GB1567444A - Preparation of substituted succinic acid esters - Google Patents

Description

(54) THE PREPARATION OF SUBSTITUTED SUCCINIC ACID ESTERS (71) We, THE UPJOHN COMPANY, a corporation organized and existing under the laws of the State of Delaware, United States of America, of 301 Henrietta Street, Kalamazoo, State of Michigan, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to processes for preparing derivatives of succinic acid esters, and to the use of those succinate ester derivatives in processes for making useful acid compounds.

More particularly, this invention provides an improved process for preparing esters of a-acetyl-a'-methylsuccinic acid, which are useful as intermediates for preparing esters of o-methyl-a'-acetyl-a'-(5-methyl-3-oxohexyl)succinic acid esters which are known to be useful in processes for preparing useful drug acids such as flubriprofen and ibuprofen, i.e.

2-(p-isobutylphenyl)propionic acid.

It is known that diethyl a-acetyl-a'-methylsuccinate can be prepared in about 63 percent yield by reacting ethyl acetoacetate with ethyl a-bromopropionate in the presence of sodium hydroxide, potassium iodide and water. See Chem. Abs. 62, 13037c abstracting (Zh. Pukl. Khim, 38(2), pp 436-7 (1965). Also, J. Chem. Soc. (London), 4633-40 (1970) reports that this same diester can be prepared in about 47 percent yield by reacting ethyl acetoacetate with ethyl ct-bromopropionate in the presence of sodium in ethanol. Similar disclosures are found at Chem. Abs. 54, 10852h: Chem. Abs. 49. 1565c of J. Chem. Soc.

(London) 3313 (1953); and Chem. Abs. 38, 2332 of J. Ind. Chem. Soc., 20, 173-7 (1943).

However, it has been found in the studies when led to this invention that neither the aqueous basic system nor the ethanolic basic systems allowed the above alkylation to occur with the less expensive ethyl 2-chloropropionate in place of the ethyl 2-bromopropionate.

We have found that, using the 2-chloropropionate ester at moderate temperatures 400-500C.), no significant alkylation reaction occurs; under more vigorous conditions higher temperature), using these base systems, 2-chloropropionate and acetoacetate ester starting materials are consumed but little diethyl a-acetyl-a-methyl-succinate ester accumulates in the product, evidence that this valuable succinate ester intermediate is somewhat unstable and is converted to undesired. useless by-products in the reaction mixture.

According to the present invention, a process for preparing a diester of a-acetyl-a'methylsuccinic acid comprises reacting a mixture of an ester of acetoacetic acid and an ester of a-chloropropionic or a-bromo-propionic acid at a temperature of from 50"C to the reflux temperature of the mixture in a substantially non-polar. aprotic organic liquid having a dielectric constant below 11 at 25"C., in the presence of (i) a solid deprotonating base having a surface area equivalent to a size no larger than 60 mesh. (ii) a solid/liquid phase transfer catalyst and (iii) a catalytic amount of iodide ions.

The reaction mixture resulting from the process of the invention can be used per se in further chemical processing steps to contact and react the a-acetyl-a'-methylsuccinate ester content thereof with vinyl isobutyl ketone (or the corresponding Mannich base in the presence of an alkylating agent) and an alkali metal base in a polar solvent to form a diester of a-methyl-a'-acetyl-a'-(5-methyl-3-oxohexyl)-succinic acid which is a non-cyclic aliphatic precursor to iboprofen, which is obtained by heat treatment according to procedures known in the art. See, for example, British Patent Specification No. 1.265.800. Belgian Patent Specification No. 820,267, or U.S. Patent Specification No. 4.008.270.

In one particularly preferred embodiment of the process of this invention, ethyl acetoacetate and ethyl a-chloro-propionate or ethyl a-bromopropionate are heated together at 90 to 1100C in a liquid medium containing benzene, toluene or xylene in the presence of potassium carbonate, potassium iodide and tetrabutylammonium bromide, to form diethyl a-acetyl-a'-methylsuccinate.

In a second particularly preferred embodiment of the process of this invention, ethyl chloropropionate is reacted with ethyl acetoacetate in toluene at 75 to 80"C in the presence of tricaprylyl methylammonium chloride (as phase transfer agent), potassium iodide (as a source of iodide ions) and potassium carbonate, milled to a size below 80 mesh (as deprotonating base), to form diethyl a-acetyl-a'-methylsuccinate.

It has been found that the process of this invention can provide the stabilising basic conditions needed for the formation of the o-acetyl-a'-methylsuccinate diester from the more economical 2-chloropropionate esters. For example, it has been found that under otherwise identical conditions i.e. 78"C., K2CO3 as base, potassium iodide, (KI) as iodide ion source, and Aliquat 336 as phase transfer agent. the diethyl cr-acetyl-cr'-methylsuccinate has a half-life of about 2 hours in absolute ethanol; in toluene (as used in this invention) the half-life of this diester is extended to over 70 hours. Thus, we have found that alkylation of the acetoacetate ester with the 2-bromopropionate or 2-chloropropionate ester in toluene or heptane (or an equivalent non-polar liquid organic medium), using dry, milled alkali metal carbonate, a phase transfer catalyst and potassium iodide gives over 70 percent yield of the a-acetyl-a'-methylsuccinate diester with only 2.6 percent of o-alkylation and 2.9 percent formation of enol-lactone by-products. Using solvents such as methylene chloride for this process results in the formation of a reduced amount of a-acetyl-a'-methylsuccinate ester product contaminated with from 20 to 30 percent of o-alkylated material of the formula AlkOOC-CH(CH3)-O-C(CH3)=CH-COOAlk where Alk denotes the alkyl ester group, e.g., ethyl. which does not separate easily, and the ester terminated chains are in cis-configuration with respect to the double bond. It is best practice of the process of this invention to make the alkylation of the acetoacetate ester with the 2-bromopropionate or 2-chloropropionate ester to form the a-acetyl-a'-methylsuccinate diester as complete as possible.

Thus, the above chemistry provides an improved, practical chemical process by which important 2-aryl-alkanoic acid drug and agriculturally significant esters and acids therefrom can be prepared swiftly from inexpensive aliphatic component chemicals.

The acetoacetic acid ester starting materials are known compounds and the particular ester is not critical. See for example British Patent Specification No. 1.265.800. The ester should be one which is soluble in the substantially nonpolar. organic liquid medium. The C16 esters are preferred and the ethyl ester is more particularly preferred. Also. the a-bromopropionate and a-chloropropionate esters starting materials are known compounds, and the particular ester group is not critical but should be one which makes the ester compound soluble enough in the substantially nonpolar organic liquid solvent medium to react. The C, to C6-alkyl esters. and particularly the ethyl ester. are preferred.

The substantially nonpolar organic liquids function as solvents for the ester reactants in the process of this invention and are organic liquid compounds or mixtures thereof which have dielectric constants of below 11, and preferably below 5, at 25"C. See. e.g., Lange's Handbook of Chemistry, 9th Edition, (1956). pp 1222-1225. Examples of solvent liquids for this purpose includes benzene, toluene. xylene. cyclohexane. heptane. nonane. chloroform and bromobenzene. The preferred nonpolar. aprotic solvent for use herein is toluene and mixtures thereof.

The solid/liquid phase transfer agents are generally quaternary ammonium. sulfonium or phosphonium salts which function to assist contact between the solid and liquid materials in the mixture. Examples of such phase transfer agents include the tetra (C16 alkyl)ammonium halides such as tetrabutylammonium bromide. and other known quaternary salts available for this purpose. as well as crown ethers. e.g.. those described in U.S.Patent Specification No. 4,001.279. as well as the patent references cited therein, and sulfonium (R3S) salts such as the tris(C~s alkyl)sulfonium acid di(C~s alkyl) phenyl-sulfonium salts, e.g., trimethvlsulfonium iodide. trisdodecylsulfonium sulfate, dioctodecylmethylsulfonium chloride, dimethylphenylsulfonium nitrate and diundecyl-p-toluylsulfonium sulfate, and phosphonium (R4P+) salts such as the tetra (CI--18 alkyl) phosphonium and mixed alkyl arylphosphonium salts such as tetrabutylphosphonium chloride. trimethylphenylphosphonium iodide, methyl triphenylphosphonium sulfate. and the like. A commercially available example of such a phase transfer agent is sold under the trade name i Aliquat 336" which is believed to be tricaprylyl methylammonium chloride.

The iodide ion can be provided in any economical, soluble form in at least a catalytic amount. Alkali metal iodide salts such as sodium and potassium iodides are preferred.

Ammonium iodide, and alkaline earth metal iodides such as calcium iodide, could also be used but are less preferred for reasons of cost and less efficiency with them. It can also be supplied by the iodide ion of a phase transfer agent salt, above. The catalytic amount of iodide ion can be a small amount, less than molar proportion to the ester reactants.

The deprotonating base, such as alkali metal carbonates, orthophosphates, C16 alkoxides and hydroxides (as opposed to Lewis bases generally), is preferably present in an amount at least about stoichiometrically equivalent to each of the ester reactants. The deprotonating base is preferably oven dried to remove at least most of any adhering water therefrom. It can be provided as a finely milled powder, below 60 mesh, and preferably below 100 mesh. or in some other high surface area contact for equivalent in surface area thereto, such as in highly porous pressed composite granules, tablets or pellets. which will act as the deprotonating base in these reaction mixtures.

The reaction mixture of the above ingredients is stirred or otherwise agitated to provide efficient contact of the liquid and solid components of the mixture for a time sufficient to effect as complete a reaction as is efficiently possible. At temperatures below 50"C., the reaction times are generally too slow to be acceptable for commercial scale operations.

Stirring the mixture for about six hours at about 75"-100"C. is generally about the optimum time and temperature for most efficient yields when the ethyl esters of the reactants are being used.

The a'-acetyl-a'-methylsuccinate diester product can be recovered friom the reaction mixture by conventional means, if desired. but since it is usually contemplated to use these esters as intermediates for further reaction, such recovery is usually not necessary.

Another advantage of preparing the a-acetyl-a'-methyl-succinate ester in the manner described herein is that it allows for the simple preparation of the a-acetyl-a-(5-methyl-3osohexyl)-a'-methylsuccinate ester therefrom in the same vessel and solvent medium in which the a-acetyl-a'-methylsuccinate ester was prepared. The a'-acetyl-a'-(5-methyl-3- oxohexyl)-a-methylsuccinate ester is described in Belgian Patent Specification No. 820,267, and is an intermediate which can be prepared in processes for preparing ibuprofen, the anti-inflammatory drug. The process of this invention thus allows a complex chemical sequence to be carried out with minimum equipment and labour.

When ethyl acetoacetate is reacted with ethyl a-chloropropionate or ethyl abromopropionate in the presence of a deprotonating base (KCO3) and toluene. diethyl a-acetyl-a'-methylsuccinate and potassium chloride or potassium bromide are formed in solution. This solution may be reacted in either of two ways to form diethyl a-acetyl-a-(5 methyl-3-oxohexyl)-ct'-methylsuccinate. In the first method. isobutyl vinyl ketone. potassium hydroxide and a polar solvent are used. In the second method. N.N-diethyl-5-methyl3-oxohexylamine, dimethyl sulfate, additional potassium carbonate and a polar solvent are used.

The specific reactions described above for the preparation of the diethyl ester may be generalised for all esters and, as is preferred in this invention. for all C, 6 esters. In general, when the reaction of the acetoacetate ester and the a-halopropionate ester to form the a-acetyl-a'-methylsuccinate diester in solution is completed, the mixture containing the diester may be treated with either isobuytl vinyl ketone per se and base plus a polar solvent or an N,N-di(Cl~6 alkyl)-N-(5-methyl-3-oxohexyl)amine Mannich base precursor thereto (prepared by known procedures from a dialkylamine, paraformaldehyde and isobutyl vinyl ketone) plus an alkylating agent such as a di(C16 alkyl)sulfate, e.g.. dimethylsulfate. or a C16 alkyl iodide, e.g., methyl iodide, and additional deprotonating base which serves to convert the alkylated Mannic base to isobutyl vinyl ketone ill situ as well as to catalyze the Michael reaction between the isobutyl vinyl ketone and the a-acetyl-a' -methylsuccinate diester derivative in the presence of some added polar solvent. preferably a C16 alkanol or an N,N-bis-(C16 alkyl)formamide.

When the Mannich base, e.g., N,N-diethyl-N-(5-methyl-3-oxohexyl)amine is added to the a-acetyl-a'-methyl-succinate diester to form the a-acetyl-a-(5-methyl-3-oxohexyl)-a'methylsuccinate diester, it is preferred to limit the additional deprotonating base, e.g., potassium carbonate, as closely as possible to not more than the amount which was used in the production of the a-acetyl-a'-methylsuccinate diester itself. This is because at high (apparent) pH the a-acetyl-a'-methylsuccinate intermediate is 0-alkylated by the alkylating agent, e.g., dimethylsulfate. When the isobutyl vinyl agent ketone is being generated in situ, dimethylsulfate is preferably added at low temperatures. say 0 to 5 ., to suppress N,N-dialkyl-N-methylamine elimination which could occur at higher temperatures since it consumes dimethyl sulfate. Only after the Mannich base is quaternized and essentially absent (as determined by gas liquid chromatogrophy or other equivalent analysis of samples of the reaction mixture) is a more polar organic liquid solvent. preferably a C16 alkanol, e.g., ethanol, or an N,N-C16 to C6 - dialkylformamide. and more deprotonating base, e.g., potassium carbonate, or potassium hydroxide, added to initiate the Michael reaction between the Mannich base and the a-acetyl-a'-methylsuccinate diester. When added deprotonating base brings the aopparent pH to about 11.5, the Michael reaction will occur.

At about pH 13, aldolization (which is acceptable) will occur. Addition of the polar solvent such as a C1 to C6-alkanol, e.g., ethanol, is necessary for Michael reaction. The addition of the polar solvent, e.g., alcohol, is made after quaternization of the Mannich base is complete so that dimethyl sulfate is not consumed by the alcohol or other polar solvent. The size (surface area), dryness and stirring of the deprotonating base, e.g., potassium carbonate, is important to reproducibility of this heterogeneous reaction. Control of these quaternization, base addition and polar solvent addition factors is not difficult, however, once one is aware of the parameters discussed. We can predict to within about 1 percent the amount of deprotonating base required to attain the pH to start the Michael addition.

When the vinyl ketone intermediate, e.g., isobutyl vinyl ketone, used to make ibuprofen, is prepared by distillation or by pyrolysis of the Mannich base hydrochloride [see British Patent Specification No. 1,265,800; Belgian Patent Specification No. 820,267; and Tetrahedron Letters, 4739 (1968)l, the use of dimethyl sulfate is avoided. Distilled isobutyl vinyl ketone is also described by T.A. Spencer et al. "The Course of the Mannich Reaction with Methyl Isobutyl Ketone...." in J. Orq. Chem. 32 1234 (1967). When the isobutyl vinyl ketone or other vinyl ketone is used directly, a rapid and efficient base catalyst for use in this second step of the process is ethanolic potassium hydroxide which is added slowlv to the nonpolar solvent solution of the a-acetyl-a-'-methylsuccinate diester. The base, e.g., ethanolic potassium hydroxide, operates by converting the phase transfer agent. e.g., Aliquat 336 or tetrabutylammonium bromide. used in the preparation of the a-acetyl-a-'- methylsuccinate diester, to the quaternary ammonium hydroxide which promotes the formation of the non-cyclic Michael adduct, e.g., dialkyl -acetyl-a-(5-methyl-3-oxohexyl) Ct- '-methylsuccinate used in the production of ibuprofen.

Continued base treatment of the reaction mixture between the a-acetvl-a'- methylsuccinate diester and the isobutyl vinyl ketone to form the ct-acetyl-a-(5-methyl-3- oxohexyl)-ot'-methylsuccinate ester gives an aldol condensation to form the respective esters of 2-(4-isobutyl-2-oxo-cyclohex-3-enyl)propionic acid and u-methyl-ct-(4-isobutyl-2- oxo-cyclohex-3-enyl)- succinic acid. Both the esters and the corresponding acids are intermediates in the syntheses of iboprofen.

The non-cyclic diester of a-acetyl-a-(5-methyl-3-oxohexyl)-a'-methylsuccinic acids can be isolated by known methods such as extraction and distillation. This non-cyclic ester. and also the cylcic esters. or any combination thereof, and their free acids can then be used as intermediates to prepare ibuprofen. The intermediary of succinate diester for this purpose is implicit in British Patent Specification No. 1,265.800. and is explicit in Belgian Patent Specification No. 820.267. In addition, improved processes for using the non-cyclic succinate diester as an intermediate to prepare ibuprofen are described in U.S. Patent Specification No. 4,008,270 and in British Patent Application No. 30424/77 (Serial No.

1563877).

The invention is further described and exemplified by the following detailed Examples which are not intended to limit the scope of the invention.

Example 1.

Ethyl acetoacetate (75 mmoles. 9.51 ml.), ethyl a-chloropropionate (75 mmoles. 9.48 ml.), milled (about 100 mesh) potassium carbonate (13.8 g.). potassium iodide (1.0 g.), tetrabutylammoniumbromide (1.0 g.) and toluene (90 ml.) were placed in a 250 ml.

3-necked flask and stirred in a 100"C. bath for about 6 hours. Then a sample of the resulting reaction mixture was analyzed by the gas liquid chromatography (glc) assay method on a 6 foot. 2 percent OV 17 column and showed that 71.8 percent of the theoretical yield of diethyl a-methyl-a'-acetylsuccinate had been produced. This toluene solution of diethyl a-methvl-a'-acetylsuccinate is useful directly in processes for preparing other useful compounds such as ibuprofen which are known anti-inflammatory drug acid compounds.

Example 2 Preparation of diethyl a-acetyl-a'-methylsuccinate. and use of the reaction mixture of this ester to form diethvl o-methyl-a'-(5-methyl-3-oxohexyl)-a-acetylsuccinate A 1.0 g. portion of Aliquat 336 (tricaprylyl methyl ammonium chloride). 35.0 ml. of toluene, 9.51 ml. (75 mmole) of ethyl acetoacetate. 9.48 ml. (75 mmole) of ethyl chloropropionate. 1.0 g. ( < 60 mesh) of potassium iodide. and 100 milliequivalents. 13.8 g.

of less than 80 mesh. oven-dried potassium carbonate are placed in a 250 ml. 3-necked flask equipped with a condenser. mechanical stirrer and thermometer. The mixture is stirred at 7-8 C. for about 6 hours to ensure formation of diethyl a-acetyl-a'-methylsuccinate, without substantial decomposition by further heating.

Then 7.5 ml. of ethanol is added and the mixture is cooled to 0. C. Mannich base, N,N-diethyl-N-(5-methyl-3-oxohexyl)amine, 90 percent pure, 20.0 ml., is added Diemthyl sulfate, 16.0 ml. (172 mmole) is added over 1.3 hours while controlling the temperature to below about 3"C. The mixture is stirred for 5 hours and 20 minutes as the temperature was allowed to rise gradually from 0 to 310C. in about 62 minutes and then cooled again to 20 to 24"C. over 4 hours while 8.8 g of potassium carbonate is added in four portions (at 24 minutes, 44 minutes, 1 hour and 10 minutes, and 1 hour and 40 minutes) from the reaction starting time. After overnight storage at -5 C. the mixture is stirred again at 15-20"C. for two hours to ensure as complete a reaction as possible.

For workup, the resulting reaction mixture is mixed with 50 ml. of water and the aqueous and organic phases were allowed to separate. The aqueous phase is washed with 40 ml. of toluene. The toluene phases are washed with two 35 ml. portions of saturated brine (NaCi) solution. Additional 3rd, 4th and 5th washes with saturated brine solution (22 ml. each) are also conducted to more completely neutralize the organic phase product mixture (the pH was lowered from 12.6 to 6.5 by these washes). These additional washes are not essential.

The toluene phases are combined, dried with sodium sulfate. concentrated and distilled.

The distillate is collected in five fractions; fractions 2, 3 and 4, b.p. 154-176 C., are taken as containing the product in a total weight of 19.074 g. for these fractions, or 5U.8 mmole (67.7 percent yield, based on ethyl acetoacetate), of diethyl a-methyl-a'-(5-methyl-3-oxohexyl)- a'-acetylsuccinate. Alternatively, crude non-distilled mixture product can be used directly in ibuprofen synthesis.

Example 3 Preparation of diethyl a-methyl-a'-acetyl-a'-(5-methyl-3-oxohexyl)succinate from diethyl a-acetyl-a'-methylsuccinate and prepared vinyl isobutyl ketone To a 105.5 ml. (50 mmole) solution of diethvl a-acetyl-a'-methylsuccinate in toluene, prepared as described in Example 2 in a 250 ml. 3-necked flask there was added 28.0 ml.

(100 mmole) of vinyl isobutyl ketone in a 49.3 percent solution, 0.813 g./ml. Then 8.0 ml. of a 101 mg./ml. solution of potassium hydroxide (14.4 m equivalents) in ethanol was added.

The mixture was stirred for 6 hours at room temperature and then 2.5 ml. (4.5 m equivalents) of the same ethanolic potassium hydroxide solution was added and the reaction was allowed to continue for 4 more hours.

Saturated brine (25 ml.) and water (5 ml.) were added and the phases were separated.

The toluene phase was washed with brine (30 ml.) and then with brine (30 ml.) containing 0.27 g. of sodium bisulfate. Aqueous phases were backwashed in sequence with toluene (30 ml.). The combined toluene phases were dried over sodium sulfate. filtered and concentrated to an oil weighing 26.63 g. The oil was distilled and the distillate was collected in three fractions.

Oil Bath, Pressure Fraction ( C.) B.P.( C.) (mm.Hq) Wt (q.) 1 < 100 < 50 0.30-0.32 0.183 2 < 160 90-128" 0.28-0.30 0.280 3 180-215 155-185 0.22-0.30 18.172 Analysis of fraction 3 by gas liquid chromotography showed that it contained (a) 7.59 mmole of ethyl 2-(4-isobutyl-2-oxo-cyclohex-3-enyl)propionate; (b) 23.30 mmole of diethyl a-methyl-a' -acetyl-a' (5-methyl-3-oxohexyl)-succinate: and (c) 11.94 mmole of ethyl 2-(4-isobutyl-2-oxo-1 -carboethoxy-cyclohexenyl )propionate. or a total of 42.89 mmole of 85.8 percent yield. A residue of 2.20 g. remained.

Each of these products (a), (b) and (c) (separately or in a mixture) in the fraction 3 mixture can be converted to the useful drug acid. ibuprofen. by known procedures. and thus the whole of fraction 3 would be used for that purpose.

Alternatively, the crude undistilled mixture of (a). (b) and (c) can be converted directly to ibuprofen by the heat treatment procedures referred to above.

In summary, this invention provides a process improvement in which a-acetyla'methylsuccinate esters can be produced in a stabilizing reaction medium which permits the use of mild conditions as well as the use of the less reactive a-chloropropionate esters as starting material. The process conditions favor the formation of the a-acetyl-a'methylsuccinate ester intermediates while minimizing its decomposition which lower yields of the desired a-acetyl-a'-methylsuccinate ester intermediates. and the desired products resulting therefrom.

WHAT WE CLAIM IS: 1. A process for preparing a diester of a-acetyl-cr'-methyl-succinic acid which comprises reacting a mixture of an ester of acetoacetic acid and an ester of a-chloropropionic or a-bromopropionic acid at a temperature of from 50"C to the reflux temperature of the mixture in a substantially nonpolar, aprotic organic liquid having a dielectric constant below 11 at 25 C., in the presence of (i) a solid deprotonating base having a surface area .equivalent to a size no larger than 60 mesh, (ii) a solid/liquid phase transfer catalyst and (iii) a catalytic amount of iodide ions.

2. A process according to claim 1 in which the nonpolar, aprotic organic liquid has a dielectric constant below 5 at 25"C.

3. A process according to either preceding claim in which each ester radical is a C1 -6 alkyl group.

4. A process according to claim 1 in which ethyl acetoacetate and ethyl Ct- chloropropionate or ethyl a-bromopropionate are heated together at 90 to 1100C in a liquid medium containing benzene, toluene or xylene in the presence of potassium carbonate, potassium iodide and tetrabutylammonium bromide. to form diethyl a-acetyl-a'- methylsuccinate.

5. A process according to claim 1 in which ethyl chloropropionate is reacted with ethyl acetoacetate in toluene at 75 to 80"C in the presence of tricaprylyl methylammonium chloride, potassium iodide, and potassium carbonate, milled to a size below 80 mesh, to form diethyl a-acetyl-a'-methylsuccinate.

6. A process according to claim 1 substantially as described in Example 1 or Example 2.

7. A diester of a-acetyl-a'methylsuccinic acid when prepared by a process according to any preceding claim.

8. A process for preparing a diester of a-methyl- '-acetyl-a'(5-methyl-3-oxohexyl) succinic acid which comprises reacting the cr-acetyl-a'-methylsuccinate diester prepared by a process according to any of claims 1 to 6 with isobutyl vinyl ketone and an alkali metal base in a polar solvent.

9. A process according to claim 8 in which a nonpolar. aprotic organic liquid containing a di (Cl~,alkyl) ester of Ct-acetvl-ct'-methylsuccinate is reacted with vinyl isobutyl ketone and a C16 alkanol solution of the base. to form a di(Cl alkyl)a-methyl-a'-(5-methyl-3- oxohexyl) succinate ester.

10. A process according to claim 9 in which a toluene solution of diethyl a-acetyl-a'- methvlsuccinate is reacted with vinyl isobutyl ketone and potassium hydroxide in ethanol

Claims (14)

**WARNING** start of CLMS field may overlap end of DESC **. resulting therefrom. WHAT WE CLAIM IS:

1. A process for preparing a diester of a-acetyl-cr'-methyl-succinic acid which comprises reacting a mixture of an ester of acetoacetic acid and an ester of a-chloropropionic or a-bromopropionic acid at a temperature of from 50"C to the reflux temperature of the mixture in a substantially nonpolar, aprotic organic liquid having a dielectric constant below 11 at 25 C., in the presence of (i) a solid deprotonating base having a surface area .equivalent to a size no larger than 60 mesh, (ii) a solid/liquid phase transfer catalyst and (iii) a catalytic amount of iodide ions.

2. A process according to claim 1 in which the nonpolar, aprotic organic liquid has a dielectric constant below 5 at 25"C.

3. A process according to either preceding claim in which each ester radical is a C1 -6 alkyl group.

4. A process according to claim 1 in which ethyl acetoacetate and ethyl Ct- chloropropionate or ethyl a-bromopropionate are heated together at 90 to 1100C in a liquid medium containing benzene, toluene or xylene in the presence of potassium carbonate, potassium iodide and tetrabutylammonium bromide. to form diethyl a-acetyl-a'- methylsuccinate.

5. A process according to claim 1 in which ethyl chloropropionate is reacted with ethyl acetoacetate in toluene at 75 to 80"C in the presence of tricaprylyl methylammonium chloride, potassium iodide, and potassium carbonate, milled to a size below 80 mesh, to form diethyl a-acetyl-a'-methylsuccinate.

6. A process according to claim 1 substantially as described in Example 1 or Example 2.

7. A diester of a-acetyl-a'methylsuccinic acid when prepared by a process according to any preceding claim.

8. A process for preparing a diester of a-methyl-å'-acetyl-a'(5-methyl-3-oxohexyl) succinic acid which comprises reacting the cr-acetyl-a'-methylsuccinate diester prepared by a process according to any of claims 1 to 6 with isobutyl vinyl ketone and an alkali metal base in a polar solvent.

9. A process according to claim 8 in which a nonpolar. aprotic organic liquid containing a di (Cl~,alkyl) ester of Ct-acetvl-ct'-methylsuccinate is reacted with vinyl isobutyl ketone and a C16 alkanol solution of the base. to form a di(Cl alkyl)a-methyl-a'-(5-methyl-3- oxohexyl) succinate ester.

10. A process according to claim 9 in which a toluene solution of diethyl a-acetyl-a'- methvlsuccinate is reacted with vinyl isobutyl ketone and potassium hydroxide in ethanol.

to form diethvl a-methvl-a'-acetvi-a'-5-methvl-3-oxohexvl) succinate.

11. A process according to any of claims 8 to 10 in which preformed isobutyl vinyl ketone is added to the mixture containing the a-acetyl-a'-methvlsuccinate diester.

12. A process according to any of claims 8 to 10 in which the isobutyl vinyl ketone is formed in sitit by adding to the mixture containing the u-acetvl-a'-methvls;ccinate diester a N,N-bis(C1 -6 alkyl )-N-(5-methyl-3-oxohexyl) amine, an alkylating agent. deprotonating base and a polar solvent.

13. A process according to claim 8 substantially as described in Example 2 or Example 3.

14. A diester of a-methyl-a'-acetvl-a'-(5methvl-3-oxohexvl) succinic acid when prepared by a process according to any of claims 8 to 13.