml three-necked flask, 28.0 ml (100 mmol) of vinyl isobutyl ketone in the form of a 49.3% solution (0.813 g / ml) are added. Then 8.0 ml of a solution of potassium hydroxide (14.4 meq) in ethanol is added with 101 mg / ml of solution added. Now the mixture is stirred for 6 hours at room temperature and then with 2.5 ml (4.5 mequivalents) the same ethanolic potassium hydroxide solution added. The reaction will then continue for a further 4 hours calmly.

After adding 25 ml of saturated brine and 5 ml of water

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the two phases are separated from each other. The toluene phase is mixed with 30 ml of brine and then with 30 ml of brine washed with 0.27 g of sodium bisulfate. The aqueous phases are then backwashed with 30 ml of toluene. The combined toluene phases are dried over sodium sulfate, filtered and concentrated to give 26.63 g of an oil. The oil obtained as evaporation residue is distilled, the distillate being collected in three fractions:

fraction oil bath
Tempe
ratur ° Kp
⁰ C
C. pressure
mbar weight
G 1
2
3 <100
< 160
180-215 <50 °
90-128 °
155-185 0.40-0.43
0.37-0.40
0.29-0.40 0.183
0.280
18,182

Analysis of fraction 3 by gas / liquid chromatography shows that it contains (a) 7.59 mmoles of ethyl 2- (4-isobutyl-2-oxo-cyclohex-3-enyl) propionate, (b) 23.30 mmoles Diethyl-Ot-methyl-Ot ¹ -acetyl-ίΧ ¹ - (5-methyl-3-oxohexyl) succinate and (c) 11.94 mmol of ethyl 2- (4-isobutyl-2-oxo-1-carboethoxy- cyclohexenyl) propionate, so a total of 42.89 mmol (85.8% yield) contains. A remainder of 2.20 g remains.

All products (a), (b) and (c) of fraction 3 can be converted into the valuable medicinal acid in a conventional manner Ibuprofen are transferred. Thus, the entire Fraction 3 can be used for this purpose.

On the other hand, the non-distilled crude mixture (a), (b) and (c) can be obtained directly through the aforementioned heat treatment be converted into ibuprofen.

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In summary, it can be seen that the process according to the invention provides oil ^{-acetyl-oil 1-methylsuccinic acid esters in a better way.} This takes place in a stabilizing reaction medium which enables both the use of mild reaction conditions and the use of less reactive fX-chloropropionic acid esters as starting materials. The process conditions favor the formation of the Oc-acetyl- <X'-methylsuccinic acid ester intermediates with the greatest possible reduction in their decomposition, as a result of which the yield of the desired iX-acetyl-iX ¹ -methyl succinic acid ester intermediates and the products that can be prepared therefrom would decrease.

Claims (14)

Claims 1. Process for the preparation of diesters of OC-acetyl-Ot. ¹ methy! Succinic acid, characterized in that an ester of acetoacetic acid as long as in a practically non-polar, aprotic, organic liquid with a dielectric constant, determined at a temperature of 25 ⁰ C, below about 11 at a temperature of about 50 ⁰ C to at the reflux temperature of the mixture in the presence of a deprotonizing base of a surface corresponding to a particle size below at least about 0.246 mm (60 mesh) with an ester of an (N-halopropionic acid, the halogen content of which consists of chlorine or bromine, until the respective diester of <A -Acetyl- <* .'- methy! Succinic acid forms. 2. The method according to claim 1, characterized in that a non-polar, aprotic, organic liquid having a dielectric constant, measured at a temperature of 25 ^° C., of less than about 5 is used. 809838/0592 - 2- 2Büo424 3. The method according to claim 1, characterized in that the ester residues of the reactants acetoacetate and <x _{-halopropionate consist of C-- to C g} -alkyl residues. 4. The method according to claim 2, characterized in that one ethyl acetoacetate in a liquid medium with benzene, toluene or xylene in the presence of potassium carbonate, Potassium iodide and tetrabutylammonium bromide a temperature of 90 ° to 11O ° C with ethyl-tX-halogenpropionate converts until diethyl iX-acetyl-Oc'-methylsuccinate has formed. 5. The method according to claim 1, characterized in that in addition the Oc-acetyl-OO -methylsuccinic diester combined with isobutyl vinyl ketone and a base and allowed to react until a mixture with the diester the Ot-Methyl-Ov? -acetyl- ^ - (5-methy 1-3-oxohexyl) succinic acid has formed. 6. The method according to claim 5, characterized in that a non-polar, aprotic, organic liquid mixture with a di (C ₁ - to Cg-alkyl) ester of O-acetyl-? C -methy! Succinic acid with vinylisobutyl ketone and a C- to Cg-alkanol solution of a base and allowed to react until a mixture with a di- (C- to Cg-alkyl) -Ofr-methyl-O? -acetyl-oc ¹ - (5-methyl -3-oxohexyl) succinic acid ester. 7. The method according to claim 6, characterized in that a toluene solution of diethyl GHacetyl-Qc'-methylsuccinate with vinyl isobutyl ketone and potassium hydroxide in ethanol combined and allowed to react until a mixture with diethyl O ^ -methyl-flvf-acetyl-OVj - (5-methyl-3-oxohexyl) succinate has formed. 809838/0592 8. The method according to claim 5, characterized in that preformed isobutyl vinyl ketone per se is added to the mixture containing the (X-acetyl-Ov ^{1 -methylsuccinic acid diester).} 9. The method according to claim 5, characterized in that the isobutyl vinyl ketone reactant is formed in situ by adding the Os-acetyl-W-methylsuccinic diester an N ₇ N-BiS (C ₁ - to Cg-alkyl) -N- ( 5-methyl-3-oxohexyl) amine, an alkylating agent, a deprotonizing base and a polar solvent are added. 10. A process for the preparation of a diester of (X-acetyl-OC-methylsuccinic acid by reacting an ester of a ^ • -halopropionic acid with an acetoacetic acid ester, characterized in that an ester of acetoacetic acid is used in a practically non-polar, aprotic, organic liquid a dielectric constant, determined at a temperature of 25 ⁰ C, below about 11 at a temperature of about 50 ° C to the reflux temperature of the mixture in the presence of a phase transfer catalyst, a catalytic amount of iodide ions and a solid deprotonizing base in a practically anhydrous form of a surface corresponding to a Particle size below at least about 0.246 mm (60 mesh) is reacted with the ester of a (X-halopropionic acid, the halogen component of which consists of chlorine or bromine, until the diester of CA-acetyl-Qf'-methylsuccinic acid has formed. 11. The method according to claim 10, characterized in that such a dielectric constant, determined at a temperature of 25 ⁰ C, of less than about 5 is used as the non-polar, aprotic liquid. 809838/0592 12. The method according to claim 10, characterized in that that the ester residues of the acetoacetic acid ester and Ot-halopropionic acid ester from C ..- to Cg-alkyl residues exist. 13. The method according to claim 12, characterized in that one fithylacetoacetate and ethyl-flfr-chloropropionate as long as in a solution medium with benzene, toluene or Xylene in the presence of potassium carbonate, potassium iodide and tetrabutylammonium bromide at one temperature can react from 90 ° to 11O ° C until diethyl-Ocacetyl-Oc-methylsuccinate has formed. 14. The method according to claim 12, characterized in that one fithylchlorpropionate as long as in a toluene mixture with tricaprylylmethylammonium chloride as phase transfer catalyst, potassium iodide as iodide ion supplier, potassium carbonate of a particle size below about 0.175 mm (80 mesh) as deprotonizing base at a temperature of 75 ° to 80 ° C. can react with ethyl acetoacetate until diethyl Oc-acetyl-0 « ¹ methyl succinate has formed. 809838/0592