FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PREPARATION OF NAL DERIVATIVES FROM NOROXYMORPHONE"
2. APPLICANT:
(a) NAME: RUSAN PHARMA LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: 58-D, Government Industrial Estate, Charkop, Kandivali (West),
Mumbai - 400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF INVENTION:
The present invention relates to process for conversion of Noroxymorphone (Formula-I) to Nal derivatives of Formula-II & their acid addition salts. The Nal derivatives of the present invention are known to possess narcotic agonist/antagonist properties with very low side effects and find extensive use in chronic pain management as well as treatment for alcohol addiction.
BACKGROUND OF THE INVENTION:
Natural opiates including morphine have been used for many years as potent opiate analgesics. However, these natural opiates have low potency with severe side effects. They are used in high dose to achieve the desired pain control.The high dose used results in several side effects such as nausea, omitting, euphoria, constipation etc. & also leads to habit formation of opiate used. In order to avoid these side effects, recently, semisynthetic opiates (Formula-II), having high potency & low toxicity are developed.
The synthesis of these semi synthetic Nal derivatives (Formula-II) of commercial importance, are known, starting from opium alkloids :Thebaine, Morphine, Codiene and oripavine of formula-Ill (all of them are narcotic/controlled, substances) via norderivatives e.g. 14-hydroxy normorphinone, Noroxycodone, Noroxymorphone, Noroxymorphol etc derived from opium alklods (formula-Ill). The known synthesis being multistep(8-10 Steps) synthesis with long time cycles ,are not ideally suited for commercial exploitation for the manufactureof all 4-products (formula-II) as a group.

Where (A): Mophine → R=H (B) Oripavine → R=H
Codeine →R=CH3 Thebaine → R=CH3
The availability of Noroxymorphone(a non-norcotic/non-controlled substance) in commercial quantities at competitive prices has opened up the possibility of synthesizing

all 4-products in 2 to 3 steps, from noroxymorphone, as common intermediate (Scheme-I) & thus control inventory (without any regulatory hassle) & incorporate flexibility of manufacturing either of the 4-products as per needs of customer & also meet the delivery schedule as per customers requirement.

Scheme -1 A substantial advance has been made in the synthesis of morphine derivatives using Noroxymorphone by introducing suitable alkyl groups at the nitrogen atom.
Noroxymorphone (7,8 dihydro-14-hydroxy normorphinone) which is derived from naturally occurring opiates such as morphine, codiene, oripavine and thebaine, is considered as a potential precursor for the preparation of synthetic opiates bearing the basic frame work with the ring chirality, additional chiral center at C14 as given in formula-I;
Morphinan-6-ols such as nalbuphine is a semi-synthetic narcotic, partial agonist-antagonist analgesic used for the relief of moderate to severe pain. It can also be used as a supplement to balance anesthesia, for preoperative and postoperative analgesia, and for

obstetrical analgesia during labour and delivery. There are many prior arts which disclose the preparation of nalbuphine.
US2010/0036128 disclose catalytic hydrogenation of noroxymorphone with Pt02 or Platinum with support including on carbon. The solvent used is selected from aqueous solvent such as water, a mixture of water and water miscible co solvent such as C1-C4 alcohols, DMF, DMAc, NMP, THF. The base used is aq. sodium hydroxide to maintain the pH in the range of 12.5-13.5).
US2010081818 disclose a process for the conversion of 6-keto morphinan to a 6-[alpha]-hydroxy morphinan in the presence of a ruthenium, rhodium, or iridium asymmetric catalyst and a hydrogen source i.e TEA/formic acid. The solvent preferably is acetonitrile, DMAc or a combination of acetonitrile and methanol. Further, N-alkylation of noroxymorphone is carried out using alkyl bromide in presence of organic or inorganic base and in solvents selected from acetone, acetonitrile, ethyl acetate, DMF, DMAc, NMP, DMSO, etc.
WO2011/021029 discloses hydrogenation of 6-keto group using gaseous hydrogen in the presence of a heterogeneous catalyst consisting of palladium on carbon, rhodium on carbon, platinum on carbon, iridium on carbon, ruthenium on carbon and mixtures thereof and a solvent, to yield the 6-hydroxy morphinan alkaloid, wherein the reduction is carried out preferably at a pH in the range of about 5 to about 7.
GB1119270 discloses in example 5, method(c) reduction of 14-hydroxydihydro-normorphinone to 14-hydroxydihydro-normorphine in presence of NaBH4. Further, 14-hydroxydihydro- normorphine. is treated with cyclobutylmethyl bromide in presence of DMF at 70°C for one week to obtain Nalbuphine.
Naloxone (17-allyl- 4,5a-epoxy- 3,14-dihydroxymorphinan- 6-one) is an opioid antagonist used to counter the effects of opiate overdose, such as heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system.

CA734464 claims N-allylation of noroxymorphone (compound of formula I) with allyl bromide (R'X) in presence of dehydrohalogenating agent such as sodium or potassium bicarbonate or an organic amine such as dimethyl aniline. The solvent used is either methanol or ethanol. Further, conversion to hydrochloride occurs in presence of ethanol and ethanolic hydrochloric acid.
US2010/0256176 describes in the example N-allylation of noroxymorphone hydrochloride with allyl bromide in DMF as solvent and sodium bicarbonate at 60°C, precipitated and concentrated from aq. sodium hydroxide. The hydrochloride salt is obtained by treating naloxone base with acetone and c. HCL
US3393197 titled "Nu-substituted-14-hydroxydihydronormorphines" granted on 16th July, 1968 discloses conversion of noroxymorphone to Nu-substituted-14-hydroxydihydronormorphines wherein in the process step 1 includes reaction of reaction of dihydro-14-hydroxynormorphinone with allyl bromide in presence of solvents such as DMF and tertiary amines like triethyl amine followed by reduction of the keto group to obtain the desired product.
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. Processes for the preparation are known in the art from noroxymorphone.
US3332950 discloses preparation of N-Cyclopropylmethyl-14-
Hydroxydihydronormorphine, wherein, dihydro-14-hydroxynormorphinone is reacted with cyclopropylmethyl bromide in presence of DMF as a solvent at a temperature of 70°C for one week to obtain the desired product in approx. 33-34%. Nalmefene hydrochloride [17-(cycIopropylmethyl)-4,5alpha-epoxy-6-methylene morphinan-3,14diol hydrochloride] is a known opioid receptor antagonist which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonist derived from the opioid system. The clinical usefulness of Nalmefene as antagonist comes from its ability to promptly and selectively reverse the effects of respiratory depression, a side effect when narcotics are administered.

Nalmefene as its hydrochloride has been primarily developed for use in the management of alcohol dependency, for the treatment of other addictions such as pathological gambling and addiction to shopping.
Nalmefene though has structural similarity to opiate antagonist Naltrexone, however, it differs structurally from Naltrexone at C-6 where -C=0 is replaced with =CH2 (methylene group) which considerably increases binding affinity to the u.-opioid receptor. Nalmefene has high affinity for the other opioid receptors (K and 5 receptors) and is known as "universal antagonist' as a result of its ability to block all three receptor types.
Nalmefene is prepared from Noroxymorphone via Naltrexone where the methylene group is inserted at C-6 position using Wittig reaction. The Wittig reaction is a known organic reaction for introduction of olefmic bond into the molecule containing the carbonyl group.
The Wittig reaction consists of two stages where in the first stage a phosphorous ylide is obtained by reaction of suitable phosphonium salt with a base and in the second stage the ylide formed is reacted with a carbonyl compound to obtain the desired alkene.
Prior arts are known for the preparation of Nalmefene by Wittig reaction. The preparation is described by Hahn and Fishman (J. Med. Chem, 1975,18,259-262) where naltrxone is reacted with ylide which is obtained by reacting methyl triphenylphosphonium bromide with sodium hydride in DMSO. An excess of ylide of about 60 equivalents is used for the reaction. It is apparent from the industrial point of use that the method disclosed by Hahn and Fishman is industrially not feasible as the reaction uses a large excess of the ylide. This amounts to large production of phosphorous by-products which need to be removed as it may have undesirable effect on nalmefene purity. Further, the use of sodium hydride as a base is difficult to handle as it is highly inflammable. The nalmefene free base obtained by Hahn and Fishman process is isolated by chromatography.
US4535157 disclose the preparation of nalmefene by combining potassium t-butoxide and methyltriphenylphosphonium bromide in presence of tetrahydrofuran to obtain the

ylide and further reacting with naltrexone. About 3 equivalents of ylide are employed in the process. Though the said patent does not use sodium hydride as a base, the process does have certain disadvantage specifically in the use of water soluble THF as a solvent. There is a chance of considerable loss of the end product nalmefene during the multiple extractions using water leading to low yields, unless re-extraction is carried out using water immiscible solvent. Further, multiple purification steps are carried out to remove phosphine -oxide impurity. The process disclosed in said patent thus uses high volume of solvents, there is extensive operational costs making the process costly and industrially not favorable.
US4751307 discloses preparation of nalmefene by Wittig reaction in presence of anisole as solvent and potassium t-butoxide as base. About four equivalents of ylide are used in the process. The product formed is isolated by extraction in water at acidic pH and then precipitating at basic pH to obtain nalmefene base.
WO2010/136039 disclose preparation of Nalmefene hydrochloride from Naltrexone in a Wittig reaction where MTHF is used both in the formation of ylide and subsequent reaction with the carbonyl compound. In said patent, the molar ratio of phosphonium salt, MTPPB and MTHF ranges from about 1 : 1 to about 4:1, more preferably about 3:1. For formation of ylide, equimolar ratio of MTPPB and the base potassium t-butoxide are used. The amount of MTHF relative to naltrexone (v/w) used is in the range of 2:1 to about 6:1. The use of 2-methyltetrahydrofuran though provide efficient phase separations during the aqueous work up and reducing the loss of the product formed when THF is used as solvent (US4535157), it is a costly solvent, and it is necessary to maintain low temperature as it is "inversely soluble" in water. That is, it has a unique property having decreasing solubility with increasing temperature. Moreover, low temperature needs to be maintained throughout the process to achieve high solubility which on large scale is difficult.
The preparative processes for the preparation of synthetic opiates mentioned above still require improvements from industrial purposes and the therapeutic advantages of said opiates. It is therefore desirable to seek a commercially feasible route that overcomes the

drawbacks of the said processes and produces the desired compounds in good yield and purity through improved process conditions. Moreover, an improvement in the Wittig reaction employed for the preparation of nalmefene from naltrexone is needed to obtain the product in good yield and purity.
Solvents may sometimes be a critical parameter in the synthesis process. Appropriate selection of solvents associated with low toxicity, high solubility, easier separations from the reaction mixture become necessary to effect commercially, industrially feasible process and which may enhance the yield and purity of the desired product. Further, in the preparation of nalmefene as seen above in prior art processes, large equivalents of ylide used in the process lead to formation of undesirable phosphorous impurities and hence wastage of the reagents. It is in this respect that the present invention proposes to provide an improved Wittig process for the preparation of nalmefene from naltrexone that overcomes the drawbacks of the known procedures and improves upon in the choice of solvent and reaction conditions which will make the process more desirable.
SUMMARY OF THE INVENTION:
In view of the above requirements, the present invention discloses an improved, efficient, selective process for the preparation of Nal derivatives of formula (II) and their acid addition salts from noroxymorphone (Formula I) in good yield and purity.

Formula-I Formula-II
Nalbuphine→ R=H, R*=Cyclobutylmethyl, X= a-OH Naloxone → R=H, R= Allyl, X- O Naltrexone → R=H, R-Cyclopropylmethyl, X=0
Nalmefene → R=H, R'=Cyclopropylmethyl, X- CH2


In an aspect, the present invention provides a short, efficient, selective process for the preparation of Nal derivatives of formula II,
II wherein, R is H; Rl represents allyl, cyclopropylmethyl, cyclobutylmethyl; X is 'O',
'CH2' or 'a-OH' and represent either a double bond or a single bond; from noroxymorphone (Formula I) comprises;
a. N-alkylation of noroxymorphone/ a compound of Formula I; with an alkyl
halide R'-M; wherein R' is selected from allyl, cyclopropylmethyl, & M is
selected from CI, Br; in presence of triethylamine and optionally a high
boiling solvent (>100°C) to obtain the crude base selected from naloxone or
naltrexone;
b. optionally reducing selectively noroxymorphone to a-noroxymorphol prior to
N-alkylation of a-noroxymorphol with R'-M, where R' is cyclobutylmethyl &
M is Br; to obtain the crude base nalbuphine; and
c. isolating and purifying the crude base.
In another aspect, the present invention further provides a process for the preparation of Nalmefene from Naltrexone obtained from the process described above.
The Nal derivatives obtained by the process of the present invention may be formulated into pharmaceutical composition along with pharmaceutically acceptable excipients for treatment of chronic pain management as well as for treatment for alcohol addiction.
DETAILED DESCRIPTION OF THE INVENTION:

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
The present invention provides an improved, short, efficient, selective process for the preparation of NAL derivatives of Formula-II in good yield and purity from noroxymorphone (Formula I).

wherein, R is H; Rl represents allyl, cyclopropylmethyl, cyclobutylmethyl; X is 'O', 'CH2' or 'a-OH' and represent either a double bond or a single bond;
The compounds of Formula-II are important as therapeutic agents being non-addicting, having analgesic properties in addition to agonist/ antagonist properties. Hence, the present inventor has further researched to provide a process for the preparation of these complex Nal derivatives by using noroxymorphone derived from opium alkaloids and specific solvents, reagents and reaction conditions to get the desired product.
In this context, the present invention is therefore specifically directed to provide a short, efficient process that employs noroxymorphone derived from optimum and specific solvents, reagents and reaction conditions to get the desired products of formula-Il, in 2 to 3 steps & thus providing a process which is cost effective & suitable for commercial exploitation as a group of these Nal derivatives.
Particularly, the invention encompasses suitable substitution at the nitrogen atom of Noroxymorphone using suitable and specific reagents, reaction conditions to make the process commercially feasible. Moreover, choice of Noroxymorphone (Non-narcotic/Non-controlled substance) as the starting compound eliminates the difficulties such as, regulatory hassles,

removal of N/O-methyl group, introduction of 14-hydroxy group, occurring in the natural opiates (Narcotic/Controlled substances) which involves regulatory control on storage & handling of these opiates & thus limiting the use of these opiates.
Consequently, in an embodiment, the improved, short, efficient and selective process for the preparation of compounds of Formula-II,

11
wherein, R is H; Rl represents ally], cyclopropylmethyl, cyclobutylmethyl; X is '0\ 'CH2' or
'α'-OH' and represent either a double bond or a single bond; from noroxymorphone comprises;
a. N-alkylation of noroxymorphone a compound of Formula I; with an alkyl
halide R'-M; wherein R' is selected from allyl, cyclopropylmethyl,
cyclobutylmethyl & M is selected CI, Br; in presence of triethylamine and
optionally a high boiling solvent (>100°C) to obtain the crude base
selected from naloxone or naltrexone;
b. optionally reducing selectively noroxymorphone to a-noroxymorphol prior
to N-alkylation of a-noroxymorphol with R'-M, where R' is
cyclobutylmethyl & M is Br; to obtain the crude base nalbuphine; and
c. isolating and purifying the crude base.
The base so obtained may be converted to its pharmaceutical acceptable acid addition salt.
Examples of the high boiling solvent that are suitably used in combination with the base triethylamine include either aromatic hydrocarbons such as substituted benzene such as

,Where R"=H, C-l to C-4 mono or di-alkyl group substituted at 1,2 or 1,3 or

1,4 etc. e.g. benzene, toluene, xylenes; ethyl,/propyl,/butyl, benzenes etc. or aprotic solvent such as DMSO. The solvent may be substituted with an excessive amount of the organic base.
The reaction temperature is adapted to suit the scope of temperature of the reaction with minimal degradation or by-product formation.
The crude product so obtained is further isolated and purified by methods such as extraction, crystallization using solvents such as water, ketonic solvent like acetone, halogenated hydrocarbons and like. The purified base may further be converted to its acid addition salt.
In one of the embodiment, the present invention provides a process for the preparation of naloxone from noroxymorphone including the following steps;
a. adding noroxymorphone, triethylamine(2-3equv) and allyl bromide to aromatic
hydrocarbon solvent(2-7V), heating at reflux for about 12 hours till completion
of reaction;
b. pouring the reaction mass into water, filtering and drying to obtain the crude
base;
c. purifying the crude base of step (b) in a ketonic solvent to yield pure naloxone.
d. Naloxone pure is converted to it's hydrochloride salt by treating with acetone-
HC1 by a process known in the art.
Scheme 2
The process is depicted in Scheme 2 below:


According to scheme 2, toluene is added Noroxymorphone, Triethyl amine and Allyl bromide at 25-30°C and heated to 95-100°C for about 7 hrs. After completion of the reaction, the reaction mass is poured into water and the solid separated is filtered and dried to give crude base. The crude mixture is purified by dissolving in acetone to obtain pure base.
In another embodiment, the present invention provides a process for the preparation of nalbuphine from noroxymorphone which includes;
a. reducing noroxymorphone selectively to a-noroxymorphol by a process known in
the art;
b. adding, cyclobutyl methylbromide (1.5-2equv) and triethylamine (2-2.5equv) to a-
noroxymorphol of step (a);at room temperature and further heating to 80-85 °C for
about 10 hours till completion of reaction to obtain nalbuphine;
c. cooling the reaction mass of step (b) slowly to room temperature followed by
washing with water, filtering and drying.
d. purifying crude nalbuphine of step (c) by crystallizing from alcoholic solvent
cooling, filtering & drying to obtain pure nalbuphine, and
e. converting nalbuphine to it's hydrochloride salt using THF-HC1, according to a
process known in the art.

Scheme 3
The process is given below in Scheme 3:

To a solution of Triethyl amine is added a-Noroxymorphol (obtained from noroxymorphone by a process known in the art) and cyclobutyl methyl bromide at room temperature. The mixture is heated to 80-90°C for 10 hrs. After the reaction is complete, the reaction mass is cooled slowly to room temperature followed by addition of water to the reaction mass. The mixture is stirred for 1 hr at 30-35°C , filtered and further washed with water followed by drying under reduced pressure. The crude nalbuphine is further purified by crystallizing from alcoholic solvent followed by cooling, filtering & drying to obtain pure nalbuphine which is converted to its pharmaceutically acceptable hydrochloride salt by a process known in the art.
In yet another embodiment of the instant invention, the process for the preparation of Naltrexone comprises;
a. adding noroxymorphone, triethylamine(l-5equv), cyclopropyl methyl bromide(l-
3equv) and DMSO(2-7V), heating at 50-55°C for about 10 hours till completion
of reaction;
b. cooling to room temperature, pouring the reaction mass onto aq. HC1 followed by
basifying with liquor ammonia, extracting in halogenated hydrocarbon solvent;
c. separating unreacted noroxymorphone from aq. layer, distilling the solvent and
purifying crude naltrexone.
The process is given below in Scheme 4:

Scheme-4
As per scheme 4, to a solution of DMSO is added Noroxymorphone, Triethyl amine and cyclopropyl methyl bromide in 5 lots under stirring at 50-55°C. The reaction mass is stirred for 10 hrs at 50-55°C. After the reaction is complete, the reaction mass is cooled to

room temperature and poured onto aqueous HC1 solution. It is then basified with liquor ammonia and extracted with halogenated hydrocarbon such as methylene dichloride. Unreacted insoluble noroxymorphone is separated from aqueous layer. The solvent methylene dichloride is distilled out completely the crude mixture which is further purified by dissolving in acetone.
In yet another embodiment, the present invention provides a process for the preparation of nalmefene from naltrexone using improved Wittig reaction.
The improvement is done in the use of less toxic DMSO than other members of this class, such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrroIidone, and HMPA, is also high boiling. DMSO dissolves both polar and non-polar compounds, being weakly acidic can tolerate relatively strong bases and can be used in the preparation of ylide. The use of DMSO leads to highly efficient process for the preparation of nalmefene. DMSO is used in the formation of ylide and for dissolving naltrexone.
Accordingly, in an embodiment, the improved process for preparing nalmefene from naltrexone is characterized in the following steps which include;
a. dissolving equhrtolar methyltriphenylphosphonium bromide (MTPPB) and
potassium tertiary butoxide in dimethyl sulfoxide (DMSO) wherein the ratio of
the solvent relative to the phosphonium salt (MTPPB) is in the range of 0.8 (v/w)
at 17-20°C with stirring for about 2 hours to obtain ylide;
b. adding solution of naltrexone base dissolved in DMSO (2V ) dropwise at room
temperature to the ylide formed in step (1) until completion of reaction to obtain
nalmefene;
c. isolating and purifying the product.
In the process, the steps (a) and (b) may be performed simultaneously in the same vessel or may be performed successively.
In the process, equimolar quantity of methyltriphenylphosphonium bromide (MTPPB) and the base potassium tertiary butoxide are used. The mixture is added to the solvent,

DMSO where the ratio of the solvent relative to the phosphonium salt (MTPPB) is in the range of 0.8 (V/W)
The reaction of methyltriphenylphosphonium bromide (MTPPB) and the base potassium tertiary butoxide results in formation of ylide. The amount of DMSO relative to Naltrexone is in the range of 1.5-3V. Accordingly, Naltrexone dissolved in DMSO (2V) is reacted with ylide to obtain nalmefene.
After completion of the reaction and prior to extraction, decomposition of the product is done with saturated ammonium chloride solution to bring the pH of the solution to approx. 8. The solution is extracted using a solvent that allows the impurities to remain in the solution and permits the preparation of hydrochloride salt. The solvent is selected from alcohols, ethers, ketones, halogenated hydrocarbons; preferably halogenated hydrocarbons such as chloroform, methylene dichloride etc; preferably chloroform. The product obtained after extractions is washed with water, dried and purified by forming its hydrochloride salt in halogenated hydrocarbon to remove unwanted impurities. The crude hydrochloride salt is basified and purified by column chromatography.
Thus, according to the process, to a solution of DMSO is added potassium tertiary butoxide and methyltriphenylphosphonium bromide and the mixture is stirred for 2 hrs at 17-20°C, where the ratio of the solvent relative to the phosphonium salt (MTPPB) is in the range of 0.8 (V/W). This is followed by addition of solution of Naltrexone base dissolved in DMSO dropwise to the reaction mass. The mixture is stirred for about 6 hrs at 25-30°C until completion of reaction is indicated by TLC. The reaction mass is quenched with saturated ammonium chloride solution and extracted in a halogenated hydrocarbon. The organic layer is washed with water and dried over sodium sulphate, concentrated and further purified by forming crude hydrochloride salt in a halogenated hydrocarbon such as chloroform for removing impurities like ylides, bisnalmefene and phosphonium oxides. The crude hydrochloride salt is again converted into base and purified by column chromatography using silica.

Further, Nalmefene obtained may be converted to its pharmaceutical addition salt, preferably its hydrochloride salt. The hydrochloride salt is obtained by reacting Nalmefene free base dissolved in acetone with hydrochloric acid. The reaction is carried out at a temperature 0-50°C for one hour.
The process of the instant invention is given below in Scheme5:

Scheme-5:
Thus, as seen from above, the present invention meets the objective for the synthesis of complex Nal derivatives of formula II using a simple, commercially feasible process. The said Nal derivatives of formula II are known to possess narcotic agonist/antagonist properties with very low side effects & find extensive use in chronic pain management as well as treatment for alcohol addiction.
The Nal derivatives obtained by the process of the present invention, including naloxone, naltrexone, nalmefene and nalbuphine may be formulated into pharmaceutical composition along with pharmaceutically acceptable excipients.
The present invention relates to the use of the compound of Formula II and its pharmaceutically acceptable salts for chronic pain management as well as for treatment of alcohol addiction.
The present invention provides a method of treatment or prevention of chronic pain or alcohol addiction to a subject by administering an effective amount of the compound of Formula II along with one or more suitable pharmaceutical carriers/exicipients in suitable dosage forms. Active ingredient(s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.

Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
Example-1: Preparation of Naloxone
To a solvent, Toluene 5 volume (500 ml) is added Noroxymorphone 100 g (0.348 mole), Triethyl amine (0.696 mole) and Allyl bromide (0.522 mole) at 25-30°C and further heated to 95-100°C for 7 hrs. After the reaction is complete, reaction mass is poured into water. Solid is filtered and dried to give crude base. Yield 109 g (95.6%) with HPLC purity 96.05%, m.p.: 168-172°C. The crude mixture is purified by 1.22 volume acetone to give 85% pure base with HPLC purity 98.7% m.p.: i75-l78°C.
Example-2: Preparation of Naloxone
To a solvent, Xylene 5 volume (250 ml) is added Noroxymorphone 50 g (0.17 mole), triethyl amine 35.19 g (0.348 mole) and Allyl bromide 31.61 (0.26 mole) at 25-30°C and heated to 130-140°C for 10 hrs. After completion of the reaction, reaction mass is poured into water. Solid is filtered and dried to give crude base. Yield: (82 %) with HPLC purity 87.24% which on purification with acetone produce pure base with 70% yield, m.p.: 176-178°C.
Example-3: Preparation of Nalbuphine A: Preparation of a-Noroxymorphol
Preparation of a-Noroxymorphol from Noroxymorphone was carried out following known method (ref. used: US 2010/0036128)
B: Preparation of Nalbuphine
To a solution of Triethyl amine 3 volume (15 ml) is added Noroxymorphol 5 g (0.016 mole), Cyclobutyl methyl bromide 4.8 g (0.032 mole) at 25-30°C and heated to 80-90°C for 10 hrs. After completion of reaction, the reaction mass is cooled slowly to 25-30°C followed by addition of water 5V-10V to the reaction mass. Stirred for 1 hr at 30-35°C ,

filtered it and washed with 2 X 3 V water and followed by drying for 8-14 hrs u/v (600-700mm/Hg)at55-60°C.
Yield: (90%). HPLC purity 95.03%.
The nalbuphine base obtained as above is converted to it's hydrochloride salt (pharmacopoiel grade) by a known process ((ref. used: US 2010/0036128; US 2010081818; WO2011/021029).
ExampIe-4: Preparation of Naltrexone
To a solution of DMSO 3 volume (300 ml) is added Noroxymorphone 100 g (0.346 mole), Triethyl amine 100 g (0.99 mole) and Cyclopropyl methyl bromide 65 g (0.481 mole) in 5 lots under stirring at 50-55°C temperature. The reaction mass is stirred for 10 hrs at 50-55°C. After the reaction is complete, the reaction mass is cooled to room temperature and poured onto aqueous HC1 solution. It is then basified with liquor ammonia and extracted with methylene dichloride 12.5 volume (1250 ml). Unreacted insoluble noroxymorphone is separated from aqueous layer. Methylene dichloride is distilled out completely to yield 107 g (94.89%) with HPLC purity 98.04 %, m.p.: 162-1680C. This crude mixture is further purified by 1.22 volume acetone. Yield: 82% with HPLC purity 99.73%; m.p.: 166-168°C.
The naltrexone obtained as above is converted to it's hydrochloride salt (meeting EP specifications) by a literature known method.
Example-5: Preparation of Nalmefene (ref. used: US 4535157; WO2010/136039)
To a solution of THF (10 volume, 1950 ml) is added potassium tertiary butoxide (296 g, 2.64 mole) and methyltriphenylphosphonium bromide (941.5 g,2.63 mole) and stirred for 2 hr followed by addition of a solution of Naltrexone base (150g,0.439 mole) in THF (3 volume) dropwise. The reaction mass is stirred for 6 hrs. After completion of reaction, reaction mass is quenched with saturated ammonium chloride solution and purified by forming crude Hydrochloride salt in chloroform for removing impurities like ylides,

bisnalmefene and phosphonium oxides. This Crude Hydrochloride salt is again converted into base and purified by column chromatography using silica. Yield: 96% with HPLC purity 99.2%; m.p.: 187-180C.
ExampIe-6: Preparation of Nalmefene (Instant invention)
To a solution of DMSO (5 volume, 25 ml) is added potassium tertiary butoxide (9.87 g, 0.087 mole) and methyltrip'henylphosphonium bromide (31.4 g, 0.087 mole) and is stirred for 2 hrs at 17-20°C. This is followed by addition of solution of Naltrexone base (5 g, 0.014 mole) in DMSO (2 V) dropwise and reaction mass is further stirred for 6 hrs at 25-30°C. After completion of reaction (-90% conversion on TLC), reaction mass is quenched with saturated ammonium chloride solution (15 ml) and extracted with methylene dichloride (50 ml). Organic layer is washed with water and dried over sodium sulphate, concentrated and further purified by forming crude hydrochloride salt in chloroform for removing impurities like ylides, bisnalmefene and phosphonium oxides. The crude hydrochloride salt (yield 96%) is further converted into base and purified by column chromatography using silica. M.p.: 187-190°C.(Iit. 188-190°C,MERCK INDEX)
Example-7: Preparation of Nalmefene Hydrochloride
To the solution of acetone 5 volume (567 ml) is added Nalmefene pure base (113.5 g 0.334 mole) and stirred for 30 minutes at 25-30°C. To this solution is added 35 ml hydrochloric acid drop wise and stirred the reaction mass at 0-50°C for 1 hr. Filtered at 0-50°C and product is washed with chilled acetone (1 volume) followed by drying for 8 hrs u/v (600-700 mm/Hg) at 45-50°C till constant weight. Yield: 97.5%, HPLC purity: 99.11% .Specific optical rotation of 5.0% w/v(water) solution (on anhydrous basis): -165°

We claim,
1. An improved, short, efficient, selective process for the preparation of compounds of Formula II,

wherein, R is H; Rl represents allyl, cyclopropylmethyl, cyclobutylmethyl; X is '0'CH2' or 'ct-OH' and represent either a double bond or a single bond; from
noroxymorphone (Formula I) comprises;
a. N-alkylation of noroxymorphone a compound of Formula I with R'-M
wherein, R' is selected from allyl, cyclopropylmethyl; M is CI, Br; in
presence of triethylamine and optionally a high boiling solvent (<100°C) to
obtain the crude base selected from naloxone or naltrexone;
b. optionally reducing noroxymorphone to a-noroxymorphol prior to N-
alkylation of a-noroxymorphol, with a compound of Formula II, R'-M,
wherein R' is cyclobutylmethyl; M is bromine, to obtain the crude base
nalbuphine; and
c. isolating, purifying the crude base.
2. The improved, short and efficient process according to claiml, wherein the high boiling solvent selected from either aromatic hydrocarbons such as substituted
benzene, ,wherein R" represent independently H, C-l to C-4 mono or di-
alkyl group substituted at 1,2 or 1,3 or 1,4 etc. such as benzene, toluene, xylenes; ethyl,/propyl,/butyl, benzenes etc. or aprotic solvent such as DMSO.

3. The process for preparation of naloxone from noroxymorphone according to claim 1,
comprises;
a. adding noroxymorphone, triethylamine (2-4equv) and allyl bromide(1.5-2.5
eqv) to aromatic hydrocarbon solvent (5-8V), heating at reflux for about 12
hours till completion of reaction;
b. pouring the reaction mass into water, filtering and drying to obtain the crude
mass;
c. purifying the crude mixture of step (b) in a ketonic solvent (1-2V).
4. The process for preparation of naloxone according to claim 3, wherein the aromatic hydrocarbons selected from toluene or xylene.
5. The process for preparation of nalbuphine from noroxymorphone according to claim 1, comprises;
a. reducing noroxymorphone to a-noroxymorphol by a process known in the art;
b. adding noroxymorphol of step (a), cyclobutyl bromide (1.5-2 equv) and
triethylamine(2.2-5equv) at room temperature and further heating to 80-85°C
for about lOhours till completion of reaction;
c. cooling the reaction mass of step (b) slowly to room temperature followed by
washing with water, filtering and drying.
6. The process for the preparation of Naltrexone from noroxymorphone according to
claim 1, comprises;
a. adding noroxymorphone, triethylamine (l-5equv), cyclopropyl methyl
bromide (l-3equv) and DMSO(2- 7 V), heating at reflux for,about 10 hours till
completion of reaction;
b. cooling to room temperature, pouring the reaction mass onto aq. HCI followed
by basifying with liquor ammonia, extracting in halogenated hydrocarbon
solvent;
c. separating unreacted noroxymorphone from aq. layer, distilling the solvent
and purifying the crude product.

7. A process for the preparation of Nalmefene from Naltrexone obtained from step (a)
of claim 1, characterized in the steps comprises;
a. dissolving equimolar methyltriphenylphosphoniurn bromide and potassium
tertiary butoxide in dimethyl sulfoxide (DMSO) wherein the ratio of the
solvent relative to the phosphonium salt (MTPPB) is in the range of 0.8
(V/W) at 17-20°C with stirring for about 2 hours to obtain ylide;
b. adding solution of naltrexone base dissolved in DMSO dropwise at room
temperature to the ylide formed in step (a) until completion of reaction to
obtain nalmefene; and
c. isolating and purifying the product.
8. The improved process for preparing nalmefene according to claim7, wherein the amount of (v/w) of DMSO relative to Naltrexone is in the range of 1.5-3V.
9. The improved process for preparing nalmefene according to claim7, wherein nalmefene is converted to it's hydrochloride in acetone-HCl.