Title of Invention

A PROCESS FOR PRODUCING RIVASTIGMINE AND NOVEL INTERMEDIATES THEREOF

Abstract The invention relates to a novel advantageous process for producing the rivastigmine drug. The process is based on the fact that the compound 3-((S)-1-((S)-1-phenylethylamino)ethyl)phenol is advantageously obtained as an intermediate product and can further be reacted into rivastigmine.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule!3)
1 TITLE OF THE INVENTION: A process and intermediate product for the
production of Rivastigmine
2. APPLICANT (S)
(a) NAME: RATIOPHARM INDIA PRIVATE LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies Act 1956
(c) ADDRESS: 402, Omega, Hiranandani Business Park, Powai Mumbai 400 076
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed.

Technical field
The invention relates to a novel process for producing the active substance rivastigmine and advantageous intermediate products of the process. Based on known starting substances, the process supplies rivastigmine in good yield, in excellent optical purity and in only a few processing steps. Therefore, the process has definite economic advantages.









is the international non-proprietory name for the centrally active acetylcholine
esterase inhibitor 0-{3-[(S)-1-(dimethylamino)ethyl]phenyl}-N-ethyl-N-
methylcarbamate. The active substance is approved for treating Alzheimer's disease and is commercially available in the form of the hydrogen tartrate salt.
EP-A-193 196 discloses rivastigmine in the form of a racemate and a process for the production thereof. Here, substantially a compound of formula

is reacted with an isocyanate or a carbamoyl chloride. The process is not advantageous since for the production of rivastigmine an enantiomer separation would have to be carried out in the last processing step. Rivastigmine per se is disclosed in DE-A 38 05 744. This publication also
describes a manufacturing process in which rivastigmine is obtained in the form
-1-

of a racemate as a free base by amidation of a-m-hydroxyphenylethyldimethylamine with a corresponding carbamoyl halide. The
racemate is prepared by separation of the enantiomers using known methods
e.g. using di-O.O'-p-toluyl tartaric acid.
More recent processes for producing rivastigmine are disclosed in WO 03/101917 and WO 2004/037771. The process of WO 03/101917 proceeds via a compound of formula

N ,CH3
O-C-N
NC2H5

and calls for a number of purification and racemate resolution steps. The process of WO 2004/037771 is based on the optically active compound



i.e. (3-(S)-1-(dimethylamino)ethylphenol), and reacts it with a compound of formula



I wherein X represents a leaving group. The compound of formula

,N(CH3)2

is also disclosed in Chung-Pin Chen et al. Tetrahedron Letters, Vol. 32 (49), (1991), 7175-7178 as compound 8c'. This and other a-arylethylamines are
disclosed as important intermediate products for the production of active substances, reference being also made in particular to DE-A 38 05 744, i.e. the basic patent for rivastigmine. Chen et a/, prepare the compound of formula


by reacting the corresponding a-arylethanol with HN3, while as per process disclosed in WO 2004/037771, this compound is obtained by means of reductive amination of a methoxyacetophenone. The reaction of 3-(S)-1-dimethylamino)ethylphenol with a compound






which is described in WO 2004/037771, is rather disadvantageous since the compounds
are not commercially available but have to be produced in a costly and time-consuming manner. In addition, the compounds are not very stable and are difficult to handle.
Objects of this invention
It is the object of this invention to provide novel processes for producing rivastigmine, by means of which rivastigmine can be obtained economically with only some processing steps and in a good optical and chemical purity, complex racemate resolutions being dispensed with where possible. It is also an object of
3

this invention to provide advantageous intermediate products for use in these
processes.
These objects are achieved by the subject matter of the claims.
Detailed description
The process according to the invention is based inter alia on the surprising finding that the new intermediate compound 3-((S)-1-((S)-1-
phenylethylamino)ethyl)phenol (V) wherein R = H

(V)
or the corresponding compound with protected hydroxyl group can be obtained in good optical purity and yield from commercially available starting compounds and can be reacted into rivastigmine in an easy way and with few processing steps. In particular, it is also possible to obtain the intermediate compound as described in WO 2004/037771 and in Chen et al. of formula (VI)

(VI)
from intermediate compound (V)

(V)
with the stereochemistry of the asymmetric carbon atom being maintained. According to the invention the compound of formula (VI)

(VI)

is thus not produced via an acid as intermediate product as in Chen et al. or via a racemic mixture which has to be separated in a complex way as in WO 2004/037771, but on the basis of commercially available starting products in only
a few steps while maintaining the stereochemistry of the starting compound. It is also possible to convert the advantageous intermediate compound (V)


(V)
provided according to the invention or the compound protected correspondingly at the OH group into rivastigmine by means of a process which does not proceed via the intermediate compound (VI)


-[The compound of formula (V)

(V)
wherein R represents a hydrogen atom or a hydroxyl protecting group, can easily be produced, based on the known and commercially available compounds.
According to advantageous embodiments of the invention, the process is started from compound V where residue R represents a hydrogen atom. Residue R can also represent a common hydroxyl protecting group, such as described in "Protecting Groups in Organic Synthesis", Theodora W. Green and Peter G.M. Wuts, 2nd edition, 1991, John Wiley and Sons, or other standard textbooks of organic chemistry, for example. The hydroxyl protecting group can be introduced
5

or cleaved at any time of the process according to methods known in the prior art. However, according to the invention residue R is preferably a hydrogen atom, and another advantage of the process according to the invention is that a
protection of the hydroxyl group of the starting and intermediate compounds is usually not necessary in the synthesis of rivastigmine.
In a particularly preferred embodiment, the compound of formula (V)


HO
(V)


can be produced from the commercially available compounds 3-hydroxyacetophenone



and (S)-l-phenylethanamine



according to the following reaction scheme




HO





3-hydroxyacetophenone can be condensed with (S)-l-phenylethanamine in Known manner, e.g. in a conventional organic solvent or mixture of solvents, in particular a dipolar aprotic solvent, such as acetone, dichloromethane or an ether or ester, in particular tetrahydrofurane (THF) or ethyl acetate. The condensation is preferred to take place in the presence of an organic base, e.g. a tertiary amine such as trimethylamine or triethylamine, and in the presence of a suitable catalyst, such as titanium tetrachloride or titanium isopropoxide. As a result of the condensation, the compound of formula (IV)

is obtained which can be either isolated or preferably hydrogenated directly as usual. The hydrogenation is preferred to take place using a complex metal hydride, such as lithium aluminum hydride, sodium borohydride or lithium borohydride, in particular with sodium borohydride, in a suitable solvent, preferably an organic solvent or a mixture of solvents, in particular a polar aprotic solvent, such as an alcohol. Particularly preferred solvents are C1-C4 alcohols, in
particular methanol or ethanol.
Customary reprocessing supplies a mixture of the compounds 3-((S)-1-((S)-1-
phenylethylamino)ethyl)phenol and 3-((R)-1-((S)-1-phenylmethylamino)ethyl)-phenol

However, the undesired (R)-(S)-enantiomer is usually not present or is only present in very small, non-disturbing amounts so that the undesired enantiomer does not have to be cleaved off. Therefore, racemate resolution is usually not necessary. Where appropriate, the undesired enantiomer, i.e. the compound of formula (V), can be separated in known manner should this be desired.
7

The compound of formula (V)

(V)
i.e. 3-((S)-1-((S)-1-phenylethylamino)ethyl)phenol, can be converted into rivastigmine in various ways. In a preferred embodiment, the compound of formula 3-((S)-1-((S)-1-phenylethylamino)ethyl)phenol is initially converted into 3-((S)-1-(dimethylamino)ethyl)phenol. This can be done by direct hydrogenation of the compound of formula (V)



for example, with the stereochemistry being maintained. The hydrogenation can be carried out with hydrogen using a common catalyst, such as platinum on carbon or palladium on carbon, preferably palladium on carbon (Pd/C), under acidic conditions. It is possible to use a mixture of conventional organic solvents by adding an acid soluble in the solvent, however, it is preferred to directly use an organic acid such as acetic acid as the solvent. It is preferred to then methylate compound 3-((S)-1-aminoethyl)phenol



while maintaining the stereochemistry, by using e.g. using formic acid and formaldehyde:



N(CH3)
HO
3#2

3-((S)-1 -aminoethylphenol 3-{(S)-1 -(dimethylamino)ethyl)phenol
8

In an alternative embodiment, the compound of formula (V)

(V) is initially N-methylated to give the compound of formula (VII)

(VII) The methylation can be effected by reacting the compound of formula (V)

(V)
with formic acid and formaldehyde. The compound of formula (VII) is then preferably isolated and hydrogenated as described above by means of hydrogen and a suitable catalyst such as platinum on carbon or palladium on carbon so as to form 3-((S)-1-(methylamino)ethyl)phenol of the formula



3-((S)-1-(methylamino)ethyl)phenol can then be methylated into the compound of formula

(VI)
conditions being usable corresponding to those described above in the
methylation of compound (V)
9


i.e. a mixture of formic acid and formaldehyde. The compound of formula (VI)

(V)


(VI)
can further be reacted into rivastigmine in known manner, e.g. as described in WO 2004/037771, i.e. by reaction with such a carbamoyl halide of formula (C2H5)(CH3)NC(0)X, X representing a halogen atom. As to details of this process reference is made to WO 2004/037771.
In a preferred process, the compound of formula (VI) 3-(S)-1-dimethylaminoethylphenol can also be reacted into rivastigmine with tnphosgene and then with methylethylamine and preferably a metal hydride, such as sodium hydride, according to the following reaction scheme:













With respect to the method of WO 2004/037771 an additional advantage of this
10


process is that the commercially available and stable triphosgene is used instead of the unstable compound

which is difficult to handle. This particularly advantageous process in which 3-(S)-((1-dimethylamino)ethyl)phenol of formula (VI) is reacted with triphosgene and then with methylethylamine into rivastigmine is not limited to the use of a compound of formula (VI) which was made in accordance with the process particularly advantageous according to the invention. The invention also relates to a process in which 3-(S)-((1-dimethylamino)ethyl)phenol produced according to the prior art is reacted with triphosgene and methylethylamine into rivastigmine.
In an alternative embodiment, which does not proceed via the compound of formula (VI)

(VI)
the compound of formula (V)

(V) can initially be converted into the compound of formula (VII)

(VII)
as described above, which is then converted either analogously to the method described in WO 2004/037771 by reaction with the carbamoyl halide of formula (C2H5)(CH3)NC(0)X, X representing a leaving group, or again by reaction with
11

ethylmethylamine and triphosgene in the presence of a metal hydride, such as Sodium hydride, as shown in the examples, into the compound of formula (VIII)

(VIII)
i.e. N-(1-(S)-(3-ethylmethylcarbamoyloxyphenyl)ethyl-N-(S)-methyl-1-phenyl-ethanamine. As described above for the compound of formula (VII) this compound can be cleaved by hydrogenation, e.g. using a catalyst such as palladium on carbon or platinum on carbon, preferably palladium on carbon, in a suitable solvent, as described above, in particular ethanol, so as to obtain the compound of formula (IX)


(IX)
i.e. 3-((S)-1 -(methylamino)ethyl)phenylethylmethylcarbamate. compound of formula (IX)

Then, the




(IX)
can be methylated using the reaction conditions described above for the methylation of the compound of formula


i.e. using formic acid and formaldehyde, which directly yields rivastigmine of formula (I)
12







(I)

An advantage of the above reactions is that the stereochemistry is substantially
maintained and therefore expensive racemate resolutions can usually be
avoided, above all at a later stage of the reactions.
The three reaction paths most preferred according to the invention are outlined
below:
1st reaction path




3-hydroxyacetophenone (S)-1 -phenylethanamine




3-((SM-((S)-1-Phenylethylamino)-ethyl)phenol

(1 S)-N-((S)-1 -(3-Hydroxyphenyl)ethyl-N-methyl-1 -phenylethanamine






3-((S)-1 -(Methylamino)-ethylphenol 3-((S)-1 -(Dimethylamino)-ethyl)phenol


H-HO-

COOH
-OH -H
COOH



3-((S)-1 -(Dimethylamino)ethyl)-phenylethylmethylcarbamate

Rivastigmine hydrogen tartrate

13

2nd reaction path









3-hydroxyacetophenone (S)-1 -Phenylethanamine





3-((S)-1-((S)-1-phenylethylamino)-ethyl)phenol

(1S)-N-((S)-1-(3-hydroxyphenyl)ethyl-N-methyl-1 -phenylethanamine





N-(1-(S)-(3-ethylmethylcarbamayloxyphenyl)ethyl)-N-(S)-methyl-1 -phenylethanamine





3-((S)-1 -(methylamino)ethyl)-phenylethylmethylcarbamate

3-((S)-1 -(dimethyla mino)ethyl)-phenylethylmethylcarbamate




H-HO-

COOH
-OH -H
COOH



Rivastigmine hydrogen tartrate 14

3rd reaction path





3-hydroxyacetophenone (S)-1 -phenylethanamine





3-((S)-1-((S)-1-phenylethylamino)-ethyl)phenol

3-((S)-1 -aminoethyl)phenol


3-((S)-1-(dimethylamino)ethyl)phenol
and further reaction as in the first reaction path.
Rivastigmine can be converted in many ways, as described in the prior art, e.g. in WO 2004/037771 but also in other publications, into a pharmaceutical ly compatible salt, in particular into the hydrogen tartrate salt. For this purpose, rivastigmine is reacted as usual with L-(+)-tartaric acid and reprocessed as described in the examples.
The following examples explain the invention.
15


Example 1
Preparation of 3-((S)-1-
25 g 3-hydroxyacetophenone an 2? 4 g (S)-1-phenylethanamine in 150 ml THF were cooled to 0 to 5°C in a round bottom flask. Thereafter, 55.7 g triethylamine (TEA) was added. 26.15 g titanium tetrachloride was added drop-wise to the reaction mixture over a period of 15 minutes. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction mixture was filtered through a celite bed, and the celite bed was washed with 100 ml THF. The THF was evaporated under reduced pressure. The residue was taken up in 219.5 ml ethanol and cooled to 0 to 5°C. At this temperature, 6.8 g sodium borohydride was added to the reaction mixture in portions over a period of 15 minutes. The reaction mixture was stirred at ambient temperature for 5 hours, and the progress of the reaction was monitored by thin-layer chromatography (50 % EtOAc/n-hexane, Rt (product) ~ 0.5). Having terminated the reaction, the solvents were evaporated under reduced pressure. The residue was taken up in 100 ml water and filtered. The filter cake was washed with 150 ml hot ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The resulting product was washed with cold 50 ml 50 % ethyl acetate/n-hexane.
21.6 g (49.3 %) of the end product was obtained as colorless solid. The purity was 96.9 %, the angle of rotation [ 16

Example 2
Preparation of 3-{(S)-1^(S)-1-phenylethy1amino)ethy1)phenol

88 ml titanium isopropoxide was added drop-wise to 10 g 3-hydroxyacetophenone and 9.46 ml (S)-l-phenylethanamine in 18.36 ml ethyl acetate in a round bottom flask at ambient temperature over a period of 15 minutes. The reaction mixture was stirred at ambient temperature for 3 hours. 100 ml ethanol were added to the reaction mixture which was cooled to 0 to 5°C. At this temperature, 2.7 g sodium borohydride was added in portions to the reaction mixture over a period of 15 minutes. The reaction mixture was stirred at ambient temperature for another 3 hours. The progress of the reaction was monitored by thin layer chromatography (50 % EtOAc/n-hexane, Rt (product) ~ 0.5). Having completed the reaction, the solvents were evaporated under reduced pressure. The residue was taken up in 200 ml water and pH was adjusted to about 9 by adding about 100 ml of a 10 % sodium carbonate solution. The reaction mixture was filtered, and the residue was washed with 500 ml acetone. The acetone was evaporated under reduced pressure. Residual traces of water were drawn off with toluene (3 x 50 ml).
13.3 g (75.14 %) of the end product was obtained as a grayish white solid. The purity was 98.8 %, the melting point was 188 to 190°C. The optical angle of rotation [a]24D (C = 1, methanol) was determined to be -146.01°.
17

Example 3
Preparation of (1S)-N-((S)-1-{3-hydroxyphenyl)ethyl)-N-methyl-1-phenyl
ethanamine



HO

50 g 3-((S)-1-((S)-1-phenylethylamino)ethyl)phenol was placed in a round bottom flask. 47.68 g formic acid was added at ambient temperature. Then, 50.43 ml 37 % formaldehyde was added drop-wise to the solution at ambient temperature. The reaction mixture was stirred at 60 to 70°C for 10 hours. The progress of the reaction was monitored by thin layer chromatography (50 % EtOAc/n-hexane, Rf (product) ~ 0.6). Having completed the reaction, formic acid was evaporated under reduced pressure and 100 ml water was added. The pH value of the solution was at about 2.5. 100 ml n-hexane was added, the organic layer was separated and discarded. The procedure was repeated 2 times with 100 ml n-hexane each. Thereafter, the aqueous phase was cooled to 0 to 5°C and about 120 ml of a 40 % sodium hydroxide solution was added up to a pH value of about 7.5. The aqueous layer was extracted with 3 x 100 ml ethyl acetate, the combined organic extracts were dried on sodium sulfate, and the solvent was evaporated under reduced pressure.
50.02 g (94.5 %) of the end product was obtained as brown, rubber-like liquid. The purity was 98.3 %, the melting point 98.6 to 96.9°C. The optical angle of rotation [a]25D (C = 1 in chloroform) was -52°.
Example 4
18
Preparation of 3-((S)-1-

20 g (1S)-N-((S)-1-(3-hydroxyphenyl)ethyl-N-methyl-1-phenylethanamine and 2 g 10 % Pd/C in 75 ml ethanol were charged in a hydrogenation flask. Hydrogenation was carried out at 70 psi. The progress of the reaction was monitored by thin layer chromatography (20 % MeOH/CHCi3, Rf (product) ~ 0.2).
After the reaction was complete, the reaction mixture was filtered on a celite bed, and the celite bed was washed with 50 ml methanol. The solvents were evaporated under reduced pressure. The solid residue was taken up in 50 ml petrol ether, and heating to 55 to 60°C was carried out followed by decantation. This procedure was carried out with a total of 5 x 50 ml petroleum ether. Thereafter, remaining traces of petroleum ether were evaporated under reduced pressure. 8.5 g (73 %) of the end product was obtained as grayish white solid with a purity of 97 %. The melting point was 171 to 173.5°C, the optical purity [ Example 5
Preparation of 3-((SH-aminoethyl)phenol

25 g 3-((S)-1-((S)-1-phenylethylamino)ethyl)phenol and 2.5 g 10 % Pd/C in 135 ml glacial acetic acid were charged in a hydrogenation flask. Hydrogenation was carried out at 70 psi for 24 hours. The progress of the reaction was monitored by thin layer chromatography (100 % EtOAc, Rt (product) -0.1). Having completed the reaction, the reaction mixture was filtrated on a celite bed, and the celite bed was washed with 25 ml acetic acid. The acetic acid was removed under reduced pressure. The residue was washed with 100 ml ethyl acetate. 12 g (84 %) of the end product was obtained as a colorless solid having a purity of 95.3 % and a melting point of 148.9 to 151.8°C. The optical purity was [a]25D (C = 1 in methanol) was -20°.
19

Example 6
Preparation of 3-{(S)-1-{dimethylamino)ethyl)phenol



HO

10 g 3-((S)-1-(methylamino)ethyl)phenol, 12.7 ml formic acid and 16.1 ml 37 % formaldehyde were heated in a round bottom flask up to 60 to 70°C. The reaction mixture was stirred at 60 to 70°C for 10 hours. The progress of the reaction was monitored by thin layer chromatography (20 % MeOH/CHCl3, Rt (product ~ 0.4). After completing the reaction, the formic acid was evaporated under reduced pressure, and 100 ml water was added. The reaction mixture was extracted with 100 ml n-hexane. The layers were separated, and the aqueous layer was extracted with 4 x 100 ml n-hexane. The n-hexane layers were discarded. The pH of aqueous layer was adjusted to about 7.5 to 8 by addition of about 60 ml of a 10 % sodium hydroxide solution. The aqueous layer was extracted with 3 x 100 ml ethyl acetate, a pH of 7.5 to 8 being retained. The combined organic extracts were dried on sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from 10 ml ethyl acetate. 9 g (82.5 %) of the end product was obtained as grayish white crystalline solid in a purity of 98.1 %. The melting point was 108 to 112°C. The optical purity [a]25D
(C=1 MeOH)was-51.4°.
Example 7
Preparation of 3-((S)-1-(dimethy1amino)ethy1)phenol




69.95 ml formic acid, 50 g 3-((S)-1-aminoethyl)phenol and 88.87 ml 37 % formaldehyde were heated to 70°C in a round bottom flask. The reaction mixture
20

was stirred at 70°C for 10 hours. The progress of the reaction was monitored by thin layer chromatography (20 % MeOH/CHCI3, Rf (product ~ 0.4). After
completing the reaction, the formic acid was evaporated under reduced pressure, and 250 ml water was added. The reaction mixture was extracted with
2 x 250 ml hexane. pH of aqueous layer was adjusted to 7.5 to 8 by addition of 110 ml 40 % sodium hydroxide solution. The reaction mixture was extracted with
3 x 250 ml ethyl acetate. The combined organic extracts were dried on sodium sulfate, and the ethyl acetate was removed under reduced pressure. The residue was recrystallized from 40 ml hot ethyl acetate.
13.4 (22.25 %) of the end product was obtained as slightly brown crystalline solid having a purity of 98.3 %. The melting point was 108 to 112°C. The optical purity (A)25D (C = 1, MeOH) was 51.4°.
Example 8
Preparation of 3-((S)-1-amate
(Rivastigmine)




17.9 g triphosgene was added to 100 ml chloroform in a round bottom flask at 0°C. 12.9 g pyridine was added drop-wise to this solution at 0 to 5°C and then 14 ml ethylmethylamine was also added drop-wise. Cooling was stopped and the reaction mixture was stirred for 30 minutes. Chloroform was removed under reduced pressure (7 mm Hg) at 35°C. The residue was taken up in 100 ml N-hexane. The hexane layer was added at 0 to 5°C to a mixture of 10 g 3-((S)-1-(dimethylamino)ethyl)phenol, 300 ml acetonitrile and 3 g 60 % sodium hydride in a 1 I three-neck round bottom flask. The reaction mixture was stirred at ambient temperature for 20 hours. The progress of the reaction was monitored by thin
21

layer chromatography (20 % MeOH/CHCI3 Rt (product) ~ 0.3). After completing the reaction, the solvents were removed under reduced pressure (7 mm Hg). The resulting residue was cooled to 0 to 5°C, and quenched with 100 g ice until a pH of about 8.5 was achieved. The reaction mixture was extracted with 3 x 100 ml n-hexane. The combined organic extracts were dried on sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified on column chromatography (silica gel, gradient 80 % EtOAc/n-hexane 10 % MeOH/CHCI3).
11 g (70.96 %) of the end product was obtained as yellow liquid having a purity of 96.7 %. The angle of rotation [a]25D (C = 5, EtOH) was -28.1°.
Example 9
Preparation of 3-((S)-1-(dlimethylamino)ethyl)phenylethylmethylcarbamate
(Rivastigmine)




44.89 g triphosgene was added to 250 ml chloroform in a round bottom flask at 0 to 5°C. 33.3 ml pyridine was added drop-wise to this solution at 0 to 5°C over a period of 10 minutes. 35.09 ml ethylmethylamine was added drop-wise to the reaction mixture at 0 to 5°C over a period of 30 minutes. The reaction mixture was stirred at ambient temperature for 30 minutes. The solvents were evaporated under reduced pressure (10 mm Hg) at 35°C. The residue was taken up in 150 ml n-hexane. 25 g 3-((S)-1-(dimethylamino)ethyl)phenol in 300 ml THF was charged in a separate 1 I three-neck flask and cooled to 0°C. 24 g 60 % sodium hydride was added in portions at 0 to 5°C over a period of 30 minutes. The hexane layer from the first round bottom flask was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 12 hours. The progress of the reaction was monitored by thin layer chromatography (20 % MeOH/CHCI3, Rf (product) ~ 0.5). After completing the reaction, the solvent was removed under reduced pressure. The residue was cooled to 5 to 10°C and
22

quenched with 150 ml ice water. The mixture was extracted with 4 x 150 ml ethyl acetate. The combined organic extracts were dried on sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, gradient 70 % EtOAc/n-hexane-10 % MeOH/CHCl3). Fractions containing desired compound were concentrated. 100 ml Ethanol was added to concentrated residue and was heated to 55°C with 0.5 g activated carbon and subsequently filtered through a celite bed and celite bed was washed with 50 ml ethanol. The solvent was evaporated under reduced pressure.
32 g (84.6 %) of the end product was obtained as a brown liquid in a purity of 98.3 %. The angle of rotation [a]25D (C = 5, EtOH) was -28.1 °.
Example 10
Preparation of N-(1-(SH3-ethylmethylcarbamoyloxyphenyl)ethyl)-N-(S)-
methyl-1 -phenyl-ethanamine

50 ml chloroform was added to 9.1 g triphosgene at 0 to 5°C in a round bottom flask. 6.32 ml pyridine was added drop-wise to this solution. Then, 6.86 ml ethylmethylamine was added drop-wise to the reaction mixture at 0 to 5°C. The reaction mixture was stirred at ambient temperature for 30 minutes. The solvents were evaporated at 35°C under reduced pressure (7 mm Hg). The residue was taken up in 20 ml n-hexane and filtered off. The salt was washed with 20 ml n-hexane. The n-hexane solutions were combined and added to a mixture of 5 g (1S)-N-((S)-1-(3-hydroxyphenyl)ethyl)-N-methyl-1-phenylethan-amine, 32 ml THF and 1.44 g 60 % sodium hydride at 0 to 5°C. The reaction mixture was stirred at ambient temperature for 3 hours. The progress of the reaction was monitored by thin layer chromatography (30 % EtOAc/n-hexane, Rt
(product) ~ 0.7). After completing the reaction, the solvents were evaporated at
23

55°C under reduced pressure (7 mm Hg). The residue was quenched with about 10 ml ice water. The reaction mixture was extracted with 6 x 20 ml ethyl acetate, and the combined organic extracts were dried on sodium sulfate. The solvent
was evaporated, and the residue was purified on column chromatography (silica
gel, 10 % EtOAc/n-hexane).
5.4 g (81.8 %) of the end product was obtained as colorless liquid having a purity
of 98.49 %. The optical angle of rotation [a]25D (C = 1 in CHCI3) was -58.4°.
Example 11
Preparation of 3-
5.4 g N-(1-(S)-(3-ethylmethylcarbamoyloxyphenyl)ethyl)-N-(S)-methyl-1-phenyl-ethanamine, 0.54 g 10 % Pd/C and 27 ml ethanol were charged in a hydrogenation flask. Hydrogenation was carried out at 70 psi for 8 hours. The progress of the reaction was monitored by thin layer chromatography (50 % EtOAc/n-hexane, Rf (product) ~ 0.5). After completing the reaction, the reaction mixture was filtered through a celite bed, and the celite bed was washed with 25 ml methanol. The solvents were removed under reduced pressure. 3.3 g (88.1 %) of the end product was obtained as light red liquid. The purity was 91.7 %, the angle of rotation [a]25D (C = 1 in CHCl3) was -38.5°.
Example 12
Preparation of 3-((S)-1-(dimethylamino)ethyl)phenylethylmethylcarbamate
(Rivastigmine)
2.2 g 3-((S)-1-methylamino)ethyl)phenylethylmethylcarbamate, 1.63 ml formic acid and 2.06 ml 37 % formaldehyde were heated to 60 to 70°C in a round
24

bottom flask. The reaction mixture was stirred at 60 to 70°C for 10 hours. The progress of the reaction was monitored by thin layer chromatography (10 % MeOH/CHCl3, Rt (product) -0.1). After completing the reaction, the formic acid
was evaporated under reduced pressure and 25 ml water was added. The layers
were separated, and the aqueous layer was extracted with 2 x 25 ml n-hexane. The n-hexane layers were discarded. The pH of aqueous layer was adjusted to about 7.5 to 8 by adding about 50 ml of a 10 % sodium hydroxide solution. The aqueous layer was extracted with 2 x 50 ml ethyl acetate, a pH of 7.5 to 8 being retained. The combined organic extracts were dried on sodium sulfate. The solvent was evaporated under reduced pressure.
1.4 g (60.82 %) of the end product was obtained as a brown liquid. The purity was 99.5 %. The angle of rotation [ Example 13
Hydrogen tartrate salt of rivastigmine

COOH
COOH

4.8 g 3-((S)-1-(dimethylamino)ethyl)phenylethylmethylcarbamate, 43.2 ml acetone and 2.59 g L-(+)-tartaric acid were charged in a round bottom flask. 14.4 ml water was added drop-wise to this mixture. The reaction mixture was heated to 60°C for 5 hours. Acetone was evaporated under reduced pressure. Residual water was removed by co-distillation with 3 x 50 ml toluene. The residue was washed with 3 x 50 ml petroleum ether, and the rest of the petroleum ether was evaporated under reduced pressure. The residue was taken up in 50 ml ethanol and a pinch of activated carbon was added. Heating to 50°C was carried out for 5 minutes. The reaction mixture was filtered through a celite bed, and the celite bed was washed with 25 ml ethanol. The solvents were evaporated under reduced pressure. The residue was taken up in 25 ml isopropanol, and a small amount of the pure end product was used for inoculation. The solvent was evaporated under reduced pressure. The residue was washed with 50 ml ethyl
25

acetate, heated to 50°C and decanted. The procedure was repeated 3 times with 50 ml ethyl acetate each. Ethyl acetate residues were removed under reduced pressure. 4.8 g (62.5 %) of the end product was obtained as colorless solid. The purity was determined to be 99.6 %, the melting point was 122 to 125°C. The angle of rotation [a]25D (C = 5, EtOH) was +6°.
Example 14
Hydrogen tartrate salt of rivastigmine

COOH
COOH

30 g 3-((S)-1-(dimethylamino)ethyl)phenylethylmethylcarbamate, 90 ml ethanol and 17.98 g L-(+)-tartaric acid were heated to 60 to 70°C in a round bottom flask. The reaction mixture was stirred at 60 to 70°C for 30 minutes. 420 ml ethyl acetate was added drop-wise to the reaction mixture at the same temperature over a period of 15 minutes. The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was filtered under a nitrogen atmosphere. The filter cake was washed with 100 ml ethyl acetate and dried at 50 to 55°C in a oven for 3 hours.
36 g (75.1 %) of the end product was obtained as colorless solid. The purity was determined to be 99.8 %. The melting point was 120 to 122.8°C. The angle of rotation [(a)25D (C = 5, EtOH) was +6°.
In the above description, ambient temperature and room temperature are 25°C.
26

We claim,
1. A process for producing a compound of formula (I)

3 -3 (|)
or a pharmaceutically compatible salt thereof, characterized in that a compound of formula (V)

(V),
wherein R represents a hydrogen atom or a hydroxyl protecting group, is reacted to give the compound of formula (I)

■3 - 3 (|)
and, where appropriate, the compound of formula (I) is converted into a pharmaceutically compatible salt thereof.
2. The process according to claim 1, characterized in that the compound of formula (V)

(V) is obtained by hydrogenation of the compound of formula (IV)
27

(IV).


3. The process according to claim 2, characterized in that the hydrogenation is carried out with a metal hydride.
4. The process according to claim 2 or 3, comprising the steps of a) reacting a compound of formula (II)

(II) wherein R represents hydrogen or a hydroxyl protecting group, with a
compound of formula (III)

(III)
to give a compound of formula (IV)

(IV)
wherein R is as defined above, b) hydrogenating the compound of formula (IV)

(IV) wherein R is as defined above, to give a compound of formula (V)
28


RO
(V)

wherein R is as defined above, c) reacting the compound of formula (V)

(V) wherein R is as defined above, to give the compound of formula (I)

(I)
and
d) where appropriate, converting the compound of formula (I) into a pharmaceutically compatible salt thereof.
5. The process according to any of claims 1 to 4, wherein the compound of formula (V)

(V)
is methylated to give the compound of formula (VII)

(VII)


RO

wherein R is as defined in claim 1, which is then further reacted to give the compound of formula (I).
29

6 The process according to any of claims 1 to 5, wherein the compound of formula (V)




wherein R is as defined in claim 1, is converted into the compound of formula (VI)


(VI)
wherein R is as defined above, which is then further converted into compound of formula (I).

the

7. The process according to claim 6, wherein the compound of formula (VI) is reacted with triphosgene and subsequently with ethylethylamine to give the compound of formula (I).
8. The process according to any of claims 1 to 5, wherein the compound of formula (V)

(V)
wherein R is as defined in claim 1, is reacted into the compound of formula (VIII)

(VIII)
which is further reacted into the compound of formula (I).
30

9. The process according to any of claims 1 to 8, wherein the residue R is a hydrogen atom.
10. The compound of formula (V)

(V)
wherein R is as defined in claim 1.
11. The compound of formula (IV)

(IV)
wherein the residue R is as defined in claim 1.
12. The compound of formula (VII)

(VII)
wherein R is as defined in claim 1.
13. The compound of formula (VIII)


31




(VIII)

14. The compound of formula


NH
HO

15. The compound of formula


NH
HO

16. The compound of formula


NH
HO

nd.
Dated this the day of 22™ of June 2005


32

Dr Gopakumar G. Nair Agent for the Applicant Gopakumar Nair Associates

Abstract
The invention relates to a novel advantageous process for producing the
rivastigmine drug. The process is based on the fact that the compound 3-((S)-1-((S)-1-phenylethylamino)ethyl)phenol is advantageously obtained as an intermediate product and can further be reacted into rivastigmine.

Documents:

747-mum-2005-abstract(24-6-2005).pdf

747-mum-2005-abstract(granted)-(9-2-2011).pdf

747-mum-2005-abstract.doc

747-mum-2005-abstract.pdf

747-mum-2005-cancelled pages(14-12-2010).pdf

747-mum-2005-cancelled pagse(12-8-2009).pdf

747-mum-2005-claims(24-6-2005).pdf

747-mum-2005-claims(amended)-(12-8-2009).pdf

747-MUM-2005-CLAIMS(AMENDED)-(14-12-2010).pdf

747-MUM-2005-CLAIMS(AMENDED)-(22-11-2010).pdf

747-mum-2005-claims(granted)-(9-2-2011).pdf

747-mum-2005-claims.doc

747-mum-2005-claims.pdf

747-mum-2005-correspondence(10-2-2011).pdf

747-MUM-2005-CORRESPONDENCE(14-12-2010).pdf

747-mum-2005-correspondence(20-6-2007).pdf

747-MUM-2005-CORRESPONDENCE(22-11-2010).pdf

747-MUM-2005-CORRESPONDENCE(IPO)-(10-2-2011).pdf

747-mum-2005-correspondence(ipo)-(18-8-2010).pdf

747-mum-2005-correspondence-received.pdf

747-mum-2005-description(complete)-(24-6-2005).pdf

747-mum-2005-description(granted)-(9-2-2011).pdf

747-MUM-2005-FORM 1(12-8-2009).pdf

747-mum-2005-form 1(24-6-2005).pdf

747-mum-2005-form 18(20-6-2007).pdf

747-mum-2005-form 2(24-6-2005).pdf

747-mum-2005-form 2(granted)-(9-2-2011).pdf

747-MUM-2005-FORM 2(TITLE PAGE)-(12-8-2009).pdf

747-mum-2005-form 2(title page)-(24-6-2005).pdf

747-mum-2005-form 2(title page)-(granted)-(9-2-2011).pdf

747-MUM-2005-FORM 26(22-11-2010).pdf

747-MUM-2005-FORM 3(12-8-2009).pdf

747-mum-2005-form 3(24-6-2005).pdf

747-mum-2005-form-1.pdf

747-mum-2005-form-2.pdf

747-mum-2005-form-26.pdf

747-mum-2005-form-3.pdf

747-mum-2005-marked copy(22-11-2010).pdf

747-MUM-2005-OTHER DOCUMENT(22-11-2010).pdf

747-MUM-2005-REPLY TO EXAMINATION REPORT(12-8-2009).pdf

747-mum-2005-specification(amended)-(12-8-2009).pdf

747-mum-2005-wo international publication report(24-6-2005).pdf


Patent Number 246030
Indian Patent Application Number 747/MUM/2005
PG Journal Number 06/2011
Publication Date 11-Feb-2011
Grant Date 09-Feb-2011
Date of Filing 24-Jun-2005
Name of Patentee RATIOPHARM INDIA PRIVATE LIMITED
Applicant Address 402,OMEGA, HIRANANDANI BUSINESS PARK, POWAI,MUMBAI
Inventors:
# Inventor's Name Inventor's Address
1 Ramakrishna Rao 7-102/54,Sai Enclave, Habshiguda, Hyderabad - 500 007
2 Mukesh Padmakar Shewalkar Flat No. 7, Kailash Apartments, Jyoti Nagar,Aurangabad.
3 Chandrashekar Ramarao 7-102/54,Sai Enclave,Habshiguda, Hyderabad-500 007.
4 Rama Rao Venkata Alla 7-102/54,Sai Enclave,Habshiguda, Hyderabad-500 007.
PCT International Classification Number F02C1/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA