Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups

Definitions

• the invention concerns a new method for the preparation of (i?)-JV-methyl-3-(2- methylphenoxy)-3-phenylpropylamine hydrochloride of formula (R)-I
• Atomoxetine formerly called tomoxetine, is a therapeutically useful substance with influence on central nervous system.
• the molecule of the substance is chiral; the (i?)-(-)-enantiomer is more effective as an anti-depressant or for treatment of ADHD (EP 0 052 492 Al).
• the necessary steps for preparation of the substance include demethylation, which is well described in literature, e.g. EP 0 052 492 Al.
• resolution of racemic atomoxetine by means of ( ⁇ S)-(+)-mandelic acid is also described, hi US patent 4,777,291, racemization of the (+)-enantiomer of atomoxetine with a strong base, such as for example n-butyllithium, is described.
• organometals e.g.
• n-butyllithium for racemization of the undesirable enantiomer of atomoxetine is not suitable for industrial production because they have usually to be used in an inert atmosphere, and further these strong bases react violently with water or alcohols.
• the atomoxetine molecule contains a relatively acidic hydrogen (NH); for racemization (elimination of the hydrogen on the asymmetric carbon), more than 1 equivalent of the base is necessary.
• the organometallic bases are also disadvantageous due to their relatively high price.
• a leaving group in the sense of nucleophilic substitution is used for preparation of the substance of formula IV or of atomoxetine, it is possible to use a weaker base for formation of the o-cresolate, but the reaction occurs directly on the asymmetric carbon and therefore racemization can again take place.
• a method of preparation of atomoxetine, which is summed up in Scheme 2, according to this invention eliminates the above-mentioned disadvantages.
• the invention is based on the preparation of racemic N-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenyl ⁇ ropylamine of formula VIII as an intermediate for production of atomoxetine.
• the preparation of atomoxetine according to the invention continues with resolution, wherein racemic iV-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenylpropylamine of formula VIII reacts in a solution of an organic solvent with an optically active acid producing a mixture of diastereoisomers, which are subsequently separated via crystallization and converted to respective (R) and (S) enantiomers of N-benzyl-N-methyl-3 -(2-methylphenoxy)-3 -phenylpropylamine by treatment with an organic or inorganic base.
• the (i?)-enantiomer of ⁇ /-benzyl- ⁇ /-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula (R)-VIII is further subjected to debenzylation using an alkyl or aryl chloroformate producing an alkyl/aryl (i?)-3-(2-methylphenoxy)-3-phenylpropylmethyl carbamate of formula (R)-IX, which is then hydrolyzed in a basic environment, yielding the base of (i?)-JV-methyl-3- (2-methyphenoxy)-3-phenlypropane amine, which is finally converted, by means of hydrochloric acid, to (i?)-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine hydrochloride of formula (R)-I.
• the undesirable ( ⁇ S)-enantiomer of N-benzyl-N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine of formula (S)-VIII can be returned to the process of preparation after its racemization using an inorganic or organic base in an organic solvent environment.
• the starting 3-benzylmethylamino-l-phenyl-l-propanone hydrochloride of formula V is preferably prepared by reaction of acetophenone, paraformaldehyde and iV-methylbenzylamine (so-called Mannich reaction) in an appropriate solvent and in the presence of an acid.
• Suitable solvents include C 1 through C 4 alcohols and water or a mixture of these solvents; hydrochloric acid or sulfuric acid turned out to be suitable acids.
• N-Benzyl- ⁇ /-methyl-3-hydroxy-3-phenylpropane amine hydrochloride of formula VI can be prepared from 3 -benzylmethylamino-1 -phenyl- 1-propanone hydrochloride of formula V by conventional reduction with a suitable reduction agent such as for example LiAlH 4 , NaBH 4 or diborane, in a suitable solvent, e.g. tetrahydrofuran, methanol, ethanol, water or a mixture of these solvents. It proved advantageous to use 0.5 to 1 equivalent of sodium tetrahydroborate dissolved in a mixture water/methanol.
• the reaction time at a temperature from 0 to 50 °C is roughly 2 to 24 hours.
• N-Benzyl-iV-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII can be prepared by reaction of the compound of formula VI with 2-fluorotoluene.
• reactivity of 2-fluorotoluene is relatively low for this nucleophilic aromatic substitution; for obtaining at least a satisfactory yield (above 50 %) it is necessary to use long reaction times, high temperatures and/or strong bases for quantitative formation of the anion of the compound of formula VI.
• R a represents a Cl through C5 aliphatic saturated hydrocarbon residue, or a C6 through C12 aromatic or alkylaromatic hydrocarbon residue.
• the compound of formula VII then, by reaction with o-cresol in a suitable solvent such as acetone, acetonitril, dimethylsulfoxide, using a base such as potassium tert-butanolate, potassium carbonate, sodium methanolate, yields N-benzyl-iV-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII in a high total yield (roughly 90 %).
• reaction time at a temperature of 20 through 80 °C is roughly 2 to 24 hours.
• 7V-Benzyl-iV-methyl-3-(2-methylphenoxy)-3- phenylpropane amine of formula VIII was identified by the 1 H ⁇ MR method.
• Racemic N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII is subjected to reaction with an optically active acid selected from the group including tartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid and their sodium, potassium and lithium salts, mandelic acid and camphorsulfonic acid, preferably with mandelic acid, resulting in a mixture of diastereoisomeric salts.
• N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII which has not been described in literature so far, has an advantage compared to JV,iV-dimethyl-3-(2- methylphenoxy)-3-phenylpropane amine in its ability to crystallize with chiral, enantiomer- enriched acids such that a salt is obtained that contains only one enantiomer of JV-benzyl-JV- methyl-3-(2-methylphenoxy)-3-phenylpropane amine, m attempts at crystallization of N 1 N- dimethyl-3-(2-methylphenoxy)-3-phenylpropanamine with chiral, enantiomer-enriched acids only a crystalline salt containing the two enantiomers of iV,7V-dimethyl-3-(2-methylphenoxy)- 3-phenylpropaneamine in the ratio 1:1 was obtained.
• Another aspect of the invention is a reaction of (i?)-N-benzyl-iV-methyl-3-(2-methylphenoxy)- 3-phenylpropylamine of formula (R)-VIII with an alkylchloro formate of formula ClCOOR, wherein R is selected from the group OfC 1 -C 5 alkyls or C 6 -C 12 aryls or alkylaryls, particularly with phenyl, ethyl or methylchloroformate, in a suitable solvent, such as for example toluene, yielding an alkyl/aryl (i?)-3-(2-methylphenoxy)-3-phenylpropylmethyl carbamate of formula (R)-IX.
• alkylchloroformates are known as agents suitable for N- demethylation of iV,N-dimethylalkylamines, e.g. EP 0 052 492 Al. According to this invention, alkylchloroformates have surprisingly turned out to be suitable also for selective removal of the benzyl group during reaction with N-benzyl-iV-methyl-3-(2-methylphenoxy)-3- phenylpropylamine. N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula VIII can be converted to N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine also by other debenzylation methods, e.g.
• alkyl/aryl (i?)-3-(2-memylphenoxy)-3-phenylpropylmethyl carbamate of formula (R)-IX is then first hydrolyzed with an alkali metal (K, Na 5 Li) hydroxide in a solvent environment, preferably DMSO, producing the base of (i?)-N-methyl-3-(2-methylphenoxy)-3- phenylpropanamine, and then converted to (i?)-N-methyl-3-(2-methylphenoxy)-3- phenylpropanamine hydrochloride of formula (R)-I using hydrochloric acid.
• K alkali metal
• Another aspect of the invention is racemization of the undesired (5)-iV-benzyl-N-methyl-3-(2- methylphenoxy)-3-phenylpropylamine of formula (S)-VIII, thanks to which it is possible to obtain significantly higher yield of the process.
• the base of ( ⁇ S)-iV-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenylpropylamine is obtained after separation of the salt of the (R)- enantiomer of 7V-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine with mandelic acid and evaporation of the mother liquors, by means of an aqueous solution of an inorganic or organic base, extraction with an organic solvent and evaporation of the volatile fractions. Subsequently, racemization is performed using an inorganic or organic base, such as for example alkali metal (K, Na, Li) hydroxides or alcoholates (e.g.
• K, Na, Li alkali metal hydroxides or alcoholates
• Racemization takes place also in less polar or low- boiling solvents with addition of a phase transfer catalyst from the group of crown ethers, polyethyleneglycols and quaternary ammonium or phosphonium salts, particularly tetrabutylammoniumbromide or 18-crown-6.
• a phase transfer catalyst from the group of crown ethers, polyethyleneglycols and quaternary ammonium or phosphonium salts, particularly tetrabutylammoniumbromide or 18-crown-6.
• Figure 1 presents an XRPD diffraction pattern of the crystalline form of atomoxetine prepared according to Example 10.
• Figure 2 presents a recording of DSC analysis.
• Aqueous concentrated HCl is added dropwise to a solution of benzylmethylamine (129.1 ml) in 2-propanol (600 ml). Then, paraformaldehyde (39.64 g) and acetophenone (116.7 ml) are added. The mixture is refluxed for 6 hours. After gradual cooling down to 0 0 C, the mixture is stirred for 1 hour. Precipitated crystals are sucked off and washed with 2-propanol. The yield was 261 g (90 %) of substance V.
• the mixture is stirred at 0 up to 10 °C for 4 hours, then under gradual heating up to the room temperature for another 4 hours and further at the room temperature for another 8 hours.
• Methanol is evaporated at reduced pressure; the mixture is mixed with toluene (400 ml) and water (100 ml). The organic phase is separated, shaken up with 100 ml water and evaporated.
• N-Benzyl-N-methyl-3-hydroxy-3-phenylpropaneamine hydrochloride VI (292 g), prepared according to Example 2, is partially dissolved in CHCl 3 (600 ml). SOCl 2 (117 ml) is added dropwise at such a rate that the mixture refluxes. The solution is then refluxed for 3 hours. Subsequently, the mixture is cooled with ice and the first fraction of crystals is sucked off. The mother liquors are evaporated at reduced pressure and the evaporation residue is stirred up with acetone. Crystals are sucked off and washed with acetone. The total yield was 292 g (94 %) of substance of formula VII.
• N-Benzyl-N-methyl-3-chloro-3-phenylpropaneamine hydrochloride VII (310 g), prepared according to Example 3, is mixed in DMSO (800 ml) and o-cresol (103 ml) and K 2 CO 3 (414 g) are added to the resulting mixture. The mixture is stirred vigorously at the room temperature for 24 hours. After the reaction is complete, toluene (400 ml) and then water (1,600 ml) are added to the stirred mixture. The organic layer is separated; the aqueous one is shaken up with toluene (100 ml). The combined organic fractions are shaken up with water (2x 100 ml) and evaporated.
• Example 5 iV-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropaneamine oxalate N-Benzyl-7V-methyl-3-hydroxy-3-phenylpropane amine VI (20 g), prepared according to Example 2, is mixed in DMSO (800 ml) and 2-flurotoluene (12.2 ml) and KOH (19 g) are added to the resulting mixture. The mixture is stirred vigorously at 100 °C for 48 hours. After cooling down to 25 °C, toluene (100 ml) and then water (200 ml) are added to the stirred mixture. The organic layer is separated; the aqueous one is shaken up with toluene (50 ml).
• Example 6 (i?)-N-Benzyl-7V-methyl-3-(2-methyl ⁇ henoxy)-3-phenylpropaneamine-(5)-mandelate N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropaneamine VIII (345 g), prepared according to Example 4, is dissolved in toluene (100 ml) under reflux and a solution of (S)- (+)-mandelic acid (76 g) in toluene (400 ml) is added. The solution is then evaporated. The evaporation residue is dissolved in tBuOMe (1,200 ml) under boiling, inoculated, and stirred at 45 0 C for 20 hours.
• Example 8 iV-Benzyl-N-methyl-3-(o-tolyloxy)-3-phenylpropanamine (VIII) Ground KOH (0.045 g) is added to a solution of ( I S)-N-benzyl-N-methyl-3-(2-methylphenoxy)- 3-phenylpropaneamine (S)-VIII (1.38 g) in DMSO (6 ml) and the mixture is stirred under heating at 100 °C for 1 hour. After cooling down to the room temperature, the mixture is diluted with water (10 ml) and the racemic product is extracted with toluene (10 ml).
• Example 9 iV-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine (VIII) t-BuOK (0.3 g) is added to a solution of (£)-N-benzyl-N-methyl-3-(2-methylphenoxy)-3- phenylpropane amine (S)-VIII (4.14 g) in DMSO (15 ml) and the mixture is stirred under heating at 90 °C for 1.5 hours. After cooling down to the room temperature, the mixture is diluted with water (30 ml) and the racemic product is extracted with toluene (30 ml).
• Phenylchloro formate (6 ml) is added dropwise to the solution at 80 °C over 10 minutes. The solution is then stirred at 80 °C for 30 min. After cooling down to 50 °C, methanol (6 ml) is added dropwise. After cooling down to the room temperature, the solution of alkyl/aryl (R)-3- (2-methylphenoxy)-3-phenylpropylmethyl carbamate (R)-IX is evaporated. Crude alkyl/aryl (R)-3-(2-methylphenoxy)-3-phenylpropylmethyl carbamate (R)-IX is dissolved in DMSO (85 ml) and 5M KOH (50 ml) is added dropwise at 50 °C over 10 minutes.
• the solution is then heated at 100 °C for 30 minutes. After cooling down to the room temperature, toluene (100 ml) and water (100 ml) are added. The organic layer is separated and the aqueous one is shaken up with toluene (50 ml). The combined organic fractions are shaken up with water and evaporated.
• the crude base of the product is dissolved in 5 ml of tert-butylmethylether, atomoxetine seeds are added and aqueous coned. HCl (3 ml) is added dropwise at 0 0 C. Precipitated crystals are sucked off and then re-crystallized from ethylmethylketone.
• the yield was 7.4 g (63 %) of (/?)-(-)-atomoxetine hydrochloride, optical purity 99.8 % ee (CE), chemical purity 99.7 % (HPLC).
• the XRPD diffraction pattern of the crystalline form of atomoxetine hydrochloride is presented in Fig. 1, the recording from DSC analysis is in Fig. 2.
• Table 1 Values of diffraction angles 2 ⁇ , interplanar distances d and relative intensities of characteristic peaks of crystalline form of atomoxetine hydrochloride.

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  • 2005-07-21 CZ CZ20050473A patent/CZ296345B6/cs not_active IP Right Cessation
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