CA1052388A - ALIPHATIC .beta.-KETO ESTERS - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A process for the production of aliphatic .beta.-keto esters by reacting a dialkyl ketone with a dialkylcarbonate in the pre-sence of an at least equivalent quantity of a basic conden-sation agent based on the dialkyl ketone at a reaction temperature of 20 to 80°C and the reaction product is subsequent-ly converted by acidification into the .beta.-keto ester.
By carrying out the condensation reaction in the presence of hexamethylphosphoric acid triamide as solvent advantageously higher yields of 20 to 50 % can be obtained by the inventive process if compared to convential processes.

Description

1~5~' 3~

This invention relates to a process fo.r the l).roduc-tion ol ali~)hatic ~-keto esters, more es~ec~ially sterica]ly hind-erc(l aliphatic ~-keto esters, in excellent yields. The synthesis of ~-keto esters is known and is describe(l, for examl)le as Claisen's condensati.on, :in numerous -tex-t book:3 and pllbl.ications. In general, carboxylic acid esters are reacted as the carbonyl component with C-l-l-acid carboxylic acid csters to .form ~-keto carboxylic acid esters in an inert ~olvent in -the presence of at least equimolar quantities of basic catalysts such as, Ior example sodium hydride, sodium am:idc, triphenyl methyl sodium and alkali meta] alcollolates, as con(lensation agents. Mixed ester condensations are general]y only carried out with form:ic acid esters as the carbonyl componen-t because i.t is only in this l~ay that it is possible to obtain clearly defined reaction products.
Examples of condensation reactions of this kind are described in articles in "J.Amer.Chem.Soc." 72, 1352 (1950);
66, 862 (1944); 66, 1768 (1944); 63, 2252(1941); h3, 3156 (1941), and in American Patent Specifications No.2,407,942 ænd 2,367,632.
Unfortunately,the yields obtained from these reactions, in the case of sterically hindered aliphatic ~-keto esters such as, for example, pivaloyl acetic esters, only amount to around IlO~o, even in cases where strongly basic catal.ysts such as sodium hydride, sodium amide in liquid ammonia or triphenyl methyl sodium9 are used. Hitherto, condensation agents which are easi.er to handle in preparative terms, such as alkali metal a].coholates, have only produced very poor yields, for example in the case of pivaloyl acetic ester, because the ~~keto ester formed during the condensation reaction presumably has a higher level of reactivity than the starting compound to lQS'~3~38 be reacted, ~hich can give rise to numerous secon~ary reactions ; during the condensation reaction.
Accordingly, it has already been propose~ -to ~ro~luce ~3-keto esters by reacting aceto acetic esters with acid chlorides in the presence of magnesium alcoholates, ~oll.owed by hy~rolytic dissociation of the reaction produc-t to form the required ~-keto ester, as described in Br:itish Patent Speci.l'ication No.1,000,709. Unfortunately, this method is also attended by numerous difficulties in practice so that, Ior examl)le in -the case of pivaloyl acetic ester, the yi.elds obta:ined generally amount to no more than ~0~0. Si.nce for example the ~evel of activity of commerical-~ra~le magnesium alcoholate is not sul'ficient, the magnes:ium alcoholate're-quired for the reaction always had to be freshly prepared, which can give rise to considerable difficulties in large-scale working. In addition, the pivalic acid chloride re-quired for the reaction is difficult to process on account of its pungency, and the temperature at which the reaction i~
: carried out is di~ficult to control, even in cases where freshly prepared magnesium alcoholate is used. Furthermore, alkaline dissociation of the ~-diketo carboxylic acid ester formed as intermediate results in the formation not only of pivaloyl acetic ester but also, through a secondary reaction, in the formation of aceto-acetic ester and pivalic acid.
Accordingly, the pivaloyl acetic ester thus formed can only be obtained with difficulty in pure form from the mixture of ~-keto esters by distillation.
Accordingly, there is in practice a need to find a preparatively simple process by which it is possible to produce 3 aliphatic ~-keto esters, more especially sterically hindered ~-keto esters, in higher yields and in greater purity than is possible by conventional processes.
It has now heen found that aliphatic ~-keto esters, more ~o~

especially sterically hindered aliphatic~ -keto esters, can be obtained in improved yields by reacting dialkyl ketones with dialkyl carbonates and at least equimolar quantities of a basic condensation agen~ in known manner, using hexamethyl phosphoric acid triamide as solvent.
It has been found that, in cases where hexamethyl phosphoric acid triamide is used as solvent, it i5 possible to obtain an increase in yield of from 20 to 50% by comparison with conventional reactions.
Accordingly, the invention relates to a process of producing an aliphatic R -ketoester which comprises the steps of preparing a solution of dialkyl-carbonate, wherein the alkyl groups are of 1 to 4 carbon atoms a basic condensation agent for ketone condensation and a hexamethylphosphoric acid triamide, gradually adding a dialkylketone of the formula o Rl -C-CH2 _R2 wherein Rl represents a secondary or tertiary alkyl group of up to 18 carbon atoms or a primary alkyl group which is the same as -CH2R2, R2 represents hydrogen or an alkyl group of 1 to 4 carbon atoms or Rl and R2 together re-present an alkylene chain of formula -(CH2)n , wherein n is 3, 4 or 5 to com-plete an aliphatic 5-, 6- or 7-membered ring to said solution, said condens-ation agent being in a molar ratio of 1:1 or more based on the ketone, heat-ing said condensation reaction mixture to a temperature of from 20 to 80C

until a reaction product is obtained and subsequently acidifying the reaction product to produce the aliphatic ~-ketoester.
Basic condensation agents suitable for use according to the invention include alkali or alkaline earth metal alcoholates such as sodium methylate, sodium ethylate, potassium ethylate, potassium-t- butylate or magnesium ethylate, sodium amide, sodium hydride and triphenyl methyl sodium. Of the alcoholates, potassium-t-butylate is preferred.
The quantity in which the basic condensation agent is used should be at least equivalent to the quantity in which the dialkyl ketone is used.

~35~3~1!3 In cases where the alcoholates are used as condensation agents, it is pre-ferred to use an excess of approximately 5%, although this may even be higher, especially in the case of potassium-t-butylate. In cases where sodium hydride is used as the condensation agent, it is preferred to use more than 2 mols of sodium hydride per - 4a -105~31~B
mol of dialkyl ketone used Dialkyl carbonates suitable for use in accordance with the invention are compounds corrcsponding to thc following ~cneral formula:

O
I R - 0 - C - 0 - R' in which the radicals R and R' may be the same or diLferent and represent alkyl radicals ~re~rably wi~ 1 t~ 4 car ~ abDms,such as propyl, isopropyl, methyl and, in particular, ethyl. The preferred dialkyl carbonate is diethyl carbonate.
The quantity in which the dialkyl carbonate is used should be at least equivalent to the quantity in which the dialkyl ketone is used. However, the dialkyl carbonate is preferably used in a 2- to 10-molar excess.
The hexamethyl phosphoric acid triamide used as solvent should be employed in such a quantity that it accelerates the reaction to a sufficient extent. It is preferred to use at least 0 1 mol of hexamethyl phosphoric acid triamide per - 20 mol of dialkyl ketone to be reacted as solvent.
The hexamethyl phosphoric acid triamide may of course be used in larger quantities. If desired, the e~cess hexa-methyl phosphoric acid triamide can be recovered from the aqueous ph~se by extraction with chloroform after the reaction mixture has been trea-ted in the usual way on completion of the reaction, and reused.
~ he process according to the invention is suitable for the reaction of standard, known alkyl ketones and is parti-cularly suitable for the reaction of ketones of the kind which can only be reacted with dialkyl carbonates with difficulty or in poor yields by conventional ~ethods.
In principle, methyl alkyl ketones or methyl alkyl A-G 1235 - 5 _ ~5~3~
ketones which are monosubstituted, especially monoalkylated~
on tho methyl group~ are suitable Lor use as the dialkyl ketones which may be reacted in accordarlce with the invention to f~rm ~-keto esters, and can be reacted in high yields.
Naturally, monoalkylated methyl alkyl ketones also include ketones of the kind whose alkyl subs$ituents together form a multimemebered aliphatic ring.
It is in practice o$ particular advanta~e to react methyl alkyl ketones substituted or unsubstituted on the methyl group in accordance with the invention to form sterically hindered ~-keto esters which, in the following, is intended to signiiy that the reactivity of the ketone used for the reaction is influenced by substituent in~luences so tha-t the ketones in question could only be reacted to form ~-keto esters in moderate yields by convention~l methods.
Accordingly, dialkyl ketones suitable for use in accor-dance with the invention are compounds corresponding to the following general ~ormula:
O

II R - C - C~2 - R

in which Rl represents an alkyl radical preferably with 1 ~ 18 ~ bon atons, such as methyl, ethyl, propyl, butyl, dodecyl, octadecyl, more especially isopropyl or t-butyl, and R2 represents hydrogen or an alkyl group with 1 to 4 carbon atoms, more especially methyl or ethyl, in addition to wllich Rl and R2 may together represent the atoms required to com-p]ete a multi-membered aliphatic ring, more especially 5- to 7-membered aliphatic ring, such as a cyclopentanone, cyclohexanone or cycloheptanone ring.

~05'~

Exa~ples of dialkyl ketones which can be reacted in accordance with the invention to form high yields of ~-keto esters, are pinacolone, diethyl ketone, methyl isopropyl ketone and cyclohexanone.
Accordingly, ~he process according to the invention is particularly suitable for the production of pivaloyl acetic esters which are acquiring incrcasing significancc in practice for the preparation of pivaloyl yellow couplers lor photo-graphic purposes. It is of advantage in the process according to the invention to avoid an excess of dialkyl ketone in the reaction mixtllre consisting of the hexamèthyl phosphoric acid triamide, the dialkyl carbonate and the basic condensation agent This can with advantage be achieved by adding the ketone slowly and uniformly to the reaction mixture, so that there is only ever a small quantity o~ unreacted ketone present in the reaction mixture. The solvent, hexamethyl phosphoric acid triamide, can with advantage be diluted by the addition of another inert organic solvent. q'he preferred, additional solvent is the dialkyl carbonate used for the reaction. Benzene, toluene and xylene are also suitable.
The dialkyl ketone can be added to the reaction mixture either directly or in solution in an inert solvent. In cases where alcoholates are used as the condensation agent, it is of adv~ntage for the particular alcohol formed in the reaction mixture to be removed during -the reaction by simultaneous distillation, and for its concentra~tion to be kept as low as possible Ideally9 the alcohol should actually be removed from t;he reaction mixture at the moment it is formed. In general, the reaction is carried out by using the alcoholates corresponding to the dialkyl carbonate. However, it is preferred for example, especially where diethyl arbonate is used3 to prepare the sodium ethylate in si-tu by 1eacting A-G 1235 _ 7 _ ~;)5~
sodium metal with diethyl carbonate and directly using it for the reaction. As already mentioned, the reaction temperature is in the range from 20 to 80C, and the f~actions of alcohol formed during the reaction are distilled oif through a column, optionally under a light vacuum of 100 to 500 Torr. Where it is used for example in molar quantities, the ketone is continu-ously added over a period of preferably moxe than 2 hours.
In the context of the invention, the term "continuous addition", apart from continuous addition in its strict sense, is also meant to include addition in small quantities and at brief time intervals as obtained, for example, by dropwise addition or with peristaltic pumps.
In cases where sodium hydride is used as the condensa-tion agent, about 1/10 of the ketone to be used is initially added to the solvent mixture of hexamethyl phosphoric acid tri-amide and, optionally, another inert solvent, and to ~he dialkyl carbonate and condensation agent~ and the reaction mixture briefly heated to a temperature of from 50 to 80C. After the reaction has started, the reaction mixture is cooled to around 40C and the rest of the ketone is added slowly and continuously as described above. As already mentioned, the reaction temperature in the process according to the invention should be kept in the range from 20 to 80C.
On completion of the reaction, the alkali salts of the ~-keto esters are directly obtained and may either be immediate-ly further reacted or converted in the usual way by acidification (aqueous HCl-, aqueous H2SO4 or acetic acid) into the free ~-keto ester, the pH-value being adjusted to about 6. Following extraction of the reaction products with an organic solvent, for example ethyl acetate or toluene, the esters are purified preferably by distillation.
Where chloroform is used, the solvent, hexamethyl phos-phoric acid triamide, is enriched in the organic phase whichcan be removed during the subsequent distillation stage.
flowever, since the ~-keto esters fo~med are used as inter-mediate products for the production of yellow couplers, the solvent does not have to be removed because it does not inter-fere with the subsequent reaction.
Where the process according to the invention is carried out with sodium ami~e as the condensation agent, a substanti-ally quantitative conversion of the dialkyl ketone and a yield o O r corresponding pure ~-keto ester of more than 90~0 in the case of pivaloyl acetic ester are obtained. Where sodium hydride is used as the condensation agent, it was possible to obtain yields of 90~, whilst the yields obtained in the case of potassium-tert.-butylate were still in excess of 60~o and, in the case of sodium ethylate, of the order of ~0%. Hitherto, it had not been possible to obtain yields of this order in corresponding reactions carried out by conventional methods where the yields have always been some 20 to 50% lower than those quoted above.

AJG 1235 _ 9 _ 1~15'~3~3~

.~

Preparation of pivaloyl ace-tic esters 1. 23 ~ of sodium were slowly introduced in sma]l portions into ~40 cc of diethyl carbonate, followed by heating to boiling - I)oint. After a reaction time of 15 minutes, all of the sodium had been converted into sodium ethylate. The reaction solu-tion ~as then cooled to 60C and 500 cc of benzene and 200 cc O r hexamethyl phosphoric acid triamide were added. A solution I0 of 100 g of pinacolone in 250 cc of benzene was then added drop~rise over a period of 3 hours at a temperature of 50 to 60C and under a vacuum o1` 1~0 Torr. ana benzene and ethanol simultaneously distilled off. Another 500 cc of benzene were then added and distillation continued. The total reaction time was 9 hours.
After cooling, the reaction mixture was poured into water, acidi~ied and a~ter extraction with ethyl acetate or toluene the solvent was distilled off. The residue containing the pivaloyl acetic ester was purified by distillation. The yield - 20 was 30 % of pivaloyl acetic acid ethyl ester.

2. A solution of 100 g of pinacolone in 500 cc of benzene was added dropwise over a period of 4 hours at 50C/150 Torr ; to a solution of 500 cc of benzene, 900 cc of diethyl car-bonate, 125 g of potassium-tert,~butylate and 200 cc of he~a-methvl phosphoric acid triamide, and ben~ene and ethanol slowly dist:illed off. After the ketone had been added, another 500 cc of benzene were added dropwise. The totaL reaction time was 9 hours. The reaction mixture was then treated and distilled in the same way as described in 1 above. The yield was 54~0 of pivaLoyl acetic acid ethyl ester.

3. 250 g of potassium-tert.-butylate were suspended in a solution of ~l80 cc O-r diethyl carbonate and 100 cc of hexa-methyl phosphoric ac-id triamide, followed by the gradual ~10~3~
drop~ise addition of 100 g pinacolone at 45~C/normal pressure.
On completion o~ the addition, the mixture was stirred for l hour at 45~C and, after cooling, alcohol, water and finally hydrochloric acid carefully added one after the other to the reaction mixture. The reaction mixture was then treated and purified in the same way as described in l above. The yield was 67% of pivaloyl acetic acid ethyl ester.

4. 325 g o~ sodium hydride (80~ solution in paraffin oil3 were suspended in 2500 cc of diethyl car~onate and 5Q0 cc of hexamethyl phosphoric acid triamide, 50Q g of pinacolone (92%) were then slo~ly added dropwise at 45 to 50C. ancl, on completion of the addition the reaction mixture was treated as described in 3 above. The yield was 91% of pivaloyl acetic acid ethyl ester.

5~ The procedure was as in test 4 above, except that 60 g of sodium hydride in 850 cc of diethyl carbonate, 500 cc of benzene and 200 ml of hexamethyl phosphoric acid triamide, and 100 g of pinacolone (92%) were used, and the reaction temperature was kept at 35C. The yield was 78%~

6. The procedure was as in test 5 above, except that no benzene was used and the reaction temperature was kept at 2Q to 30C. The yield was 72%~

7~ The procedure was as in test 4 above, except that 65 g o$ s~dium hydride in 480 cc of diethyl carbonate and 100 cc of hexamethyl phosphoric acid triamide~ and 100 g of pinacolone (92%~ were used and the reaction temperature was kept at 65C.
The yield was 65%.

8~ The procedure was as in test 4 above, except that 390 g of sodium hydride in 2900 cc of diethyl carbonate and 300 ml 3Q of hexamethyl phosphoric acid triamide, and 600 g of pinacolone (92%~ were used. The yield was 87%a

9. 60 g of sodium hydride were suspended in 450 cc of di-~3S'~38 methyl carbonate and 100 cc of hexamethyl phosphoric acid triamide. lQO g o~ pinacolone (92~) were added slowly at 45C and on completion of the addition, the reaction mixture was proce~sed as described in 3 above. The yield was 83.5 of pivaloyl acetic acid methyl ester.
lO. The procedure was as in test 9 above 9 except that 325 g of sodium hydride in 1800 cc of dimethyl carbonate and 200 cc of hexamethyl phosphoric acid triamide, and 500 g of pina~olone (92%) were used. The yield was 82~. ~
The pivaloyl acetic esters obtained according to the methods 1 - 10 above can be converted by reacting equimolar amounts of pivaloyl acetic esters and an substituted aniline such as e.g.
2-chlor-5-G~',4'-di-t-amylphenoxybutylamid ~aniline in an inert organic solvent such as xylol or benzene to a pivaloylacetic acid anilide coupler compounds e.g. of the formula t-butyl-~o-cH2-coNH- (~

NHCO ( CH2 ) 3-- ~3 C5H

C5Hll The pivaloylaoetic acid anilide coupler compounds can be used in known manners ~or the preparation of photographic images in color photographic materials e.g. as following:
2 mmol of the above mentioned coupler are solved in 3 ml of acetic acid ethylester and af-ter the addition of 1 g of di-butylphthala-te are emulsified by 60 C to 20 ml of a 5 gelatin solution in known manner. The emulsion contains ; 0,10 g sodium salt of dodecylsulfonic acid.
The emulsion was then added to 85 g of a 7,5 % gelatin solu--tion which contains in dispersed form 1,93 g of silver bromide 3~ and diluted with wa-ter to read -the viscosi-ty wh~ch is necessary for casting the emulsion. The emulsion is then 3~

cast onto a transparent support of cellulose triacetat and dried7 The photographic material is then developed after image-wise exposure behind a grey step wedge in a color developer containing N,N-diethyl-p-phenylene-d:iamine as color developer substance.After normal bleaching and fixing a yellow step wedge was obtained ha~ing an absorption maximum of 436 nm.

Preparation of 3-keto-4-methyl valeric acid ethyl ester

10 g o~ methyl isopropyl ketone were added to a solution of 400 cc of benzene, 850 cc o~ diethyl carbonate, 200 cc of hexamethyl phosphoric acid triamide and 60 g of sodium hydride (80~ in paraf~in oil), and the reaction mixture was heated to 70 to 80C. After the reaction had started, the reaction mixture was cooled to approximately 30C, and a solution of 76 g of methyl isopropyl ketone in 200 cc o~ benzene was added dropwi~e over a period o~ 2 hours at that temperature.
After the reaction mixture had stood overnight, methanol was carefully added to it with cooling, followed by acidi~ic~tion with aqueous hydrochloric acid. The reaction mixture was then treated a~ described in Example 1.1. The yield wa~ 81 o~ 3-keto-4 methyl valeric acid ethyl e~ter.
The compound of Exa~ple 2 can be converted with anilines toc~-methyl-propionylacetanilides e.g. according to the method described above which can be used in p~otographic materials as so called white couplers. The ~L-alkyl substi-tuted B-keto-carbonic-acid-anilides react with o~idized color developer substance~ Df the p-phenylene diamine type to form compounds which are not colored~ Thus they are used in color photographic materia~ in photo~raphic layers for ~iminishing A G 12~5 _ ~ _ ~s~
the color fog produced by a certain amount of oxi.dation products of color deve.loper substances which is pres:ent even in unex-posed areas of th.e pho-tographic image due to diffusion processes.

Preparation of 2-methyl-3-keto valeric acid ethyl ester The proceduxe was as in Example 2, except that diethyl ketone was used instead o~ methyl isopropyl ketone. The yield was 72~ of 2-methyl-3-keto valeric acid ethyl ester.
EXAMpLE 4 Preparation of 2-carbethoxy cyclohexanone . Th.e procedure ~as as in Example 2, except that cyclohexanone was used instead of methyl isopropyl ketone.
The yield was 85% of 2-carbethoxy cyclohexanone.
The aforementioned compound can be converted by reaction with anilines into valuab.le white couplers suitable for use in color photographic materials.

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process of producing an aliphatic .beta.-ketoester which comprises the steps of preparing a solution of dialkyl-carbonate, wherein the alkyl groups are of 1 to 4 carbon atoms, a basic condensation agent for ketone con-densation and a hexamethylphosphoric acid triamide, gradually adding a dial-kylketone of the formula wherein R1 represents a secondary or tertiary alkyl group of up to 18 carbon atoms, or a primary alkyl group which is the same as -CH2R2, R2 represents hydrogen or an alkyl group of 1 to 4 carbon atoms or R1 and R2 together represent an alkylene chain of formula -(CH2)n-, wherein n is 3, 4 or 5 to complete an aliphatic 5-, 6- or 7-membered ring to said solution, said con-densation agent being in a molar ratio of 1:1 or more based on the ketone, heating said condensation reaction mixture to a temperature of from 20 to 80°C until a reaction product is obtained and subsequently acidifying the reaction product to produce the aliphatic .beta.-ketoester.

2. A process of claim 1 wherein the dialkyl carbonate used is of the formula R - O - ? - O - R' wherein R and R' represent alkyl groups of from 1 to 4 carbon atoms.

3. A process of claim 1, wherein the dialkylketone is introduced into a molar solution of excess dialkylcarbonate based on the ketone.

4. A process of claim 1 wherein the basic condensation agent is sel-ected from the group consisting of alkali and alkaline earth metal alcoholate, sodium amide, sodium hydride and triphenyl methyl sodium.

5. A process of claim 4 wherein the basic condensation agent is sodium methylate, sodium ethylate, potassium ethylate, potassium-t-butylate or magnesium ethylate.

6. A process of claim 1 wherein as basic condensation agent an alkali or alkaline earth metal alcoholate in an excess of 5 % based on the dialkylketone is used.

7. A process of claim 1 wherein as basic condensation agent sodium hydride in an amount of 2 mols per mol of dialkylketone is used.

8. A process of claim 2 wherein in the formula of the dialkylcarbonate R and/or R' represent propyl, isopropyl, methyl and/or ethyl groups.

9. A process of claim 1 wherein the dialkylcarbonate used is diethylcarbonate.

10. A process of claim 1 wherein the hexamethylphosphoric acidtriamide is used in an amount of 0,1 mol per mol of dialkyl-ketone.

11. A process of claim 1 wherein in the formula of the dialkylketone R1 represents a methyl, ethyl, propyl, isopropyl, butyl, t-butyl, dodecyl or octadecyl group and R2 represents hydrogen or an alkyl group containing 1 to 4 carbon atoms or R1 and R2 together represent the atoms required to complete a 5- to 7-membered aliphatic ring.

12. A process of claim 11 wherein R2 represents a methyl or an ethyl group.

13. A process of claim 11 wherein R1 and R2 together represent the atoms required to complete a cyclopentanone, cyclohexanone ring.

14. A process of claim 1 wherein the dialkylketone used is pinacolone, diethylketone, methylisopropyl, ketone or cyclohexanone.

15. A process of claim 1 hwerein the hexamethyl phosphoric acid triamide used is diluted with an inert organic solvent.

16. A process of claim 15 wherein the inert solvent used is selected from the group consisting of benzene toluene or xylene.