ITMI20121347A1 - EFFICIENT METHOD FOR THE PREPARATION OF MITIGLINID WITH HIGH PURITY - Google Patents

Description

Description of the patent for industrial invention entitled:

“EFFICIENT METHOD FOR THE PREPARATION OF MITIGLINIDE

HIGH PURITY "

Field of the invention

The present invention relates to a new process for the synthesis of high purity Mitiglinide.

Background of the invention

Mitiglinide (I) is a hypoglycemic drug used for the treatment of type 2 diabetes.

The preparation of Mitiglinide (I) and its dihydrate calcium salt (II) is described in EP507534 (US5202335).

The main synthesis method described in the aforementioned patent involves the regioselective reaction of benzylidensuccinic anhydride III with cis-hexahydroisoindoline to give monoamide IV, the reduction of which provides the racemic mitiglinide V (scheme 1).

Scheme 1

An alternative route, described for an analog of mitiglinide (having a methyl in para on the benzene ring), includes the conversion of succinic acid VI into the corresponding acid chloride VII and then into the diester VIII by esterification with p-nitrophenol. The diester then reacts regioselectively with cis-hexahydroisoindoline to obtain monoamide IX, the hydrolysis of which gives V as a racemic mixture (scheme 2).

Scheme 2

Both these synthesis pathways lead to a racemic product which requires an expensive resolution with chiral amines or through the formation of diastereomers by reaction with chiral alcohols [Chem. Pharm. Bull. 45, 1518 (1997)]. In addition, the method illustrated in Scheme 2 requires two chromatographic purifications in addition to using a highly toxic reagent such as p-nitrophenol.

The same patent also describes a synthesis route for obtaining mitiglinide in the optically active form (I) starting from a hemiester of (S) -2-benzylsuccinic acid (X), as illustrated in diagram 3, passing through the monoester monoester XI . The synthesis of monobenzyl ester X is not described.

Scheme 3

In Chem. Pharm. Bull. 46, 337 (1998) an efficient and practical synthesis for the preparation of mitiglinide is described. It starts from (S) -2-benzylsuccinic acid XII and passes through the formations of some esters, such as di-p-nitrophenyl ester XIII (scheme 4). This then reacts regioselectively with cis-hexahydroisoindoline to give XIV which is finally hydrolyzed to mitiglinide (I) and converted to the calcium II salt. In addition to the diester with p-nitrophenol, other diesters are described including those with N-hydroxysuccinimide and N-hydroxybenzotriazole.

Scheme 4

WO9832736 describes the preparation of a bis-imidazolide, similarly to diester XIII, which in situ is reacted with cis-hexahydroisoindoline and then hydrolyzed to give crude mitiglinide, which is purified through the benzyl ester XI.

Other known processes for the synthesis of mitiglinide include the asymmetric hydrogenation of benzylidenesuccinic acid monoamide (IV) (US6133454); selective hydrolysis of racemic mitiglinide ethyl ester with alpha-chymotrypsin [Synthetic Communications, 37, 2153 (2007)] or the formation of the stereocenter by diastereoselective alkylation of a substrate in which a chiral auxiliary is present [e.g. Oppolzer's sultame, Helvetica Chimica Acta, 87, 1935 (2004)].

The synthesis that uses (S) -2-benzylsuccinic as starting material seems potentially the most suitable for the definition of an industrial process for the preparation of mitiglinide, since this optically active acid is commercially available with excellent enantiomeric purity. However, the application of the procedure described in scheme 4, which involves the treatment of p-nitrophenol (or other alcohol) first with donyl chloride and then with (S) -2-benzylsuccinic acid, did not give an acceptable result. due to the predominant formation of (S) -2-benzylsuccinic anhydride. It was then tried to synthesize diester XIII through the formation of (S) -2-benzylsuccinic acid chloride even though this synthesis route has been described for racemic benzylsuccinic acid with low yields and purity (scheme 2). Another problem encountered in the process is that the enantiomeric purity of the mitiglinide obtained is lower than that of the starting (S) -2-benzylsuccinic acid. Furthermore, the p-nitrophenol used for the synthesis of the diester is a substance considered highly toxic.

Description of the invention

Unexpectedly, we found a process that allows high purity mitiglinide to be obtained with high yields without any racemization being observed throughout the process. Furthermore, p-nitrophenol can be advantageously replaced by N-hydroxysuccinimide, which is non-toxic and is easily removed from the process.

The invention therefore provides a process, illustrated in diagram 5, which includes:

a) Conversion of (S) -2-benzylsuccinic acid XII into the corresponding acid chloride XV;

b) Esterification of XV with N-hydroxysuccinimide to diester XVI; c) Regio-selective reaction of diester XVI with cis-hexahydroisoindoline to give monoamide monoester XVII;

d) Hydrolysis of the ester group of XVII obtaining mitiglinide (I) e, optionally

e) Salification of mitiglinide to the corresponding calcium dihydrate salt Scheme 5

Detailed description of the invention

(S) -2-benzylsuccinic acid is commercially available. Its enantiomeric purity can be easily checked by chiral chromatography.

Step ah conversion of (S) -2-benzylsuccinic acid XII into the corresponding acid chloride XV

This step can be accomplished by one of several known methods for converting a carboxylic acid into the corresponding acid chloride [for example: Comprehensive Organic Transformations, Richard C. Larock, ed. John Wiley & Sons, II edition (1999), page 1929].

The reaction can be carried out using donyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. as the chlorinating agent, preferably donyl chloride.

The chlorinating agent is preferably used in a molar ratio between 2 and 20 with respect to (S) -2-benzylsuccinic acid XII.

The reaction can be carried out with one of the above mentioned chlorinating agents in the presence of a catalytic amount of DMF. Preferably the reaction is carried out using donyl chloride in the presence of a catalytic amount of DMF.

The amount of DMF used is between 0.05 and 1.0 mL per gram of (S) -2-benzylsuccinic acid XII, preferably between 0.05 and 0.5 mL per gram of (S) -2-benzylsuccinic acid XII.

An aprotic solvent is used such as dichloromethane, toluene, xylene, or the chlorinating agent itself, preferably donyl chloride.

The reaction is carried out at a temperature between room temperature and the boiling temperature of the solvent used, preferably between 40 ° C and the boiling temperature of the solvent used, more preferably between 60 ° C and 80 ° C.

The reaction time ranges from 1 hour to 24 hours, preferably from 2 to 8 hours, more preferably from 4 to 6 hours.

To isolate the XV acid chloride, the reaction mixture is concentrated under vacuum, preferably at a pressure of less than 100 mBar and in a time of less than 2 hours.

The product is obtained as oil, in virtually quantitative yield, and used as it is in the following step.

Step b): esterification of XV with N-hydroxysuccinimide to diester XVI

The preparation of the diester is carried out by reaction of the acid chloride XV with N-hydroxysuccinimide in an aprotic solvent at a controlled temperature in the presence of a suitable acid acceptor.

This step is critical for the quality of the final product. EP507534 reports the use of triethylamine as an acid acceptor. We have observed that the use of this base causes, to varying degrees, the inversion of the stereocenter, producing the diester XVIII and then leading in the continuation of the synthesis to the formation of the mitiglinide enantiomer (XIX) and therefore to a mitiglinide of enantiomeric purity lower than that of the starting (S) -2-benzylsuccinic acid.

This problem can be overcome by using organic bases that have a pKa lower than 10 (pKa of triethylamine ca. 10.7) or in the presence of an inorganic base such as an alkaline or alkaline earth metal carbonate or phosphate.

Preferred inorganic bases are for example sodium, potassium, cesium, magnesium or calcium carbonate, or sodium or potassium phosphate. Preferred organic bases are for example N-methylmorpholine, pyridine, lutydin, collidine, picoline. Preferably, amines such as N-methylmorpholine, pyridine and lutidine are used, more preferably pyridine.

The ratio of N-hydroxysuccinimide to acid chloride XV is between 3.0 and 2.0 molar equivalents, preferably between 2.5 and 2.0, more preferably between 2.3 and 2.0.

The molar ratio between the base and the acid chloride XV is generally comprised between 3.0 and 2.0; preferably between 2.5 and 2.0, more preferably between 2.2 and 2.0.

Preferably, the sequence of operations provides that N-hydroxysuccinimide is dissolved in the reaction solvent, the base and then a solution of the acid chloride XV are added.

The base is added to a solution of N-hydroxysuccinimide in an aprotic solvent such as dichloromethane, toluene, tetrahydrofuran, acetonitrile or dioxane. Preferably the base is added to a solution of N-hydroxysuccinimide in dichloromethane.

The mixture of the base and N-hydroxysuccinimide is maintained at a temperature between 0 and 25 ° C, preferably between 0 and 10 ° C, more preferably between 0 and 5 ° C.

The concentration of N-hydroxysuccinimide in the reaction solvent is preferably between 0.3 g / mL and 0.1 g / mL.

The XV acid chloride obtained in Step a) is dissolved in the reaction solvent at a concentration between 1.0 g / mL and 0.1 g / mL, preferably between 0.8 g / mL and 0.3 g / mL.

The resulting solution of the acid chloride XV is transferred into the N-hydroxysuccinimide solution while maintaining the reaction temperature preferably between 0 and 25 ° C, more preferably between 0 and 10 ° C, even more preferably between 0 and 5 ° C.

Diester XVI can be isolated by crystallization from organic solvent in a particularly high enantiomeric purity, equal to that of the starting benzylsuccinic acid, not obtainable with the methods described above. The compound of formula XVI in enantiomerically pure form constitutes a further object of the invention.

Step c): regioselective reaction of diester XVI with cis-hexahydroisoindoline to give monoester monoester XVII

The preparation of the monoester monoamide XVII is preferably carried out by reaction of the diester XVI with cis-hexahydroisoindoline or one of its salt in an aprotic solvent at a controlled temperature. If a cis-hexahydroisoindoline salt is used, a suitable acid acceptor is used, which can be an inorganic base, such as an alkaline or alkaline earth metal carbonate, bicarbonate, hydroxide or phosphate, or an aliphatic or aromatic tertiary amine.

Preferably dichloromethane, toluene, THF, acetonitrile or dioxane is used as the reaction solvent, optionally mixed with water.

The molar ratio between cis-hexahydroisoindoline and diester XVI is comprised between 1.5 and 1.0, preferably between 1.2 and 1.0.

If a cis-hexahydroisoindoline salt is used and therefore a suitable acid acceptor, the molar ratio between the base and the diester XVI is comprised between 3.0 and 1.0, preferably between 2.5 and 1.0.

The reaction is carried out at a temperature generally comprised between -10 and 25 ° C, preferably between -5 ° C and 10 ° C, more preferably between -5 ° C and 5 ° C.

The regioselectivity of the reaction can be obtained in a surprisingly high way by operating at a temperature between -5 ° C and 5 ° C.

Operating under these conditions, the formation of the XX regioisomer can be contained within 0.2%. Any traces of XX are then eliminated with the crystallization of XVII.

Step d): hydrolysis of the ester group of XVII to give mitiglinide The hydrolysis of the ester group of XVII is preferably carried out in water or in a mixture of water and protic solvent, such as methanol, ethanol, 1-propanol, 2-propanol.

An alkaline hydroxide or carbonate, preferably sodium hydroxide, is preferably used as the base.

The base is used in a molar ratio with the monoester monoester XVII comprised between 3.0 and 1.0, preferably between 3.0 and 2.0.

The reaction is carried out at a temperature between 20 ° C and the boiling temperature of the solvent, preferably 20 ° C and 40 ° C.

Mitiglinide is generally obtained as an oil by concentration of a solution in an organic solvent, and used as it is in the following step.

Step e !: salification of mitiglinide to the corresponding dihydrate calcium salt

The preparation of the calcium salt of Mitiglinide is carried out starting from Mitiglinide in the form of acid in water or its mixture with an organic solvent in the presence of a base for treatment with an aqueous solution of calcium chloride. The organic solvent can be methanol, ethanol, 1-propanol, 2-propanol, acetone, dioxane, THF, acetonitrile, DMF.

The base used can be an inorganic base such as an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or ammonia, preferably sodium hydroxide or ammonia.

The process is now further illustrated by the following examples.

EXAMPLE 1

(S) -2-Benzyl-butanedioyl dichloride (XV)

(S) -2-benzylsuccinic acid (100 g; R enantiomer content <0.2%) is added to a solution of thionyl chloride (500 mL) and DMF (6 mL). The mixture is heated to the reflux temperature of the solvent and kept under stirring for about 4h. Then the solvent is evaporated under reduced pressure isolating the acid chloride as a reddish oil.

EXAMPLE 2

Bis- (2,5-dioxo-pyrrolidin-1-yl) ester of (S) -2-benzyl-succinic acid, (XVI)

To a mixture in which N-hydroxysuccinimide (122 g) and pyridine (59 mL) are suspended in dichloromethane (500 mL), cooled to a temperature between 0 and 5 ° C, acid chloride XV, obtained in example 1, dissolved in dichloromethane (250 mL). Once the addition is complete, the mixture is washed with 1N HCl, then with saturated aqueous solutions of NaHC03 and NaCl. The solvent is evaporated under reduced pressure to give a residue which is recrystallized from ethyl acetate to obtain the diester as a white solid (170.6 g, yield 88.1%).

For analytical purposes, an aliquot of diester XVI is hydrolyzed with soda and the (S) -2-benzylsuccinic acid obtained analyzed by chiral chromatography (Column Chiralpak AD): enantiomer content R <0.2%).

EXAMPLE 3

Bis- (2,5-dioxo-pyrrolidin-1-yl) ester of (S) -2-benzyl-succinic acid, (XVI)

The acid chloride XV is slowly added to a mixture of N-hydroxysuccinimide (5.80 g) and N-methylmorpholine (5.5 mL) in dichloromethane (60 mL), cooled to a temperature between 0 and 5 ° C, obtained as described in example 1, dissolved in dichloromethane (20 mL). Once the addition is complete, the mixture is washed in sequence with 1N HCl and saturated aqueous solutions of NaHC03 and NaCl. The solvent is evaporated under reduced pressure to give a residue which is recrystallized from ethyl acetate to obtain the diester as a white solid (6.02 g, yield 62.3%).

For analytical purposes, an aliquot of diester XVI is hydrolyzed with soda and the (S) -2-benzylsuccinic acid obtained analyzed by chiral chromatography (Column Chiralpak AD): enantiomer content R <0.2%).

EXAMPLE 4

Bis- (2,5-dioxo-pyrrolidin-1-yl) ester of (S) -2-benzyl-succinic acid, (XVI)

To a mixture of N-hydroxysuccinimide (6.08 g) and potassium carbonate (7.30 g) in dichloromethane (60 mL), cooled to a temperature between 0 and 5 ° C, the acid chloride XV, obtained as described in example 1, dissolved in dichloromethane (20 mL). Once the addition is complete, the mixture is treated as described in example 3, obtaining the diester as a white solid (4.66 g, yield 48.5%).

EXAMPLE 5

2, 5-Dioxo-pyrrolidin-1-yl ester of (S) -2-benzyl-4- (3aS, 7aR) -octahydroisoindol-2-yl-4-oxo-butyric acid (XVII)

A solution of cis-hexahydroisoindoline (54 g) in dichloromethane (320 mL) is added to a solution of diester XVI (165 g), obtained as described in examples 2-4, in dichloromethane (1000 mL) cooled to a temperature ranging from 0 and 5 ° C. The mixture is brought to room temperature, left to stir for about 12h, then concentrated at reduced pressure. The residue is taken up with ethyl acetate and washed with water, 0.5M NaOH and finally again with water. The solvent is evaporated to give a solid which is recrystallized from ethyl acetate / cyclohexane. The monoester monoamide is obtained as a white solid (152 g, 90% yield) and the regioisomer XX in an amount lower than 0.2% (HPLC).

EXAMPLE 6

Mitiglinide (I)

Monoester monoamide XVII (149 g), obtained as described in example 5, is treated with IN NaOH (approx. 1 L). The mixture is left under stirring for 4h, then ethyl acetate is added to the reaction flask and the two phases separated. The aqueous phase is brought to pH = 2 by adding 1N HCl and the product extracted with ethyl acetate. The solvent is evaporated under reduced pressure to give Mitiglinide as a colorless oil (111 g, yield 97.6%).

The analysis of the enantiomeric purity of mitiglinide (Sumichiral OA 3300) shows an isomer (R) content lower than 0.2%).

EXAMPLE 7

Mitiglinide calcium salt dihydrate (II)

Mitiglinide (120 g) is dissolved in H20 (1000 mL) by adding NH3acq. 30% (96 mL). The mixture is left under stirring for 30 minutes, then an aqueous solution of CaCl2 (59 g) is dropped into the flask. The precipitate formed is collected by filtration and recrystallized with aqueous EtOH to give Mitiglinide calcium salt dihydrate as a white solid (101 g, yield 75.4%, HPLC purity 99.6%).

COMPARATIVE EXAMPLE 1

Bis- (2,5-dioxo-pyrrolidin-1-yl) ester of (S) -2-benzyl-succinic acid, (XVI)

Acid chloride XV (obtained as described in example 1) dissolved in dichloromethane (20 mL). Once the addition is complete, the mixture is washed with 1N HCl, then with saturated solutions of NaHC03 and NaCl. The solvent is evaporated under reduced pressure to give a residue which is recrystallized from ethyl acetate to obtain the diester as an almost white solid (8.90 g, yield 92.1%). The product is treated with 2N NaOH to hydrolyze both its ester functions; the diacid thus obtained is analyzed in HPLC to evaluate the percentage of the R enantiomer. The latter appears to be present in an amount equal to 3.4%.

Claims (5)

CLAIMS 1. A process for preparing mitiglinide which includes: a) Conversion of (S) -2-benzylsuccinic acid into the corresponding acid chloride XV; b) Esterification of XV with N-hydroxysuccinimide to diester XVI; c) Regio-selective reaction of diester XVI with cis-hexahydroisoindoline to give monoamide monoester XVII; d) Hydrolysis of the ester group of XVII to give mitiglinide (I) and, optionally e) Salification of mitiglinide to the corresponding dihydrate calcium salt (Π). 2. A process according to claim 1 wherein step b) is carried out in the presence of organic bases having a pKa lower than 10 or of an inorganic base. 3. A process according to claim 2 in which the bases are selected from alkali or alkaline earth metal carbonates or phosphates, N-methylmorpholine, pyridine, lutidine, collidine, picoline. 4. A process according to one or more of claims 1 to 3 wherein step c) is carried out at a temperature ranging from -5 ° C to 5 ° C. 5. Compound of formula XVI with enantiomeric purity equal to that of the starting benzylsuccinic acid.