Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/16—Preparation of optical isomers
  • C07C231/20—Preparation of optical isomers by separation of optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

• the present invention relates to a novel process for the preparation of (2R)-2- (acetylamino)-N-benzyl-3-methoxypropanamide, an active ingredient used for curing neuropathies, known by the name of Lacosamide and represented by the formula of structure I indicated below
• Lacosamide is an active ingredient used in the pain therapy and for curing various diseases of the nervous system among which epilepsy. Though the action mechanism is not completely clear, it seems that it operates on the sodium channels of the neurons reducing their activity. Furthermore, Lacosamide is thought to be involved in the restoration of the damaged neurons.
• a further alternative synthesis method is that indicated in the patent application EP 2067765 where, before the methylation of hydroxyl, the amino group is protected with a hindered group such as the trityl.
• the present invention relates to a novel synthesis of Lacosamide which uses D,L- serine as starting material, where the methylation reaction of hydroxyl is carried out using an inexpensive base such as NaOH and an inexpensive alkylating agent, non-toxic and non-carcinogenic, such as the methyl p-toluenesulfonate; the R enantiomer is isolated from the racemic mixture of Lacosamide after selective hydrolysis of the acetamide, salification of the racemic mixture with a chiral acid (HX*) in an organic solvent, resolution of the diastereoisomeric mixture, preferably by precipitation of the R enantiomer, and subsequent acetylation of the optically pure intermediate.
• an inexpensive base such as NaOH
• an inexpensive alkylating agent non-toxic and non-carcinogenic, such as the methyl p-toluenesulfonate
• the R enantiomer is isolated from the racemic mixture of Lacosamide after selective hydrolysis of the
• the present invention relates to a novel synthesis of Lacosamide which uses D,L- serine methyl ester, of formula II, as starting material, preferably in the form of hydrochloride, easily obtainable from D,L-serine by the extensively described methods.
• the product of formula II is converted into the product of formula V by reaction first using benzylamine and subsequently using acetic anhydride (or an acetyl halide, preferably acetyl chloride, or using a mixed anhydride), according to the following scheme.
• the first reaction is preferably carried out directly in benzylamine (from 2 to 10 equivalents), or in an aprotic polar solvent, such as for example THF, at a temperature comprised between 0° C and the reflux temperature, preferably at 30- 40° C;
• the second reaction is carried out by reacting the compound IV with acetic anhydride (or with an acetyl halide, preferably acetyl chloride) in an aprotic polar solvent, such as for example THF, at a temperature preferably comprised between 10 and 40° C, preferably between 15 and 30° C, even more preferably between 20 and 25° C.
• the compound V can be prepared from the D,L-serine methyl ester acetamide of formula III, available in the market, by reaction with benzylamine; also in this case the reaction is preferably carried out directly in benzylamine (from 2 to 10 equivalents), or in a suitable organic solvent, preferably an aprotic polar solvent, such as for example THF, at a temperature comprised between 0°C and the reflux temperature of the solvent, preferably at about 65° C.
• the compound V is converted into the compound VI by methylating the hyd present in the molecule.
• the methylation reaction can be carried out by dissolving the compound V in a suitable organic solvent and placing it at contact with an alkylating agent in the presence of an organic or inorganic base, at a temperature preferably comprised between 20 and 40° C, preferably between 30 and 35° C.
• the solvent is preferably an aprotic polar solvent, such as for example THF.
• the alkylating agent is preferably selected from among methyl iodide, dimethyl sulfate, methyl mesylate and methyl para-toluenesulfonate; it is preferably methyl para-toluenesulfonate.
• the organic base is preferably selected from among tertiary amines NR]R 2 R 3; where R] , R 2 and R 3 the same or different from each other, are linear or branched C]-C 4 alkyl chains; the preferred tertiary amine is triethylamine.
• the inorganic base is preferably a hydroxide of an alkaline-earth or alkaline metal, such as KOH or NaOH.
• the inorganic base can be used in aqueous solution.
• a phase transfer catalyst for accelerating the reaction is preferably a salt of tetrabutylammonium having hydroxide, hydrogen sulfate, chlorine, bromine or iodine as the counterion.
• the compound VI racemic Lacosamide
• the compound VII is converted into the compound VII by hydrolysis in aqueous solution with an inorganic mineral acid, preferably HCl, at a pH preferably comprised between 0 and 2; such hydrolysis reaction is preferably carried out at the reflux temperature.
• the compound VII is then extracted, after the neutralization of the acid, in an organic solvent, preferably in an aprotic apolar solvent, such as for example CH 2 C1 2 , CHC1 3 or C 2 H 4 C1 2 .
• the compound VII is then precipitated as salt VIII with a chiral acid (HX*), preferably D, such as for example dibenzoyl tartaric, tartaric, camphorsulfonic, mandelic, 2-chloromandelic, 3-chloromandelic, 4-chloromandelic acid; for the purposes of the present invention, the acid is preferably 2-chloromandelic, even more preferably 2-(S)-chloromandelic acid.
• the chiral acid is used at an amount preferably comprised between 0.5 and 1.5 equivalents.
• the precipitation is preferably carried out in an aprotic polar organic solvent, such as for example ethyl acetate or isopropyl acetate, even more preferably isopropyl acetate.
• the salt VIII quantitatively precipitates from this solvent as a diastereoisomeric mixture.
• the salt VIII thus obtained is further solubilised in a suitable mixture of solvents capable of allowing selective precipitation of only one enantiomer, preferably the desired enantiomer IX alone.
• a suitable mixture of solvents is constituted by an aprotic organic solvent and a pro tic solvent.
• the aprotic organic solvent is preferably selected from among THF, methyl-THF, ethyl acetate, isopropyl acetate; aprotic polar organic solvents, such as ethyl acetate and isopropyl acetate are however preferred.
• the protic solvent is instead preferably selected from among Ci-C 4 alcohols (for example, methanol, ethanol, isopropanol, n-butanol, i-butanol, s- butanol) and water; preferably, a mixture of ethyl acetate and ethanol is used. According to a further preferred aspect of the invention, 10 to 40 volumes of aprotic organic solvent per volume of protic solvent are used.
• the compound IX is acetylated in the presence of an acylating agent in a suitable organic solvent, preferably apolar aprotic, even more preferably an ether, in the presence of an amount of water comprised between 0 and 50% by weight with respect to the compound IX, preferably between 5 and 20%, to obtain Lacosamide.
• a suitable organic solvent preferably apolar aprotic, even more preferably an ether
• the C 2 -C 8 ethers such as for example the methyl rt-butyl ether, are particularly preferred for the purposes of the present invention;
• the acetic anhydride is the preferred acylating agent (alternatively an acetyl halide, preferably acetyl chloride, can be used);
• the acylation reaction is preferably carried out between 0 and 40° C, preferably between 20 and 25°C.
• HX* has the previously listed meanings and, in the preferred aspect of the invention, it is 2-(S)-chloro-mandelic acid.
• Rischo reflux 63.5 g of compound VI, 850 ml of water and 65 g of 37% HC1 are loaded into a 2 litre reactor provided with a mechanical stirrer, reflux condenser, thermometer and inerted with nitrogen. The mixture is heated to reflux and it is kept under stirring for 6 hours, then it is cooled to 20-25°C. The pH is corrected to 11.5 ⁇ 0.5 with 30% sodium hydroxide. The resulting mixture is extracted 2 times with 300 ml of dichloromethane. The combined organic phases are concentrated to small volume, 300 ml of ethyl acetate and 35 g of 2-(S)-chloromandelic acid are added. Half of the solvent is distilled and it is left under stirring at room temperature up to complete precipitation. The solid is filtered and dried under vacuum at 40°C. 84.3 g of the diastereoisomeric mixture VIII are obtained.

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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Saccharide Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2010
  • 2010-01-29 IT ITMI2010A000127A patent/IT1398044B1/it active
  • 2010-12-22 WO PCT/IB2010/056014 patent/WO2011092559A1/en not_active Ceased
  • 2010-12-22 US US13/575,152 patent/US8796488B2/en not_active Expired - Fee Related
  • 2010-12-22 JP JP2012550525A patent/JP5779592B2/ja not_active Expired - Fee Related
  • 2010-12-22 RU RU2012131215/04A patent/RU2585762C2/ru not_active IP Right Cessation
  • 2010-12-22 EP EP10814670.5A patent/EP2528892B1/en not_active Not-in-force
  • 2010-12-22 ES ES10814670.5T patent/ES2495815T3/es active Active
  • 2010-12-22 KR KR1020127022484A patent/KR101766506B1/ko not_active Expired - Fee Related
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• 2012
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