DESC:Technical field of invention
The present invention relates to a short, simplified and eco-friendly process for producing Nalbuphine or its pharmaceutically acceptable salts thereof. In particular, the process of the present invention avoids use of any hazardous, corrosive and pyrophoric chemicals and the resultant product formed is substantially free of impurities.

Background and prior art
Nalbuphine which is chemically known as (–)-17-(cyclobutylmethyl)-4,5a-epoxymorphinan-3,6a,14-triol, a semi-synthetic narcotic used commercially as partial agonist-antagonist analgesic for relief of moderate to severe pain.

It is chemically related to widely used narcotic antagonist, Naloxone, and the potent narcotic analgesic, oxymorphone.

Nalbuphine is synthesized from normorphinan compounds such as noroxycodone, noroxymorphone, noroxymorphol that lack substitution on the nitrogen atom of the heterocyclic ring and contains 14ß-OH group. These normorphinan compounds are derived from naturally occurring opiates such as morphine, codeine, oripavine and thebaine. Nalbuphine is the only opioid analgesic that is not a controlled substance in the United States.

Nalbuphine was first reported in GB1119270 (which has US equivalent, US3393197). Two methods are described in example 5 of GB’270 for the preparation of nalbuphine. Method (a) discloses reaction of 14-hydroxydihydronormorphinone with cyclobutyl carbonyl chloride in DCM followed by reduction using LiAlH4 in THF; whereas method (b) discloses reacting 14-hydroxydihydronormorphinone with cyclobutylmethyl bromide in DMF followed by reduction with NaBH4 to give nalbuphine. The processes are given in Scheme 1 below:

Scheme 1

US4667037 relates to preparation of nalbuphine by demethylation of the precursor using hydrobromic acid as shown in Scheme-2 below:

Scheme 2

Demethylation of N-cyclobutylmethyl-14-hydroxydihydronorcodeine is carried using 48% hydrogen bromide in presence of MgBr2 at reflux for over a 30 to 60 minutes followed by work up to obtain nalbuphine.

WO9532973 discloses the preparation of nalbuphine as shown in Scheme 3 below:

Scheme 3

Accordingly, a-noroxymorphol is reacted with cyclobutanecarbonyl chloride to form N,O3- bis(cyclobutylcarbonyl)-a-noroxymorpholand/orN-cyclobutylcarbony1-a-noroxymorphol followed by reducing the N,O3-bis(cyclobutylcarbonyl)-a-noroxymorphol and/or N-cyclobutylcarbonyl-a- noroxy morphol with LiAlH4 to produce nalbuphine.

Synthetic Communication 1992 discloses demethylation, from its precursor, using DL methionine /methane sulfonic acid.

WO2006035195 discloses the preparation of nalbuphine from noroxymorphone and cyclobutane carboxaldehyde, via reductive alkylation, as shown below in Scheme 4.

Scheme 4
Indian patent application no. 2909/MUM/2009 filed by the present applicant discloses preparation of nalbuphine from thebaine with ß-epimer content less than 0.1%. The process comprises of ten steps. Step VIII relates to conversion of intermediate compound 14-hydroxy nordihydro codeine to N-cyclobutyl carbonyl -14- hydroxy nordihydrocodeine using cyclobutyl carbonyl chloride. This is followed by reduction of N-cyclobutyl carbonyl-14-hydroxy nordihydrocodeine using LiAlH4 to yield N-cyclobutyl methyl-14-hydroxy nordihydrocodeine and further demethylation of hydroxy protected group (at C-3) using hydrobromic acid and sodium bromide to obtain the end product.

Nalbuphine which contain an ortho-alkoxyphenolic moiety can undergo auto oxidative carbon-carbon coupling to yield primarily the 2, 2’ dimer. Further, during synthesis difference in the orientation of the hydroxyl moiety at the 6-position lead to formation of ß-epimer of nalbuphine.

In light of the above, the present inventors observed that there is a scope to develop a more simplified process for synthesis of nalbuphine substantially free of impurities and without using corrosive chemicals like thionyl chloride, hydrobromic acid and pyrophoric chemical such as LiAlH4 and the use of cyclobutyl carbonyl chloride unlike the art.

Further, to avoid the use of corrosive hydrobromic acid used in 3-O-demethylation, the present inventors were inspired to use alkane thiol as demethylating agent which was earlier used by them in their US Patent No. US8981097.

Summary of the invention
In lieu with the aforesaid, there is provided herein a short, simplified and eco-friendly process for producing Nalbuphine or its pharmaceutically acceptable salts, substantially free of impurities, using 14-hydroxy nordihydrocodeine as the starting material.
In an aspect, the process comprises direct condensation of cyclobutyl methyl bromide with 14-hydroxy nordihydrocodeine to obtain methyl nalbuphine.

In another aspect of the invention, the 3-O-demethylation of methyl nalbuphine is performed using alkane thiol in presence of a strong base to yield nalbuphine in good yield and purity.
In yet another aspect, nalbuphine is converted into its hydrochloride salt using conventional methods.

Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention discloses a short, simplified and eco-friendly process for producing nalbuphine or its pharmaceutically acceptable salts, substantially free of impurities, comprising;
a. Condensing 14-hydroxy nordihydrocodeine and cyclobutyl methyl bromide in presence of base, potassium iodide in a solvent at a temperature of 50 to 70°C to obtain methyl nalbuphine; and
b. 3-O-Demethylating methyl nalbuphine with a C2-C7 alkanethiol in presence of base and solvent to yield nalbuphine.

The alkane thiol is selected from the group consisting of straight chain n-alkane thiols, branched chain alkane thiols, cyclic alkane thiols, dithiols, alkali metal salts thereof, and mixtures thereof. Preferably, the alkane thiol is selected from the group consisting of ethanethiol, pentanethiol, heptanethiol, and mixtures thereof.

The solvents for the process are selected from polar protic or aprotic solvents such as ethanol, propanol, isopropanol, DMF, THF, acetone and the like.

The base is selected from organic or inorganic base. The organic base is selected from ethylamine, trimethylamine, pyridine, potassium tertiary butoxide and the like. The inorganic bases are selected from alkali or alkaline earth metal carbonates and bicarbonates.

3-O-demethylation can be performed at a much lower temperature than the prior art method using alkane thiol in presence of base. The lower temperature reduces the formation of undesirable impurity which tends to form when the reaction is performed at a higher temperature for example between 210°C and 220°C. This can impact the yield and purity of the final product.

In an embodiment, the 3-O-demethylation of methyl nalbuphine is carried at a temperature in the range of 120-135°C for 2-4 hrs.

Nalbuphine obtained by the process of the present invention is substantially free of impurities such as methyl nalbuphine, beta-nalbuphine and bisnalbuphine. The use of 14-hydroxy nordihydrocodeine as the starting material also reduces the steps of the process and renders the synthesis economical.

In yet another embodiment, Nalbuphine is converted into its hydrochloride salt using conventional methods.

The details of the invention given in the examples which are provided below are for illustration only and therefore these examples should not be construed to limit the scope of the invention.

Examples:
Example 1:
Preparation of methyl nalbuphine by N-alkylation with cyclobutyl methyl bromide:
Charged 14-hydroxy nordihydrocodeine (53 g), sodium carbonate (50 g), potassium iodide (5.2 g) and cyclobutyl methyl bromide (32.7 g) in 300 mL DMF. The reaction mass was heated to 60°C and maintained for 48 h at the same temperature. The reaction mass was quenched into 3.2 L water maintaining temperature at 25°C, when a solid precipitated. On filtration, methyl nalbuphine was obtained (44 g ; 77 % yield); (HPLC 99.07 %).

Example 2:
Charged 14-hydroxy nordihydrocodeine (120g), sodium carbonate (112.73g), potassium iodide (11.76 g) and cyclobutyl methyl bromide (73.94 g) in 1.2 L DMF. The reaction mass was heated to 55°C and maintained for 40 h at same temperature. The reaction mass was quenched into 5.0 L water maintaining temperature at 25°C, when a solid precipitated. On filtration, methyl nalbuphine was obtained (93.4 g Yield 71.1%); (HPLC 96.17%).

Example 3:
Preparation of Nalbuphine
Potassium tert. butoxide (52.96 g) was added portion wise over a period of 30 minutes to a solution of pentane thiol (43.17 g) in 440 mL DMF at 25 °C. During addition, reaction mass temperature increased to 55°C. Reaction mass stirred for 30 minutes. Then methyl nalbuphine (44 g) was added to reaction mass and the mixture was stirred at 125°C for 2 h. During the process TLC / HPLC shows absence of starting material. Then the reaction mass was quenched by adding slowly into a solution of ammonium chloride (132g) in 2.5 L water, when a solid precipitated. The solid was washed with 500 mL water and 500 mL cyclohexane to give Nalbuphine (38.2 g 90% yield); (HPLC 99.62%).

Example 4:
Potassium tert. butoxide (108.9 g) was added portion wise over a period of 30 minutes to a solution of pentanethiol (88.3 g) in 900 mL DMF at 25 °C. During addition, reaction mass temperature increased to 55°C and the mixture was stirred for 30 minutes. Then methyl nalbuphine (90 g) was added to the reaction mass and the mixture was stirred at 130°C for 3 h. During the process TLC shows absence of starting material. Then the reaction mass was quenched by adding slowly into a solution of ammonium chloride (270 g) in 5 L water, when a solid precipitated. The solid was washed with 1 L water and 1 L cyclohexane to give Nalbuphine (60 g; Yield 69.28%); (HPLC 98.0%).

Nalbuphine base obtained is further converted to its pharmaceutical salt by a method known in the art.

Industrial Advantages:
• Short, simplified and eco-friendly process for producing nalbuphine by avoiding the use of cyclobutyl carbonyl chloride, pyrophoric chemical like lithium aluminium hydride and corrosive chemicals like thionyl chloride (for alkylation) and hydrobromic acid (for O-demethylation).
• The process is simple, employs work up with water, for preparation of nalbuphine during both the alkylation and demethylation stages.
,CLAIMS:1. An eco-friendly process for producing nalbuphine or its pharmaceutically acceptable salts, substantially free of impurities, comprising;
a) Condensing 14-hydroxy nordihydrocodeine and cyclobutyl methyl bromide in presence of base, potassium iodide in a solvent at a temperature of 50 to 70°C to obtain methyl nalbuphine; and
b) 3-O-Demethylating methyl nalbuphine with a C2-C7 alkanethiol in presence of base and solvent to yield nalbuphine.

2. The process according to claim 1, wherein, the alkane thiol is selected from the group consisting of straight chain n-alkane thiols, branched chain alkane thiols, cyclic alkane thiols, dithiols or alkali metal salts thereof, and mixtures thereof.

3. The process according to claim 2, wherein, the alkane thiol is selected from the group consisting of ethanethiol, pentanethiol, heptanethiol, and mixtures thereof.

4. The process according to claim 1, wherein, the solvents for the process are selected from polar protic or aprotic solvents such as ethanol, propanol, isopropanol, DMF, THF, and acetone.

5. The process according to claim 1, wherein, the base is organic base selected from ethylamine, trimethylamine, pyridine, potassium tertiary butoxide or inorganic base selected from alkali or alkaline earth metal carbonates and bicarbonates.

6. The process according to claim 1, wherein, the 3-O-demethylation of methyl nalbuphine is carried at a temperature in the range of 120-135°C for 2-4 hrs.
7. The process according to claim 1, wherein, the Nalbuphine obtained is substantially free of impurities such as methyl nalbuphine, beta-nalbuphine and bisnalbuphine.

8. The process according to claim 1, wherein, the Nalbuphine is optionally converted into its hydrochloride salt.