COMPLATE AFTER PROVISIONAL LEFT ON
2 3 FEB 2006
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION :
"PROCESS FOR PREPARATION OF BENZAZEPINE"

2. APPLICANT (S)
(a) NAME
(b) NATIONALITY
(c) ADDRESS

Emcure Pharmaceuticals Ltd.
India
12/2 F-ll Block, M.I.D.C, Pimpri, Pune- 411 018.

3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL
The following specification describes the invention

COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION (Description shall start from next page)
5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble - "l/we claim" on separate page)
6. DATE AND SIGNATURE (to be given at the end of last page of specification)
7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page)
Note:-
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'Complete address of the applicant should be given stating the postal index no./code, state and
country
'Strike out the column which is/are not applicable.

FIELD OF INVENTION
This invention relates to a process for manufacture of galanthamine in an enantio enriched form by stereoselective reduction to get the desired isomer of galanthamine. It also discloses the method for escalating the chiral and chemical purity of galanthamine and galanthamine salts.
BACKGROUND OF THE INVENTION
Galanthamine is an alkaloid of the morphine group, which can be obtained from plants viz snowdrops (Galanthus woronowii, G. nivalis etc.) and other Amaryllidaceae. Racemic Galanthamine (I) is extracted from daffodil bulbs. (-) Galanthamine (II), and its derivatives thereof, are useful for the treatment of Alzheimer's disease.
OH OH

( I ) (II)
Barton and Kirby, J. Chem. Soc. (1962) 806, disclosed the first synthetic route to galanthamine (II) from racemic narwedine, which had been prepared in very low yield. Further, (-) narwedine was crystallized preferentially, when (+) galanthamine or a mixture of (+) galanthamine and (+) epigalanthamine were present, and used this to resolve racemic narwedine.
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MeO
MeO v Br 0 (VII)

Racemic Galanthamine Racemic Epigalanthamine
(I) (IA)

Scheme I: Method as disclosed in Journal Of Heterocyclic Chemistry 25, 1809 (1988) for preparation of Racemic Galanthamine.
Jerzy Szewczykm, Anita H. Lewin and F.I. Carroll disclosed a process for synthesizing racemic galanthamine, as shown in Scheme (I), which comprises reaction of isovanillin (III) and tyramine (IV) to yield N-(4-hydroxyphenethyl)-(3-hydroxy-4-methoxy)benzylamine (V). Further, N-formylation and bromination gave N(-4-hydroxyphenethyl)-N-(2-bromo-5-hydroxy-4-methoxy)benzyl formamide (VI), which under oxidative cyclization with potassium ferricyanide gave narwedine type enone (VII). Further, reduction with lithium aluminium hydride gave a mixture of racemic
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galanthamine (I) and racemic epigalanthamine (I-A), which needed to be separated by flash column chromatography.
This process has several disadvantages, which limits its scope on an industrial scale, they are,
a) multiple steps are required, like conversion of amine functionality to formamide to avoid oxidation of amine functionality, subsequent reduction of the same to N-methyl moiety;
b) separation of galanthamine and epigalanthamine by column chromatography, increasing the manpower, solvent usage, time and hence the cost for the cycle for each run.
Tetrahedron (1989), 45(11), 3329-45 describes a process for preparation of racemic galanthamine (I) by making use of potassium ferricyanide for oxidative coupling as shown in Scheme II. The amine (VIII) is reacted with the acid chloride yielding the intermediate (X), which on oxidative coupling gave the dienone (XI), which further on reduction gave racemic galanthamine. This scheme has the disadvantage of resolution of racemic galanthamine and epigalanthamine, which limits its industrial application.
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Scheme-II: Method for preparation of racemic galanthamine as disclosed in Tetrahedron (1989), 45(11), 3329-45.
Wen-Chung Shieh and John A. Carlson disclosed the crystallization of racemic narwedine in the presence of racemic galanthamine from a solvent / amine base mixture, to give (-)- narwedine in good yield. Further, seeding a solution of racemic mixture with (-) narwedine in ethanol / triethylamine mixture, resulted in the crystallization-induced asymmetric transformation of (-)- narwedine. However, the shortcomings of this process are that for the resolution of narwedine on a large scale, the narwedine has a tendency to self-seed, sometimes giving material of poor enantiomeric excess, or even the opposite enantiomer of narwedine. For the purpose of industrial manufacture these factors compromise the reproducibility of the process.
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Scheme III: Method for preparation of galanthamine as disclosed in Tetrahedron
Letters (1998), 39 (15), 2087-2088
The authors Laszlo Czollner et al disclosed a synthesis of galanthamine as shown in Scheme III. The oxidative cyclisation of (XII) using potassium ferricyanide generated bromoformyl narwedine (XIII), which on protection yielded propylene glycol (XIV), which was reduced to racemic narwedine (XV) using LiAlH4. The racemic narwedine was converted to (-) narwedine using seeding and then reduced to galanthamine using L-Selectride. However, the process is tedious as requires protection using glycol and deprotection of the same. Moving ahead, the seeding process of narwedine used can also sometimes give the poor enantiomeric excess as narwedine has a tendency to self-seed. Further, there is danger to handle narwedine as it is a sensitizing agent and can cause allergic skin reactions.
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Scheme IV: Method for the preparation of galanthamine according to Tetrahedron
Letters 39 (1998) 6777-6780
The authors David A. Chaplin et al disclosed a diastereomeric salt resolution of the alkaloid with di-p-toluoyl -D- tartaric acid as shown in Scheme (IV). However, this process uses first resolution step and then reduction step. The reduction step uses LiAlH4 It is known to use free narwedine with low selectivity ( approximately 7:4 mixture of galanthamine to epigalanthamine along with minor amounts of dihydrogallanthamine from over reduction). L-Selectride, however proved superior and reduced the narwedine salts with complete regio and distereoselectivity to galanthamine with no side products. However, the temperature of the reaction and the rate of the addition of L-Selectride were found to be critical to achieve the reduction of (-)-narwedine. One can therefore easily notice that the process utilized for obtaining galanthamine by this method requires rigid reaction conditions. Further, handling of
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narwedine is also dangerous as it is a sensitizing agent and can cause allergic reactions to skin. The cost of narwedine is also high, making the overall process inefficient for industrial scale up.



N-CHO PIFA
N-CHO
— OR
N-CHO
MeO
Deprotection and Michael Addition
MeO
Oxidative Coupling

OR (XVIII)


MeO
(II)
Scheme (V) : Method for the preparation of galanthamine as disclosed in Angew.Chem 2004,43,2659-2661.
This publication disclosed a method for the synthesis of galanthamine using phenyliodine(III) bis(trifluoroacetate) (PIFA) as an oxidant. This invention avoided the highly allergenic intermediate narwedine, but involved the complex reagent PIFA. As shown in scheme, the oxidative coupling of (XVI) using (PIFA) gave (XVII), which underwent Michael Addition to give (XVIII). The overall reaction sequence was of 14 steps, which demands higher manpower, increased time cycle, higher utilities etc, further increasing the cost of the product obtained by this route. Hence this process is not advisable on the industrial scale.
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Scheme (VI) : Method for preparation of galanthamine as disclosed in WO 2004/042116.
WO 2004/042116 described the process for preparation of galanthamine, according to Scheme (VI), by making use of oxidative phenolic coupling reaction of (XIX) to yield (XX). The reaction utilizes an electrochemical cell for the oxidative coupling which is very expensive and tedious on an industrial scale. However, making use of the cell on an industrial level is not feasible, due to large scale and also the cleaning of the cell is a tedious job. Hence, this method for producing galanthamine, using electrochemical cell is not suitable for commercial purpose.
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US 6407229 discloses the preparation of Galanthamine and its derivatives. The process involves the condensation of aldehyde and the amine to form imine, which on reduction gives secondary amine. Further, the formylation of the NH group of secondary amine is carried out, which is followed by the oxidative cyclisation. Subsequent reduction and debromination results in the final product.
However, this process has certain disadvantages. The reduction conditions are stringent ( requirement of-78 °C), which makes the process less feasible on production scale, as well as it becomes costly. The process requires special utilities. Further, the purification of the product requires the chromatographic techniques, which is more cumbersome.
US 6617452 Bl describes the use of galanthamine as an eye ointment in treatment of narrow angle glaucoma. However, neither the intact skin nor the cornea permit absorption of active substance salts. For this reason, it is not possible to use galanthamine hydrobromide or galanthamine hydrochloride. This patent does not teach the enrichment of the galanthamine or its salts, with respect to its optical purity. This patent is only with respect to the galanthamine, obtained from natural sources.
The purification process is always with respect to the impurities present in the material, which is to be purified. Further, the impurities present are certainly related to the source of the compound to be purified. US 6,617,452 B2 teaches the recrystallization procedure. However, the impurities present in the natural extract would be different from the impurities present in the synthetic process. The literature patent neither teaches as to how the synthetically obtained galanthamine can be purified (to achieve the desired chemical purity) nor the process of enrichment of synthetically obtained galanthamine or its salts, having unacceptable optical purity. Hence, there is a need to develop the process by which the chemical purity and optical purity of the desired isomer of galanthamine or its salts can be obtained.
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US 6087495 Bl discloses the enantiomeric enrichment of galanthamine salt in which the counter ion is achiral. It also discloses the enrichment of enantiomerically enriched galanthamine salt. This patent discloses the process to obtain enantiomerically enriched galanthamine hydrobromide by using seeding method. The seed crystals used are (-) galanthamine hydrobromide. Thus, even to obtain seed crystals, there is a need to have a process, which can provide (-) galanthamine hydrobromide with the higher optical purity. Further, the enantiomeric enrichment of (-) galanthamine hydrobromide from racemic galanthamine hydrobromide gives very poor enantiomeric excess.
This invention also discloses the enantiomeric enrichment of an enantiomerically enriched salt of galanthamine. The enrichment of (-) galanthamine hydrobromide is carried out by crystallizing (-) galanthamine hydrobromide using EtOH as a solvent. However, use of EtOH on an industrial scale is the major limitation. In various countries, in order to obtain EtOH, one needs the government permit. Also, the cost of ethanol is high, which makes the process costlier. Further, solubility of galanthamine hydrobromide is also very poor in ethanol. Thus, the higher quantities of ethanol are necessary, which need to be avoided.
Use of L-selectride as a reducing agent has certain disadvantages. L-selectride is costly, highly flammable and a corrosive reagent. It is explosive when dry. It causes burns, irritation of eyes, skin and respiratory system. Reacts violently with water and emits explosive gases. This reagent may impair fertility. It may also cause long term effects in the environment. Taking into consideration these adverse effects, there remains a need to find a better reducing agent in place of L-Selectride, which can be conveniently used on industrial scale.
Hence, there remains a need to develop a process for increasing the enantiomeric excess of galanthamine and its salts, which gives industrial feasibility, good enrichment and is cost effective at the same time.
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In view of the above shortcomings, it was necessary to develop alternate synthetic route, which would give compound of formula (II) with high purity and good yield.
The present inventors have developed a synthetic route for preparation of galanthamine, starting from methylamine and 4-benzyloxyphenyl acetyl chloride, which not only suppresses the need for complicated separation of racemic galanthamine from epigalanthamine but also gives galanthamine of high purity and in good yields.
The present inventors have also made an approach to prepare galanthamine by avoiding the highly allergic intermediate narwedine.
The present invention makes use of selective reducing agents for selective reduction to avoid the formation of mixture of galanthamine and epigalanthamine, which is complicated to separate, thus decreasing the yields.
In the present invention, the racemic galanthamine formed is separated to give galanthamine by reacting it with a chiral acid.
Further, the present invention also makes an approach to expand a method for enhancing the enantiomeric excess of galanthamine salts like galanthamine hydrobromide and galanthamine tartarate. The present embodiment also describes the reprocessing course of action in case of chiral purity failure and chemical (RS) purity failure of galanthamine salts.
OBJECT OF THE INVENTION
First object of the present invention is to provide an improved process for the preparation of galanthamine of formula (II) by a synthetic route, which is novel from the routes disclosed in prior art.
Second object of the invention is to provide galanthamine by avoiding the highly allergic intermediate i.e. narwedine.
Third object of the invention is to provide galanthamine with high optical purity.
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Fourth object of the invention is to provide galanthamine in appreciable yields.
Fifth object of the invention is to provide a selective reduction process to obtain galanthamine substantially free from epigalanthamine.
Sixth object of the invention is to provide a simple, industrially feasible, economical and safe method to prepare galanthamine of high purity and high yields.
Seventh object of the invention is to provide a process, using novel intermediate (XXIX).
Eighth object of the invention is to provide a method for increasing the enantiomeric excess of galanthamine salts, which avoids making use of seeding step.
Ninth object of the invention is to bring about an enrichment of (-) galanthamine without making use of the seeding process to achieve almost 100% chiral purity and recovery of the resolving agent used in the subsequent process.
Tenth object of the invention is to provide an economical and industrially feasible
method for increasing the chemical purity and enantiomeric excess of galanthamine
salts.
Eleventh object of the invention is to provide the alternative procedure for reduction
while avoiding the use of L-selectride.
SUMMARY OF THE INVENTION
One aspect of the invention relates to a process for the preparation of galanthamine of formula (II) of high purity and good yield.
Another aspect of the invention relates to a selective reduction method for preparation of galanthamine, which comprises reaction of methyl amine (XXI) with 4-benzyloxyphenyl acetyl chloride (XXII), to give an acetamide (XXIII), which on reduction with LiAlH4 gives a phenyl amine (XXIV). This phenyl amine on further
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treatment with the substituted benzoyl chloride (XXV) gives a substituted N-methyl benzamide (XXVI), which on further debenzylation and cyclisation with K3Fe(CN)6 gave the dienone (XXVIII). The dienone on reduction with L-selectride/Sodium borohydride gave the enol form (XXIX), which was treated with LiAIH4 / Vitride for debromination and the reduction of amide.
The racemic galanthamine (I) thus obtained was separated to galanthamine (II) using di-p-toluoyl D -(+) tartaric acid or di-p-toluyl-(-)tartaric acid. Thus, this method used for the preparation of galanthamine is safer, as it avoids the use of highly sensitizing allergic intermediate agent narwedine.
The galanthamine (II) obtained is converted into its hydrobromide salt by making use of hydrobromic acid, which is used as an active pharmaceutical ingredient in many of the formulations of galanthamine.
However, during process of preparation, the desired chiral purity or the desired chemical purity of the salt may not be obtained. In such case of chiral purity failure, to increase the chiral purity of the same, the hydrobromide salt is broken down to its free base, which is converted to its tartarate salt and then further the tartarate salt is converted to the desired salt, especially hydrobromide, through the free base. The enriched tartarate salt obtained in the process can also be directly converted to galanthamine salt e.g. hydrobromide using hydrobromic acid.
In case of chemical purity failure, to increase the chemical purity of the hydrobromide salt, the same is broken down to its free base, which is further converted to its hydrobromide by using hydrobromic acid.
For the enantiomeric enrichment of the chiral purity of the galanthamine tartarate salt, the same is broken down to its free base, further converted to the tartarate salt, which is converted to the galanthamine hydrobromide via the galanthamine free base. As solubility of (-) galanthamine is very low in ethanol, this operation of conversion of the same to its tartarate salt through its free base to (-) galanthamine hydrobromide, with high purity, facilitates easy operation on an industrial scale. The enantiomeric
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enrichment of the galanthamine tartarate salt can also be done by recrystallization, using
various solvents.
DETAILED DESCRIPTION OF THE INVENTION
Galanthamine of formula (II) is obtained by a process summarized in Scheme (VII).
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Scheme (VII): Emcure's Scheme for the preparation of galanthamine hydrobromide.
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The present invention describes the selective reduction process for the preparation of galanthamine. The reaction sequence includes the reaction of methyl amine (XXI) with 4-benzyloxyphenyl acetyl chloride (XXII) in presence of NaOH to give 4-benzyloxy N-methyl Acetamide (XXIII). This amide is further reduced with LiAIH4 to give 5-benzyloxy N-methyl phenyl amine (XXIV) which on treatment with 5 benzyloxy 2 bromo 4 methoxy benzoyl chloride gives 5-benzyloxy-N-(4-benzyloxyphenethyl)2-bromo-4-methoxy-N-methylbenzamide (XXVI). This compound on further treatment with HBr gave 5-hydroxy-N-(4-hydroxyphenethyl)-2-bromo-4-methoxy-N-methylbenzamide (XXVII).
The intermediate (XXV) can be prepared from 5-hydroxy-2-bromo-4-methoxy benzaldehyde by benzylation to give 5-benzyloxy-2-bromo-4-methoxy benzaldehyde, which on treatment with K2Cr2O7 or KMn04 can give 5-benzyloxy-2-bromo-4-methoxy benzoic acid, which on treatment with SOCl2 can give the benzoyl chloride (XXV).
The intermediate (XXIV) can be prepared from tyramine by bringing formylation of NH2 group, benzylation of hydroxy at the fourth position, and reduction with lithium aluminium hydride or Vitride to give intermediate (XXIV).
The intermediate (XXVII) can also be prepared by the route of Scheme (II) (Tetrahedron (1989), 45(11), 3329-45) the only difference being the methylation, which needs to be carried out if started with tyramine. Also, if needed the phenolic -OH groups can as well be protected before condensation step.
This product on treatment with K.3Fe(CN)6 gave a cyclised product (XXVIII), which on treatment with reducing agents selected from the group comprising of L-Selectride, K-Selectride, KS- Selectride, LS- Selectride, DiBAl, REDAL, 9-BBN, Sodium borohydride, sodium-cyanoborohydride, chiral oxazaborolidine agent(CBS)/NaBH4, CBS/BH3.H2S, BH3.H2S etc. either independently or in presence of acids such as Lewis acids like AICI3, ZnBr2 , BCI3 etc., gave reduction of the ketone to give the alcohol (XXIX), which on further treatment with reducing agents selected from the group comprising of LiAlH4 , Vitride etc., gave racemic galanthamine (I). Racemic
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galanthamine (I) was separated using di-p-toluoyl -D- (+) tartaric acid or di-p-toluyl- (-) tartaric acid to give galanthamine (II).
According to the present invention the reduction of compound (XXVIII) is carried out by using L-Selectride. The reduction is selective, wherein the ketone functionality is reduced, while keeping the amide functionality intact.
In another aspect of the present embodiment, the inventors have developed a process for reduction of compound (XXVIII), by making use of Sodium borohydride as a reducing agent. Sodium borohydride is cheap reagent. It is easily available. It can be stored easily. It is less harmful and less explosive reagent. The work up conditions using sodium borohydride reagent are less stringent.
The reduction by using NaBILi is carried out at 0 to 5 °C.
Thus, galanthamine was obtained in good yields and high purity by selective reduction and by avoiding the highly sensitizing agent narwedine as summarized in Scheme (VII).
Galanthamine is also obtained by using the intermediates prepared according to Scheme (VIII).
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This reaction sequence includes (a) conversion of compound (XXX) to compound (XXXI) by bromination (b) conversion of (XXXI) to (XXXII) by demethylation (c) conversion of (XXXII) to (XXXIII) by benzylation and (d) conversion of (XXXIII) to (XXXIV) by oxidation.
The second part of the scheme involves (a) conversion of tyramine (XXXV) to aldehyde (XXXVI) (b) conversion of (XXXVI) to (XXXVII) by benzylation and (c) conversion of (XXXVII) to (XXIV). Further, the acid chloride (XXV) and the amine (XXIV) are reacted as per Scheme (VII).
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For any pharmaceutical substance, the chemical purity as well as the chiral purity is of utmost importance. In case of failure of the said purities, the reprocessing is necessary. After formation of galanthamine hydrobromide from (-) galanthamine salt, the chiral purity or the chemical purity of the salt may not be obtained to the desired extent. For this reason, the reprocessing step of galanthamine salt at appropriate stage becomes crucial. According to the present invention, the following procedures for the improvement of the same are given:
(A) To improve the chiral purity of the galanthamine salt:
The reprocessing of galanthamine salt e.g. galanthamine hydrobromide, in case of chiral purity failure, is carried out by conversion of galanthamine hydrobromide to free base. This conversion is done using solvent methylene dichloride and ammonia as base. This free base is converted to galanthamine tartarate salt using di-p-toluyl-(-)-tartaric acid and the resulting tartarate salt having acceptable optical purity is converted into galanthamine free base, which is then converted to galanthamine hydrobromide using hydrobromic acid, which results in an increased chiral purity of galanthamine hydrobromide. The galanthamine tartarate salt obtained with acceptable optical purity can be directly converted to hydrobromide salt using hydrobromic acid. (Scheme IX). The same procedure is also applicable for the enrichment of galanthamine salts, in general.
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Scheme (IX)

If the galanthamine tartarate salt formed is not having the chiral purity as per the expectation, reprocessing of the same becomes indispensible. Under such circumstances, the galanthamine tartarate salt is converted into the free base using methanol and ammonia, which is then converted to the tartarate salt using di-p-toluyl-(-)-tartaric acid . The tartarate salt thus obtained is converted to the free base, which is further converted to the galanthamine hydrobromide with an improved chiral purity. The galanthamine tartarate salt with the unpassing chiral purity can also be enriched by making use of recrystallisation process using various solvents such as ketones, alcohols, esters, hydrocarbons, amides, water etc. The galanthamine tartarate salt with passing chiral purity can be directly converted to galanthamine salt e.g. hydrobromide with desired chiral purity by making use of hydrobromic acid. (Scheme X).
Scheme (X)




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(B) To improve the chemical purity of the galanthamine salt:
In case of the chemical purity failure of galanthamine salt, the said salt is broken down to its free base using methanol and ammonia, which is again converted to galanthamine salt giving a high chemical purity. The said methodology is illustrated in Scheme XI, with respect to galanthamine hydrobromide. If needed, the purification by recrystallization of appropriate substrate can be carried out.
Scheme (XI)

The present invention is illustrated by way of the following examples, but not restricted to the only examples disclosed.
EXAMPLES
Example 1: Preparation of 5-Benzyloxy-N-(4-benzyloxyphenylethyl)-2-bromo-4-methoxy-N-methylbenzamide (XXVI)
5-Benzyloxy-2-bromo-4-methoxybenzoic acid (XXXIV) (1.0 kg; 2.967 moles), thionyl chloride (0.35 litres) and dimethyl formamide in methylene dichloride (0.01 liters) were charged to a flask with stirring. The reaction mixture was heated to 30-35°C for half an hour. The reaction mixture was cooled. 4-benzyloxy-N-methyl-phenylethylamine (XXIV) (0.715 kg; 2.967 moles) dissolved in methylene chloride (5.0 litres) was added separately to the above formed compound of formula (XXV). The reaction mixture was cooled. Sodium carbonate was added to the reaction mixture. The reaction mixture was further heated to 25-30°C and then stirred at for 3-4 hours. After completion of reaction,
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water (2.5 litres) was added to the reaction mixture and stirred for 30 minutes. The organic layer was separated and concentrated completely under vacuum.
Yield: 1.5 kg
% Yield: 90%.
Example 2: 5-Hydroxy-N-(4-hydroxyphenethyl)2-bromo-4-methoxy-N-methylbenzamide (XXVII)
5-Benzyloxy-N-(4-benzyloxy-phenethyl)-2-bromo-4-methoxy-N-methyl- benzamide (XXVI) (1 kg; 1.785 moles) was added to methanol (15.0 litres) at 28 - 30 °C. Hydrobromic acid (12.0 litres) was then added at 28 - 32 °C. The reaction mixture was heated to 55 - 60 °C. After completion of reaction, the reaction mixture was cooled. The reaction mixture was quenched with water and stirred. Methylene dichloride (4.0 litres) was added and the reaction mixture was stirred for half an hour. The mixture was allowed to settle and the bottom layer was filtered. The product was dried.
Yield: 0.47 kg
% Yield: 67.8%.
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Example 3: Preparation of compound of formula (XXVIII)
Water (10.0 litres) was added to sodium bicarbonate (2 kg; 23.69 moles) and potassium ferricyanide (2.5 kg; 7.59 moles). A mixture of 5-Hydroxy-N-(4-hydroxyphenethyl)-2-bromo-4-methoxy-N-methylbenzamide (XXVII) (1 kg; 2.63 moles) ethylene dichloride (250 litres) and tetrabutyl ammonium bromide (0.086 kg;0.267 moles), were added to the above mixture with fast stirring. The reaction mass was heated to 60-70°C and refluxed for 3-4 hours. The reaction mixture was filtered and washed with ethylene dichloride (15.0 litres). The ethylene dichloride layer was separated. The aqueous layer was extracted with ethylene dichloride (1.0 litre). The ethylene dichloride layer was concentrated. The thick residue was diluted under stirring with n-hexane (18.0 litres). The mixture was stirred for 30 minutes, and the solid separated out was filtered and dried.
Yield: 0.5 kg
% Yield: 50%.
Example 4-A: Preparation of compound of formula (XXIX)
The cyclised product (XXVIII) (1.0 kg; 2.64 moles) was added to tetrahydrofuran (10 litres) at 25-30 °C. L-Selectride (4 litres) was added dropwise to the cooled reaction mixture at -15° to -10°C. After completion of reaction, methanol (1.0 litres) was added. The reaction mixture was concentrated and water (5.0 litres) followed by methylene dichloride (5.0 litres) were added. The solid was filtered through hyflo. The methylene dichloride was separated. The aqueous layer was extracted with methylene dichloride (1.5 litres). The solvent was distilled out completely. The slurry was triturated with isopropyl alcohol (2.5 litres) and stirred for 30 minutes at 28 - 32 °C. The solid was filtered and dried 28-32°C under vacuum for 6-7 hours.
Yield: 0.8 kg % Yield: 79.36%.
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Example 4-B: Preparation of compound of formula (XXIX)
The cyclised product (XXVIII) (50.0g; 0.132 moles), diglyme (50 ml) and methanol (200 ml) were charged in a round bottom flask. The reaction mixture was cooled to 0-5° C. Sodium borohydride (12.5 g; 0.3289 moles) was added maintaining the temperature. The reaction mass was maintained below 5° C for 2-3 hours. After completion of the reaction the mass was quenched with water. Methylene dichloride (400 ml) was added with stirring. The organic layer was separated and degassed under vacuum. The crude solid was purified by column chromatography.
Example 5-A: Racemic Galanthamine (I)
Tetrahydrofuran (10 litres) and compound (XXIX) (1.0kg; 2.63 moles) were charged into a round bottom flask and stirred at 28 - 32 °C. Vitride (2.3 litres; 7.8 moles) was added dropwise at 28 - 32 °C and the reaction mass was refluxed for 2 to 3 hours. After completion of the reaction, the reaction mixture was cooled to 28-32 °C. Methanol (1.5 litres) was added dropwise and stirred for 30 minutes. The reaction mixture was concentrated under vacuum at 40 - 50° C. Water (5.0 litres) and methylene dichloride (5.0 litres) were added and stirred for 30 minutes. The reaction mixture was filtered and washed with methylene dichloride (3 litres). The organic layer was separated and the aqueous layer was extracted with methylene dichloride (2.0 litres). The methylene dichloride layer was concentrated under vacuum at28-32°C. Yield: 0.67 kg % Yield: 90%.
Example 5-B: Racemic Galanthamine (I)
Toluene(5 litres) and compound (XXIX) (1.0kg; 2.63 moles) were charged into a round bottom flask and stirred at 28 - 32 °C. Vitride (2.3 litres; 7.8 moles) was added dropwise at 28 - 32 °C and the reaction mass was refluxed for 2 to 3 hours. After completion of the reaction, the reaction mixture was cooled to 28-32 °C. The reaction
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mixture was filtered and washed with methylene dichloride (5 litres). The organic layer was separated and the aqueous layer was extracted with methylene dichloride (10.0 litres). The methylene dichloride layer was concentrated under vacuum at 28 - 32 °C.
Example 5C: Racemic Galanthamine (I)
In a round botom flask, was prepared the solution of tetrahydrofuran (140 ml) and compound of formula (XXIX) (10 gm) under stirring. Lithium aluminum hydride (3.0 gm) was added slowly to the reaction mixture. The temperature of the reaction was slowly raised in an hour. The temperature was maintained at 60-65°C for a period of 3-4 hours. After completion of the reaction, the reaction mixture was cooled at 0-5°C. To the reaction mixture ethyl acetate was added dropwise and stirred for thirty minutes. To the reaction mixture, water (10 ml) was added and stirred. The reaction mass was filtered. The residue was washed with ethyl acetate. The ethyl acetate layer was concentrated completely to give 5.1 gm of compound. Yield: 5.1 gm % Yield: 68.0%.
Example 6: (-) Galanthamine (II)
Methanol (2.0 litres) and racemic galanthamine (I) (1 kg; 3.48 moles) were charged in a round bottom flask. Di-p-tolyl tartaric acid (1.32 kg; 3.48 moles) was added to the mixture at 28 - 32 °C and stirred for 1 hour. The reaction mixture was cooled to 0 - 5 °C and stirred at 0 - 5 °C for 24 hours. The solid was filtered and dried. The solid was charged in water (5.0 litres). The pH was adjusted to 9-10 with 25% aq. ammonia solution (0.24 litres). The product was extracted using methylene chloride (4.5 litres). The methylene chloride layer was concentrated completely under vacuum. Yield: 0.3 kg % Yield: 30%.
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Reprocessing in case of chiral purity failure of galanthamine tartarate salt:
Example 6a: Recrystallization of Galanthamine tartarate.
The failing (-) Galanthamine tartarate salt (optical purity 96.64% ee) was charged with methanol (25 ml). The reaction mixture was heated to 60-65°C for 30 minutes. The reaction mixture was cooled to 0-5°C. The solid was filtered and suck dried. Chiral Purity- 98.47%.
Example 6b: Conversion of Galanthamine tartarate to Galanthamine free base:
(-) Galanthamine tartarate salt (5 g; 0.0074 moles) (96.64% ee), water (15 ml) and methylene chloride (10 ml) were charged together in a round bottom flask. Aqueous ammonia solution (2 ml) was added dropwise under stirring till the pH of the aqueous solution reached to 9 to 9.5 and stirred for 15 minutes at 25-27° C. The organic layer was separated. The aqueous layer was extracted with methylene dichloride (20 ml). The organic layer was concentrated. Yield: 1.9 g % Yield: 89.2%.
Example 6c: Conversion of Galanthamine free base to Galanthamine tartarate salt:
To the residue of example 6b, methanol (4 ml) was added and stirred for 15 minutes for complete dissolution. Charcoal (norrit, 0.1 g) was added and stirred for 30 minutes at 25-27 °C. The charcoal was filtered through hyflo and washed with methanol (5.0 ml). p-Di-tolyl tartaric acid (2.5 g; 0.0064 moles) in methanol (10 ml) was added at 28 - 32 °C and stirred at 28 - 32 °C for 1 hour. The reaction mixture was cooled to 0 - 5 °C and stirred at 0 - 5 °C for 24 hours. The solid was filtered and washed with chilled methanol (lml) and dried. Chiral Purity- 98.23% ee.
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Example 6d: Conversion of Galanthamine tartarate to galanthamine free base:
Water (10 ml) was added in a round bottom flask followed by addition of galanthamine-tartarate salt obtained in example 6c. The pH of the reaction mixture was adjusted to 9-10 with 25% ammonia solution (2.0 ml) and extracted with methylene dichloride (30 ml). The methylene dichloride layer was separated and concentrated under vacuum. Yield 1.5 g % Yield: 78.9%.
Example 6e: Conversion of Galanthamine free base to galanthamine hydrobromide:
(-) Galanthamine free base (1.5g; 0.0052 moles), obtained in example 6d was added in ethanol (11.0 ml) and stirred for 15 minutes for dissolution. Charcoal (norrit) was added and stirred for 30 minutes at 25-32°C. The reaction mixture was filtered and washed with ethanol (4.0 ml). The filtrate was concentrated up to 6 volumes and hydrobromic acid (0.7 ml; 0.004148 mole) was added dropwise at 25-32 °C and stirred for 30 minutes at 25 - 32 °C. The reaction mixture was then cooled to 0 °C to 5 °C and stirred at 0-5 °C for 2 hours. The solid obtained was filtered, dried and then washed with chilled ethanol (0.5 ml). The solid was dried under vacuum at 25-32°C.
Yield: 1.9 g % Yield: 98.9%.
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Example 7: (-) Galanthamine Hydrobromide.
(-) Galanthamine (II) (1 kg; 3.48 moles) obtained from Example 6, was dissolved in ethanol (6.0 litres). Hydrobromic acid 48% (0.58 litres; 3.48 moles) was added dropwise at 25-32 °C. The reaction mixture was stirred for 30 minutes at 25 - 32 °C. The reaction mixture was cooled to 0 °C and stirred at 0-5 °C for 2 hours. The solid was filtered and dried under vacuum at 25-32°C.
Yield: 1.13 kg
% Yield: (88%).
Reprocessing in case of chiral purity failure of galanthamine hydrobromide:
Example 7a: Conversion of Galanthamine HBr to Galanthamine free base:
(-) Galanthamine hydrobromide (43.Og; 0.11 moles) (optical purity 96.34%), water (130.0 ml) and methylene chloride (75.0 ml) were charged in a round bottom flask together. Aqueous ammonia solution (20.0 ml) was added dropwise under stirring till the pH of the aqueous solution reached to 9 to 9.5. The mixture was stirred for 15 minutes at 25-27 °C. The organic layer was separated and the aqueous layer was extracted with methylene dichloride (150.0 ml). The organic layer was concentrated.
Example 7b: Conversion of Galanthamine free base to Galanthamine Tartarate Salt:
Methanol (50.0 ml) was added to the residue of example 7a and stirred for 15 minutes for complete dissolution. Charcoal (norrit) was added to the reaction mixture and stirred for 30 minutes at 25-27 °C. The mixture was filtered and washed with methanol (15.0 ml). p-Di-tolyl tartaric acid (43.0 g; 0.11 moles) in methanol (175 ml) was added at 28 -
29

32 °C and the mixture was stirred at 28 - 32 °C for 1 hour. The mixture was cooled to 0 - 5 °C and stirred at 0 - 5 °C for 24 hours. The solid was filtered, washed with chilled methanol (20.0 ml) and dried.
Example 7c: Conversion of Galanthamine tartarate salt to Galanthamine free base:
Water (130.0 ml) was charged to above galanthamine-tartarate salt obtained in example
7b. The pH of the mixture was adjusted to 9-9.5 with 25% ammonia solution (20.0 ml).
Further extraction was carried with methylene dichloride (150.0 ml). The methylene
dichloride layer was concentrated completely under vacuum.
Yield: 26 g
% Yield: 77.54%.
Example 7d: Conversion of galanthamine free base to galanthamine Hydrobromide:
Ethanol (200.0 ml) and (-) galanthamine free base (26 g; 0.09 moles) obtained from example 7c, were charged in a round bottom flask and stirred for 15 minutes till dissolution. Charcoal (norrit) was added and stirred for 30 minutes at 25-32°C. The charcoal was filtered through hyflo and washed with ethanol (60.0 ml). The solution was concentrated under vacuum to 6 volumes. Hydrobromic acid (13.0 ml; 0.0770 moles) was added dropwise at 25 - 32°C and stirred for 30 minutes at 25 - 32°C. The reaction mixture was cooled to 0 °C to 5°C and was stirred at 0-5°C for 2 hours. The solid was filtered. The solid was washed with chilled ethanol and dried under vacuum. Yield: 31 g
%Yield: (93%).
(Optical purity 100% ee)
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Example 7e: Conversion of galanthamine tartarate salt with passing optical purity to galanthamine hydrobromide salt with passing optical purity:
(-) Galanthamine tartarate salt (5.0 g; 0.0074 moles) (optical purity = 98.4%) and ethanol (25 ml) were charged in a round bottom flask while stirring. Hydrobromic acid (3.5 ml) was added and the reaction mixture was further stirred for 1-2 hours. The reaction mixture was cooled to 5-10°C. The solid was filtered and suck dried well.
Yield: 2.7 g
%Yield: (99%)
(Optical purity 99.01% ee)
Reprocessing in case of chemical purity failure of galanthamine hydrobromide;
Example 7f: Conversion of Galanthamine Hydrobromide to galanthamine free base
(-) Galanthamine hydrobromide (5.0 g; 0.1358 moles) obtained (RS purity 98.90%), water (15.0 ml) and methylene dichloride (15.0 ml) were charged in a round bottom flask. Aqueous ammonia solution (2.0 ml) was added dropwise under stirring till the pH of the aqueous solution reached to 9 to 9.5. The mixture was stirred for 15 minutes at 25-27 °C. The organic layer was separated and the aqueous layer was extracted with methylene dichloride (30.0 ml). The organic layer was concentrated to a residue.
Yield: 3.8 g % Yield: 97.4%.
Example 7g: Conversion of Galanthamine free base to Galanthamine HBr:
31

(-) Galanthamine free base (3.8 g; 0.0132 moles), obtained from example 7e was added to ethanol (30.0 ml) and stirred for 15 minutes till dissolution. Charcoal (norrit) was added and stirred for 30 minutes at 25-32 °C. The mixture was filtered and washed with ethanol (8.0 ml). The solution was concentrated under vacuum to 6 volumes. Hydrobromic acid 48% (1.8 ml; 0.015 moles) was added dropwise at 25 - 32 °C and stirred for 30 minutes at 25 - 32 °C. The mixture was cooled to 0 °C to 5 °C and stirred for 2 hours. The solid was filtered and dried under vacuum. The solid was washed with chilled ethanol (1.0 ml) and dried under vacuum at 25 - 32 °C.
Yield: 4.8g
% Yield: 98.56%
(RS purity 99.53%)
32

Claims: -
1. The selective reduction process for preparation of galanthamine which involves: a) use of a reducing agent to reduce the ketone functionality,

b) use of a reducing agent to reduce the amide functionality.

2. The process according to claim la, wherein the reducing agent used for reduction of the ketone group is selected from the group comprising of L-Selectride, K- Selectride, KS- Selectride, LS- Selectride, DiBAL, REDAL, 9-BBN, NaBH4, sodium-cyanoborohydride, CBS/NaBH4, CBS/BH3.H2S, BH3.H2S .
3. The process according to claim 2, wherein the reducing agent used for reduction of the ketone group is L-Selectride.
4. The process according to claim 2, wherein the reducing agent used for reduction of the ketone group is sodium borohydride.
5. The process according to claim lb, wherein the reducing agent used for the reduction of the amide functionality is Vitride.
6. The process according to claim lb, wherein the reducing agent used for the reduction of the amide functionality is Lithium Aluminium Hydride.
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7.
8. The process according to claim 1, wherein the amide formed after reduction is compound of formula (XXIX).
9. The process for preparation of galanthamine salt, wherein the chiral purity of galanthamine salts is increased.
10. The process for preparation of galanthamine salt, wherein the chemical purity of galanthamine salt is increased.
11. The process according to claim 5 wherein, the chiral purity of galanthamine salt is increased comprising the steps:

a) converting galanthamine tartarate salt with unpassing chiral purity to galanthamine free base;
b) converting free base to tartarate;
c) converting galanthamine tartarate to galanthamine free base;
d) converting free base to galanthamine hydrobromide.

12. The process according to claim 5 wherein, the chiral purity of galanthamine tartarate salt is increased by making use of recrystallisation of galanthamine tartarate salt with unpassing chiral purity by making use of solvents like ketones, esters, amides, aldehydes, alcohols, water, hydrocarbons etc.
13. The process according to claim 5 wherein, the chiral purity of galanthamine hydrobromide salt is increased comprising the steps:

a) conversion of galanthamine hydrobromide with unpassing chiral purity to galanthamine free base;
b) conversion of galanthamine free base to galanthamine tartarate;
c) conversion of galanthamine tartarate to galanthamine free base;
d) conversion of galanthamine free base to galanthamine hydrobromide salt
14. The process according to claim 6 wherein, the chemical purity of galanthamine
hydrobromide salt is increased comprising the steps:
a) conversion of galanthamine hydrobromide with unpassing chemical purity to galanthamine free base;
b) conversion of galanthamine free base to galanthamine hydrobromide.
34

15. The process for the conversion of galanthamine tartarate salt to galanthamine hydrobromide salt and the process for increasing the chiral purity of galanthamine salt as substantially described herein.
16. The compound of formula (XXIX),
OH


as substantially described herein.

35

ABSTRACT
This invention discloses a process for manufacture of galanthamine, which involves a stereo-selective reduction step to get the desired isomer of galanthamine. The current embodiment also discusses the method for improving the chiral and chemical purity of galanthamine and galanthamine salts.