ITMI20132039A1 - "METHOD FOR THE PREPARATION OF SYNTHETIC INTERMEDIATES" - Google Patents

Description

Description of the patent for industrial invention entitled:

"METHOD FOR THE PREPARATION OF SYNTHETIC INTERMEDIATES" in the name: DIPHARMA FRANCIS s.r.l.

based in: Baranzate (Milan)

* 3⁄4 = *

The present invention relates to a process for the preparation of derivatives of phenyl-2-methyl-propanoic acid, and in particular of 2- [4- (4-chloro-butyryl) phenyl] -2-methyl propanoic acid, useful as intermediate in the preparation of the drug fexofenadine hydrochloride.

STATE OF THE TECHNIQUE

The use of derivatives of phenyl-2-methyl-propanoic acid, and in particular of 2- [4- (4-chloro-butyryl) phenyl] -2-methyl propanoic acid of formula (A)

COOH

as an intermediate, in the preparation of fexofenadine and its salts it is known for example from US 4,254,129 and from US 5,750,703. A key point in the preparation of fexofenadine, according to the methods described therein, is the use of 2- [4- (4-chloro-butyryl) phenyl] -2-methyl propanoic acid, in the form of substantially pure para regioisomer. According to US 5,750,703, this intermediate is obtained by a process comprising the use of a cyclopropyl-ketone of formula (B) as a key intermediate

Indian patent application IN 1225DEL2006 describes a method for obtaining the 2- [4- (4-chloro-butyryl) phenyl] -2-methyl propanoic acid of formula (A), reported above, as a substantially pure para-isomer, through a process that includes:

the condensation of a compound of formula (C),

CI- (CH2) 3-COX

where X is a halogen atom, with 1-acetoxy-2-methyl-2-phenylpropane of formula (D)

CH,

/ X -CH2OCOCH3

CH,

Φ)

to obtain a compound of formula (E), containing more than 80% of para isomer,

CH, OCOCH

the acid hydrolysis of a compound of formula (E) to obtain a compound of formula (F),

0

ChLOH

the oxidation of an alcohol of formula (F) to obtain an acid of formula (G), and finally

CH,

-COOH

there CH,

o (G)

its purification to remove the meta isomer, for example by crystallization from an organic solvent.

This method has some notable disadvantages from the point of view of industrial production. The oxidation of an alcohol of formula (F) to obtain an acid of formula (G) is carried out with potassium permanganate in substantially stoichiometric quantities, which in terms of weight is greater than the mass of substrate to be oxidized. Therefore, a corresponding amount of manganese dioxide is formed as a by-product of the reaction. At the end of the reaction, in an industrial plant the separation by filtration of this solid by-product from the reaction mixture is quite complex, both because of the large mass of heavy metal present, and because the solid mass of manganese dioxide tends to incorporate the oxidized product of formula (G). The experimental example that describes the preparation of the oxidized product of formula (G), as raw, in fact reports at least three washes with an organic solvent and various extractions with solvent mixtures. The manganese dioxide resulting from the reaction then requires its disposal, with a considerable increase in costs.

It should also be noted that one of the purifications described therein is carried out by means of two successive extractions with a 20% solution of potassium carbonate. Given the basic environment, it is not possible to exclude that in such conditions a mixture of isomers of formula (B), having the above formula, may also form, which can further lower the yield of the raw product in the reaction.

Patent application EP 648 759, in a process for preparing analogues of fexofenadine, describes the oxidation of the alcoholic function in a compound having the following formula (FI)

RO OR

where X is a halogen atom, and R is, for example, alkyl, through the use of Jones' reagent, in acetone. Jones' reagent, which consists of a solution of chromic acid in a mixture of sulfuric acid in water, is nowadays absolutely unusable in an industrial-scale process, in particular for the use of extremely polluting chromium.

There is therefore the need to provide an alternative process, which can find a valid industrial application for the preparation of derivatives of phenyl-2-methyl-propanoic acid, and in particular of 2- [4- (4-chloro-butyryl acid ) phenyl] -2-methyl propanoic of formula (A) as a substantially pure para-isomer.

The inventors of the present invention have discovered that the industrial-scale preparation of a phenyl-2-methylpropanoic acid derivative, as a substantially pure para-isomer, of formula (ΪΙΪ), as defined herein, can be carried out by a process comprising the oxidation of a compound of formula (II), as defined herein, with the oxidizing agent (2,2,6,6-tetramethylpiperidin-1-yl) oxyl, also known as TEMPO, to obtain a compound of formula (I ), as a mixture of isomers, as defined here, and its subsequent isolation from this mixture of isomers.

SUMMARY OF THE INVENTION

The invention provides a method for the preparation of derivatives of phenyl-2-methyl-propanoic acid, and in particular of 2- [4- (4-chlorobutyryl) phenyl] -2-methyl propanoic acid, in particular as para substantially pure isomer, by a synthetic process comprising the use of the oxidizing agent (2,2,6,6-tetramethylpiperidin-1-yl) oxyl, also known as TEMPO, and the use of such acid in a method for the preparation of fexofenadine or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides, as a first object, a process for the preparation of a compound of formula (I), as a mixture of isomers, or one of its salt, or one of its alkyl ester,

COOH

o (T)

where X is a halogen atom, comprising the oxidation of a compound of formula (II), as a mixture of isomers,

CH, OH

o (Π)

where X is as defined above, with an oxidizing agent, in the presence of a catalytic system comprising TEMPO, at a pH of between about 2.5 and about 8.0; and, if applicable, the conversion of a compound of formula (I) into its salt or an alkyl ester thereof.

A salt of a compound of formula (I) is typically a pharmaceutically acceptable salt thereof.

An alkyl ester of a compound of formula (I) can be a C] -C6alkyl ester, preferably CrC4alkyl, for example methyl, ethyl or isopropyl.

A mixture of isomers of a compound of formula (T), or of formula (Π), can have a content in para-isomer and meta-isomer, for example, from about 50 to 90% in para-isomer and the remaining to complement 100% in meta-isomer.

A halogen atom X can be, for example, chlorine or bromine, preferably chlorine.

An oxidizing agent can be for example an alkaline hypochlorite, for example sodium or potassium, preferably sodium, optionally in the presence of a catalytic amount of an alkaline bromide, typically KBr.

The amount of alkaline hypochlorite, in particular sodium hypochlorite, used can be comprised between about 1.5 and about 3.0 moles of alkaline hypochlorite per mole of substrate, preferably between about 1.9 and 2.5 moles per mole of substrate .

A catalytic amount of alkaline bromide, for example KBr, can be comprised between 0.05 and 1 mole per mole of substrate.

Or said oxidizing agent can be an alkaline chlorite, for example sodium or potassium, preferably sodium, optionally in the presence of a catalytic amount of an alkaline hypochlorite, for example sodium or potassium, preferably sodium.

The amount of alkaline chlorite, in particular sodium chlorite, used can be comprised between about 1.5 and about 3.0 moles of alkaline chlorite per mole of substrate, preferably between about 1.9 and 2.5 moles per mole of substrate.

A catalytic amount of alkaline hypochlorite can be comprised between 0.05 and 1 mole per mole of substrate, typically between 0.05 and 0.2 per mole of substrate.

Preferably the oxidizing agent is used in the reaction mixture in aqueous solution.

A catalytic system comprising TEMPO comprises, but is not limited to TEMPO itself either in oxidized or reduced form, or a derivative thereof, as known in the art.

A derivative of TIME is for example a compound selected from the group comprising 4-hydroxy-TIME, 4-methoxy-TIME, 4-ethoxy-TIME, 4-acetamino-TIME, 4-benzoyloxy-TIME, 6-amino-TIME, N , N-dimethylamino-TEMPO, 4-oxo-TEMPO, 4-acetamido-TEMPO, and polymer versions of TEMPO such as poly [(6- [1,1,1,3-tetramethylbutyl) amino] -s-triazine -2,4-diyl, and [(2,2,6,6-tetramethyl-4-piperidyl) imino] hexamethylene [(2,2,6,6-tetramethyl-4-piperidyl) imino].

Said reagent can be used as such free or supported on an inert matrix, such as for example silica or polyethylene glycol; preferably it is used in free form.

The oxidation reaction can be carried out at a controlled pH of between about 2.5 and about 8.0, preferably in a pH of between about 5 and about 7.

The pH control can be preferably carried out in the presence of an aqueous buffer system, typically a buffer system formed for example by acetic acid / sodium acetate or NaEl2P04 / Na2HP04, preferably acetic / sodium acetate.

The reaction can be carried out in the presence of an aprotic apolar solvent, typically, a linear, branched or cyclic, aliphatic or aromatic C5-C7 alkane, for example hexane, pentane or cyclohexane, or benzene or toluene; a C4-C3⁄4 tertiary alcohol, for example tert-butanol; a C 1 -C 4alkyl ester of a carboxylic acid, for example ethyl acetate, butyl acetate, isopropyl acetate; an aprotic polar solvent, typically acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably acetonitrile; or an acyclic or cyclic ether, for example methyl tertbutyl ether tetrahydrofuran or dioxane; or a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; or a mixture formed by two or more, preferably two or three, of said solvents and / or water. Preferably the reaction can be carried out in a toluene / water or acetonitrile / water mixture.

The reaction mixture, depending on the solvent used, can be a monophasic or biphasic system.

The reaction can be carried out in a temperature range between about 10 ° C and about 65 ° C, preferably between about 20 ° C and about 40 ° C.

The conversion of an acid of formula (1) into a salt thereof, typically a pharmaceutically acceptable salt thereof, or an alkyl ester thereof, can be carried out according to known methods.

According to another aspect of the invention, a compound of formula (III), as a substantially pure para-isomer, having the following formula

CH,

\\ / -COOH

o CH,

(III)

where X is a halogen atom, it can be isolated from a mixture of isomers of formula (II), for example by a process comprising a fractional crystallization method. This method can for example be carried out as reported in US 5,750,703 or in IN 1225DEL2006.

The experimental examples shown here to illustrate a preferred method of implementing the invention, highlight the high yield of this preparation method. It should also be noted that the by-product that is formed in the oxidation process is sodium chloride, which is non-toxic to humans and non-polluting for the environment. Furthermore, the sodium chloride remains dissolved in the aqueous phase and is easily separable from the reaction medium, without resorting to laborious and expensive industrial operations. These results, combined with the simplicity with which this oxidation method can be carried out, therefore make the same method particularly advantageous for preparing a compound of formula (I) with high yield on an industrial scale.

According to a further aspect, the invention provides a method for preparing fexofenadine or a salt thereof, which includes the use as starting material of 2- [4- (4-chloro-butyryl) phenyl] -2 acid -methyl propanoic of formula (III), as a substantially pure para-isomer, as obtained herein.

For example fexofenadine, or a salt thereof, having the following formula (IV), can be obtained by a process, comprising

(CH2) 3-CH-C COOH

the reaction of an alkyl ester of an acid of formula (III), as a substantially pure para-isomer,

CH,

\\ / -COOH

CH,

O (III)

where X is a halogen atom, with a piperidine compound of formula (V)

(V)

to obtain an alkyl ester of a ketone compound of formula (Vi),

(CH2) 3-C- COOH

the hydrolysis of the ester group and the reduction of the carbonyl group into a compound of formula (VI), and, if necessary, the conversion of a compound of formula (IV) into a pharmaceutically acceptable salt thereof, in particular hydrochloride.

An alkyl ester of a compound of formula (III) or of formula (VI) can be a CrC6alkyl ester, preferably C1-C4alkyl ester, for example methyl, ethyl or isopropyl.

The preparation of a ketone compound of formula (VI), the hydrolysis of the ester group and the reduction of the carbonyl group in a compound of formula (Vi) to obtain fexofenadine, and possibly its conversion into a salt thereof, can be carried out in according to known methods, for example as reported in US 5,750,703. A compound of formula (II) can be prepared, for example, as previously reported in IN 1225DEL2006.

The following examples illustrate the invention.

Example 1: Synthesis of 2- [4- (4-Chlorobutyryl) phenyl] -2 ~ methylpropanoic acid (mixed with about 15% of 2- [3- (4-Chlorobutyrril) phenyl] -2-methylpropanoic acid) .

To a solution obtained by dissolving 2- [4- (4-Chlorobutyrril) phenyl] -2-methylpropan-1-ol (5.0 g, 19.6 mmoles) (containing about 15% of 2- [3- (4 -Chlorobutyryl) phenyl] -2-inethylpropan-1-ol) and TEMPO (2,2,6,6-tetramethyl-lpiperidin-1-oxyl) (0.156 g, 1.0 mmol) in acetonitrile (20 ml) is added a 0.67 M buffer solution of sodium phosphate at pH = 6.7 (30 ml). Under vigorous stirring, a solution obtained by dissolving 80% NaC102 (4.9 g, 43.3 mmoles) in H20 (10 ml) and a 9.2% NaOCl solution, further diluted with F120 (5 ml), are added. The biphasic mixture thus obtained is kept under vigorous stirring for 2 hours at 25 ° C. At the end of the reaction, Na2SO3 (5.5 g; 43.6 mmoles) is added, the phases are separated, the organic phase is dried with Na2SO4 and filtered. The solvent is evaporated under reduced pressure. The product (3.8 g; 14.9 mmol, 76% yield) is presented as brown oil. 1H-NMR (300 MHz, CDC13): δ = 7.95 (d, 2H), 7.50 (d, 2H), 3.67 (t, 2H), 3.16 (t, 2H), 2.23 (m, 2H), 1.63 (s, 6H).

Example 2: Synthesis of 2- [4- (4-Chlorobutyryl) phenyl] -2-methylpropanoic acid (mixed with about 15% of 2- [3- (4-Chlorobutyrril) phenyl] -2-methylpropanoic acid) .

To a solution obtained by dissolving 2- [4- (4-Chlorobutyrril) phenyl] -2-methylpropan-1-ol (10.0 g, 39.3 mmoles) (containing about 15% of 2- [3- (4 -Chlorobutyryl) phenyl] -2-methylpropan-1-ol) and TEMPO (2,2,6,6-tetramethyl-lpiperidin-1-oxyl) (0.310 g, 2.0 mmol) in toluene (40 ml) is added a 0.9 M sodium acetate / 0.3 M acetic acid buffer solution at pH = 5 (40 ml). Under vigorous stirring, a 9.2% NaOCl solution (3.2 g, 4.0 mmol) and a solution obtained by dissolving 80% NaC102 (9.8 g, 86.7 mmol) in H20 (20 me). The biphasic mixture thus obtained is kept under vigorous stirring for 3 hours at 35 ° C. At the end of the reaction, Na2SO3 (11.0 g, 87.3 mmoles) is added, the phases are separated, the aqueous phase is washed with toluene (20 ml), the combined organic phases are dried with Na2SO4 and filtered. The solvent is evaporated under reduced pressure. The product (8.0 g; 29.8 mmoles, 76% yield) appears as a brown solid. 1H-NMR (300 MHz, CDC13): δ = 7.95 (d, 2H), 7.50 (d, 2H), 3.67 (t, 2H), 3.16 (t, 2H), 2.23 (tu, 2H) , 1.63 (s, 6H).

Example 3: Purification of 2- [4- (4-Chlorobutyrnl) phenyl] -2-methylpropanoic acid.

The 2- [4- (4-Chlorobutyrril) feml] -2-methylpropanoic acid (8.0 g, 29.8 mmol) as obtained in the previous example and containing about 15% of 2- [3- acid (4-Chlorobutyryl) phenyl] -2-methylpropanoic, was dissolved at 55 ° C in a mixture consisting of cyclohexane (18 ml) and methyl terbutyl ether (4 ml). The solution thus obtained was cooled to 40 ° C, cyclohexane (20 ml) was added and the suspension was slowly cooled to 10 ° C over 3 hours. The solid obtained was filtered and 6.4 g of product (23.8 mmoles) were obtained, having an HPLC purity equal to 90.01% (meta isomer 6.57%).

Claims (10)

CLAIMS 1. Process for the preparation of a compound of formula (I), as a mixture of isomers, or one of its salt, or one of its alkyl ester, COOH where X is a halogen atom, including the oxidation of a compound of formula (Π), as a mixture of isomers, CH, -CH X <'> // 2OH CH, O (II) where X is as defined above, with an oxidizing agent, in the presence of a catalytic system comprising TEMPO, at a pH of between about 2.5 and about 8.0; and, if applicable, the conversion of a compound of formula (I) into its salt or an alkyl ester thereof. 2. Process according to claim 1, where the oxidizing agent is an alkaline hypochlorite, for example of sodium or potassium, optionally in the presence of a catalytic amount of an alkaline bromide, typically of KBr. 3. Process according to claim 2, wherein the quantity of alkaline hypochlorite is comprised between about 1.5 and about 3.0 moles of alkaline hypochlorite per mole of substrate, preferably between about 1.9 and 2.5 moles per mole of substrate. 4. Process according to claim 2, wherein the amount of alkaline bromide is comprised between 0.05 and 1 mole per mole of substrate. 5. Process according to claim 1, where the oxidizing agent is an alkaline chlorite, for example of sodium or potassium, optionally in the presence of a catalytic amount of an alkaline hypochlorite, for example of sodium or potassium, preferably sodium. 6. Process according to claim 5, wherein the amount of alkaline chlorite, in particular sodium chlorite, can be comprised between about 1.5 and about 3.0 moles of alkaline chlorite per mol of substrate, preferably between about 1.9 and 2.5 moles per mole of substrate. 7. Process according to claim 5, wherein the amount of alkaline hypochlorite is comprised between 0.05 and 1 mole per mole of substrate, typically between 0.05 and 0.2 per mole of substrate. 8. Process according to claim 1, wherein a catalytic system comprising TEMPO is selected from the group comprising TEMPO itself, an oxidized or reduced form thereof, and a derivative thereof. 9. Process according to each of claims 1 to 8, where the oxidation reaction is carried out in a temperature range between about 10 ° C and about 65 ° C, preferably between about 20 ° C and about 40 ° C. Process according to each of claims 1 to 9, further comprising the use of a compound of formula (1) in a method for preparing fexofenadine, or a salt thereof.