CA1048054A

CA1048054A - Process for the preparation of p. isobutyl hydratropic acid

Info

Publication number: CA1048054A
Application number: CA218,480A
Authority: CA
Inventors: Leandro Baiocchi
Original assignee: Aziende Chimiche Riunite Angelini Francesco ACRAF SpA
Current assignee: Angelini Acraf SpA
Priority date: 1974-04-11
Filing date: 1975-01-23
Publication date: 1979-02-06
Also published as: FR2267303A1; AR201607A1; JPS553336B2; DE2452459A1; FR2267303B1; BE820267A; ES429691A1; JPS50135026A; NL7414715A; ATA858674A; JPS5614654B2; JPS50135049A; AT338251B; FI340974A; GB1462407A

Abstract

ABSTRACT OF THE DISCLOSURE:
P. Isobutyl-hydratropic acid having the formula:
(I) is obtained by treating a compound of the general formula:

Description

~4~5~
The present in~ention is concerned with a new process for preparing p. isobutyl~hydratropic acid7 or 2-(4-isobutyl-phenyl)-propionic acid, having the following formula:

(CH3)2~1CH2 ~ CH_COOH (I) ~he above compound, which has been given the generic name o~ "Ibuprofen"7 is widely used in therapy as an antiinflam-matory, analgesic and antirheumatic agent.
~our methods of synthesis of the compound (I) are kno~n up to date. The first method (Brit. Pat. 971,700; 1964) consists in -the transformation o~ p. isobutyl-acetophenone, by means of a Willgerodt reaction, into 1-(4-isobutyl-phenyl)-acetic acid. ~he acid is then esterified, reacted with ethyl carbonate and transformed into diethyl-2-(4-isobutyl-phenyl)-malonate. A
methylation is then carried out'with methyl iodide, followed by a hydrolysis and successive decarboxylation.
~rench patent no, 1,545,270 (1968) descri'bed the trans-formation of p. isobutyl-acetophenone into 3-(4-isobutyl-phenyl)-

2,3-epoxybutyric ester by means of ethyl chloroacetate1 ~he pro-duct is then hydrolized and transformed into 2-(4-isobutyl-phenyl)-propanal by thermic decomposition. ~his aldehyde is then oxidi-zed to the corresponding acid with AgN03~ anhydrous potassium butylate or permanganate.
~he third method, claimed in ~rench patent no. 1,549,728 (1968) conæists in the transformation of p. isobutyl-acetopheno ne into the corresponding hydantoin with ammonium carbonate and potassi~m cyanide in aqueous ethanol solution. The hydantoin is hydrolyzed to aminoacid and the latter is then deaminated to give compound (I).

5~
~ rom a simple examination of the above three me-thods, it appears evident that the second and third ones require the use of expensive or dangerous reactants, such as silver nitrate - ox potassium cyanide, while the first method, which would be more suitable for a preparation on an industrial scale, seems to be rather complicated. In all these three methods, however, the starting product, which is already aromatic, is the same: p.
isobutyl-acetophenone.
~he fourth method is described in Brit Pat. 1,265,800.
~his method starts with the synthesis o~ methyl or ethyl 2-(4-isobutyl-2-oxocyclohex-3-enyl)-propionate. ~hese compounds are only obtained as by-products according to the methods of prepa-ration disclosed in said patent and no yields are mentioned.
~hese produc-ts, or their corresponding acids, are then aromatized to p. isobutyl-hydratropic acid by heat treatment in the presence of pyridine hydrochloride. Since no yields of this second opera-tion are reported in the patent, Applicants have repeated the experiments mentioned in examples 2, 4, 8 and 12 in their labo-ratories and obtained7 however, very poor quantities o~ the pro~
duct sought (yields inferior to 5~o). ~he conclusion of Applicants' experiments is that the method reported in the ~rit. Pat~
1,265,800 for the synthesis of p. isobutyl-hydratropic acid has no possible application on an industrial scale.
The subject invention proposes to provide a process which does not require the use of expensive or dangerous reactants, nor -the difficult preparation of 2-(4-isobutyl-2-oxocyclohex-3-enyl) propionic acid. ~he method according to the present inven-tion is in fact based on an original aromatization reaction which takes place when a dialkyl ~7~-acetyl-oC-~ 5-methyl-3-oxo)-hexyl 7~ methyl-succinate of the general formula (II):

~8~)5~

\ ll I 1 3 (II) ~H - ~H2 C - CH2aH2 ~ C - CH - COOR
CH3 a OOR' wherein R and R' are identical or different and each represent an alkyl radical having from 1 to 5 carbon atoms9 is heated at a temperature of from 200 to 240C, in the presence of strong acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, chlorosulfonic acid, p. tol~ensulfonic acid, in aqueous solution;
where dxy acid is preferred; use is made of an addition salt of the strong acid with an organic base as, for example, triethyla-mine, pyridine or other pyridine bases~ quinolin~, isoquinoline or their derivatives, as halohydrates, arylsulfonates, trifluoroa-cetates, methanesulfonates or mixtures with arylsulfochlorides.
~he molar ratios between the acidic reactant and com pound (II) generally range between 3 and 109 and the heating times do not exceed 3 hours.
The deri~atives of formu:La (II) are not described in the literature; they can, however, be easily prepared by various methods. It is possible, for example, to start from ethyl ~-acetyl- O~-methyl-succinate~ known since 1881 (Ann. 206, 320) and react this product with isobutyl-vinyl-ketone (J. Org. Chem.
32, 1234, 1967). Instead of isobutyl-~inyl-ketone, the corres-ponding Mannich base, or a quaternary deri~ative of that base, can be reacted. Methyl, propyl, butyl or amyl esters can also be used instead of ethyl esters: isobutyl--vinyl-ketone can also be condensed first with acetoacetic ester9 introducing then the residue of the halopropionic ester. In a very convenient method for industrial preparation, of which Applicants are reporting hereinafter some non restrictive examples, the isolation of com-pound (II) may even be a~oided. The product can thus be directly ~ 4~1~S~
obtained by txeating acetoacetic ester with an alkyl ~-halopro-pionate and isobutyl-vinyl-ketone7 treating then the reaction mixture with aqueous HCl, or with other acidic reactants such as those previously mentioned.
The two reactions mentioned above for the preparation of compounds of the general formula (II) may be schematized as ~ollows:
CH CO COOR~

3 ~ CH ~ CH3 0 CH \ CH-CH2-C-C~I=CH2 ~~~~~ COMPOU~D (II) CH3 \ COOR ~ CH3 ~
isobutyl-vinylketone CH3-c-aH2-aooRl + CH3-CH-COOR CH3-c-cH-cH-c OR
X COOR' wherein R and Rt have the aforesaid meanings and X represents a halogen atom.
' It must be noted that the compounds (II), when R and R~'are identical, always exist as mixtures of diastereomers. In the,particular case when R and R9 both represent an ethyl group, the two couples of diastereomers were separated by column chro-matography and each of the two couples was submitted to acidic I treatment, according to the present in~ention. ~o difference in ; the yield of p. isobutyl-hydratropic acid was noticed by starting either from one or tha other of the two couples.
The subject invention will now better illustrated with reference to the following non-restrictive examples.

~0 ~ _~
~thyl ~-acetyl-G~'-methyl-succinate (20 g ~ O.087 moles) was added to a solution of sodium (100 mg) in anhydrous ethanoi 1q3~8~154 ~20 ml). ~he resulting solution was cooled with ice and water, and added dropwise with freshly prepared vinyl-isobutyl-ketone ~10 g ~ 0.086 moles).
~he solution was kept under stirring for 3-4 hours at room temperature, and then poured into water, extracted with ether and dried on sodium sulfate. It was distilled and a co-lourless oil (14 g) was collected at 170-177 (0.7 mm ~g).
Analysis:
calc.: C 63.13 H 8083 ~or C18H306 found: 63.45 8.53 ~hin ~ayer Chromatograph~ (silica - eluant: hexane-ether 1:1) indicated the distilled product to be formed b~ the two couples of diastereomers (A and ~); four additional different products were also noticed, in a negligible quantity, and were not further examined.
EXAN~Iæ 2 A and ~
A chromatographic column 90 cm high and having a dia-meter o~ 5 cm packed with 900 g of Merck silica gel 70-230 mesh9 was prepared. The retention volume was of 1400 ml of a solvent formed b~ a mixture of cyclohexane-ether (6:4). 14 g. of the dis-tilled product obtained in example 1 were dissol~ed in ether (15 ml) and added to the column, prepared as abo~e. ~ractions of 25 ml each were collected.
After 69 fractions containing the retention volume and the solvent, the following products were obtained:
fractions 70 to 74:1 g of a colourless oil (impurity) fractions 75 to 97 : 4.5 g of a colourless oil (couple A) fractions 98 to 104 : 1 g of a colourless oil (mixture A ~
fractions 105 to 1?2: 4.5 g of a colourless oil (couple ~) 8~S~
fractions 123 to 132 : 1 g of oil (couple B ~ tail impurity) fractions 133 to 137: 0.4 g of a colourless solid (tail impu-rity) fractions 138 to 148 : 0.6 g of a colourless solid (tail impu rity~
~he checking of the single fractions was effected on ~.I,.a. si-lica Dqerck ~ 254.
E:luant Rf A Rf B
hexane-ether 1-1 0.35 0.25(solvent run equal to 10 cm) he~ane~ether 6-4 0.45 0.35 (double elution solvent run equal to 15 cm) Detectors: a) iodine vapours b) 5~ solution of sulfuric acid (5' at 110) c) 10% ethanol solution of phosphomolibdic acid (51 at 110) ~he elementar analysis and the N~l[R spectrum of couples A and B were in accord~ce wi-th their structure.
EXA~
EthyloC _acetyl ~ -/ r5-methyl-3-oxo)-hexyl 7-~- methyl succinate (10 g) obtained as described in example 1 (b.p~ 170-177 at 0.7 mm Hg) and 36% ESl (50 ml) were heated at 230 for 1 hour and a half in a sealed tube. After cooling, the tube was opened, the solution was diluted in water and extracted with ether. ~he ethereal extract was shaken with a 10% ~aOH solution.
The alkaline clear solution was then brought to a pH of 6~5-7 with HCl, extracted with ether and then made strongly acidic.
~he p. isobutyl-hydratropic acid thus obtained was then separated, filtered, washed and dried. 4.8 g of the product were obtained, m.p. 71-3.
Similarly~ p. isobutyl-hydratropic acid was also ob-tained by heating compound (II) in a sealed tube with 47 and 3~%
hydrobromic acid, with 357~ sulfuric acid, with 307~ chlorosulfonic ac~d, ~ 4~
with35~ p.~oluenesulfonic acid, attemperatures ranging between 200 230for periodsvarying from 45 minutesto 1hour and a half.
~X~ E 4 Ethyl ~-acetyl- ~-~ 5-methyl-3-oxo)-hexyl 7_ ~ -methyl succinate was added -to pyridine hydrochloride (30 g); the resul-ting solution was heated in a ba-th thermostated at a temperature of 230, under stirring for 1 hour and a half. ~he solution was cooled, the brown mass was dissolved in water (100 ml) and the brown oil which separated was extracted with ether. ~he ethereal extract was shaken with a 10% ~aOH solution: the alkaline clear solution was acidified with HCl 1:1; the p. isobutyl-hydratropic acid thus obtained was separated as small particles of a greyish solid which was filtered, washed with water and dried. 5.3 g of the product were obtained, m.p~ 69-71. The melting point rose to 74-75 when the product was crystallized from petroleum ether.
In the course of similar experiments~ ethyl ~-acetyl- ~
-~ 5~methyl-3-oxo)-hexyl 7-c~'-me-thyl succinate, was treated with quinoline hydrochloride, with ~-picoline hydrochloride and hy-drobromide, with triethylamine hydrochloride, with isoquinoline hydrochloride9 with pyridine benzenesulfonate, or p. toluenesul-fonate, or naphtalenesulfonate or methanesulfonate or trifluoroa-ceta~e, at temperatures ranging between 200 and 2409 for periods varying from 1 to 2 hours. In every case, p. isobutyl-hydratro-pic acid was obtained with good yields.
~X~ E 5 Ethyl ~-acetyl- ~'-methyl-succinate (10 g) was added, all at once, to sodium (50 mg) dissolved in anhydrous ethanol (10 ml). ~hen, after cooling with ice and under stirring, freshly prepared vinyl-isobutyl-ketone (10 g) was added dropwise. ~he mixture was kept under stirring for 4 hours at room temperature, then it was poured into a 500 ml flask containing pyridi~e hy-drochloride (60 g) and the mixture was heated at 2~0Q for 1 hour ~4~3~S~
and a half under stirring. ~he brown mass was cooled, dissolved in water (150 ml) and extracted with ether; the ethereal extracts were shaken with 10% ~aOH (100 ml) and the alkaline solution, diluted with water (500 ml) was acidified with HCl 1:1 (45 ml).
lhe p. isobutyl-hydratropic acid thus obtained was separated as small particles of a brownish solid, which was filtered, washed with water and dried. Yield: 7 g, m.p. 69-71.
EXAN~IE 6 Methyl acetoacetate (22.5 g) was added to a solution of sodium (4:5 g) in anhydrous e-thanol (100 ml). ~he resulting so-lution was heated under reflux for 5 minutes, cooled and, after addition of ethyl ~-bromopropionate (35 g), was refluxed under stirring for 5 hours.
The solution was then cooled, filtered ~rom sodium bromide and~ after removing most of the alcohol under reduced pressure, poured into a small quantity of water. The oil which separated was extracted with ether and dried on sodium sulfate.
After evaporation of the solvent 9 an oily residue (35 g) was ob-tained~hich wasadded toa solution o~ sodium (175 mg) in anhydrous ethanol (~5 ml). Vinyl_isobutyl_ketone (35 g) was added drop-wise to the cooled solution, under stirring at room temperature and ~or 3 hours; the mixture was then allowed to stand at rest over night. ~he reaction product as such was poured into a 1000 ml flask containing~-picoline hydrochloride (210 g~. ~he miæture was kept for 1 hour and a half at 230 under stirrin~, and then cooled. ~he brown mass was dissolved in water (400-500 ml) and the oil which separated was extracted with ether.
~he ethereal extracts were concentrated to dryness, and the bro~m residue was treated with 10~ NaOH solution (200 ml) in which it was almost completely soluble. It was once more extracted with ether in alkaline medium, then the a~ueous solution was acidif~ed wi-th HCl 1:1 (100 ml). ~he p.isobutyl hydratropic acid which ~8--3 (;J4B~354 separated was filtered~ washed with water and dried. After crys-tallization ~rom petrol ether, 12 g o~ almost pure product were obtained.

t. butyl acetyl-acetate (10.5 g) was added to a solu-tion of sodium (1.4 g) in anhydrous ethanol (40 ml). A~ter hea-ting under reflux for 5 minutes, the solution was cooled and ethyl 6~bromo-propionate (10 g) was added; the resulting solution was then heated under re~lux for 5 hours~ under stirring. The solu-tion was cooled, filterea from the sodium bromide which separa-ted and most of the alcohol was removed under reduced pressure.
It was then poured into water; the oil which separated was ex-tracted with ether and dried on sodium sulfate. After evapora-tion of the solvent, an oily residue was obtained ( 11. 65 g) which was added to a solution of sodium (120 mg) in anh~drous ethanol (25 ml?. Vinyl_isobutyl_ketone (10.5 g) was slowly added to the --~ cooled solution, under stirring. ~he solution was kept at room temperature and under stirring for three hours, and then one night at rest; it was thereafter poured into water, the pH was brought to about 6.5 with a few drops of acetic acid and the solution was extracted with ether. The ethereal extracts, after drying on sodium sulfate, were concentrated under reduced pres sure: the oily residue (12 g) was treated9 in a sealed tube, with 47% hydrobromic acid (25 ml) for 1 hour and a half at 230.
The solution was cooled, diluted with water (150-200 ml) and ex-tracted with ether. The ethereal ex-tracts were shaken with a 10%
NaOH solution (100 ml~ and then with water. The aqueous alkaline solution was brought to pH 6,5-7 with HCl 1:1 and extracted again with ether7 then strongly acidified (red Congo indicator) again with HCl 1:1. p. isobutyl-hydratropic acid separated, which was filtered, was~ed with water and dried. Yield: 2.1 g.

_9_ 8~

MethylG~_ace-tyl~o(~-methyl-succinate (J. ahem. Soc.
1933, 811) (5,8 g) was addea to a solution of sodium (35 mg) in anhydrous methanol (10 ml) and then, slowly and gradually cooling the solution, vinyl-isobutyl-ketone (6.5 g) was also added. ~he solution was kept under stirring9 at room temperature, for 3 hours, and then one night at rest. It was then poured into wa-ter, extracted with ether, and the extracts were dried on Na2S04.
After evaporation of the solvent, a colourless oil was left, from which methyl ~-acetyl-c<-~ 5-methyl-3-oxo)-hexyl 7-G<~-methyl-succinate was obtained with good yields. b.p. 145-150 at 0.2 mm.
The analysis and the ~R spectxum were in accordance with the structure.
The distilled product whichg similarly to what was des-cribed in example 1, was formed by the mixture of two couples of diastereomers, was treated with different acidic reactants, cho-sen among those aforementioned, at temperatures of about 230.
In all cases9 p. isobutyl-hydratropic acid was obtained with good yields.

--10..

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the preparation of a dialkyl .alpha.-acetyl-.alpha.-[(5-methyl-3-oxo)-hexyl/-.alpha.'-methyl-succinate of the general formula:

(II) wherein R and R' are identical or different and each represent an alkyl radical having from 1 to 5 carbon atoms, which comprises:
a) reacting an alkyl .alpha.-acetyl-.alpha.'-methyl succinate of the general formula:

(III) wherein R and R' have the aforesaid meanings, with isobutyl-vinylketone or a Mannich base thereof or a quaternary derivative of said base, or b) reacting an acetoacetic ester of the formula:

(IV) with an alkyl .alpha.-halopropionate of the formula:

(V) in which formulae R and R' have the aforesaid meanings and X

represents a halogen atom, and further reacting the resulting product with isobutylvinyl ketone.

2. Process according to claim 1, wherein R and R' each represent an ethyl group.

3. Process according to claim 1, wherein R is ethyl and R' is methyl.

4. Process according to claim 1, wherein R is ethyl and R' is t-butyl.

5. Process according to claim 1, wherein R and R' each represent a methyl group.

6. Process according to claim 1, which comprises the further step of treating the compound of the formula (II) obtained with a strong acid in aqueous solution or with an addition salt of a strong acid with an organic base, at a temperature ranging from 200 to 240°C to form p. isobutyl-hydratropic acid of the formula:

(I)

7. Process according to claim 6, which comprises reacting an acetoacetic ester of formula (IV) with an alkyl .alpha.-halopropionate of formula (V), reacting the resulting product with isobutylvinylketone to obtain a reaction mixture containing a compound of formula (II), and treating said reaction mixture with a strong acid in aqueous solution or with an addition salt of a strong acid with an organic base, at a temperature ranging from 200 to 240°C.

8. Process according to claims 6 or 7, wherein R
and R' each represent an ethyl group.

9. Process according to claims 6 or 7, wherein R
is ethyl and R' is methyl.

10. Process according to claims 6 or 7, wherein R
is ethyl and R' is t-butyl.

11. Process according to claims 6 or 7, wherein R and R' each represent a methyl group.

12. Process according to claims 6 or 7, wherein X
represents a chlorine atom.

13. Process according to claims 6 or 7, wherein the acidic reactant and the compound of formula (II) are reacted in a molar ratio comprised between 3 and 10.

14. Process according to claims 6 or 7, wherein the acidic reactant and the compound of formula (II) are heated over a period not exceeding 3 hours.

15. Process according to claims 6 or 7, wherein the strong acid is selected from the group comprising hydrochloric acid, hydrobromic acid, sulfuric acid, chlorosulfonic acid and p-toluenesulfonic acid.

16. Process according to claims 6 or 7, wherein the organic base is selected from the group comprising triethylamine, pyridine, quinoline and isoquinoline.

17. Process according to claims 6 or 7, wherein the compound of formula (II) is treated with hydrochloric acid in aqueous solution.

18. Process according to claims 6 or 7, wherein the compound of formula (II) is treated with .alpha.-picoline hydro-chloride.

19. Process according to claims 6 or 7, wherein the compound of formula (II) is treated with pyridine hydrochloride.

20. Dialkyl .alpha.-acetyl-.alpha.-[(5-methyl-3-oxo)-hexyl/-.alpha.'-methyl-succinates of the general formula:

(II) wherein R and R' are identical or different and each represent an alkyl radical having from 1 to 5 carbon atoms, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.

21. Compound according to claim 20, wherein R and R' each represent an ethyl group, whenever obtained by a process according to claim 2 or its obvious chemical equivalents.

22. Compound according to claim 20, wherein R is ethyl and R' is methyl, whenever obtained by a process according to claim 3 or its obvious chemical equivalents.

23. Compound according to claim 20, wherein R is ethyl and R' is t-butyl, whenever obtained by a process according to claim 4 or its obvious chemical equivalents.

24. Compound according to claim 20, wherein R and R' each represent a methyl group, whenever obtained by a process according to claim 5 or its obvious chemical equivalents.