WO2007026373A2

WO2007026373A2 - Process for preparing rivastigmine

Info

Publication number: WO2007026373A2
Application number: PCT/IN2005/000293
Authority: WO
Inventors: Mukarram Siddiqui Mohammed Jaweed; Bhargav Krishnaji Upadhye; Vikas Chandra Rai; Hanfi Zia
Original assignee: Wockhardt Limited
Priority date: 2005-09-01
Filing date: 2005-09-01
Publication date: 2007-03-08
Also published as: WO2007026373A3

Abstract

An improved process for the preparation of Rivastigmine is disclosed.

Description

Process for preparing Rivastigmine

Field of the invention

The present invention relates to an improved process for the preparation of N-ethyl-3-[l- dimethyl amino) ethyl]-N-methylphenyl carbamate (hereinafter referred to as Rivastigmine) of formula (I) or its pharmaceutically acceptable salts, wherein '*' denotes the presence of a chiral centre.

Formula I

This invention also relates to an improved process for the preparation and purification of other compounds that can be used as intermediates in the synthesis of Rivastigmine.

Background of the invention

Rivastigmine is a known selective inhibitor of acetylcholineesterase in brain and is a leading therapeutic agent in the treatment of the Alzheimer's disease. The racemic form of Rivastigmine was first disclosed in US Patent No. 4,948,808 incorporated herein by reference. There is also disclosed a general process for the synthesis of phenylcarbamates of formula (I) by reacting a suitable aminophenol with isocyanate or carbamoyl halogenides. US Patent No. 5,602,176, which is also incorporated herein by reference, claims highly active (ιS)-Rivastigmme and also discloses a process for the manufacture of (5)-Rivastigmine by resolving racemic-Rivastigmine using (+)-di-O,O-p-toluoyl-tartaric acid monohydrate in methanol/water system. This process performs chiral resolution in the last step, and therefore produces almost equal amounts of the undesired (i?)-Rivastigmine, thereby lowering overall process efficiency. PCT patent application No. WO 2004/037771, which is also incorporated herein by reference, discloses an improved manufacturing process for (5)-Rivastigmine, which attempts to obviate the problems inherent in the US Patent No. 5,602,176 by starting with optically pure S-aminophenol. The existing manufacturing processes for the synthesis of Rivastigmine suffer from several drawbacks including difficulties in availability of the starting materials, overall process yield and product purity. Availability of starting materials and especially the suitable aminophenol is a major issue. Two general methods are available in prior art for the synthesis of aminophenol of formula (II), which is an important intermediate during the synthesis of Rivastigmine.

Formula II

According to one of the methods reported by Chen et al. {Tetrahedron Letters, 32., 7175, 1991), the said aminophenol can be prepared by enantioselective reduction of 3- hydroxyacetophenone using diborane in presence of a chiral ligand to obtain, in the first step, a chiral hydroxy compound. The hydroxy group is then converted into dimethylamino group through a sequence of reactions to obtain the desired aminophenol of formula (II). In a second method reported by Jiang et al. (Huadong Shifan Daxue Xuebao Ziran Keyueban, 61, 2001), 3-hydroxyacetophenone is reacted with hydroxylamine and the reaction product is hydrogenated using Raney Nickel. The amino compound thus obtained is then N-methylated using formic acid and formaldehyde to give the desired aminophenol of formula (II).

The above mentioned process for the synthesis of the intermediate aminophenol may not be suitable on a commercial scale owing to the number of steps and the reagents involved. Yet another issue lies in the purity levels of the final carbamate product. The conventional purification methods currently used, yield only moderately pure (purity < 96%) carbamate. In view of this, there is an urgent need to develop an improved process for the manufacture of Rivastigmine and related compounds, which is free of the prevailing difficulties. Applicants of the present invention have successfully investigated the possibility of designing such an improved process, which is described herein. Summary of the invention

Accordingly, the present invention provides an improved process for the preparation of enantiomerically pure Rivastigmine of formula (I)

Formula I

comprising:

(a) contacting 3-hydroxyacetophenone with dimethylamine hydrochloride in presence of a reducing agent to give the aminophenol of formula (II)

Formula II

(b) contacting the aminophenol of formula (II) with carbamoyl halide of formula (III)

Formula (III)

wherein X is Cl, Br or I; in presence of a base to give the carbamate of formula (I)

(c) purifying the product obtained in step (b) by converting it into the oxalate salt, isolating the oxalate salt, and regenerating the pure carbamate of formula (I) by contacting the oxalate salt with a base, and

(d) resolving the racemic carbamate obtained in step (c) with a chiral resoluting agent. In one embodiment of the invention, the said reducing agent in step (a) of the instant process is a metal hydride.

In yet another embodiment of the invention, any of the steps (a) to (c) is conducted in presence of a solvent or a mixture of solvents.

In a further embodiment of the present invention, there is provided a process for the preparation of pharmaceutically acceptable salts of Rivastigmine according to the instant process, further comprising the step of converting the Rivastigmine base into its desired salt.

In yet another embodiment of the invention the provides an improved process for the preparation of (5)-Rivastigmine hydrogen tartarate further comprising the step of contacting (5)-Rivastigmine base with tartaric acid in presence of ethanol.

Further aspects and embodiments of the invention may become apparent to those skilled in the art from a review of the following detailed description, taken in conjunction with the examples and the claims. It must be understood that that the present disclosure is intended as illustrative only, and is not intended to limit the invention to the specific embodiments described herein.

Detailed description of the invention

The present invention relates to an improved process for the manufacture of enantiomerically pure Rivastigmine (N-ethyl-3-[l-dimethylamino)ethyl]-N-methylphenyl carbamate) of formula (I) or its pharmaceutically acceptable salts comprising:

Formula II

Formula (III)

(d) resolving the racemic carbamate obtained in step (c) with a chiral resoluting agent.

According to the present invention, the improved process for the preparation of Rivastigmine comprises in the first step, contacting 3-hydroxyacetophenone with dimethylamine hydrochloride in presence of a reducing agent. The said reducing agent used in step (a) of the instant process is a metal hydride. Typical examples of metal hydride reducing agents without any limitation include sodium borohydride (SBH), sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminium hydride (LAH) and alike. The instant process may be conducted in presence or absence of solvent. If a solvent is used, wide variety of solvents such as alcohols, ketones, ester, ethers, amides and alike or a mixture thereof may be employed. The product aminophenol obtained in step (a) may optionally be isolated, purified further or as it submitted to the next step.

In the next step, aminophenol of formula (II) obtained in the step (a) above is condensed with ethylmethylcarbamoyl halide of formula (III) in presence of a base wherein X is Cl, Br or I to give carbamate of formula (IV). Preferably, the said ethylmethylcarbamoyl halide is ethylmethylcarbamoyl chloride. The instant process of condensation is conducted in presence of a base. A wide variety of bases can be used in the reaction. Typical examples of such bases include without any limitation, metal alkoxide (e.g. sodium ethoxide, sodium methoxide, potassium tert-butoxide and alike); metal hydroxides (e.g sodium hydroxide, potassium hydroxide); organic amines (e.g triethylamine, l,8-diazabicyclo[5.4.0] undec-7-ene (DBU); l,5-diazabicyclo[2.2.0] non-5-ene (DBN); l,4-diazabicyclo[2.2.2] octane (DABCO), tri-tert- butylamine etc.) and alike. The instant process may be conducted in presence or absence of solvent. The solvent is preferably inert during the reaction.

The product carbamate obtained in step (b) is then purified by converting the crude carbamate (II) into its oxalate salt, isolating the oxalate salt and then regenerating the pure carbamate (II) using a base. The conversion of carbamate to its oxalate salt can be effected using several procedures. In one of the preferred method, the carbamate (II) is contacted with the oxalic acid in presence of a solvent, such as acetone to give a crystalline oxalate salt. The isolated oxalate salt is then treated with a base, preferably ammonia, to regenerate the pure carbamate (I). Other than ammonia, several other inorganic or organic bases capable of regenerating pure carbamate from its oxalic acid salt can be employed if desired.

The purified carbamate obtained in step (c) is a racemic mixture of corresponding (R) and (S) isomers and needs to be further resolved. In another embodiment, the resolution of the racemic carbamate obtained in step (iii) into its component (R) and (S) enantiomers is achieved by using a chiral resolving agent. Typically, the racemic mixture is contacted with a chiral resolving agent in presence of a solvent to give a chiral salt. The solvent selected is such that individual salts have different solubilitities in the selected solvent or a solvent mixture. The salts are then separated on the basis of their solubility and then subjected to hydrolysis to regenerate optically pure base. In one of the preferable embodiments of the invention, the racemic (I) carbamate is resolved to get pure (^-Rivastigmine base using di- O,O-/>-toluoyl-Z)-tartaric acid. Typically, the racemic carbamate (I) is treated with di-O,O-p- toluoyl-ZMartaric acid in methanol to crystallize di-/>-toluoyl-Z⁾-tartarate of S-carbamate, which is then separated and treated with aqueous ammonia to give pure S-isomer of the carbamate i.e. (»S)-Rivastigmine.

The pure carbamate such obtained can be further converted into various pharmaceutically acceptable salts using known methods, if desired. In yet another preferred embodiment, the ()S)-Rivastigmine obtained is further converted into its hydrogen tartrate salt by contacting (jS)-Rivastigmme base with tartaric acid in presence of ethanol and then isolating the product. The present invention is described in more details with reference to the following examples that are only illustrative and should not be construed as a limitation on the scope of the invention.

Examples

Example 1: Aminophenol (II)

A mixture of 3-hydroxyacetophenone (0.68kg), dimethylamine hydrochloride (0.81kg) and sodium cyanoborohydride (0.315kg) is refluxed in methanol for 23 to 30 hours. After complete disappearance of starting material, as checked by TLC, methanol is distilled out under vacuum and the residue thus obtained is dissolved in water (5 ltr). The contents are basifϊed to pΗ. 10 using aqueous ammonia and extracted with ethyl acetate (3 x 3 ltr). Combined ethyl acetate extracts are washed with water dried over sodium sulphate and concentrated under reduced pressure to give thick oil. This oil is dissolved in isopropyl ether (3 ltr) under heating and allowed to cool to O⁰C. The crystalline solid obtained is filtered at the Buchner funnel under vacuum and dried in oven at 6O⁰C to give the titled aminophenol (II) as a light yellow crystalline solid.

Yield obtained: 0.57 kg

Purity by HPLC: 99%

Melting range: 89 to 90⁰C

Mass spectrometry: peak at m/z 166 (m+1)

¹H-NMR data in CDCl₃: δ 1.4 (d, 3H), 2.3 (s, 6H), 3.3 (q, IH), 6.9 (m, 3H), 7.2 (m, IH), 8.0 (brs, IH).

XRD data (2Θ values):

11.78, 12.08, 12.58, 13.86, 15.64, 17.26, 17.60, 17.82, 18.50, 18.66, 20.04, 20.62, 22.54, 23.82, 24.18, 25.36, 25.92, 27.00, 27.94, 28.88, 28.94, 30.80, 31.62, 32.00, 32.10, 32.54, 33.50, 35.04, 35.84, 36.48, 37.36, 38.16, 39.60 Example 2:(R/S) carbamate

A mixture of aminophenol II (0.825kg), potassium tert-butoxide (0.560kg), 25% toluene solution of ethylmethylcarbamoyl chloride (2.20kg) is stirred in tetrahydrofuran at ambient temperature for 24 hours. After complete disappearance of the starting material (as checked by TLC) reaction is worked up by pouring the contents in water (20ltr) and acidified topR 2 using hydrochloric acid. The organic layer is separated and discarded. Aqueous layer is basified to pR 11 using ammonia solution and extracted with isopropyl ether (3 x 31tr).

Combined extract is washed with water, dried over sodium sulphate and concentrated under reduced pressure to give (R/S) carbamate of formula (I) as a thick yellowish brown oily material.

Yield: 1.10 kg

Purity by HPLC: 98%

Mass spectroscopy: Peak at m/z 251 (m+1)

IR (KBr): 1713cm^'1 (carbamate C=O stretching)

IH-NMR data in CDCl₃: δ 1.2 (m, 3H), 1.4 (d, 3H), 2.2 (s, 6H), 3.0 (d, 3H), 3.25 (q, IH), 3.50 (m, 2H), 7.0 (m, 3H),

7.3 (m, IH).

Example 3: Oxalate salt of (R/S) carbamate

A mixture of (R/S) carbamate (1.17 kg), oxalic acid (0.560 kg) and acetone (4.50 ltr) is refluxed on a water bath for one hour. It is then cooled to 0⁰C and stirred for 1 hour. Crystalline oxalate salt thus obtained is filtered at the Buchner funnel under vacuum and dried in oven at 60⁰C for 2 hours to get a colourless, crystalline oxalate salt.

Yield: 1.10 kg Purity by HPLC: 100% Melting range: 115 to 119⁰C

IH-NMR data in CD₃OD δ 1.2(m, 3H), 1.7 (d, 3H), 2.8(s, 6H), 3.0 (d, 3H), 3.5 (m, 2H), 4.5 (q, IH), 7.2 to 7.6 (m, 4H) Example 4: (ιS)-Rivastigmine

(R/S) carbamate (1.10kg) obtained in Example 3 is reacted with di-p-toluoyl-D-tartaric acid (1.70 kg) in methanol (7.3 ltr) under stirring for one hour. It is then cooled to O⁰C and stirred for 2 hours. Crystalline solid thus obtained is filtered at Buchner funnel under vacuum. Wet solid is re-crystallized from methanol and dried at Buchner funnel under vacuum for 2 hours to give the colourless crystalline di-/»-toluoyl-Z>-tartrate of S-Rivastigmine.

Yield: 1.50 kg

Melting range: 142 to 144⁰C

Specific rotation [a] ²° : +82° [c=l, methanol]

A mixture of di-p-toluoyl-Z⁾-tartrate salt of S-Rivastigmine (1.50 kg), water and isopropyl ether (1.0 ltr) is stirred and pH adjusted to 10 using liquor ammonia to separate the layers. Aqueous layer is extracted with isopropyl ether (2 xl.O ltr). Combined isopropyl ether extract is washed with water, dried over sodium sulphate and concentrated under reduced pressure to give iS-Rivastigmine as a colourless thick oily mass.

Yield: 0.450 kg

Assay by HPLC: 99.99%

Specific rotation [α] £° : -32° [c=5, ethanol]

Water layer (from free base formation) was charcoalized and acidified slowly with hydrochloric acid at low temperature. The solid obtained was filtered dried under reduced pressure to recover di-^»-toluoyl-D-(+) tartaric acid.

Example 5: (i?)-Rivastigmine

(R/S) carbamate (1.10kg) obtained in Example 3 is reacted with di-p-toluoyl-.D-tartaric acid (1.70 kg) in methanol (7.3 ltr) under stirring for one hour. It is then cooled to 0⁰C and stirred for 2 hours. Crystalline solid thus obtained is filtered at Buchner funnel under vacuum. Mother liquor (filtrate from salt formation) is concentrated and basified with liquor ammonia upto /Η 12.0, extracted with isopropyl ether. The organic layer is washed with water, dried over sodium sulfate and concentrated at reduced pressure to give the R enriched carbamate. The R enriched carbamate is then treated with di-/?-toluoyl-Z-(-) tartaric acid (1.0 equivalent) in methanol to give a solid salt, which is re-crystallized from methanol and basified with liquor ammonia to give i?-(+)-carbamate (Rivastigmine free base) having more than 99% enantiomeric purity (as per Chiral HPLC analysis). Specific optical rotation [α] ™ : +32° [C = 5, Ethanol].

Example 6: (S) Rivastigmine hydrogen tartrate

A mixture of (S)-Rivastigmine (example 4, 0.45 kg), tartaric acid (0.27 kg) and absolute alcohol (2 ltr) is refluxed under stirring for 1 hour. The contents are then cooled to 0⁰C and further stirred for 4 hours. Crystalline solid thus obtained is filtered at Buchner funnel under vacuum and dried in vacuum oven at 50 to 6O⁰C for 4 hours to give colourless crystalline Rivastigmine hydrogen tartrate.

Yield: 0.60 kg

Assay by HPLC: 100%

Melting Range: 123 to 126⁰C

Specific rotation [α] ™ : 5.5° [c=5, ethanol]

IR Spectroscopy (KBr): peak at 1719 cm-1 ... [Carbamate C=O stretching]

IH-NMR data in CDCl₃: δ 1.2 (m, 3H), 1.7 (d, 3H), 2.75(s, 6H), 3.0 (d, 3H), 3.3 (q, IH), 3.5 (m, 2H), 4.4 (s, 2H), 7.2

(m, IH), 7.4 (m, 3H)

DSC: Endothermic peak at 126.83°C.

XRD data 2(θ) values:

5.12, 5.40, 10.20, 11.76, 12.30, 14.02, 14.70, 15.32, 16.46, 17.16, 17.60, 18.14, 18.64, 20.48, 21.06, 23.08, 23.66, 24.78, 25.62, 26.34, 27.74, 28.22, 28.84, 29.18, 30.24, 30.94, 31.52, 32.72, 33.12, 33.54, 33.60, 33.86, 35.80, 36.26, 36.84, 37.36, 37.88, 38.10, 38.40, 38.72

Claims

ClaimsWe claim:

1. A process for preparing enantiomerically pure Rivastigmine (N-ethyl-3-[l- dimethylamino)ethyl]-N-methylphenyl carbamate) of formula (I) comprising:

Formula I

Formula II

Formula (III)

2. The process according to claim 1 wherein the reducing agent is a metal hydride

3. The process according to claim 1 wherein the reducing agent is selected from a group comprising of sodium borohydride (SBH), sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminium hydride (LAH)

4. The process according to claim 1 where the step (c) comprises contacting crude carbamate with oxalic acid in presence of acetone to give a crystalline oxalate salt followed by treatment of the said crystalline oxalate salt with ammonia to give the pure carbamate.

5. The process according to any of the claims 1 to 4, wherein the said enatiomerically pure Rivastigmine is (R)- Rivastigmine

6. The process according to any of the claims 1 to 4, wherein the said enantiomerically pure Rivastigmine is (S)- Rivastigmine

7. A process for the preparation of enantiomerically pure (jS)-Rivastigmine comprising:

Formula II

(b) contacting the aminophenol of formula (II) with carbamoyl halide of formula (HI)

Formula (III)

wherein X is Cl, Br or I; in presence of a base to give the carbamate of formula (I) (c) purifying the crude carbamate by contacting with oxalic acid in presence of acetone to give a crystalline oxalate salt followed by treatment of the said crystalline oxalate salt with ammonia to give the pure carbamate.

(d) contacting the racemic carbamate obtained in step (c) di-jc»-toluoyl-£>-tartaric acid in presence of methanol to obtain a solid product, and

(e) contacting the solid product obtained in step (d) with ammonia to give the said enantiomerically pure (5)-Rivastigmine.

8. An improved process for the preparation of enantiomerically pure (i?)-Rivastigmine comprising:

Formula II

Formula (III)

(c) purifying the crude carbamate by contacting with oxalic acid in presence of acetone to give a crystalline oxalate salt followed by treatment of the said crystalline oxalate salt with ammonia to give the pure carbamate.

(d) contacting the racemic carbamate obtained in step (c) di-/>-toluoyl-ZMartaric acid in presence of methanol to obtain a solid product, and

(e) separating the solid product and the mother liquor (f) contacting the mother liquor obtained in step (e) with ammonia to give the desire enantiomerically pure (R)-Rivastigmine.

9. An improved process for the preparation of (>S)-Rivastigmine hydrogen tartrate comprising:

Formula II

Formula (III)

(d) contacting the racemic carbamate obtained in step (c) di-p-toluoyl-D-tartaric acid in presence of methanol to obtain a solid product.

(e) contacting the solid product obtained in step (d) with ammonia to give the said enantiomerically pure (6)-Rivastigmine.

(f) contacting the product of step (e) with tartaric acid in presence of absolute alcohol to give pure (£)-Rivastigmine hydrogen tartrate.

0. Rivastigmine hydrogen tartrate having following characteristics XRD peaks (at 2Θ) 5.12, 5.40,

10.20,

11.76,

12.30, 14.02, 14.70, 15.32, 16.46, 17.16, 17.60, 18.14, 18.64, 20.48, 21.06, 23.08, 23.66, 24.78, 25.62, 26.34, 27.74, 28.22, 28.84, 29.18, 30.24, 30.94, 31.52, 32.72, 33.12, 33.54, 33.60, 33.86, 35.80, 36.26, 36.84, 37.36, 37.88, 38.10, 38.40, 38.72