WO2008035358A2 - Process for preparing dapoxetine - Google Patents
Process for preparing dapoxetine Download PDFInfo
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- WO2008035358A2 WO2008035358A2 PCT/IN2007/000225 IN2007000225W WO2008035358A2 WO 2008035358 A2 WO2008035358 A2 WO 2008035358A2 IN 2007000225 W IN2007000225 W IN 2007000225W WO 2008035358 A2 WO2008035358 A2 WO 2008035358A2
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- dapoxetine
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- ITJNARMNRKSWTA-UHFFFAOYSA-N CNCCC(c1ccccc1)Oc(cccc1)c1OC Chemical compound CNCCC(c1ccccc1)Oc(cccc1)c1OC ITJNARMNRKSWTA-UHFFFAOYSA-N 0.000 description 1
- HNYYXWMFLVMBCN-KRWDZBQOSA-N CNCC[C@@H](c1ccc[s]1)Oc1cc2ccccc2cc1 Chemical compound CNCC[C@@H](c1ccc[s]1)Oc1cc2ccccc2cc1 HNYYXWMFLVMBCN-KRWDZBQOSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- 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
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- 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
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- 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
Abstract
This invention relates to a new process for preparation of enantiomerically pure dapoxetine or an acid addition salt thereof i.e. S(+)-N,N-dimethyl-2-[2-(naphthalenyl oxy)ethyl]benzenemethanamine hydrochoride, a potent serotonin re-uptake inhibitor (SSRI), which comprises resolving racemic (±)-dapoxetine i.e. (±)- N,N-dimethyl-2-[2- (naphthalenyloxy)ethyl] benzene methanamine with a chiral acid so as to obtain salt of the chiral acid and (+)-dapoxetine, substantially free from (-)-dapoxetine.
Description
PROCESS FOR PREPARING DAPOXETINE Field of Invention
The present invention is concerned with a process for preparing dapoxetine, in particular a process for preparing (+)-dapoxetine in enantiomerically pure. The present invention further provides a process for preparing (+)-dapoxetine substantially free from (-) dapoxetine from racemic dapoxetine of formula (II). (+)-dapoxetine hydrochloride chemically known as S(+)-N,N-dimethyl-2-[2-
(naphthalenyloxy)ethyl]benzene- methanamine hydrochloride and represented by following formula (I), is useful as serotonin reuptake inhibitors (SSRIs).
Formula (II) Formula (I)
Background of the invention
Premature ejaculation is the most common form of ejaculatory dysfunction, affecting upto 39% of the general male population. Behavior therapy is an effective treatment in the majority of cases. However, pharmacotherapy is required in those cases of lifelong premature ejaculation. Tricyclic antidepressants and clomipramine are the most extensively studied agents for this indication, in addition to α-adrenoceptor antagonists, benzodiazepines and gabapentin. The most advanced agent under clinical development for premature ejaculation is the potent selective serotonin reuptake inhibitors (SSRIs). Dapoxetine, a compound structurally related to the antidepressant floxetine (Prozac) is enantiomerically pure and one of the important drug as an serotonin reuptake inhibitor.
Flouxetine (III), Tomoxetine (IV), Nisoxetine (V) and Duloxetine (VI) belong to the group of non-tricyclic antidepressants, which act by inhibiting the uptake of norepinephrine and serotonine (B. B. Molly et. al, USP 4018895, 19 April, 1977). A
Chemoenzymatic synthesis of Duloxetine (VI) has been reported (H. L. Liu et. ah, Chirality, 12, 26, 2000). Flouxetine hydrochloride is sold as the racemate (Prozac, Eli Lilly Co.), but recently interest has been shown for marketing the more active (R)- enantiomer as a so-called "Improved Chemical Entity" version of the drug. Tomoxetine (IV) was the first norepinephrine reuptake inhibiting antidepressant to be reported, and the (R)-enantiomer is nine times more potent than the (5)-enantiomer (A. Kumar et. ah, Tetrahedron Lett., 32, 1901, 1991). This drugs are the derivatives of 3-methylamino-l- phneylpropan-1-ol which contians a stereocenter, and retrosynthetic analysis reveals that enantiopure (i?)-3-chloro-l-phenylpropan-l-ol should be a suitable chiral building block.
Fluoxetine (III) Tomoxetine (IV)
Nisoxetine (V) Duloxetine (VI)
Technical reports vol. 6 (14) of Albany Molecular Research Inc. discloses development of novel SN AΓ reactions for new routes to Atomoxetine or Tomoxetine
(IV) and its derivatives. A series of 3-aryloxy-3-arylpropylamines have been developed in recent years as drug candidates. {Life Sciences, 1988, 43, 2049). Interestingly it is the substitution of the aiyl rings on this pharmacophore that determine different activity in diverse receptor in vivo. (i?)-Atomoxetine can be prepared by one of the proposed route in which the enantiopure benzylic alcohol moiety of (RJ-Atomoxetine was activated and displaced by a phenol to generate an ether with an inverted stereochemistry.
During the past decade, the relationship between monoamine uptake and a variety of diseases and conditions has been appreciated and investigated. For example, the hydrochloride salt of Fluoxetine (dl-N-methyl-3-phenyl-3-[4- (triflouromethyl)phenoxy]propanamine) is a selective serotonin (5-hydroxytryptamine) uptake inhibitor which has been approved by the Food and Drug Administration (FDA) for the treatment of depression and is also presently undergoing clinical evaluation for the treatment of eating disorders, alcoholism, and other disorders. Similarly, Tomoxetine hydrochloride (-)-N-methyl-3-phenyl-3-(2-methyl-phenoxy)hydrochloride) is a selective inhibitor of norepinephrine uptake that is being investigated clinically for its antidepressant activity.
These compounds are among taught in U.S. Pat. Nos. 4018895, 4194009, 4314081 as being potent blockers of the uptake of various physiologically active monoamines including serotonin, norepinephrine and dopamine. U.S Pat. No. 4207343 discloses l-phenyl-3 (substituted phenoxy)propanamines as having the ability to block the uptake of a variety of monoamines.
EP 0288188 Bl also discloses the use of dibenzoyl-d-and-1-tartaric acid to obtain enantiomerically pure S-(+)- N,N-Dimethyl-l-phenyl-3-(l-napthalenyloxy)- propanamine i.e. Dapoxetine and its hydrochloride salt thereafter by treatment with inorganic acid hydrochloric acid.
The Patent US 5023269 and US 4956388 mentions about 3-aryl oxy-3- substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine, and methods of preparing them. Furthermore, U.S. Pat. No. 5135947 discloses l-phenyl-3- napthalenyloxypropanamines and their use as selective serotonin receptive inhibitors. It further discloses to convert free amines to their corresponding pharmaceutically acceptable acid addition salts by treating with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as
para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acid.
There is, therefore, a need for an improved process for the preparation of (+)- dapoxetine which alleviates the problems associated with prior art processes as referred above. We have developed such a process, which is advantageous to yield an enantiomerically pure form of (+)-dapoxetine. In Particular, our process can be seen to achieve the above described advantage, by carrying out resolution as a final step in the reaction process (thereby obviating the opportunity for racemization during preceding intermediate process steps) and or avoiding conditions that would result in the production of intermediates products that would be prone to racemization. Summary of the invention
According to the present invention, therefore, there is provided a process for preparing (+)-dapoxetine, or an acid addition salt thereof, which process comprises: (i) resolving racemic (±)-dapoxetine with a chiral acid so as to obtain a salt of the chiral acid and (+)-dapoxetine, substantially free from (-)-dapoxetine.
(ii) converting (+)-dapoxetine prepared in step (i) to the free base or another acid addition salt thereof.
The resolution step (i) is achieved with a suitable chiral acid in a suitable solvent. The chiral acid can typically be selected from the group consisting of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid and the like. Other suitable chiral acids may be determined by testing and the use thereof in a process as described above falls within the scope of the present invention. Preferably the chiral acid employed in a process according to the present invention is (+)-di-p-toluyl tartaric acid. Suitably, the solvent employed is a aliphatic halogenated lower alkanes, cyclic or acyclic alkanes, lower alcohols, ketones etc, although again the other suitable solvents can be determined by testing and the use thereof in a process as described above falls within the scope of the present invention. A preferred solvent is methylene dichloride. The salts of (+)-dapoxetine prepared by resolution step (i) represents further aspects of the present invention, therefore a salt of a chiral acid and (+)-dapoxetine, substantially free of (-) dapoxetine. Such salts of chiral acid and (+)-dapoxetine, substantially free of (-)-dapoxetine, are useful as intermediates for preparing the free base or another acid addition salt as appropriate.
Suitable salts provided by the present invention include (+)-dapoxetine mandelate, (+)-dapoxetine tartarate, (+)-dapoxetine di-p-toluyl tartarate, (+)-dibenzoyl tartarate, (+)-dapoxetine camphor sulfonate and the like. A preferred salt according to the present invention is (+)-dapoxetine di-p-toluyl tartarate, which is useful as an intermediate for preparing the free base or another acid addition salt as appropriate.
Intermediate salts prepared according to the present invention as described above can be converted to the free base or another acid addition salt according to the step (ii) of a process according to the present invention. Suitably, an intermediate salt of the chiral acid and (+)-dapoxetine can be treated with a base, such as sodium hydroxide, to yield the free base. The free base itself can, if desired, be converted into an acid addition salt thereof.
Suitable acid addition salts which may be formed in step (ii) include those formed with pharmaceutically acceptable organic or inorganic acids and are well known to those of skill in the art. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, methanesulfonic, oxalic, para-bromophenyl sulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dionate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxynenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycollate, maleate, tartarate, methanesulfonate, propanesulfonantes, napthalene-1 -sulfonate, naphthanlene-2- sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as oxalic acid and maleic acid. A pharmaceutically preferred acid addition salt is the hydrochloride. Detailed description of the Invention
The first embodiment of the present invention it to provide a process for preparing dapoxetine, in particular a process for preparing (+)-dapoxetine in
enantiomerically pure form from the racemate of dapoxetine of formula (II) by its resolution with chiral acid to provide S(+)-N,N-dimethyl-2-[2-(naphthalehyl oxy)ethyl]benzenemethanamine chiral acid salt followed by treatment with suitable reagent to obtain S(+)-dapoxetine acid addition salt i.e. S(+)-N,N-dimethyl-2-[2- (naphthalenyloxy)ethyl]benzenemethanamine acid addition salt of formula (I).
According to the present invention, therefore, there is provided a process for preparing (+)-dapoxetine, or an acid addition salt thereof, which process comprises: (i) resolving racemic (±)-dapoxetine with (+)-di-p-toluyl tartaric acid so as to obtain (+)-dapoxetine-di-p-toluyl tartarate salt, substantially free from (-)- dapoxetine; and
(ii) converting (+)-dapoxetine di-p-toluyl tartarate salt prepared in step (i) to enantiomerically pure (+)-dapoxetine hydrochloride free foπn its (-)-isomer.
The present invention provides the process for obtaining dapoxetine hydrochloride, enantiomerically free from R-enantiomer, which is the resolution product of Dapoxetine racemate by (+)-Ditolyl tartaric acid. The product obtained by this process gives enantiomerically pure S (+)-dapoxetine hydrochloride and in good yield.
The present invention provides the process for the preparation of (+)-dapoxetine hydrochloride from the racemate depoxetine, which comprises resolving racemic (±)- dapoxetine i.e. (±)- N,N-dimethyl-2-[2-(naphthalenyl oxy)ethyl] benzene methanamine with a chiral acid so as to obtain salt of the chiral acid and (+)-dapoxetine, substantially free from (-)-dapoxetine.
One of the aspect of present .invention relates to the process for the preparation of racemic Dapoxetine of formula (II), which comprises:
(i) reacting benzene with chloropropionyl chloride under Fredle-Crafts conditions in presence Of AlCl3 in a suitable organic solvent to prepare compound (a)
(iii) condensation of compound (b) with α-naphthol in suitable organic solvent to give compound (c)
(iv) reaction of compound (c) with methane sulphonyl chloride in presence of catalyst in basic medium in suitable organic solvent followed by treatment with dimethyl amine gas to produce compound of formula (II) i.e. racemate of Dapoxetine base.
The present invention further provides a process for preparing Dapoxetine hydrochloride comprises steps: a) treating racemic dapoxetine of formula (II) with (+) di-p-toluyl tartaric acid to form compound (e).
H3Cx ^CH3
c) compound (f) is dissolved in organic acid and treatment with hydrochloric acid or organic solvent and hydrochloric acid to form dapoxetine hydrochloride.
The process for the preparation of Dapoxetine of formula (II) is depicted in below mentioned Scheme- 1.
Further aspect of present invention is resolving racemic (±)-dapoxetine by using the chiral acid from the group consisting of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid and the like, in an organic solvent from Ci to C6 linear, branched or cyclic ketone, alcohols, ethers and halogenated or non-halogenated aliphatic or aromatic solvents to obtain to obtain salt of the chiral acid and (+)-dapoxetine.
The preferred chiral acid is (+)di-p-tolyl-tartaric acid salt of (+)-dapoxetine preferably the solvent used is dichloromethane. This (+)-di-p-tolyl-tartaric acid salt of (+)-dapoxetine is converted into (+)-dapoxetine by reacting with suitable alkali preferably with sodium hydroxide. The (+)-dapoxetine is reacted with dry HCl gas in an organic medium. The (+)-dapoxetine hydrochloride (crude) formed is then purified from suitable organic solvent to obtain enantiomerically pure (+)-dapoxetine hydrochloride preferably in isopropyl alcohol.
A process according to the present invention preferably yields (+)-dapoxetine in substantially pure enantiomeric form. Thus the ratio of (+)dapoxetine : (-)dapoxetine as prepared by the present invention may be at least about 99:1, such as at least about 99.8:0.2, or more preferably at least about 99.9 : 0.1. Preferably (+)-dapoxetine prepared by a process according to the present invention has an enantiomeric purity of at least about 99.7%, or more particularly at least about 99.9%.
The scope of present invention is not limited by the description, examples and suggested uses described herein, and modifications can made without departing from the spirit of invention. Exaniple-1:
Preparation of 3-Chloro-l-phenyl-propan-l-one:
In an inert N2 environment, 4.3 L of methylene dichloride is taken into 20 L round bottom flask. 1.160 kg Of AlCl3 was added into the reaction flask at 25° to 350C. The reaction mixture was cooled to O0C to 50C. 1 kg of 3-chloropropionyl chloride is added into the reaction mixture at O0C to 1O0C during 1-2 hours followed by stirring for 30 minutes at the same temperature. 0.7 kg of benzene and 0.7 L of methylene dichloride mixture is added during 1-2 hours at O0C to 1O0C. The reaction mass is stirred for 1 hour at same temperature. The temperature is raised to 1O0C to 200C and is allowed to stir for 2 hours at the same temperature. The reaction mixture is added into the mixture of 6.0 kg of ice and 0.75 L of Cone. HCl at O0C to 50C and stirred for 30 minutes at 50C to 1O0C. The organic layer of methylene dichloride is separated at 250C to 350C. The aqueous layer is extracted with 1 L if methylene dichloride at 250C to 350C and the methylene dichloride layer is separated at the same temperature. The combined organic layer is washed with water followed by separation of methylene dichloride layer at 250C to 350C. The separated organic layer is washed 10% NaHCO3 solution. After the separation of layers the emulsion part is passed through hyflosupercel bed followed by washing with methylene dichloride. The filtrate consisting of methylene dichloride is washed with water followed by removal of methylene dichloride by distillation and vacuum. The product thus obtained is treated with hexane. The solvent hexane is then distilled off under vacuum to give compound (a). Purification:
The solution of 1.1 kg of compound (a) of example- 1 in 5 L of hexane is taken in round bottom flask at 250C to 350C. The reaction mass is heated to 400C to 5O0C and
stirred for 1-1.5 hour at 4O0C to 5O0C. The reaction mass is allowed to cool naturally to room temperature with stirring. The reaction mass is cooled at 00C to 50C followed by stirring at 1.5 hours at O0C to 50C. The product thus obtained is filtered and washed with ice chilled hexane. The product is dried under nitrogen environment. ExampIe-2:
Preparation of 3-Chloro-l-phenyl-propan-l-ol:
1 kg of pure compound (a) and 5 L of methylene dichloride is taken into the round bottom flask. The reaction mixture is stirred for 15 minutes at 250C to 350C and cooled to O0C to 50C. An ethanolic solution of NaBH4 (14Og of NaBH4 in 2.5 L of ethanol) is added into the reaction mixture at 00C to 50C over a period of 1-1.5 hours. The temperature of the reaction is raised to 1O0C to 2O0C and stirred for 3 hours at the same temperature. Dilute acetic acid (250 mL in 1750 niL of water) is added slowly into the reaction mixture with stirring at the same temperature to ensure the pH of 4.5 in 1 hour and the reaction mixture is stirred for further 30 minutes at 25°C to 350C. The methylene dichloride layer is separated. The aqueous layer is extracted with methylene dichloride. The separated organic layer is combined and washed with 5% NaHCO3 solution (pH - 8) at 250C to 350C. The layers are again separated and methylene dichloride layer is washed with water followed by further separation. The excess of solvent is removed by distillation and by applying vacuum to get compound (b). ExampIe-3:
Preparation of 3-(NaphthaIen-l-yloxy)-l-phenyl-propan-l-ol:
The reaction mixture of 730 g of α-Napthaol, 930 g of K2CO3, 1000 g of compound (b) in 5 L of DMSO is taken in round bottom flask at 250C to 350C with stirring. The temperature of the reaction mixture is raised to 850C to 9O0C. The reaction mass is stirred for 7 hours at the same temperature. Check TLC. After TLC compilation cool the reaction mass naturally to 250C to 35°C. The reaction mixture is poured in 15 kg of crushed ice with stirring. The reaction mass is extracted with toluene at same temperature. The combined toluene layers is washed with 5% NaOH solution at 250C to 350C. The emulsion formed after separation is passed through hyflosupercel. The hyflosupercel bed is washed with toluene. Further all the toluene layer is combined and washed with water. The layers are separated and toluene layer is distilled off under vacuum to get compound (c)
Purification:
The crude compound (c) 1.45 kg, 8.7 L n-hexane and 750 niL of di-isopropyl ether is taken into the round bottom flask at 250C to 350C. The reaction mass is stirred for 2 hours at the same temperature. The reaction mass is cooled to O0C to 50C. The reaction mass is stirred for 3 hours at same temperature and filter at same temperature. The product is washed with chilled with n-hexane and the product is air dried to get pure compound (c). Example-4: Preparation of Dimethyl] [3-(nahthalen-l-yloxy)-l-phenyl-propyl-amine: The mixture of 1 Kg of compound (c), 0.728 Kg of triethyl amine and 0.045 g of dimethyl amino pyridine is taken in 7.2 L of tetrahydrofuran in a round bottom flask under stirring under nitrogen atmosphere at 250C to 350C. The solution of 0.61 Kg of methane sulphonyl chloride in 1.9 L of tetrahydrofuran is added over a period of 1-1.5 hours at -50C to O0C. The yellow solid separates as soon as addition is over at the same temperature. The reaction mixture is maintained for 6.0 hours at O0C to 50C. After TLC compiles dimethylamine gas is passed at O0C to 1O0C [5.0 L of dimethyl amine on 3.5 Kg of KOH] and the reaction mixture is stirred for 40 hours at 250C to 350C. The reaction mixture is poured into 10 L of ice water after the compilation through TLC at 50C to 1O0C. Adjust the pH to acidic 0.5-1.0 by Cone. HCl at 50C to 100C. 5.0 L of Toluene is added into the reaction mixture at 2O0C to 250C. The reaction mass is stirred for 30 minutes and is allowed to settle for 30 minutes at 250C to 35°C.The layers are separated and the TLC of aqueous layer is checked. 5% NaOH solution (1.5 Kg of NaOH in 30 L water) is added to adjust the pH between 8-9 at 25°C to 350C. The product is extracted with methylene dichloride and the solvent methylene dichloride is distilled under vacuum to get residue. 2.5 L of ethyl acetate is added into the residue and the mixture is stirred for 30 minutes at 25°C to 350C. The solid product thus obtained is filtered through hyflo bed and wash with ethyl acetate. The solid material is discarded and the filtrate is subjected to distillation to separate methylene dichloride under vacuum to get compound of Formula(II) i.e. Dapoxetine Base. Example-5:
Preparation of Dimethyl] [3-(nahthalen-l-yloxy)-l-phenyl-propyl-amine p-ditoluyl tartarate salt:
The solution of 250 g of Dapoxetine Base is prepared in a 250 mL of methylene dichloride and was allowed to stirred for 15 to 20 minutes at 25° to 350C. 316.6 g of p- ditoluyl D-(+)-tartaric acid (DTTA) is added into the reaction mixture at 25° to 350C. 175 mL of methylene dichloride is further added into the reaction mixture at 25° to 350C and was allowed to stir for 30 minutes at same temperature. The solid product precipitates out. Further 825 mL of methylene dichloride is added into the reaction mixture at 25° to 350C. The reaction mixture is filtered and the bed is washed with 2 x 250 mL of methylene dichloride. The material is dried in oven at 50° to 55°C to obtain the desired product i.e. (H-)-Dapoxetine p-ditolyl tartaric acid salt [Compound (e)]. Purification:
The solution of 190 g of (+)-Dapoxetine p-ditolyl tartaric acid salt is prepared in 1560 mL of methylene dichloride at 25° to 35°C. The reaction mixture is heated to reflux temperature for 1 hour at 38° to 4O0C. The reaction mixture is cooled to 250C to 3O0C. The reaction mixture is further stirred at 1O0C to 15°C for 1 hour and is filtered at same temperature, washed with 2 x 195 mL of methylene dichloride. Final Purification:
The solution of 165 g of (+)-Dapoxetine p-ditolyl tartaric acid salt is prepared in 330 mL of methylene dichloride at 25° to 350C. The reaction mixture is heated to reflux temperature for 30 minutes at 35° to 4O0C. 495 mL of ethyl acetate is added into the reaction mixture at the same temperature within 1-1.5 hours. After the addition is over the reaction mixture is cooled to 25°C to 3O0C and stirred for 1 hour. The reaction mixture is further cooled at 1O0C to 150C and stirred for 1 hour and is filtered at same temperature, washed with 2 x 82.5 mL of methylene dichloride:Ethyl acetate (2:3) to obtain pure (+)-Dapoxetine p-ditolyl tartaric acid salt. Example-6:
Preparation of (+)-Dapoxetine Base:
The solution of 156.8 g of (+)-Dapoxetine p-ditolyl tartaric acid salt is prepared in 784 mL of methylene dichloride at 250C to 35°C. 784 mL of water is added at the same temperature and the reaction mixture is stirred for 15 minutes at 250C to 350C. The solution of 10% NaOH is prepared by adding 27.2 g of NaOH in 272 mL of water at 250C to 350C, Add 10% NaOH solution in the reaction mixture at same temperature within 1 hour. The reaction mixture is stirred for 1 hour at same temperature and is allowed to settle for 30 minutes. The organic layer and aqueous layers are separated at 250C to 35°C. The aqueous layer and 784 mL of methylene dichloride is taken in the
reaction vessel and stirred for 30 minutes. The reaction mixture is allowed to settle for 30 minutes. Both the methylene dichloride layers are combined. The organic layer of methylene dichloride and 784 mL of water are stirred for 30 minutes and allowed to settle. The layers are further separated. The methylene dichloride layer is passed through hyflosupercel bed and washed with 2 x 78 mL of methylene dichloride. The organic layer is distilled out under vacuum below 4O0C to obtain compound (f). Chiral purity = 99.81 (+); 0.19 (-). [α]D 25 [C = 1% methanol] = + 112.9° Example-7 Preparation of (+)-Dapoxetine Hydrochloride:
The solution of 60 g of Dapoxetine base is prepared in 480 mL of ethyl acetate at 25° to 350C and is stirred for 15 minutes. The reaction is filtered through fine filter hyflosupercel bed at 250C t0 35°C and the bed is washed with 2 x 60 mL of ethyl acetate. The reaction mixture is taken into the flask and cooled to 00C to 50C. The HCl gas is purged at O0C to 5°C till the pH is acidic between 1- 2. The solid material is precipitated. The purging is stopped and the reaction mixture was stirred for 1 hour at O0C to' 50C. The product is filtered at 0° to 50C and washed with 2 x 60 mL of ethyl acetate (chilled). Purification: The solution of 125.6 g of (+)-Dapoxetine Hydrochloride is prepared in 377 mL of fine filtered isopropyl alcohol at 250C to 35°C. The reaction mixture is heated at reflux temperature to obtain the clear solution. The reaction mixture is maintained at reflux temperature for 15 minutes. The reaction mixture is cooled down to 25°C to 350C within 1 hour. The product starts precipitating at 450C to 55°C. The reaction mixture is stirred at 250C to 350C for 1 hour. The reaction mass is further cooled to 1O0C to 150C and was allowed to stirred at 1O0C to 150C. The reaction mixture is washed with fine filtered isopropyl alcohol (2 x 62.5 mL) and the product is dried at 5O0C to 550C. Chiral purity = (-) Dapoxetine : Below Detection Limit MD25 [C = 1% methanol] = + 131.7° M.P. : 18O0C-1840C.
Claims
1. A process for preparing (+)-dapoxetine, or an acid addition salt thereof, which process comprises: (i) resolving racemic (±)-dapoxetine with a chiral acid so as to obtain a salt of the chiral acid and (+)-dapoxetine, substantially free from (-)-dapoxetine. (ii) converting (+)-dapoxetine prepared in step (i) to the free base or another acid addition salt thereof.
2. A process for preparing Dapoxetine of formula (II), which comprises: (i) reacting benzene with chloropropionyl chloride under Fredle-Crafts conditions in presence OfAlCl3 in a suitable organic solvent to prepare compound (a)
(a)
(ii) reduction of compound (a) with suitable reducing agent to give compound (b)
(b) (iii) condensation of compound (b) with α-naphthol in suitable organic solvent to give compound (c)
(iv) reaction of compound (c) with methane sulphonyl chloride in presence of catalyst in basic medium in suitable organic solvent followed by treatment with dimethyl amine gas to produce compound of formula (II) i.e. racemate of
Dapoxetine.
3. A process for preparing Dapoxetine hydrochloride comprises steps: a) treating racemic dapoxetine of formula (II) with (+) di-p-toluyl tartaric acid to foπn compound (e). b) treating compound (e) with base with suitable organic compound to form compound (f). c) compound (f) is dissolved in organic acid and treatment with hydrochloric acid or organic solvent and hydrochloric acid to form dapoxetine hydrochloride.
4. A process as claimed in any preceding claim, wherein said chiral acid is selected from selected from the group consisting of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid and the like.
5. A process as claimed in claim 4, wherein said chiral acid is dibenzoyl tartaric acid.
6. A process as claimed in claim 3, wherein solvent used in step (i) is selected from halogenated solvent like methylene dichloride.
7. A process as claimed in claim 3, wherein reduction in step (ii) is carried out by using reducing agent like Na BH4.
8. A process as claimed in claim 3, wherein base in step (iv) is selected from K2CO3, Na2CO3.
9. A highly pure (+)-Dapoxetine Base having purity greater than or equal to 99.95% and chiral impurity less than 0.5%.
10. A highly pure (+) dapoxetine hydrochloride having purity greater than or equal to 99.00%.
11. A highly pure (+)dapoxetine hydrochloride having chiral purity grater than or equal to 99.95%.
12. A process for preparing (+)dapoxetine hydrochloride such as herein described in accordance with the accompanying text, description and examples.
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