"Oripavine To 4,5a Epoxy 3,14 Dihydroxynormorphinan 7 Ene 6 One"
Abstract:
Disclosed herein is a process for the preparation of 4,5 α-epoxy-3,14-dihydroxynormorphinan-7-ene-6-one (Formula V) including the steps of; (i) N-demethylating 4,5 a-epoxy-3,34-diacetoxy-17-methyl morphinan-7-ene-6-one of Formula III to form N-ethoxycarbonyl-4,5 a-epoxy-3,14-diacetoxy normorphinan-7-ene-6-one of Formula (IV); and (ii) hydrolyzing compound of formula (IV) followed by purification to obtain compound of formula (V).
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Notices, Deadlines & Correspondence
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:
"Oripavine to 4, 5α-epoxy-3,14-dihydroxynormorphinan-7-ene-6-one"
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 Oripavine to 4,5 α-epoxy-3,14-dihydroxynormorphinan-7-ene-6-one[14-Hydroxynormorphinone], a key intermediate for production of important narcotic analgesics and antagonists. The present invention is also directed to certain novel intermediate.
Background of the invention
Opiate alkaloids found in opium from Papaver are known to induce strong analgesic effects by action upon opioid receptors. Examples include morphine, codeine, thebaine and oripavine as shown below.
• Mophine —» R=H Oripavine —> R=H
• Codeine -+ R=CH3 Thebaine -> R=CH3
Despite their valuable clinical properties as strong analgesics, the above opiate alkaloids are potentially highly addictive substances as it can cause psychological dependence and physical dependence as well as tolerance to the analgesic effect so that it becomes necessary to increase the dosage levels to obtain the same level of pain relief.
Morphinanes which are hydroxy substituted in the 14th position are important analgesics and/or antagonists. These drugs include semisynthetic opiates represented by a general formula as below;
• Oxycodone -» R,R1 = CH3 , X= O
• Oxymorphone— R=H,R1=CH3,X=0
• Nalbuphines R=H,Rl=Cyclobutylmethyl, X= a-OH
• Naloxone -+R=H,R1= Allyl, X= O
• Naltrexone —► R=H,R 1 =Cyclopropylmethyl,X=0
• Nalmefene —► R=H,Rl=Cyclopropylmethyl,X= CH2
These are readily synthesized from opium alkaloids like Morphine,Codeine, Oripavine & Thebaine.Synthesis of Nal derivatives from these alkaloids is accomplished essentially via Noroxymorphone .
Noroxymorphone The above mentioned opium alkaloids have the basic frame work with ring;
A,B,C,D,& E, with desired chirality at C5,C9, & C13, making them the most suited starting raw materials for semisynthetic opiates synthesis.
Besides the basic frame work & chirality as defined above, all semisynthetic opiates contain additional chiral centre at C14.
Further, the close structural scrutiny of the opium alkaloids and all semisynthetic opiates reveals that semisynthetic opiates require,
a) -OH,at C3
b) -C=0/-C = CH2 /-OH at C6
c) β-OH,atC14
d) N-R in place of N-Me ; Where R= N-Cyclopropyl methyl/N-Allyl / N-Cyclobutylmethyl; and
e) No unsaturation in ring -C
14-hydroxy morphinanes are disclosed in various patent applications. US3166559 discloses 3-lower alkoxy-4-phenyloxy-14-hydroxy-N-methylmorphinans, US4161597 describes 14-hydroxy compounds viz noroxycodone, US4260617 discloses 17-cyclopropylmethyl-14hydroxy-3-methoxymorphinan-6-one, GB1300419 relates to preparation of 3-alkoxy-N-substituted-14-acyloxy-dihydronormorphinone and CA908656 discloses method for preparation of esters of 14-hydroxy- dihydronormorphinone derivatives.
The industrial preparation of 14-hydroxy compounds however poses some difficulty. One problem encountered is removal of N/O-methyl group occurring in the natural opiates and introduction of 14-hydroxy group.
N-Demethylation of tertiary amines was traditionally achieved using cyanogen bromide in the von Braun reaction.(von BraunJ.Chem.Ber;] 900,33,1438).The limited yields and toxicity of this reagent has led to the use of chloroformate reagents.
WO2007/137782 discloses a process for the preparation of a compound of the formula (I)
Formula I
wherein X is CH2 or O or X is a protected keto group and R is H, CH3, O.CO.CH3 or a silyl protecting group, or a salt thereof, by reacting a compound of formula(II);
Formula II
with α -chloroethyl chloroformate and hydrolyzing the resulting intermediate.
The use of haloformate esters such as ethylchloroformate, vinyl chloroformate as a demethylating agent is disclosed in various patent applications such as US2005/0182258, EP0158476 and GB939287.
US4795813 describes O-dealkylation of N-substituted 3-O-alkylnoroxymorphone having the formula;
Wherein; Rl is Rll—C—
or cyano, Rl 1 is aliphatic, aryl, oxyaliphatic or aryloxy and R3 is tower alkyl,
by reaction with a Lewis acid such as boron tribromidefhighly toxic) or pyridinium
hydrochloride(high temperature > 200°C). Reaction with BBr3 is carried out in presence
of halogenated solvents at —20° to +25° C to yield noroxymorphone of formula;
The 14-hydroxy group has been introduced by oxidation of morphinans having a diene system. For example, GB939287 describes the oxidation of thebaine in formic acid with 30% hydrogen peroxide at 40-50°C to give 14-hydroxydihydronorcodeinone.
WO2008/048957 discloses conversion of oripavine to naltrexone, buprenorphine, 14-hydroxymorphinone and/or converting 14-hydroxymorphinone to oxymorphone.
WO2005/028483 discloses a multistep sequence which includes N-demethylation and oxidation of A6, A8- morphinane compound followed by reduction, in the reported procedure, N-demethylation and introduction of 14-hydroxy group is achieved by initial oxidation of 6-methoxy-N-methyl-∆6,∆8morphinane to form 6-oxo-14-hydroxy-A7-morphinane-N-oxide which is then treated with a Fe(il) based reducing agent to oxazolidine product followed by hydrolysis to get 6-oxo-14-hydroxy-A7-morphinone.However, the reaction is complicated by work-up procedures which are inefficient on large scale.
In view of the above, it becomes clear that synthesis of semisynthetic opiates from Morphine/Codeine/Oripavine/Thebaine requires a diene system in ring-C and protection of-OH at C3 as represented below, for the introduction of β-OH at C14.
where
R→ CH3or-COCH3
R' → CH3, -COCH3 or Benzyl This single but essential requirement to incorporate p-OH at CM,led to a preferable consideration of Thebaine with C3-OCH3 & Oripavine with C3-OH with an in built diene system in ring-C, as compared with morphine and codeine.
Oripavine is a minor component of opium & hence was not available on commercial quantities till recently. Thebaine, a chiral synthon, though available in commercial quantities, suffers from a draw back as it involves low' yielding demethylation step of -OCH3 at C-3 .whereas Oripavine as starting synthon does not need this O-demethylation step & now, being commercially available due to development of high Oripavine containing strain in Australia / Europe ;Orpavine is preferred as a synthon for competitive synthesis of semisynthetic opiates.
Object of the invention
The object of the present invention is to prepare a common intermediate (14-HNM) for the production of commercially important nal derivatives (e.g.Nalbuphine, Naltrexone Naloxone & Nalmephene) narcotic analgesics and/or antagonists.
Another object of the present invention is to develop a process for the preparation of the new intermediate which can be provided via N-demethylation in an efficient and commercially viable manner with satisfactory yield and purity.
Summary of the invention
Accordingly, the present invention discloses a novel intermediate, N-ethoxycarbonyl-4,5 α-epoxy-3,14-diacetoxy normorphinan-7-ene-6-one of Formula IV;
In another aspect, the present invention discloses a process for the preparation of compound of Formula V (14HNM) a valuable intermediate for the production of important narcotic analgesics and antagonists and its pharmaceutically acceptable salts.
In an aspect, the present invention discloses preparation of compound of Formula (V) starting from oripavine including the preparation of intermediates IHV.
In a preferred aspect, the invention comprises (i) N-demethylation of 4,5 α-epoxy-3,14-diacetoxy-17-methyl morphinan-7-ene-6-one (Formula III) to form N-ethoxycarbonyl-4,5 a-epoxy-3,14-diacetoxy normorphinan-7-ene-6-one of Formula IV ; (ii) hydrolysis of compound of formula IV followed by purification to obtain compound of formula (V).
Detailed description of the invention
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
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 relates to preparation of 14- HNM a compound of Formula V, an intermediate valuable for synthesizing narcotic analgesics and/or antagonists and its pharmaceutically acceptable salts.
In an embodiment, the present invention relates to preparation of compound of formula (V) starting from oripavine including the preparation of intermediates II-IV.
In a preferred embodiment, the present invention describes a process for preparation of 14-HNM(4,5a-epoxy-3,14-dihydroxynormorphinan-7-ene-6-one) a compound of Formula-V including the steps of; (i) N-demethylating 4,5 a-epoxy-3,14-diacetoxy-17-methyl morphinan-7-ene-6-one of Formula III to form N-ethoxycarbonyl-4,5 a-epoxy-3,14-diacetoxy normorphinan-7-ene-6-one of Formula (IV); and (ii) hydrolyzing compound of formula (IV) followed by purification to obtain compound of formula (V).
N-demethylation of compound of Formula III is carried out in presence of suitable demethylating agent selected from .haloformate esters such as alkyl, alkenyl, aralkyl or arylbromoformate or chloroformates; preferably chloroformate in presence of base such as sodium or potassium carbonate and solvents selected from water, dichloromethane, DMF, acetonitrile, chloroform, THF or the like either alone or in combinations thereof.
The hydrolysis of compound of Formula IV is conducted in acidic medium selected from inorganic acids and organic acids such as sulphuric acid, phosphoric acid, hydrobromic acid, hydrochloric acid, acetic acid, formic acid, arylsulphonic acids e.g.benzenesulphonic acid, p-toluene sulphonic acids etc.
In an embodiment, the oxidation of oripavine (Formula I) to intermediate of Formula II and subsequent acetylation of intermediate of Formula II to an intermediate of Formula III are carried out using oxidizing agents and acetylating agents known in the art.
Accordingly, the present invention provides a method of preparing 4, 5 α-epoxy-3,14-dihydroxynormorphinan-7-ene-6-one of Formula V;
Formula V Comprising of the steps of:
1. oxidizing4,5α-epoxy-3-hydroxy-6-methoxy'N-Methyl-morphinan-6,8diene (Oripavine) of Formula I;
1 with suitable oxidizing agent such as hydrogen peroxide in presence of formic cid, acetic acid, peroxy acids ,perchlorobenzoic acid. in non-polar solvents to form 4, 5