CA1087631A

CA1087631A - 2-phenylpropionic acid derivative and process for its preparation

Info

Publication number: CA1087631A
Application number: CA295,499A
Authority: CA
Inventors: Carlos Ferrer; Juan Colome
Original assignee: Ferrer Internacional SA
Current assignee: Ferrer Internacional SA
Priority date: 1978-01-24
Filing date: 1978-01-24
Publication date: 1980-10-14

Abstract

ABSTRACT OF THE DISCLOSURE:

A new derivative of 2-phenylpropionic acid of the formula (I) is obtained by subjecting a corresponding alkyl ester of the formula:

Description

~08~63~
The present inVention iS concerned with a new derivative of 2-phenylpropionic acid of the formula:

~ CH - O - ~ 1 3 (I) and its pharmaceutically acceptable addition salts.
The present invention also provides a process for the preparation of the above derivative according to Scheme A
Scheme A

Cl Cl CH30- ~ -CH2-CN -- 1 / 4 2 ~ CH30 ~ CH2-COOR

II O IC / 2H5 ~ III
OR

Cl COORl ~CH3/C2H5ONa Cl COOR~.

CH30- ~ -CH l)OH ~ CH30- ~ C00R2 Cl ~ 2)H+ C

CH ~ ~ IC 3 XH~or -~ HO ~ -CH-COOH
3 BrH!S04H2 ~ ~
VI Rl-OH/Ar-SO3H / VII
Cl / Cl ~ CH3 L ~ D -CH2-X ~ CH -~ ~ O~ -CH-COOR
HO- ~ -CH-COORl ~ 2 VIII / IX
1)~ ' . . .

~ CH2-0- ~ C 3 H+

. . ,- . .: , -- , . .

1~87631 The present invention also provides two variations of the process according to the above scheme A, comprising further synthesis steps for the preparation of the intermediate compound of the formula VII. From VII, the preparation of compound I
is carried out according to scheme A given above. The new processes are thoroughly described in schemmes B and C :

Scheme B C ~
Cl ~ YCH3 CH 0- ~ -CH-CN

CH30~ CH2-CN _ ~ 3 \___/ OHNa/S04H . ~(C4Hg)4 II
XH
Cl~ ~ ICH3 ~~/rH/s04H2 . ~ ' . ' HO- < ~ -CH- OOH

VII

Scheme C
Cl Cl ~ YCH3 ~ CIH3 CH30- ~ CH2 C00RlNH2Na , NH3(liq.) ~ -CH-COOR

III ~ XI
XH
~~
Cl A ICH
HO- ~ O ~ -CH-COOH

VII

According to scheme A, /3-chloro-4-methoxypheny~
acetonitrile (II) is treated, under cold conditions, with an alkanol of formula Rl-OH where Rl is a lower alkyl radical, in a strong acid, preferably sulphuric acid to give an alkyl ~3-chloro-4-methoxypheny ~ acetate tIII)~ for example, ethylic.

Compound (III) is treated with a carbonic acid derivative of formula (R2O)2CO, where R2 is an alkyl radical of low molecular weight which may be equal or not to Rl, such as diethyl carbonate,

- 2 -~ .
..,~._:. i .. '' 108763~
in a basic medium such as that constituted by an alkaline alkoxide in an alkanol of low molecular weight, to give a dialkyl /3-chloro-4-methoxypheny~/malonate (IV). Compound (IV) is methylated with a compound of formula YCH3 where Y is bromine or iodine, preferably iodine, in the presence of an alkaline alkoxide in an alkanol of low molecular weight to - give dialkyl /3-chloro-4-methoxypheny~/ methylmalonate (V).
In the preparation of compounds (IV) and (V), sodium ethoxide in ethanol is commonly used as a basic medium which is suitable for malonation and methylation. Compound (V), by basic -:
hydrolysis preferably under reflux in the presence of sodium hydroxide in ethanol (it is also possible to use other alkaline or earth-alkaline hydroxides dissolved in an alkanol of low molecular weight), subsequent acidification and decarboxylation provides a-/3-chloro-4-methoxypheny~/ propionic acid (VI).
There may be used a mineral acid, such as hydrochloric acid, for the acidification. The decarboxylation is generally carried out by heating the intermediate /3-chloro-4-methoxypheny~/
methyl malonic acid, in form of crude product, at 210-220C. :
Compound (VI) is demethylated by acid hydrolysis with an hydracide of formula XH, where X is chlorine, bromine or iodine, preferably bromine, or a mixture of sulphuric acid with bromhydric acid, the latter being a desirable reactant only when it is required to extremely accelerate the process since bromhydric acid is the only acid catalyst suitable for the reaction. The a-/3-chloro-4-hydroxypheny~J propionic acid :~
(VII) which is obtained is then treated under reflux with a low molecular-weight alkanol such as methanol, by using an aryl-sulphonic acid, as a catalyst, of formula Ar-S03H where :
Ar is a phenyl radical, which may contain one or more lower alkyl radicals to give alkyl a-~3-chloro-4-hydroxypheny ~
propionate (VIII). Compound (VIII) is treated in a basic : , - - , :: ,, , :

medium such as an alkaline or earth-alkaline carbonate in a low molecular-weight ketone, preferably acetone, with a ~-halomethyl-cyclopropane of formule P-CH2-X where X is chlorine, bromine or iodine. Thus, alkyl ~-/3-chloro-4-cyclopropylmethoxyJ-propionate (IX) is obtained which, on saponification with an alkaline or earth-alkaline hydroxide dissolved in a low molecular-weight alkanol and subsequent acidification with a mineral acid, such as hydrochloric acid, leads to the desired compound (I). Potassium hydroxide in methanol is suitably used as an alkaline hydroxide in a low molecular-weight alkanol.
Schemes B and C show two synthesis options for the preparation of the intermediate (VII) thus shortening the -number of reactions steps. Through Scheme 2, compound (II) is methylated with a compound of formula YCH3 where Y is bromine or iodine, preferably methyl iodide, in the presence of an alkaline or earth-alkaline hydroxide and an ammonium salt, sodium hydroxide and tetrabutylammonium acid sulphate being suitably used. Aliphatic halogenated hydrocarbons such as methylene chloride is commonly used as a suitable solvent for this reaction. The a-/3-chloro-4-methoxypheny~/ propioni-trile ~X) which is obtained is then hydrolized in an acid solu-tion according to the same procedure as that used in the hydrolisis of compound (VI), thus obtaining the intermediate (VII) from which the preparation of compound (I) is accomplished as in Scheme A.
In Scheme C, compound (III) is methylated with a reactant of the formula YCH3 where Y is bromine or iodine, preferably methyl iodide, in the presence of a strong base such as sodamide in liquid ammonia. Thus, ethyl ~-/3-chloro-4-methoxyphenylJ propionate (XI) is obtained. The acid hydro-lysis, preferably with bromhydric acid, leads to the intermediate ~ . . : . .

~87631 (VII), from which the preparation of compound (I) is accomplish-ed as in the scheme A given above.
The compound (I) once obtained may be transformed into its pharmaceutically acceptable addition salts according to the usual chemical methods.
The new compound, a-/3-chloro-4-cyclopropylmethyloxi-pheny ~ propionic acid (I) shows anti-inflammatory, analgesic and antipiretic properties.
The anti-inflammatory activity has been determined for compound (I) by comparison with Alclofenac, as per the Carrageenan test comprising the oral administration of the test compound suspended in oil to albino female rats with 100 g average weight one hour before the subcutaneous perfusion of 0.1 ml of 1% carrageenan in distilled water into the hind-right paw of the rat.
In Table l,the activity is expressed as the decrease rate of the induced edema volume and is hereinafter computed for a series of dosage.

_ Compound I Alclofenac _ Dose (mg/kg) Activity (%) Dose (mg/kg) Activity (%) .:
2.5 25.7 2.5 16.88 35.45 5 23.38 45.79 10 28.52 .
The antipiretic activity has been determined for compound (I) by comparison with Alclofenac. The method used consisted in inducing fever in albino male rats (100-150 g weight) by subcutaneous injection of brewer's yeast (20%
suspension in sodium chloride 0.9 % dissolution) at a dose of 10 ml/kg.

~

: - . . . .
.: , : . :. : . :~

108~7631 In Table 2, the activity is expressed as the decrease rate of the induced temperature and is hereinafter computed for a series of dosage.

Compound I Alclofenac Dose (mg/kg) Activity (%)Dose (mg/kg) Activity (%)

3.12 22 3.12 21 6.25 76 6.25 17 12.5 84 12.5 34 The toxicity of compound (I) in mice by the oral route showed LD50 values of 3.45 g/kg and LDo values of 2.13 g/kg, the LD50 for Alclofenac being 1.10 g/kg.
The higher activity of the compound of the present invention compared to Alclofenac as well as its lower toxicity makes it drug of choice for clinical treatment of diseases involving inflammatory, algesic or pyretic processes. The compound can be administered, mixed with suitable excipients, in the form of tablets, capsules, syrup, solution, etc. by the oral route as well as by rectal route at a daily dose ranging between 30 and 2,400 mg.
The invention will now be illustrated with reference to the following non restrictive examples.
Example 1 : ethyl /3-chloro-4-methoxypheny~/ acetate (III, 1 2 5) A mixture of 60.80 g of /3-chloro-4-methoxypheny acetonitrile, 100 ml of ethanol and 37.0 ml of concentrated sulphuric acid is left overnight under reflux. The cold mixture is diluted with water and extracted with ether which is washed with concentrated sodium carbonate solution and water till neutralization, it is thereafter dried and evaporated. The :
.. . ~ : ' crude product weighs 68.2 g. IR spectrum and elemental analysis agree with the proposed structure.
EXAMPLE 2 diethyl /3-chloro-4-methoxypheny~J malonate (IV, Rl = R2 C2 5) In a flask provided with a small column and a distillation device is heated at 100-110C in oil bath, a mixture of 67.2 g of ethyl /3-chloro-4-methoxypheny~J acetate and 225 ml of diethyl carbonate. Then a solution of sodium ethoxide in ethanol prepared from 8.09 g of sodium and 145 ml of absolute ethanol is added over 30 minutes.
Once all ethanol is distilled and the excess of diethyl carbonate begins to flow, heating is stopped. The residue is acidified with acetic acid and water, then extracted with ether which is washed with saturated sodium carbonate solution and water till neutralization. Once the ether is cvaporated, the residue weighs 70.2g' by distillation, 50.5 g (160-170C/l mmHg) are obtained, which on solidification in the course of time show a melting point of 45-8C. IR spectrum and elemental analysis agree with the proposed structure.
EXAMPLE 3 : diethyl /3-chloro-4-methoxypheny~J methylmalonate (V, Rl = R2 = C2 5) 58.7 g of diethyl /3-chloro-4-methoxypheny~J malonate in 45 ml of absolute ethanol are added to a solution, under stirring, of sodium ethoxide in ethanol prepared with 4.50 g of sodium and 175 ml of absolute ethanol. After adding 32 ml of methyliodide, the solution is left under reflux for 3 hours, then distilled in alcohol, diluted with water and extracted with ether which is washed and dried; once the ether is evapo-rated, the oily residue weighs 50.3 g and it is used for the ~;
following step with no more purification.
EXAMPLE 4 : a-/3-chloro-4-methoxypheny~J propionic acid (VI) The above oil (50.0 g) is left under reflux for 2 ~' :.

., , ~ - .

: :: :. : . . . ~ .

hours with a mixture of 175 ml of 5N sodium hydroxide solution and 250 ml of ethanol, then it is evaporated, extracted with ether (which is rejected) and the waters are acidified, under cooling, with concentrated hydrochloric acid, the insoluble residue is taken in ether, washed with water and dried. Once the solvent is evaporated, the residue weighs 41 g and corresponds to /3-chloro-4-methoxypheny~J methylmalonic acid.
The acid obtained is heated in an oil bath at 210-220C till complete decarboxylation (about 20 minutes). The residue is distilled and 30.2 g (140-150C/0.1 mmHg) are obtain-ed. IR and NMR spectra and elemental analysis agree with the proposed structure.
EXAMPLE 5 : a-/3-chloro-4-hydroxypheny~J propionic acid (VII) (obtained according to Scheme A) 28.4 g of ~-/3-chloro-4-methoxypheny ~ propionic acid in 175 ml of 48% aqueous bromhydric acid are left under reflux for 15 hours. The excess of bromhydric acid is evaporated under vacuum, then taken in benzene, washed and dried. Once the benzene is evaporated, the residue weighs 26.3 g and it is used for the following step with no more purification.
EXAMPLE 6 : a-/3-chloro-4-hydroxypheny~J propionic acid (VII) (obtained according to Scheme B) 35 g of a-/3-chloro-4-methoxypheny~/ propionitrile in 150 ml of 4a% aqueous bromhydric acid are left under reflux for 15 hours. The bromhydric acid is evaporated under vacuum, then the residue in benzene is washed and dried. Once the benzene is evaporated, the residue weighs 32 g and it is used for the next step with no more purification.
EXAMPLE 7 : ~-/3-chloro-4-hydroxypheny~J propionic acid (VII) -(obtained according to Scheme C) 25.0 g of ethyl ~-/3-chloro-4-methoxyphenyl/ propionate in 160 ml of 48% aqueous bromhydric acid are left under reflux .

~08763~
for 15 hours, then the bromhydric acid is evaporated under vacuum, the residue is taken in benzene, washed and dried.
Once the benzene is evaporated, the separated product weighs 23.2 g and it is used for the following step with no more purification.
EXAMPLE 8 : methyl ~-/3-chloro-4-hydroxypheny~ propionate ; ( ' 1 3) A mixture of 26.2 g of a-/3-chloro-4-hydroxypheny~/
propionic acid, 140 ml of methanol and 1.0 g of p-toluensulphonic acid is left under reflux for 15 hours. The methanol is eva-porated under vacuum, diluted with water and extracted with ether; the organic solution is washed with sodium bicarbonate solution and water. The crude product weighs 25.7 g. IR
spectrum agrees with the proposed structure.
EXAMPLE 9 : methyl ~-/3-chloro-4-cyclopropylmethyloxypheny~J
propionate (IX, Rl = CH3) 16.04 g of ~-bromomethylcyclopropane are added with`
vigorous stirring to a mixture of 25.5 g of a-/3-chloro-4-hydroxypheny~/ propionate in 80 ml of anhydrous acetone and 16.4 g of anhydrous potassium carbonate. It is left under reflux, diluted (once cooled) with water and extracted with ether, then washed with sodium carbonate solution, water and dried. The residue weighs 28.3 g. By distillation, 24.6 g (128-132C/0.20 mmHg) are obtained. nD = 1.5305. IR and NMR
spectra agree with the proposed structure.
EXAMPLE 10 : ~-/3-chloro-4-cyclopropylmethyloxy/ propionic acid (I) 13.6 g of methyl ~-/3-chloro-4-cyclopropylmethylox~
propionate are added to a dissolution of 5.66 g of potassium 3Q hydroxide in 12 ml of water and 50 ml of methanol and it is left under reflux for 2 hours. The methanol is evaporated, diluted ~ -with water and acidified with 3N hydrochloric acid, then the ; ~;

_ g _ : , , . , ~ -, . . .
-~087631 insoluble residue is extracted with ether (twice with 150 ml), washed and dried, once the ether is evaporated, the residue weighs 11.08 g. By recrystallization in hexane, 8.0 g of product are obtained. Melting point 44C. IR, RMN spectra and elemental analysis agree with the proposed structure.
EXAMPLE 11~ 3-chloro-4-methoxyphenyl/ propionitrile (X) A solution of 54.45 g of ~-/3-chloro-4-methoxypheny~/
acetonitrile and 70.95 g of methyl iodide in 250 ml of methylene chloride is added with stirring to a mixture of 66.6 g of tetrabutylammonium acid sulphate and 26.4 g of sodium hydroxide in 250 ml of water. Then, it is kept under stirring for 15 minutes, the organic layer is decanted, the methylene chloride is evaporated and the tetrabutylammonium iodide precipitates from the residue by adding ether, then filtered and the ethereal solution is evaporated thus obtaining 59 g of crude product which are distilled to give 48 g (102C/0.1 mmHg).
By cooling the distilled liquid, 10.1 g of unaltered starting product crystallize.
EXAMPLE 12: ethyl ~-/3-chloro-4-methoxypheny~/ propionate (XI, Rl 2 5) 34.53 g of ethyl /3-chloro-4-methoxypheny~/ acetate in 40 ml of anhydrous ether are added for 30 minutes to a mixture of 0.15 moles of sodamide in liquid ammonia prepared from 3.45 g of sodium and 400 ml of ammonia. After 10 minutes, 21.29 of methyl iodide in 20 ml of anhydrous ether are added for 15 minutes, then the mixture is stirred for 1 hour at -40C. The ammonia is allowed to evaporate, it is diluted with ether, then water is carefully added and the organic extract is washed with a solution of sodium bisulfite and water. By distillation under vacuum from the residue, 26.18 g are obtained (105D-8C/0.25 mmHg).

.

Claims

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

1. A process for the preparation of a compound of the formula:

(I) and its pharmaceutically acceptable addition salts, which comprises subjecting a corresponding alkyl ester of the formula:

(IX) wherein R1 is a lower alkyl radical, to a saponification reaction carried out in the presence of an alkaline or earth-alkaline hydro-xide in a lower alkanol, and subsequent acidification with a mineral acid.

2. A process according to claim 1, wherein the com-pound of the formula (IX) is obtained by reacting a compound of the formyla (VIII) wherein R1 has the aforesaid meaning with an .alpha.-halomethylcyclo-propane of the formula CH2-X where X is chlorine, bromine or iodine in a basic medium and in a low molecular-weight ketone.

3. A process according to claim 2, wherein the com-pound of the formula (VIII) is obtained by esterification of a compound of the formula:

(VII) with an alcohol of the formula R1-OH where R1 has the aforesaid meaning, in the presence of an aryl-sulphonic acid of the formula Ar-SO3H where Ar is a phenyl radical optionally containing one or more lower alkyl radicals.

4. A process according to claim 3, wherein the compound of the formula (VII) is obtained by acid hydrolysis of a compound of the formula:

(VI) in the presence of either an hydracid of formula XH where X is chlorine, bromine or iodine, or a mixture of sulphuric acid with bromhydric acid.

5. A process according to claim 4, wherein the compound of the formula (VI) is obtained by basic hydrolysis of a compound of the formula:

(V) wherein R1 and R2 are the same or different and each represents lower alkyl radical, and subsequent decarboxylation of the inter-mediate [3-chloro-4-methoxyphenyl]methylmalonic acid formed.

6. A process according to claim 5, wherein the basic hydrolysis of the compound of the formula ( V) is effected by treatment with an alkaline or earth-alkaline hydroxide in a lower alkanol, followed by acidification with a mineral acid.

7. A process according to claim 5,wherein the compound of the formula (V) is obtained by methylation of a compound of the formula:

(IV) wherein R1 and R2 have the aforesaid meaning, with a compound of formula YCH3 where Y is bromine or iodine, in the presence of an alkaline alkoxide in a lower alkanol.

8. A process according to claim 7, wherein the compound of the formula (IV) is obtained by treating a compound of the formula:

(III) where R1 has the aofresaid meaning, with a carbonic acid derivative of the formula (R2O)2CO where R2 has the aforesaid meaning, in a basic medium.

9. A process according to claim 8, wherein the compound of the formula (III) is obtained by reacting a compound of the formula:

(II) with an alkanol of the formula R1-OH where R1 has the aforesaid meaning, in a strong acid.

10. A process according to claim 3, wherein the com-pound of the formula (VII) is obtained by acid hydrolisis of a compound of the formula:

(X) in the presence of either an hydracid of formula XH where X is chloride, bromine or iodine, or a mixture of sulphuric acid with bromhydric acid.

11. A process according to claim 10, wherein the com-pound of the formula (X) is obtained by methylation of a compound of the formula:

(II) with a compound of the formula YCH3 where Y is bromine or iodine, in the presence of an alkaline or earth-alkaline hydroxide and an ammonium salt.

12. A process according to claim 3, wherein the com-pound of the formula (VII) is obtained by acid hydrolysis of a compound of the formula:

(XI) wherein R1 has the aforesaid meaning,in the presence of either an hydracid of formula XH where X is chlorine, bromine or iodine, or a mixture of sulphuric acid with bromhydric acid.

13. A process according to claim 12, wherein the com-pound of the formula (XI) is obtained by methylation of a compound of the formula:

(III) wherein R1 has the aforesaid meaning, with a compound of the for-mula YCH3 where Y is bromine or iodine, in the presence of sodamide in liquid ammonia.

14. A process according to claim 1, which comprises:
a) reacting a compound of the formula:

( I I ) with an alkanol of the formula R1-OH where R1 is a lower alkyl radical, in a strong acid to obtain a compound of the formula:

(III) treating the compound of the formula (III) with a carbonic acid derivative of the formula (R2O)2CO where R2 is a lower alkyl radical, in a basic medium to obtain a compound of the formula:

(IV) methylating the compound of the formula (IV) with a compound of formula YCH3 where Y is bromine or iodine, in the presence of an alkaline alkoxide in a lower alkanol, to obtain a compound of the formula:

(V) wherein R1 and R2 have the aforesaid meanings, subjecting the com-pound of the formula (V) to a basic hydrolysis and decarboxylating the intermediate ?3-chloro-4-methoxypheny?methylmalonic acid formed, to obtain a compound of the formula:

( VI ) and subjecting the compound of the formula (VI) to an acid hydro-lysis, in the presence of either an hydracid of formula XH where X is chlorine, bromine or iodine, or a mixture of sulphuric acid with bromhydric acid, to obtain a compound of the formula:

(VII) or b) methylating a compound of the formula:

(II) with a compound of the formula YCH3 where Y is bromine or iodine, in the presence of an alkaline or earth-alkaline hydroxide and an ammonium salt, to obtain a compound of the formula:

(X) and subjecting the compound of the formula (X) to an acid hydro-lysis, in the presence of either an hydracid of formula XH where X is chlorine, bromine or iodine, or a mixture of sulphuric acid with bromhydric acid, to obtain a compound of the formula:

(VII) or c) reacting a compound of the formula:

(II) with an alkanol of the formula R1-OH where R1 is a lower alkyl radical, in a strong acid to obtain a compound of the formula:

(III) methylating the compound of formula (III) with a compound of the formula YCH3 where Y is bromine or iodine, in the presence of soda-mine in liquid ammonia, to obtain a compound of the formula:

(XI) and subjecting the compound of the formula (XI) to an acid hydro-lysis, in the presence of either an hydracid of formula XH where X is chlorine, bromine or iodine, or a mixture of sulphuric acid with bromhydric acid, to obtain a compound of the formula:

(VII) and d) esterifying the compound of the formula (VII) obtain-ed with an alcohol of the formula R1-OH where R1 is a lower alkyl radical, in the presence of an aryl-sulphonic acid of the formula Ar-SO3H where Ar is a phenyl radical optionally containing one or more lower alkyl radicals, to obtain a compound of the formula:

(VIII) reacting the compound of the formula (VII) with an .alpha.-halomethyl-cyclopropane of the formula where X is chlorine, bromine or iodine, in a basic medium and in alow molecular-weight ketone, to obtain a compound of the formula:

(IX) and subjecting the compound of the formula (IX) to a saponifica-tion carried out in the presence of an alkaline or earth-alkaline in a lower alkanol, and subsequent acidification with a mineral acid.

15. A compound of the formula:

(I) and its pharmaceutically acceptable addition salts, whenever obtain-ed by a process according to claims 1 or 14 or their obvious chemical equivalents.