3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.
Field of Invention:
The present invention relates to an improved process for the preparation of N-substituted- 14-hydroxy-dihydronormorphine derivatives having narcotic agonist/antagonist properties along with analgesic activity. More particularly, the invention relates to an improved process for the preparation of nalbuphine or its pharmaceutically acceptable salt and certain novel intermediates useful in the synthesis.
Background and prior art:
Nalbuphine is a semi-synthetic narcotic, partial agonist-antagonist analgesic which is chemically related to widely used narcotic antagonist, naloxone, and the potent narcotic analgesic, oxymorphone. Nalbuphine hydrochloride is 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 labor and delivery.
Nalbuphine is generally prepared from normorphinan compounds (e.g.Noroxycodone, Noroxymorphone & Noroxymorphol),represented by a general formula-I, that lack substitution on the nitrogen atom of the heterocyclic ring & contains 14P-OH group.

Where: R = H & X= O (Noroxymorphone); R=CH3 & X=0 (Noroxycodone); R= H & X= a-OH (Noroxymorphol) These normorphinan compounds are derived from naturally occurring opiates such as morphine, codiene, oripavine and thebaine represented by a general formula-II;

The key synthetic step in the conversion of naturally occurring opiates (Formula-II) to normorphinans (Formula-!), is the stereoselective introduction of hydroxyl group exclusively from β-phase of the molecule by per acid oxidation. This is possible only if, the substrate contains diene system in ring-C [e.g. Thebaine & Oripavine; Morphine & Codeine needs additional steps like,(protection of C3- OH in Morphine) oxidation of C6- OH in Morphine & Codeine, followed by enolization of the C6-keto gr. to afford diene system in ring-C].These considerations led to selection of Thebaine & Oripavine as preferred synthons. Thebaine being commercially available is commonly used for the commercial synthesis of Nalbuphine.
Article by R. A. Olofson, et al. "A New Reagent for the Selective, High-Yield N- Dealkylation of Tertiary Amines: Improved Syntheses of Naltrexone and Nalbuphine", J. Org.Chem.49, 2081—2082 (1984), teaches the use of a- chloroethyl chloroformate for the demethylation of tertiary amines to secondary amines. It also discloses the synthesis of nalbuphine from 14-hydroxydihydrocodeinone.
US3332950 (Blumberg; Endo laboratories, 1967) discloses preparation of nalbuphine. Blumberg teaches reduction of N.03-bis (cyclobutyl carbonyl)noroxymorphone to nalbuphine. However the process produces β-epimer of nalbuphine as an impurity where the P-content is about 10%.
L.J.Sargent, et.al. demonstrated in J.0rg.Chem.23,1247-1251(1958) a stereospecific sodium borohydride reduction of 14-hydroxycodeinone to 14-hydroxycodeine.This stereospecific conversion of an enone in ring-C (e.g. N,0-bis(alcoxycarbonyl)-14- hydroxynormorphinone] of opiate derivatives to corresponding allylalcohol[N,0- bis(aIcoxycarbonyl)-14-hydroxynormorphine],is disclosed in US 5756745. US5756745 also discloses the use of N,0;Bis-substituted-14-hydroxy normorphinone as starting intermediate compound (obtained from Morphine) for the preparation of Nalbuphine . The protective groups are selected from alcoxycarbonyl, aryloxycarbonyl or aiylmethyl moiety that can be readily removed by hydrolysis or hydrogenolysis. The process includes producing N,0-bis(alcoxycarbonyl)-14-hydroxynormorphine & a- noroxymorphol obtained by stereospecific NaBH4 reduction of enone, followed by reduction of double bond, hydrolysis of ethyloxycarbonyl group, acylation with cyclobuty 1 carbonyIchloride and reduction with LiAlH4 of N-cyclobutylcarbonyl intermediate to produce nalbuphine.The process produces (3-epimer less than ]%.The production of N,O;0is-substituted-14-hydroxy normorphinone, from Morphine is lengthy & suffers from loss of yield.
It is an object of the invention to provide an improved process for the preparation of nalbuphine having very low levels of undesired P-epimer, starting from thebaine.
Further object of the invention is to provide certain novel intermediates for the preparation of nalbuphine.
Summary of the invention:
Accordingly, the present invention describes the preparation of nalbuphine hydrochloride form thebaine having low levels of undesirable β-epimer.
In one aspect, thebaine is oxidized using hydrogen peroxide(30%) in formic acid(85%).to 14-hydroxycodeinone(Stage-I) which is subsequently acetylated using aceticanhydride to 14-acetoxycodeinone (Stage-II).
In another aspect, 14-acetoxycodeinone (Stage-II) is demethylated with a suitable demethylating agent; eg. haloformate esters such as alkyl, alkenyl,aralkyl or arylbromoformate or chloroformates in presence of base such as sodium or potassium carbonate and solvents selected from dichloromethane, DMF, acetonitrile, chloroform, THF or the like to yield N-ethoxycarbonyl-14-acetoxynorcodeinone(Stage-III).
Further, N-ethoxycarbonyl-14-acetoxynorcodeinone (Stage-Ill) is reduced to yield novel intermediate, N-ethoxycarbonyl-14-acetoxynorcodeine (Stage-IV) wherein, the carbonyl group at C6 is reduced to hydroxyl group with exclusively β-orientation, without affecting the double bond at C7-C8 position. The reducing agent used is a mild reducing agent selected from alkali metal borohydrides such as sodium borohydride.
In another aspect, the novel intermediate Stage-IV is hydrolyzed with a base in presence of alcohol to yield N-ethoxycarbonyI-14-hydroxynorcodeine (Stage-V); a novel intermediate which is useful in the complete synthesis of nalbuphine.
In a preferred aspect, there is provided an insitu process for the conversion of 14-acetoxy codeinone (Stage-II) to N-ethoxycarbonyl-14-hydroxynorcodeine (Stage-V); a novel intermediate which is useful in the complete synthesis of nalbuphine. The intermediates obtained in the process of stage III and stage IV is also novel, however, not isolated in the process of obtaining N-ethoxycarbonyl-14-hydroxynorcodeine (Stage-V).
The in situ preparation of N-ethoxycarbonyl-14-hydroxynorcodeine from 14-acetoxy codeinone eliminates intermediate stage isolation resulting in saving of time cycle, reducing contact time of the intermediate stages containing C-14-OAc with protic solvents during the work up process, thus avoiding deterioration of the sensitive intermediates, eliminating solvent recovery , material handling, and achieving better yield and quality.
Accordingly, 14-hydroxycodeinone (Stage-I) is acetylated with a suitable acetylating agents known in prior art and specifically using aceticanhydride to 14-acetoxycodeinone (Stage- II). The Stage II product is extracted using chlorinated hydrocarbons as solvent selected from methylenechloride, chloroform, dichloroethane, etc. The organic layer containing Stage-II compound is subjected to N-demethylation. N-demethylation of 14- acetoxycodeinone (Stage-II) is carried out using a suitable demethylating agent; eg. haloformate esters such as alkyl, alkenyl, aralkyl or arylbromoformate or chloroformates in presence of base such as sodium or potassium carbonate and solvents selected from dichloromethane, DMF, acetonitrile, chloroform, THF or the like. Stage-Ill compound is extracted in the organic layer, and the organic layer containing Stage-Ill is further subjected to distillation of chloroform below 60°C under partial vacuum. The residual product is dissolved in ethylacetate-methanol solvent. N-ethoxycarbonyl-14-acetoxynorcodeinone (Stage-Ill) in ethyl acetate-methanol solvent is subjected to reduction of C6 carbonyl group to afford C6-aOH; without affecting the double bond at the C7-8 position to afford N- ethoxycarbonyI-14-acetoxynorcodeine (Stage-IV).The reducing agent employed is a mild reducing agent selected from alkali metal borohydrides, preferably sodiumborohydride. The organic layer from Stage-IV is taken for solvent distillation below 70°C under vacuum and
the pasty residue thus obtained, is dissolved in methanol is subjected to hydrolysis using alcoholic basic conditions to yield N-ethoxycarbonyl-14-hydroxynorcodeine (Stage-V).
The chlorinated hydrocarbons used as solvent for extraction of intermediates of Stage-H, Stage-Ill, and Stage-IV and is preferably chloroform.
In yet another aspect, hydrogenation of N-ethoxycarbonyl-14-hydroxynorcodeine(Stage-V) furnished novel N-ethoxycarbonyl-14-hydroxynordihydrocodeine (Stage-VI), the later intermediate on hydrolysis results in formation of 14-hydroxydihydronorcodeine (Stage-
VII) . Stage-VII is further acylated with cyclobutylcarbonylchloride as an acylating agent to obtain a novel intermediate N-cyciobutylcarbonyl-14-hydroxynordihydrocodeine (Stage-
VIII) .
The novel intermediate N-cyclobutylcarbonyI-14-hydroxynordihydrocodeine (Stage-VIII) is then further reduced to give N-cyclobutyImethyl-14-hydroxynordihydrocodeine (Stage-
IX) compound which is further demethylated at 03 to yield nalbuphine(Stage-X). Nalbuphine thus obtained is converted to Nalbuphine hydrochloride by a standard process with the epimer content less than 0.1%.
Each step of the process of the invention gives high yields and the isolated intermediates have high purity.
In another aspect, the present invention discloses the novel intermediates obtained during the synthesis of nalbuphine hydrochloride.

Also disclosed herein is an intermediate N-ethoxycarbonyl- 14-acetoxynorcodeine (Stage- IV) of formula;
Accordingly, disclosed herein is an intermediate N-ethoxycarbonyl- 14- acetoxynorcodeinone (Stage-Ill) of formula;


This invention thus describes total synthesis of nalbuphine hydrochloride such that, by virtue of the processes of this invention, nalbuphine obtained is substantially free from the β- epimer.
Thus, the present invention provides a process which comprises of the following steps: Stage-1: Oxidation of thebaine to 14-hydroxycodeinone. Stage-II: Acylation of 14-hydroxycodeinone tol4-acetoxycodeinone. Stage-Ill: Demethylation of 14-acetoxycodeinone to N-ethoxycarbonyl- 14-acetoxy norcodeinone.
Stage-IV: Reduction of N-ethoxycarbonyl- 14-acetoxynorcodeinone to N-ethoxycarbonyl
14-acetoxynorcodeine. Stage-V: Hydrolysis of N-ethoxycarbonyl-14-acetoxynorcodeine to N-ethoxycarbonyl-
14- hydroxynorcodeine. Stage-VI:Hydrogenation of N-ethoxycarbonyl-14-hydroxynorcodeinetoN- ethoxycarbonyl- 14-hydroxynordihydrocodeine.
Stage-VII: Hydrolysis of N-ethoxycarbonyl-14-hydroxynordihydrocodeine to 14-hydroxy nor dihydrocodeine.
Stage-VlII: Acylation of 14-hydroxynordihydrocodeine to N-cyclobutylcarbonyl-14-
hydroxy nordihydrocodeine. Stage-lX: Reduction of N-cyclobutylcarbonyl-14-hydroxynordihydrocodeine to N-
Cyclobutylmethyl-14-hydroxy nordihydrocodeine, Stage-X: Demethylation of N-cyclobutylmethyl-14-hydroxynordihydrocodeine to nalbuphine.
The preparation of the compounds of this invention may be exemplified with Scheme 1 that illustrates the preparation of nalbuphine hydrochloride.


According to the above scheme, the process of the invention begins with the use of naturally occurring opiate such as thebaine. Accordingly, thebaine is oxidized to 14- hydroxy codeinone(Stage-I) using suitable oxidizing agent such as hydrogen peroxide in combination with one or more of performic acid, peracetic acid and 3-chloroperoxybenzoic acid (either prepared in-situ from respective acid & H202 or pre-prepared). The solvent is selected from the group consisting of a mixture of formic acid and water, a mixture of formic acid, a mixture of methanol and water, a mixture of formic acid and isopropanol, a mixture of formic acid and water and isopropanol, a mixture of acetic acid and water and aqueous mineral acid.
14-hydroxycodeinone (Stage-I) is then acetylated with suitable acetylating agents known in prior art and specifically using acetic anhydride to yield 14-acetoxycodeinone (Stage-II).
Further, N-demethylation of 14-acetoxycodeinone (Stage-II) is carried out using suitable demethylating agents, eg. haloformate esters such as alkyl, alkenyl, arylalkyl or arylbromoformate or chloroformates in presence of base such as sodium or potassium carbonate and solvents selected from dichloromethane, DMF, acetonitrile, chloroform, THF or the like to yield N-ethoxycarbonyl- 14-acetoxynorcodeinone(Stage-III). This is followed by reduction of C6 carbonyl group without affecting the double bond at the C7-8 position to yield novel intermediate N-ethoxycarbonyl- 14-acetoxynorcodeine (Stage-IV). The reducing agent employed is a mild reducing agent selected from alkali metal borohydride, preferably sodium borohydride.
N-ethoxycarbonyl- 14-acetoxynorcodeine thus obtained is further hydrolysed with a base in presence of alcohol to N-ethoxycarbonyl- 14-hydroxynorcodeine (Stage-V).
In a preferred alternate embodiment, 14-acetoxycodeinone (Stage-II) is converted to N- ethoxycarbonyl- 14-hydroxynorcodeine (Stage-V) by insiiu process. The isolated novel intermediate (Stage-V) is useful in the complete synthesis of nalbuphine. The intermediates obtained in the process of stage-Ill and stage-IV are also novel, however, not isolated in the process of obtaining N-ethoxycarbonyl- 14-hydroxynorcodeine CStase-V).
The insitu preparation of N-ethoxycarbonyl- 14-hydroxynorcodeine from 14-acetoxy codeinone eliminates intermediate stage isolation resulting in saving of time cycle, reducing contact time of the intermediate stages containing C14-OAc, with protic solvents during the work up process, thus avoiding deterioration of the sensitive intermediates, eliminating solvent recovery and material handling, and achieving better yield and quality.
Accordingly, 14-hydroxycodeinone (Stage-I) is acetylated with suitable acetylating agents known in prior art and specifically using acetic anhydride to 14-acetoxycodeinone (Stage- II). The Stage-II product is extracted using chlorinated hydrocarbons as solvent selected from methylene chloride, ethylene dichloride, chloroform, etc. The organic layer containing Stage-II compound is subjected to N-demethylation. N-demethylation of 14- acetoxycodeinone (Stage-II) is carried out using a suitable demethylating agent; eg. haloformate esters such as alkyl, alkenyl,aralkyl or arylbromoformate or chloroformates in presence of base such as sodium or potassium carbonate and solvents selected from dichloromethane, DMF, acetonitrile, chloroform, THF or the like. Stage-Ill compound is extracted in the organic layer, and the organic layer containing Stage-Ill is subjected to distillation of solvent below 60°C under partial vacuum. The residual product is then dissolved in ethyl acetate-methanol solvent. N-ethoxycarbonyl-14-acetoxynorcodeinone (Stage-Ill) in ethyl acetate-methanol solvent is subjected to reduction of C6 carbonyl group without affecting the double bond at the C7-8 position to afford N-ethoxycarbonyl- 14- acetoxynorcodeine (Stage-IV).The reducing agent employed is a mild reducing agent selected from alkali metal borohydride, preferably sodium borohydride. The organic layer from Stage-IV, on solvent distillation of solvent below 70°C under vacuum gave pasty residue/The pasty residue dissolved in methanol & subjected to hydrolysis in alcoholic basic solution to yield N-ethoxycarbonyl- 14-hydroxynorcodeine (Stage-V).
The chlorinated hydrocarbons used as solvent for extraction of intermediates of Stage-II, Stage-Ill, and Stage-IV and is preferably chloroform.
In another embodiment,N-ethoxycarbonyl-14-hydroxynorcodeine (Stage-V) is hydrogenated using hydrogenating catalysts such as Pt, Pd/C, etc in organic acids, to yield N-ethoxycarbonyl- 14-hydroxynordihydrocodeine(Stage VI).The organic acid selected from R-COOH,where R= strait/branched alkyl chain containing CI to C4 carbon,
preferably acetic acid.The stage-IV compound further hydrolysed in mineral acid selected from hydrochloric acid, sulphuric acid, etc to yield a known intermediate, 14- hydroxynord i hyd rocodeine (Stage- VII).
14-hydroxynordihydrocodeine (Stage VII) is further acylated with acylating agent such as cyclobutylcarbonyl chloride in presence of solvent selected from THF, methylene dichloride,dichloroethane,etc and triethylamine as an acid scavenger, to yield a novel intermediate N-cyclobutylcarbonyl-14-hydroxynordihydrocodeine (Stage-VIII).
N-cyclobutylcarbonyl-14-hydroxynordihydrocodeine (Stage-VIII) is then reduced with a reducing agent known to a person skilled in the art. Preferably the reducing agent used in the process is Lithium Aluminum hydride in presence of solvent such as, THF, diethyl ether etc. to yield known intermediate, N-cyclobutylmethyl-14- hydroxynordihydrocodeine(Stage-IX) followed by demethylation of 03-protected group using hydrobromic acid and sodium bromide to afford nalbuphine(Stage X) having p- epimer content less than 0.1%.
Nalbuphine is then converted to its pharmaceutically acceptable salt preferably to its hydrochloride salt by processes known in the art.
In yet another embodiment, the present invention encompasses certain novel intermediates obtained during the total synthesis of nalbuphine.
Accordingly, the present invention discloses the intermediate N-ethoxycarbonyl- 14- acetoxynorcodeinone (Stage-Ill) of formula;




Example 1: Thebaine to 14-hydroxycodeinone
To a 50 lit all glass assembly, equipped with half moon stirrer, reflux condenser, thermowel, and an addition funnel was charged 85%formic acid (18.4 lit), stirred & followed by addition of thebaine (4.0 kg, 12.86 mole) to get a clear solution followed by addition of IPA (12.32 lit) and D.M.water (12.32 lit).Cooled to 0°C, 30%hydrogen peroxide (2.184 kg, 19.27 mole) was then added with no exotheriti observed. Maintained further at 0°C for 1.0 hr. Removed cooling bath & allowed to attain room temperature. The reaction was monitored for completion of reaction by TLC. The reaction mass was then quenched in water (25 lit) & cooled to 0°C followed by basification with liq. ammonia(35 lit) till pH 8.5-9.0. The solid precipitated was filtered & further washed with D.M water 5 lit). Aq. filtrate & washings combined were extracted with chloroform (6 lit).Distilled chloroform from organic layer & combined the residue with solid product. The solid was dried at 55- 60°C to yield 14-hydroxycodeinone (Stage-I) till LOD < 0-2% is obtained (~ 6 hr). Dry weight of product: 3.15 kg, M.P. 262-268°C; HPLC 89%; Yield 78.16%.
Example 2:14-hydroxycodeinone to 14-acetoxycodeinone
To a 20 lit 4-neck r.b.f, equipped with half moon stirrer, thermowel, reflux condenser & addition funnel assembled in a water bath, was charged acetic anhydride (6.1 lit)(6.58kg,64.6mole),stirred & followed by addition of 14-hydroxycodeinone (Stage-I) ( 3.05 kg,9.74mole) from examplel. Heated gradually to 50°C to obtain a clear solution & maintained at 50°C for 1 hr. The reaction was monitored for completion of reaction by TLC. Cooled the reaction mass to 20°C to a thick paste & further quenched in ice water (< 25°C).Stirred at 20-25°C for 30 min. Basified the reaction mass with liq.ammonia(~ 15 lit),below 30°C till pH-8.5-9.0 was attained. Filtered the solid & washed with D.M.water (5lit). Further dried at 60-65°C till constant weight of 14-acetoxycodeinone (Stage-II) is obtained (~5 hr).
Dry weight of product 3.3 kg, M.P.174-180 °C; Yield 95.37%
Example 3: 14-acetoxycodeinone to N-ethoxycarbonyl- 14-acetoxynorcodeinone
To a 50 lit all glass assembly, equipped with half moon stirrer, thermowel, reflux condenser & addition funnel, mounted in a water bath was charged 14-acetoxycodeinone (Stage-II) (3.30kg, 9.3mole) from example 2 & chloroform (l21it).Stirred to dissolve stage-II compound.To the clear solution was added potassium carbonate (1.5 kg, 10.87 mole), followed by ethylchloroformate (5.44 lit)(6.2kg,57.13mole) dissolved in chloroform(4.6 lit).Heated to reflux & maintained reflux for 8-9 hrs. The reaction was monitored for completion of reaction by TLC. The reaction mass was further cooled to room temperature & filtered the solid through hyflo bed. The hyflo bed was washed with chloroform (1.0 lit).The clear filtrate extract was further washed with 10% aq.HCl (21it x3).Washed the organic layer with water (41it x2) till neutral pH. The organic layer was subjected to distillation under mild vacuum. Isopropyl alcohol (10 lit) was then added to the residual product & cooled to 5°C. Filtered the solid & further washed with chilled IPA 0.6 lit).Unloaded 1st crop & concentrated mother liquor partly, cooled & filtered to obtain llnd crop. Combined the Ist& llnd crop & dried till constant weight of N-ethoxycarbonyl-14- acetoxynorcodeinone (Stage-Ill) was obtained. Dry weight of product 3.20 kg, HPLC: 98.7%.; Yield 83.35% Further the combined aq. HC1 extracts were basified with liq. ammonia to pH 8.5-9 & extracted with chloroform. Chloroform was distilled to obtain unreacted Stage-II —»0.15kg
Example-4:N-ethoxycarbonyl-14-acetoxynorcodeinonetoN-ethoxycarbonyl-14- acetoxy no rcodeine
To a 50 lit all glass assembly, equipped with half moon stirrer, thermowel, reflux condenser & addition funnel, mounted in water bath, was charged, N-ethoxycarbonyl- 14- acetoxynorcodeinone (Stage-III)( 3.02 kg,7.31 mole) from example-3,methanol (8 lit), ethylacetate (24 lit),acetic acid (0.1 Hit) & tetrabutyl ammonium bromide(TBAB) (0.05 kg,1.10mole%) in D.M.water (2.4 lit).Stirred to form homogenous solution & cooled to 6°C.This was followed by addition of sodium borohydride (0.15 kg,4.0 mole) in small lots, below 9°C,in about 3 hr. Maintained at 9°C for another lhr & the temperature was brought to room temperature (~ 25°C) in about 1.5-2 hr. Acetic acid (0.18 lit) was then added to attain pH «7.Distilled approx.20% of volatiles under mild vacuum followed by addition of ethylacetate (21it) to the concentrate, stirred, settled & separated the organic layer. The solvent was then completely distilled to obtain sticky solid, N-ethoxycarbonyl- 14- acetoxynorcodeine (Stage-IV)-> 3.1 kg, HPLC: 97.48%, Yield -» 95.68%
Example-5:N-ethoxycarbonyl-14-acetoxynorcodeinetoN-ethoxycarbonyl-14- hydroxynorcodeine
To a 50 lit. all glass assembly, equipped with half moon stirrer, thermowel, reflux condenser & addition funnel, mounted in water bath, was charged N-ethoxycarbonyl- 14- acetoxynorcodeine (Stage-IV) (3.095 kg, 7.46 mole)from example-4, methanol (10 lit) & sodium hydroxide (0.63 kg, 15.75 mole) dissolved in methanol (6 lit).Stirred the reaction mass at 30-35°C for 1.5 hr. The reaction was monitored for completion of reaction by TLC. Stirred for another lhr & further neutralized with acetic acid (0.4 lit) to attain pH- 7.Quenched the reaction mass in D.M water (90 lit).Stirred & filtered the solid, washed with water, suck dried & dried further at 60-65°C till constant weight N-ethoxycarbonyl- 14-hydroxynorcodeine(Stage-V) is obtained (~ 5 hr) —» collected as 1st crop. The aq. layer was further extracted with methylene dichloride (2x3 lit).Washed MDC layer with water & distilled off MDC completely to collect residue of N-ethoxycarbonyl- 14-hydroxynorcodeine (Stage-V) as Ilnd crop.
Dry weight of 1st crop + IInd crop = 2.71 kg, HPLC: 99.33%; Yield -»■ 97.27%
Exam ple-6 :N-ethoxycarbonyl-14-hydroxynorcodeine to N-ethoxycarbonyl-14- hydroxynordihydrocodeine
To a clean & dry 100 lit, S.S. 316 autoclave, was charged ethylacetate (42 lit), methanol (14 lit) & N-ethoxycarbonyl- 14-hydroxynorcodeine (Stage-V) (2.705 kg; 7.25 moles) from example-5, stirred to get the clear solution. To the clear solution was added acetic acid (0.2 lit) followed by addition of Pd / C (10%; 0.135 kg) slurry in D.M. water (0.3 lit) under N2 atm. Closed the lid air tight & applied N2 pressure (30 psi), released N2 pressure slowly & repeated the N2-pressure & release cycle. H2-pressure (25 psi) was then applied at temperature approx 25°Cfollowed by slow release. Repeated H2-pressure & release cycle twice while controlling the temperature.H2-pressure (35 psi) was further applied (watched for exothermicity), cooled if required to maintain the temperature to approx.25°C.Stirred at 25-27°C for 10 hr. The reaction was monitored for completion of hydrogenation by HPLC (if incomplete, stir till completion).Filtered the catalyst on hyflo bed under N2 atmosphere.Washed hyflo bed with ethylacetate (2 lit).D«stilled off ethylacetate under mild vacuum to yield N-ethoxycarbonyl-14-hydroxynordihydrocodeine (Stage-VI). Dry weight of product -» 2.68 kg, HPLC: 98.78%; Yield 98.7%
Exam ple-7 :N-ethoxycarbonyl-14-hydroxynordihyd rocodeine to 14-hyd roxy nordihydrocodeine
To a 50 lit all glass assembly, equipped with half moon stirrer, thermowel, reflux condenser & addition funnel, mounted in an oil bath was charged, N-ethoxycarbonyl-14- hydroxynordihydrocodeine (Stage-VI) (2.675 kg, 7.13 mole) from example-6 & aq. sulphuric acid (25%; 27 lit, 1.25 mole).Stirred & heated to 95-96°C (pot temperature; a slow reflux started).Continued stirring at 95-96°C for 2.5 hr. The reaction monitored for completion of reaction by TLC .Cooled the reaction mass to room temperature with constant stirring. Further cooled to 10°C & basified with liq. ammonia ( « 17 lit) to pH 8.5-9, below 25 °C in about 2-3 hr. Reaction mass cooled to 15°C & solid precipitated was filtered & dissolved in MDC(10 lit).Mother liquor extracted with MDC (15 lit).Both the organic layers combined & acidified with HC1 (0.75 lit) below 20°C. Filtered the solid & washed with chilled methanol (2 lit).Unloaded & solid dried at 70-75°C till constant weight of 14- hydroxynordihydrocodeine (Stage-VII) is obtained (~5 hr). Dry weight of the product -»■ 1.91 kg, HPLC: 98.84%; Yield 78.92%
Example-8:14-hydroxynordihydrocodeine to N-CyclobutyIcarbonyl-14-hydroxy- n ordihyd rocodeine
To a 10 lit 4-neck r.b.f, equipped with halfinoon stirrer, thermowel, reflux condenser & addition funnel, mounted in an oil bath, was charged, 14-hydroxynordihydrocodeine(Stage- VII)(0.395kg,1.3 mole) from example-7, methylene dichloride (5.8 lit) & triethylamine (0.4471it; 4.43 mole).Stirred & cooled the contents to 20°C followed by addition of cyclobutylcarbonylchloride (0.218 kg;1.84 mole) dissolved in methylene dichloride (0.5 lit) at 20-22°C in about 1.5 hr. Stirring was continued at 20-22°C for another 1 hr. The temperature was further raised to reflux & maintained at reflux for 2 hrs. The reaction was monitored for completion of reaction by TLC. Methylene dichloride (MDC) was then distilled out and to the residual product was added D.M.water (1.0 lit), stirred & filtered to remove any unreacted Stage-VII (Rec.St.VII:0.02 kg).The filtrate was separated into organic layer & aq. layer. Aq. layer was extracted with MDC (0.3 lit).The combined MDC layers were further washed with aq. sodium bicarbonate soln (0.13 kg dissolved in 2.5 lit D.M.water). Distilled out MDC completely and the final traces removed under vacuum. Residual product of N-cyclobutylcarbonyl-14-hydroxynordihydrocodeine (Stage-VIII) was dried under high vacuum for 4 hr.
Dry weight of product 0.415 kg, HPLC: 99.5%; Yield 97.6%
ExampIe-9:N-CyclobutyIcarbonyl-14-hydroxynordihydrocodeine to N-Cyclobutyl methyl-14-hydroxynordihydrocodcinc
To a 20 lit 4-neck r.b.f., equipped with halfmoon stirrer, thermowel, reflux condenser with a drying tube at the top & addition funnel with N2-inlet, mounted in water bath, N- cyclobutylcarbonyl-14-hydroxynordihydrocodeine(Stage-VIII)(0.5kg,1.3 mole) from exampIe-8 & THF (5 lit) were charged under nitrogen. Stirred to give a clear solution. In another 5.0 lit 4-neck r.b.f., equipped with halfmoon stirrer, thermowel, reflux condenser with a drying tube at the top & addition funnel with N2-in let,mounted in water bath, THF (2 lit) was charged under N2-stream,stirred followed by cautious addition of LAH (0.05 kg,) in small lots ,while maintaining the temperature below 40°C (exothermic reaction). LAH slurry was added to Stage-VIII solution gradually in about 3 hr, while maintaining temperature between 25-40c>C.
The Ilnd & Illrd lot of LAH (0.05 & 0.025 kg) were prepared in THF (2 & 1 lit) respectively as above & added to Stage-VIII solution as above. Total addition for LAH slurry took 12 hrs.
The reaction mixture was heated to reflux (55-58°C) & maintained at reflux for 3 hrs. The reaction was monitored for completion by TLC. this was followed by addition of ethylacetate (0.6 lit) gradually in about 1.5 hr, while maintaining temperature below 35°C.Cooled the reaction mass to 25^ followed by addition of ammonium chloride solution (0.25 kg) in water (1 lit), (exothermic reaction)in about 2 hr, while maintaining temperature below 40°C. Filtered the inorganic salts & washed with THF (2 lit). Combined the filtrate & washings & distilled out THF completely below 65°C.The residual slurry cooled to 5°C,filtered the solid & washed with chilled ethylacetate (0.11it).Collected solid product as 1st crop.
The mother liquor was further concentrated partially, cooled, filtered the solid & washed with chilled Ethylacetate (0.05 lit).Collected the solid as Ilnd crop.
The combined 1st & Ilnd crop of N-Cyclobutylmethyl- 14-hydroxynordihydrocodeine (Stage-IX) were dried at 50-55°C till constant weight is obtained (~ 4 hr). Dry weight of product -> 0.355 kg, HPLC: 95%; Yield -* 73.6 %
ExamplelO: N-Cyclobutylmethyl-14-hydroxynordihydrocodeine to Nalbuphine
Into a 2 lit 4-neck r.b.f., equipped with halfmoon stirrer, thermowel, reflux condenser & addition funnel with N2-inlet,mounted in an oil bath, were charged 49.5% hydrobromic acid (0.727 kg;4.44 mole), D.M.water (0.195 lit) & sodium bromide (0.0916 kg;0.89 mole)underN2-stream followed by addition of N-Cyclobutylmethyl-14- hydroxynordihydrocodeine(Stage VIII) (0.33 kg; 0,89mole) from exampIe-9 (reaction is exothermic).The reaction mixture was heated gradually to I02°C (Pot temperature; reflux started),in about 1 hr. Maintained at reflux for 8 hr & monitored the conversion of the reaction by TLC unti) no more change in conversion was observed. Cooled the reaction mass to 18°C, filtered the solid & washed with chilled water (0.2 lit).[preserve M.L. for Stage-IX recovery]. The solid product (Nalbuphine HBr salt) was further charged to a 5 lit r.b.f & methanol (2 lit).Stirred & heated the contents to 60°C to obtain clear solution. To a clear solution was added activated charcoal (0.01 kg) & the reaction mass was refluxed for 0.5hr, filtered hot through hyflo bed. Washed hyflo bed with hot methanol (0.2 lit).Combined the filtrate & washings & basified at 50 °C with liq. ammonia (~ 0.151it) to attain pH 9. D.M.water (1 lit) was then added & cooled the content to 8°C in about 2 hr. Filtered the solid product & washed with chilled D.M, water (2 lit).The solid nalbuphine(Stage X) obtained was further dried at 90-95°C (4-5 hr) till constant weight is obtained.
Dry weight of product (Nalbuphine) -» 0.204 kg, HPLC: 99.2% (p-Nalbuphine epimer content <0.1%).M.P. 232°C (MERCK Index 230.5°C); Yield 68.5% (based on Stage-IX consumed)
Stage-IX Recovery : Mother liquor (ex. HBr salt) was cooled to 10°C & pH was adjusted to 9 with liq. Ammonia (=0.35 lit) in about an 1 hr below 25°C.Stopped stirring & allowed to settle. The upper clear liquid layer was decanted followed by addition of IP A (0.1 lit) to the residual material. Heat to dissolve. Clear solution then cooled gradually to 10°C. Filtered the solid & washed with chilled IPA (0.051it).The solid product was further dried to constant weight.
Dry weight of recovered Stage-IX —► 0.02 kg (6% of input).
Example 11: In-situ process for Stage II-V Stage II: Preparation of 14-Acetoxycodienone
To a clean & dry 650 lit Glass line reactor was charged, acetic anhydride(l 39.7kg; 1369.6mole), stirred & added 14-hydroxy codienone (stage-I solid) ( 41.7 kg,133.2mole).Heated gradually to 50°C (clear solution) & maintained at 50°C for 1 hr. Monitored completion of reaction by TLC. Cooled reaction mass to 20°C (thick paste) & quenched in chilled(5°C) water in SS Reactor at < I0°C.Stirred at 10°C for 30 min. Basified reaction mass with liq.ammonia(~ 230 lit), at 5-6°C till pH -8.5-9.0 is attained. Filtered the so/id & washed with D.M.water (2 *41.7lit).Spim dried, the wet product, dissolved in chloroform (180 lit) while stirring. Stopped stirring & allowed to settle the layers. Separated the aqueous layer & extracted with chloroform (2x 40 lit).Combined chloroform extracts were dried over sodium sulphate (8 kg), while stirring. Filtered & washed the solids with chloroform (40 lit) .Weighed chloroform layer & taken known weight (=100 gm) of aliquot. Distilled chloroform from aliquot completely. Weighed residue from aliquot & extrapolated this residue weight to total chloroform extract weight to yield Stage-II (calculated: 49.26 kg). The total chloroform layer (328 .41 kg) was taken as such for Stage-Ill.
Stage III: Preparation of N-ethoxycarbonyl- 14-acetoxynorcodeinone
To a clean & dry Glass lined reactor with accessories, was charged, chloroform layer (328.70 kg containing Stage-II compound (derived from equivalent of 41.7 kg of Stage- I).Stirred & added potassium carbonate (22.8 kg), followed by ethylchloroformate (135.10kg) dissolved in chloroform (4.6 lit).Gradually heated to reflux & maintained at reflux for 1 lhr.Monitored completion of reaction by TLC. Cooled the reaction mass to room temperature & filtered the solid through hyflo bed, washed hyflo bed with chloroform (41.7 lit).Cleared filtrate extract with 10% aq.HCl (2 x3.751it). Washed organic layer with water (2x251it) till pH is neutral.
Weighed chloroform layer & taken known weight (~100 gm) of aliquot. Distilled chloroform from aliquot completely. Weighed the residue from aliquot & extrapolated this residue weight to total chloroform extract weight to yield Stage-Ill (Calculated: 67.70 kg).Taken total chloroform layer (564.18 kg) as such for Stage-IV.
Stage IV: Preparation of N-ethoxycarbonyl- 14-acetoxynorcodeine
To a clean & dry SS Reactor with accessories, was charged chloroform layer (564.18 kg) containing Stage-Ill compound (derived from equivalent of 41.7 kg of Stage-I).Stirred & distilled off chloroform below 60°C/under partial vacuum. Cooled to room temperature, released vacuum & charged ethyl acetate (470 lit), followed by methanol(137.6 lit), acetic acid (5.90 lit) & TBAB (0.875 kg) in water (41.7 lit). Stirred to form homogenous solution & cooled to 4+/- 2°C.Then added sodium borohydride (3.085 kg) in small lots(0.5kg* 5 + 0.585kg x 1), below 5°C,in about 3 hr. Maintained at 4+/-2°C for lhr & brought the temperature to room temperature (~ 25°C) in about ] .5-2 hr. Monitored for completion of reaction by TLC. Acetic acid (4.9 lit) was then added to attain pH =7. Weighed organic layer & taken known weight (=100 gm) of aliquot. The solvent was distilled off from aliquot completely. The residue from aliquot was weighed & extrapolated this residue weight to total organic layer weight to obtain yield of Stage-IV (Calculated: 56.21 kg).Taken total organic layer (107,72 kg) as such for Stage-V.
Stage V: Preparation of N-ethoxycarbonyl- 14-hydroxynorcodeine
To a clean SS Reactor, with accessories, was charged, organic layer containing stage-IV compound (derived from equivalent of 41.7 kg of Stage-I).Distilled off the solvent completely below 70°C, under mild vacuum. Cooled residual product to 35+/-3°C, & released vacuum. To a sticky residue was charged methanol (173.8 lit) & sodium hydroxide (11.21kg) dissolved in methanol (14 lit).Stirred reaction mass at 30-35°C for 3 hr. Monitored for completion of reaction by TLC. Stirred for 1 hr more, followed by neutralization with acetic acid (8.0 lit) to pH 7, below 35°C.Distilled off methanol completely below 60°C, under mild vacuum. Cooled & released vacuum (product starts solidifying in to a cream color solid).Charged D.M water (435 lit) to the solid product. Stirred & maintained pH, (if not, adjust to pH 7 with AcOH).Cooled the contents to 20+/- 2°C[solid separates over a period (-1-2 hr)], centrifuged the solid, washed with cold water, suck dried & unloaded. Wet weight of 1st crop —► =39-40 kg
Aq.layer (-450 lit) extracted with methylene dichloride (2 x30 lit).Washed MDC layer with water & distilled off MDC completely collect residue as llnd crop. Combined crop I & II were dried at 60-65°C till constant weight was obtained 5 hr) Dry weight of product (crop:I + II) -> 40 kg ; Over all yield : 80.5 % (based on Stage-I)